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EP1339670A1 - Substituted cyclohexane derivates and the use thereof in medicaments for treating cardiovascular diseases - Google Patents

Substituted cyclohexane derivates and the use thereof in medicaments for treating cardiovascular diseases

Info

Publication number
EP1339670A1
EP1339670A1 EP01994647A EP01994647A EP1339670A1 EP 1339670 A1 EP1339670 A1 EP 1339670A1 EP 01994647 A EP01994647 A EP 01994647A EP 01994647 A EP01994647 A EP 01994647A EP 1339670 A1 EP1339670 A1 EP 1339670A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
series
heteroatoms
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01994647A
Other languages
German (de)
French (fr)
Inventor
Susanne Röhrig
Andreas Stolle
Julio C. Castro-Palomino
Helmut Haning
Gabriele HANDKE-ERGÜDEN
Noemi Daviu-Folguera
Holger Paulsen
Josef Pernerstorfer
Stephan-Nicholas Wirtz
Henning Steinhagen
Wolfgang Thielemann
Erwin Bischoff
Ulrich Ebbinghaus-Kintscher
Peter Ellinghaus
Joachim Hütter
Thomas Krahn
Frank Wunder
Klemens Lustig
Joachim Schuhmacher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP1339670A1 publication Critical patent/EP1339670A1/en
Withdrawn legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to substituted cyclohexane derivatives, a process for their preparation and their use in medicaments, in particular for
  • Coronary artery disease is still the leading cause of death in western industrialized countries. Although numerous medications such as organic
  • Nitrates, beta blockers, calcium channel blockers and potassium channel openers are used for treatment, the effectiveness of these therapies is low. Only a slight improvement in the cardiac output can be achieved, which also disappears after the medication is stopped.
  • the probability that potassium channels are open in the cell membrane determines the level of the resting membrane potential. With increasing probability that potassium channels in the cell membrane are open, the resting membrane potential is shifted towards the potassium equilibrium potential, the membrane is thus hyperpolarized. As a result, the calcium influx decreases due to calcium channels that are dependent on savings (functional calcium antagonism). This effect is particularly pronounced in the smooth muscles of arterial blood vessels, where the reduction in intracellular calcium associated with hyperpolasation leads to vasorelaxation.
  • the voltage-dependent and calcium-activatable potassium channel of high conductivity (synonyms: BigK, BK, MaxiK, slowpoke) expressed in the small resistance vessels is mostly closed under resting conditions. However, if there is a significant drop in membrane potential and / or a strong increase in intracellular calcium concentration due to a high action potential frequency, the channel opens and the massive potassium outflow from the (Muscle) cell causes a compensatory closing of the voltage-dependent calcium channels.
  • a selective BigK modulator can therefore be used to treat both angina pectoris and arterial hypertension (see Brenner et.al., Nature 407, 2000, 870-876).
  • the object of the present invention is now to provide new substances for the prevention and / or treatment of cardiovascular diseases, diseases of the genitourinary tract and cerebrovascular diseases.
  • the present invention relates to compounds of the formula (I)
  • M represents a group -N (-R ! ) - or an oxygen atom -O-,
  • D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (-C 6 -C) alkyl, (dC 6 ) alkoxy, (-C -C 6 ) - alkoxycarbonyl or mono- or di- (-C 6 ) alkylamino may be substituted,
  • R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (CC 6 ) alkyl, optionally benzo-fused (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxyl, amino, (-C-C6) alkoxy, phenyl, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl or mono- or di- (-C 6 ) alkylamino can be substituted,
  • (C6-C ⁇ o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxy, oxo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CC 6 ) -alkyl, (C ' ⁇ -C 6 ) - Alkoxy, (-CC 6 ) alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (-C6) alkylamino may be substituted,
  • Hydrogen (-C 6 -C) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, (-C 6 ) alkoxy, mono- or di ⁇ -C ⁇ ) - alkylamino, optionally substituted by halogen, trifluoromethyl or (Ci-C 6 ) - alkoxy-substituted phenyl, biphenyl, naphthyl, optionally by
  • Halogen substituted 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or optionally substituted by hydroxyl-substituted 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 6 -C ⁇ o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to three heteroatoms of the series N, O and / or S, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by phenyl, benzyl, morpholinyl, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C ⁇ -C 6 ) - Alkyl, (- C 6 ) alkoxy, (-C-C 6 ) alkoxycarbony
  • R 4 is hydrogen, (dC 6 ) - alkyl, which in turn can be substituted by hydroxy, amino, phenyl, (C6-C ⁇ o) aryloxy, (Q- C 6 ) alkanoyloxy or (dC ⁇ -alkoxy), (C 6 - C 1 o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, in which aryl, heteroaryl and heterocyclyl in turn up to twice, independently of one another, by halogen, optionally by
  • Hydroxy substituted (-C 6 ) alkyl, (C 6 ) alkoxy, (CrC 6 ) alkoxycarbonyl, phenyl or cyano may be substituted, (C 3 -C 8 ) cycloalkyl, (C 6 ) -Alkoxycarbonyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
  • R 5 and R 6 independently of one another are hydrogen, (C6-C ⁇ o) aryl, adamantyl, (C ⁇ -C 8 ) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) -cycloalkyl, (-C-C 6 ) - alkoxy, mono- or di- (-C-C 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl with bis can be substituted to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -cycloalkyl, which can be substituted up to three times by (-C-C 4 ) alkyl, hydroxy or oxo, or 5 - or 6-membered heterocyclyl
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and by
  • Hydroxy, oxo, aminocarbonyl, (-C 6 -C) alkyl or (CrC 6 ) - alkoxy- (-C 6 ) alkyl may be substituted,
  • Heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -cycloalkyl, which up to three times, independently of one another, through (C ⁇ -C 4 ) -
  • Alkyl, hydroxy or oxo can be substituted, or 5- to 10-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-C 4 ) alkyl .
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 10-membered saturated heterocycle with up to two further hetero atoms from the series N, O and / or S, which may be up to two , independently of one another, by benzyl or (C 6 -C ⁇ o) aryl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C ⁇ -C 6 ) alkyl, (QQ) - alkoxy, (C ⁇ -C 6 ) -alkoxycarbonyl or mono- or di- (C 1 -C 6 ) -alkylamino can be substituted,
  • (C 3 -C 8 ) cycloalkyl which by (-C-C 8 ) alkyl, (C 6 -C ⁇ 0 ) aryl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, where aryl, heterocyclyl and heteroaryl in turn can be substituted up to three times, independently of one another, by halogen, trifluoromethyl, Cyano, nitro, hydroxy, (Q-Ce) - alkyl, (C 3 -C 8 ) cycloalkyl, (C ⁇ -C 6 ) alkoxy, amino, mono- or di- (C ⁇ -C 6 ) alkylamino, ( QC ⁇ alkoxycarbonyl or carboxyl may be substituted,
  • Heteroatoms from the series N, O and / or S or carboxamide can be substituted, (-C-C 6 ) alkoxycarbonyl, (C 6 -C ⁇ o) aryl, benzyl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, aryl, benzyl, heterocyclyl and heteroaryl up to three times, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy ( -C-C 6 ) - alkyl, (C 3 -C 8 ) -cycloalkyl, (C ⁇ -C 6 ) -alkoxy, amino, mono- or di- (C 1 -C 6 ) -alkylamino, (C ⁇ -C 6 ) -
  • Mono- or di- (C 1 -C 6 ) -alkylaminocarbonyl which in turn can be substituted by (- C 6 ) -alkoxy, amidosulfone, mono- or di- (Cr C 6 ) -alkylamidosulfone, which in turn can be substituted by (C ⁇ - C 6 ) - alkoxy can be substituted, can be substituted,
  • (C 6 -C ⁇ o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-C 6 ) - alkyl, (-C-C 6 ) - alkoxy, (-CC 6 ) alkoxycarbonyl or mono- or di- (-C 6 ) alkylamino may be substituted,
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- to 10-membered, optionally bicyclic heterocycle, in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and up to fourfold, independently of one another, by hydroxy, (dC 6 ) alkyl, (C ⁇ -C 6 ) alkoxy, hydroxy- (dC 6 ) alkyl, (C 1 -C 6 ) alkoxy- (C 1 - C 6 ) -alkyl, oxo, amino or mono- or di- (-CC-C6) alkylamino can be substituted,
  • R 10 is hydrogen, (-CC 6 ) - alkoxy, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn, independently of one another, up to three times by hydroxy or mono- or di- (-CC 6 ) -alkylamino can be substituted,
  • Heterocyclyl with up to three heteroatoms from the series N, O and / or S means, whereby aryl, heteroaryl and heterocyclyl in turn, independently of one another, up to three times by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C ⁇ -C 6 ) Alkyl, (dC 6 ) alkoxy,
  • R 11 represents a radical of the formula -C (0) -R 12 or -SO 2 -R 12 ,
  • R 12 is hydrogen, (C ⁇ -C6) alkyl which (4 C ⁇ -C) alkoxy can in turn be substituted by hydroxyl or (C 6 -C ⁇ 0) -aryl, 5- to 10-membered heteroaryl having up to three Heteroatoms from the series N, O and / or S, in which aryl and heteroaryl are their- on the one hand, independently of one another, can be substituted by halogen, (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR 13 R 14 or -OR 15 ,
  • R 13 and R 14 independently of one another hydrogen, (C 6 -do) - aryl, adamantyl, (C ⁇ -C 8 ) alkyl, the chain through one or two oxygen atoms
  • 15-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or with 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 3 - C 8 ) cycloalkyl,
  • N May be substituted oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (dC 4 ) alkyl,
  • R 13 and R 14 together with the nitrogen atom to which they are attached 30 form a 4- to 7-membered saturated
  • Form heterocycle which can contain up to two further hetero- can contain atoms from the series N, O and / or S and is optionally substituted by hydroxy, oxo, (-C-C 6 ) - alkyl or (dC 6 ) -alkoxy- (-C-C 6 ) alkyl
  • R 15 (C 6 -C ⁇ o) aryl, adamantyl, (dC 8 ) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 - C 8 ) -cycloalkyl, (dC 6 ) -alkoxy, mono- or di- (dC 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5 - Up to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl, which can be substituted up to three times independently
  • (-C-C 4 ) - alkyl, hydroxy or oxo can be substituted, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is hydrogen or (-C-C 4 ) - alkyl is substituted means
  • Salts of the inventive compounds are physiologically acceptable salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • mineral acids carboxylic acids or sulfonic acids.
  • Alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic are particularly preferred
  • Amines such as, for example, ethylamine, di- or triethylamine, di- or triefhanolamine, dicyclohexylamine, dimethylaminoefhanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the Neritatien according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures.
  • the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • prodrugs are those forms of the compound of the formula (I) which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form under physiological conditions (for example metabolically or solvolytically).
  • hydrates or “solvates” are forms of the compounds of the formula (I) which, in the solid or liquid state, are hydrated with water or coordinated with solvent molecules
  • hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.
  • hydrates or solvates of salts of the compounds according to the invention are also suitable.
  • Halogen stands for fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
  • CC ⁇ -C 8 ) alkyl represents a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-octyl.
  • alkyl groups with fewer carbon atoms such as (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkyl and (C 1 -C 3 ) alkyl, are derived analogously from this definition.
  • (dC 3 ) alkyl is preferred.
  • (dC 6 ) -Al anoyloxy stands for an alkyl radical which has a double bonded oxygen atom and a single bonded oxygen atom in the 1 position and is linked via the single bonded oxygen atom in the 1 position. Examples include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
  • (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6
  • Carbon atoms A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
  • Cycloalkyl stands for a cyclic alkyl radical with 3 to 8 carbon atoms.
  • Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • the corresponding cycloalkyl groups with fewer carbon atoms, such as (C 3 -C 6 ) cycloalkyl, are derived analogously from this definition. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • (Ci-Cg) - Alkoxy stands for a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms.
  • Examples include: mefhoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • the corresponding alkoxy groups with fewer carbon atoms such as (dC) alkoxy or (C 1 -C 3 ) alkoxy, are derived analogously from this definition. In general, (-C-C 3 ) alkoxy is preferred.
  • (C ( S -C ⁇ o) aryl represents an aromatic radical having 6 to 10 carbon atoms. Examples include: phenyl and naphthyl.
  • S stands for a mono- or bicyclic heteroaromatic which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic.
  • examples include: pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, oxdiazolyl, isoxazolyl, benzofuranyl, benzothienyl or
  • Benzimidazolyl The corresponding heterocycles with wemger heteroatoms such as e.g. with up to 2 heteroatoms from the N, O and / or S series.
  • 5- or 6-membered aromatic heterocycles with up to 2 heteroatoms from the series N, O and / or S such as e.g. Pyridyl, pyrimidyl, thiazolyl, oxazolyl and imidazolyl are preferred.
  • 5- to 10-membered heterocyclyl with up to 3 heteroatoms from the series N, O and / or S represents a saturated or partially unsaturated, mono- or bi- cyclic heterocycle which is linked via a ring carbon atom or a ring nitrogen atom.
  • the corresponding heterocycles with fewer ring atoms, such as 5- or 6-membered heterocyclyl, are derived analogously from this definition. Examples include: tetrahydrofuryl, pyrroüdinyl, pyrrolinyl, dihydropyridinyl, piperidinyl, piperazinyl, mo holinyl, thiomopholinyl, azepinyl.
  • 5- or 6-membered saturated heterocycles are preferred, in particular piperidinyl, piperazinyl, morpholinyl and pyrroüdinyl.
  • M represents a group -N (-R ! ) - or an oxygen atom -O-,
  • D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to two, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (dC 6 ) alkyl, (dC 6 ) - alkoxy, (C ⁇ -C 6 ) -
  • Alkoxycarbonyl or mono- or di- (C 1 -C 6 ) alkylamino can be substituted
  • R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (-C-C 6 ) alkyl, where alkyl in turn by (dC) alkoxy, phenyl, (C 3 -C 8 ) cycloalkyl or mono- or Di- (-C 4 ) alkylamino can be substituted,
  • Phenyl or 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S means, phenyl and heteroaryl in turn being up to two, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (C ⁇ -C) alkyl, (-C-C 4 ) alkoxy, (dC ⁇ alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (C 1 -C) alkylamino may be substituted,
  • (dC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, alkyl and cycloalkyl in turn up to two times, independently of one another, by (-C-C) alkoxy, mono- or di- (dC 6 ) -allcylarnino, optionally substituted by halogen, trifluoromethyl or (dC 6 ) - alkoxy-substituted phenyl, biphenyl, naphthyl or optionally substituted by halogen 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S,
  • R 4 is hydrogen, methyl, ethyl, which in turn can be substituted by hydroxy, amino, phenyl, (C 6 -C ⁇ o) aryloxy, (Ci- C 6 ) alkanoyloxy or (dC 4 ) alkoxy, phenyl, 5- or 6-membered heteroaryl with up to two heteroatoms from the N, O and / or S series, 5- or 6-membered heterocyclyl with up to two heteroatoms from the N, O and / or S series, in which phenyl, heteroaryl and heterocyclyl in turn up to twice, independently of one another, by halogen, optionally substituted by hydroxy (-CC 4 ) -alkyl, (dC 4 ) -alkoxy, (-C-C 4 ) -
  • Alkoxycarbonyl, phenyl or cyano can be substituted, Is (C 3 -C 8 ) cycloalkyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
  • R 5 and R 6 independently of one another are phenyl or (C 1 -C 6 ) alkyl, the chain of which can be interrupted by an oxygen atom and up to two times by phenyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or (C ⁇ - C 6 ) -alkoxy can be substituted,
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, in which a ring carbon atom is replaced by a hetero atom from the series N, O or S and which is replaced by hydroxyl, oxo , (-C 6 ) alkyl or (-C 2 ) alkoxy- (dC 2 ) alkyl may be substituted,
  • R 7 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which is up to two, independently of one another, by (dC 6 ) -
  • Alkyl, (-C-C6) -alkylthio or oxo can be substituted, (C 6 -C ⁇ o) -aryl, which is up to two, independently of one another, optionally by (-C-C 6 ) -alkoxy, di- (dC 6 ) alkylamino carbonyl, mono- or di- (-C 6 ) alkylamino can be substituted, Tetrahydronaphthyl, (dC 4 ) alkyl, the chain of which can be interrupted by an oxygen atom and which can be substituted up to twice, independently of one another, by phenyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or (dC 6 ) alkoxy .
  • (C 3 -C 8 ) -cycloalkyl which can be substituted up to three times, independently of one another, by (dC 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two hetero atoms from the Row N, O and / or S, where N by
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- or 6-membered saturated heterocycle, optionally with a further hetero atom from the series N, O or S, which optionally up to two, independently of one another, by Benzyl or phenyl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (dC 4 ) alkyl, (C ⁇ -C) alkoxy, (C ⁇ -C 4 ) alkoxycarbonyl or mono- or
  • R 3 means
  • (C 3 -C 5 ) cycloalkyl which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn up to two times, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxyl, (-CC 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (dC 6 ) -alkoxy, amino, mono- or di- (-C ⁇ - C 2 ) alkylamino, may be substituted,
  • R 9 denotes hydrogen or amino substituted by (dC 2 ) alkyl and phenyl
  • R 10 means hydrogen
  • R 12 represents a radical of the formula -NR 13 R 14 ,
  • R 14 represents a methyl group which is formed by hydrogen
  • Halogen, (-CC 4 ) alkoxy or amino may be substituted
  • M represents a group -N ⁇ R 1 ) - or an oxygen atom -O-
  • A represents a group -CH 2 - or a chemical bond
  • N, O and / or S or phenylene each of which can be substituted up to twice, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (-CC 4 ) -alkyl or (-C-C 4 ) -alkoxy,
  • R 1 is hydrogen, phenyl, (C 2 -C 4 ) alkenyl or (dC 4 ) alkyl, where alkyl in turn can be substituted by methoxy, (C 3 -C 6 ) cycloalkyl or mono- or dimethylamino,
  • R 2 (dC 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, where alkyl and cycloalkyl in turn up to two times, independently of one another, by methoxy, mono- or dimethylamino, optionally substituted by halogen, trifluoromethyl or methoxy, phenyl , Biphenyl, naphthyl or optionally substituted by halogen substituted 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and or S may be substituted,
  • Alkoxycarbonyl can be substituted
  • R 7 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, which is up to two, independently of one another, by (C ⁇ -C) -
  • Alkyl or methylthio can be substituted, phenyl which can be substituted up to twice, independently of one another, by optionally substituted by (-C 4 ) alkoxy, dimethylaminocarbonyl or mono- or dimethylamino, or means tetrahydronaphthyl,
  • R 8 represents (C -C 5 ) cycloalkyl, which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, where phenyl and heteroaryl in turn can be substituted up to twice, independently of one another, by (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy,
  • Amino or mono- or di- (-C 4 ) alkylamino can be substituted, and by phenyl or 5- to 10-membered heteroaryl with 'up to three heteroatoms from the series N, O and / or S is substituted, wherein Phenyl and heteroaryl for their part up to twice, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy (dC 2 ) - alkyl, (C 3 -C 6 ) - cycloalkyl, (C ⁇ -C 4 ) - Alkoxy, amino, mono- or di- (-C 4 ) alkylamino, (dC 4 ) -alkoxycarbonyl, (C ⁇ -C 4 ) -alkylcarbonylamino, (dC 4 ) -AJ-koxyc - rbonylamino, aminocarbonyl, Mono- or di- (d-C 4 ) -
  • R 9 represents hydrogen
  • D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (C ⁇ -C6) alkyl, (dC ⁇ alkoxy, (dC 6) - alkoxycarbonyl or mono- or di- (C 1 -C 6) alkylamino may be substituted,
  • R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, phenyl or Mono- or di- (-CC 6 ) -alkylamino can be substituted, (C 6 -C -o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5th - or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn being up to triple, independently of one another, by halogen, hydroxy, oxo, cyano, nitro, trifluoromethyl, Trifluoromethoxy, (-CC 6 ) alkyl, (dC 6 )
  • Alkoxycarbonyl or mono- or di- (C 1 -C 6 ) alkylamino can be substituted
  • R 2 is hydrogen, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, (dC 6 ) - alkoxy, mono- or di- (C ⁇ -C 6 ) - alkylamino, phenyl, biphenyl, naphthyl or optionally 5- to 10-membered heterocyclyl substituted by hydroxy may be substituted with up to three heteroatoms from the series N, O and / or S, (C 6 -do) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by phenyl, halogen, hydroxy,
  • R 4 is hydrogen, (-CC 6 ) - alkyl, which in turn by hydroxy or
  • (-C-C 4 ) alkoxy can be substituted, (C 6 -do) aryl, 5- to 10-glazed heteroaryl with up to three heteroatoms from the series N, O and / or S, wherein aryl and heteroaryl in turn, independently of one another, can be substituted by halogen, means (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR R or -OR,
  • R 5 and R 6 are independently hydrogen, (C 6 -C 1 o) aryl, adamantyl, (DC 8) -alkyl, whose chain may be interrupted by one or two oxygen atoms and up to three times by hydroxyl, phenyl , Trifluoromethyl, (C 3 -C 8 ) cycloalkyl, (dC 6 ) - alkoxy, mono- or di- (C 1 -C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms the series N, O and / or S or can be substituted by 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -CycloaUcyl, which can be substituted up to three times by (-C-C 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatom
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and by Hydroxy, oxo, aminocarbonyl, (-CC 6 ) - alkyl or (-C-C 6 ) - alkoxy- (dC 6 ) -alkyl can be substituted,
  • R 7 (C 6 -do) -aryl, adamantyl, (dC 8 ) -alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) - Cycloalkyl, (-C-C 6 ) alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl with up to three heteroatoms from the
  • Row N, O and / or S can be substituted, (C 3 -C 8 ) cycloalkyl, which can be substituted up to three times, independently of one another, by (C 1 -C 4 ) alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-CC 4 ) -alkyl, or
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 10-membered saturated heterocycle with up to two further heteroatoms from the series N, O and / or S, which may be up to two, independently from each other, by benzyl or (C 6 -C ⁇ o) aryl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C ⁇ -C 6 ) alkyl, (dC 6 ) alkoxy, (dC 6 ) - AUcoxycarbonyl or mono- or di- (-CC 6 ) alkylamino may be substituted, is substituted,
  • R * means a group
  • (C 3 -C 8 ) cycloalkyl which is substituted by (dC 8 ) alkyl, (C 6 -C 10 ) aryl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and or S, where aryl, heterocyclyl and heteroaryl in turn can be substituted up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, ( C ⁇ -C 6 ) - AUcyl, (C 3 -C 8 ) cycloalkyl, (C ⁇ -C 6 ) alkoxy, amino, mono- or di- (C 1 -C6) alkylamino, (C ⁇ -C 6 ) - AUcoxycarbonyl, carboxyl, substituted can,
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and the up to fourfold, independently of one another, by hydroxy, (-CC 6 ) -alkyl, (-CC 6 ) -alkoxy, hydroxy- (C 1 -C 6 ) -alkyl, (-C-C 6 ) -alkoxy- (C ⁇ - C 6 ) -aUcyl, oxo, amino or mono- or di- (-C-C 6 ) alkylamino may be substituted,
  • R 10 is hydrogen, (dC 6 ) - alkoxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn, independently of one another, up to three times by hydroxy or mono- or di- (-C-C 6 ) alkylammo can be substituted, (C 6 -do) aryl, 5- to 10-membered heteroaryl with up to three
  • Heteroatoms from the series N, O and or S or 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn, independently of one another, up to three times Halogen, hydroxy, cyano, nitro,
  • Trifluoromethyl, trifluoromethoxy, (-CC 6 ) alkyl, (CC 6 ) alkoxy, (C 1 -C 6 ) alkoxycarbonyl or mono- or di- (dC 6 ) alkylamino can be substituted,
  • R 12 is hydrogen, (-CC 6 ) alkyl, which in turn may be substituted by hydroxy or (-C-C 4 ) alkoxy, (C 6 -C ⁇ o) aryl, 5- to 10-membered heteroaryl with up to three Heteroatoms from the series N, O and / or S, in which aryl and heteroaryl may in turn, independently of one another, be substituted by halogen, (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR 13 R 14 or -OR 15 means
  • R 13 and R 14 independently of one another hydrogen, (C 6 -C ⁇ o) - aryl, adamantyl, (C ⁇ -C 8 ) alkyl, the chain of which may be interrupted by one or two oxygen atoms and up to three times by hydroxy, phenyl, trifluoromethyl , (C 3 -C 8 ) -cycloalkyl, (dC 6 ) -alkoxy, mono- or di- (-C-C 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three hetero atoms from the series N , O and / or S or by 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 3 -C 8 ) -cycloalkyl which can be substituted up to three times by ( C ⁇ -C) - Alkyl, hydroxy or oxo can be substituted, or 5- or 6-membered heterocycl
  • R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated
  • Form heterocycle which can contain up to two further hetero atoms from the series N, O and / or S and optionally by hydroxy, oxo, (dC 6 ) - alkyl or (-C-C 6 ) alkoxy- (dC 6 ) alkyl is substituted
  • R 15 (C 6 -C ⁇ o) aryl, adamantyl, (dC 8 ) alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 - C 8 ) -cycloalkyl, (dC 6 ) alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from
  • Series N, O and / or S or by 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl which can be up to triple , independently of one another, can be substituted by (-C 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is hydrogen or (-C-C 4 ) - alkyl is substituted means
  • radical in the compounds of the formula (I) can also preferably be used
  • D is phenylene, thiophenediyl, pyridinediyl, thiazolediyl, pyrimidinediyl, imidazolediyl, pyrazolediyl, Isoxazoldiyl or oxazolediyl mean that in each case up to three times, independently, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC ö ⁇ alkyl, (-C-C 6 ) - alkoxy, (dC 6 ) alkoxycarbonyl or mono- or di- (C 1 -C 6 ) -aUcylamino can be substituted.
  • the radical in the compounds of the formula (I) can be particularly preferably
  • Pyridindiyl mean, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) -alkyl, (C ⁇ -C 6 ) -alkoxy, (C ⁇ -C 6 ) - AUcoxycarbonyl or mono- or di- (dC 6 ) alkylamino can be substituted.
  • the radical in the compounds of the formula (I) can be very particularly preferably
  • Pyridinediyl mean, each up to two, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (-C-C 6 ) -alkyl, (C ⁇ -C 6 ) - alkoxy, (dC 6 ) - AUcoxycarbonyl or mono- or di- (-C-C6) -aUcylamino can be substituted.
  • radical in the compounds of the formula (I) can be very particularly preferably
  • D is 1,4-phenylene or 2,5-pyridinediyl, each up to twice, independently of one another, by halogen, hydroxyl, cyano, carboxy, nitro, Trifluoromethyl, trifluoromethoxy, (dC 6 ) alkyl, (-C-C 6 ) -AUcoxy, (C ⁇ -C 6 ) - AUcoxycarbonyl or mono- or di- (C ⁇ -C 6 ) -aUcylamino can be substituted.
  • the radical in the compounds of the formula (I) can also preferably be used
  • R 8 represents a methyl group which carries as a substituent (C 6 -C ⁇ o) aryl or 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, with aryl and heteroaryl up to triple through halogen, trifluoromethyl,
  • (dC ⁇ -alkylamidosulfone, which in turn can be substituted by (-C-C 6 ) alkoxy, can be substituted, and also up to two, independently of one another, by hydrogen, (C 3 -C 8 ) -cycloalkyl, (C ⁇ - C 8 ) -alkyl, the chain of which can be interrupted by a sulfur atom or an S (O) - or SO 2 group and up to two times by hydroxy, (C ⁇ -C 6 ) - AUcoxy, (C 1 -C 6 ) alkoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy, oxo, amino, mono- or di- (C ⁇ -C6) alkylamino, or carboxamide may be substituted (C ⁇ -C6) -alkoxycarbonyl, (C 6 -C 10)
  • R 8 stands for a methyl group which carries hydrogen as a substituent, as a further substituent (C 6 -C ⁇ o) aryl or 5- to 10-membered
  • Heteroaryl with up to three heteroatoms from the series N, O and / or S carries, wherein aryl and heteroaryl up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) -Cycloalkyl, (dC 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) alkylamino, (C ⁇ -C 6 ) alkoxycarbonyl, carboxyl, (C ⁇ -C 6 ) -AJkylcarbonylarnino, (dC 6 ) alkoxycarbonylamino,
  • (-C-C 6 ) alkoxy may be substituted, may be substituted.
  • the radical in the compounds of the formula (I) can also be very particularly preferably
  • R 8 stands for a methyl group which carries hydrogen as a substituent, as a further substituent (C 6 -C ⁇ o) aryl or 5- to " 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S carries, wherein aryl and heteroaryl up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) -cycloalkyl, (-C-C 6 ) alkoxy,
  • Oxo, amino, mono- or di- (-C 6 ) alkylamino or carboxamide may be substituted.
  • the compounds of the formula (I) according to the invention can be prepared by the following process, which comprises three different reaction sequences: In a possible reaction sequence, compounds of the formula (II)
  • Alkyl preferably methyl or tert-butyl
  • R 1 and R 2 have the meanings given above and N and V represent suitable leaving groups such as, for example, mesylate, tosylate or halogen, preferably chlorine or bromine,
  • R 16 is phenyl, (C 2 -C 5 ) alkenyl or (C 1 -C 5 ) alkyl, which is up to three times, independently of one another, by hydroxy, phenyl or mono- or di- (dC 6 ) alkylamino can be substituted means
  • the radical R 3 represents -CO -R 8 R 9 .
  • R 10 and R 11 have the meanings given above and W and W 'for suitable leaving groups such as halogen, preferably chlorine or
  • R 17 denotes (C 1 -C 5 ) alkyl which can be substituted up to three times, independently of one another, by hydroxy or mono- or di- (-C 6 ) alkylamino, in compounds of the formula (Ia)
  • Neritatien of formula (XII) can be prepared by first Neritatien of formula (Ila), optionally in the presence of an acid or base, to compounds of formula (XVI)
  • X represents a leaving group such as, for example, the corresponding symmetrical anhydride or a halogen, preferably chlorine, and R 4 has the meaning given above with the exception of ⁇ R 5 R 6 ,
  • Y represents a leaving group such as a halogen, preferably chlorine, and R 4 has the meaning given above,
  • R 2 for a radical -CO-R 4 or -SO 2 -R 4 and
  • R J stands for a radical -CO ⁇ R 8 R y .
  • the compounds of formula (I) thus obtained can optionally subsequently be reacted e.g. be converted into the corresponding salts with an acid.
  • R stands for an oxygen protecting group or a solid phase resin
  • the process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under overpressure or under underpressure (for example in a range from 0.5 to 5 bar).
  • the reactions generally take place in a temperature range between
  • Customary organic solvents which do not change under the reaction conditions are suitable as solvents for the process.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroefethylene, trichlorethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformarnide (N, N'p,
  • inorganic or organic bases can be used as bases for the process according to the invention.
  • bases preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium tert .-Butylate, or organic amines such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) , 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), pyridine, diaminopyridine, N-methylpiperidine or N-methylmorpholine.
  • alkali metals such as sodium or their hydrides such as sodium hydride
  • bases alkali metals
  • Conventional condensing agents such as carbodiimides, for example N, N'-diethyl, N, N, 'dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N-, are preferably used as auxiliaries for the amide formation.
  • EDC (3-Dimefhylaminoisopropyl) -N'-ethylcarbodimide hydrochloride (EDC), or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or
  • 2-tert-butyl-5-methyl-isoxazolium perchlorate or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline or propanephosphonic anhydride or isobutylchloroformate or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate or O- (Benzotriazol-1 -y -NjNjN'jN'-tetra-methyluronium hexafluorophosphate (HBTU) or ⁇ - (Berizotriazol-ly -NjNjN ⁇ N'-tetra-methylfluoroborate ) or 2- (2-oxo-l- (2H) - ⁇ yridyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TP
  • (IV) is preferably carried out in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C. and 70 ° C. or in dimethylformamide as solvent using sodium hydride as base at room temperature.
  • the reaction of Neritatien (Ila) with Nerbin fertilizers (Illd) is preferably carried out in dimethylformamide or tetrahydrofuran as solvent using sodium hydride as the base.
  • the oxidation of Neritatien (Ila) to Neritatien (Ilb) is preferably carried out in dimethyl sulfoxide as a solvent using sodium nitrite / acetic acid as an oxidizing agent at room temperature.
  • the amide formation in the reaction of compounds (above) with compounds (III) to compounds (IN) is preferably carried out in dimethylformamide as solvent using EDC, HOBT and / or TBTU as auxiliaries and DMAP, DIEA or ⁇ MM as base at room temperature.
  • Neritatien (Ilb) to Neritatien (IIc) takes place under the usual reaction conditions of a Hofman, Curtius or Lossen degradation.
  • the reaction preferably takes place using diphenylphosphoryl azide (DPPA) in dioxane as solvent at room temperature or in n-hexane under reflux to produce the intermediate isocyanate.
  • DPPA diphenylphosphoryl azide
  • Hydrolysis of the isocyanate is preferably carried out using potassium hydroxide as the base in acetonitrile as the solvent at room temperature.
  • Neritatien (IIc) with Neritatien (ILTa) and (Ulb) to Nerinkitch (IN) can be done in any order. It takes place just like that
  • Neritatien (XX) with Neritatien (TTTb) preferably in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C and 70 ° C or in dimethylformamide as solvent using sodium hydride as base at room temperature.
  • the first step of the reductive amination of Neritatien (IIc) with Neritatien (Hie) to Neritatien (IVa) is preferably carried out in a mixture of trimethyl orthoformate and dichloromethane as solvent or in methanol with acetic acid catalysis at room temperature.
  • the subsequent reduction is preferably carried out using tetrabutylammonium borohydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
  • reaction of compounds (IVa) with compounds (ILIb) to compounds (IV) is preferably carried out in acetonitrile as solvent using
  • hydrolysis of compounds (IV) to Neritatien (N) or Neritatien (XN-Tf) to compounds (XIX) is preferably carried out in dichloromefhan as solvent using trifluoroacetic acid as acid at room temperature or in dioxane as solvent using hydrochloric acid room temperature.
  • R 3 stands for -CO ⁇ R 8 R 9 , preferably takes place in dimethylformamide as solvent using EDC, HOBT and / or TBTU as excipients and DMAP, DIEA or ⁇ MM as base at room temperature.
  • Neritatien (V) takes place under the usual reaction conditions of Hofinan, Curtius or Lossen degradation.
  • the reaction preferably takes place using diphenylphosphoryl azide (DPPA) in dioxane as solvent at room temperature or in n-hexane under reflux to produce the intermediate isocyanate.
  • DPPA diphenylphosphoryl azide
  • the subsequent hydrolysis of the isocyanate is preferably carried out with potassium hydroxide
  • the first step of the reductive amination of Neritatien (NU) with Neritatien (NIIIc) to compounds (Ia) is preferably carried out in a mixture of tri- methyl orthoformate and dichloromethane as solvent or in methanol with acetic acid catalysis at room temperature.
  • the subsequent reduction is preferably carried out using tetrabutylammonium borohydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
  • reaction of compounds (Ia) with compounds (VTflb) to give compounds (I) is preferably carried out in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C. and 70 ° C. or in dimethylformamide as solvent using sodium hydride as Base at room temperature.
  • the oxidation of compounds (Ila) to compounds (Ild) is preferably carried out using N-methylmorpholine-N-oxide as an oxidizing agent in acetonitrile as a solvent at room temperature.
  • hydrolysis of compounds (Ild) to compounds (IX) or of compounds (Ila) to compounds (XVI) is preferably carried out in dichloromethane as solvent using trifluoroacetic acid as acid at room temperature or in dioxane as solvent using hydrochloric acid at room temperature.
  • EDC EDC
  • HOBT HOBT
  • / or TBTU auxiliary substances
  • DMAP DIEA or NMM
  • the first step of the reductive amination of compounds (X) with compounds (XI) to give compounds (XII) is preferably carried out in a mixture of trimethyl orthoformate and dichloromethane as solvent or in methanol with vinegar. acid catalysis at room temperature.
  • the subsequent reduction is preferably carried out using tetrabutylammomumborhydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
  • reaction of compounds (XU) with phosgene equivalents, preferably with trichloromethyl chloroformate, is preferably carried out in dichloromethane as solvent at 0 ° C.
  • the subsequent reaction with amines of the formula (XIII) is preferably carried out in dimethylformamide as solvent in the presence of diisopropylethylamine as base at room temperature.
  • reaction is preferably carried out of compounds (XII) with compounds (XIV) or Neritatien (XN) in dichloromethane as a solvent in the presence of diisopropylethylamine as the base * between room temperature and 50 ° C.
  • the compounds of the formula (I) according to the invention have an unforeseeable, valuable pharmacological spectrum of action.
  • the compounds according to the invention act as modulators, in particular as openers of “Big K” channels. They can be used to manufacture medicaments for the prevention and or treatment of the cardiovascular system, such as high blood pressure, heart failure and ischemic-related peripheral and cardiovascular diseases, in particular for acute and chronic treatment of ischemic diseases of the cardiovascular system, such as, for example, coronary heart disease, stable and unstable angina pectoris, peripheral and arterial occlusive diseases, thrombotic vascular occlusions, des
  • Myocardial infarction and reperfusion damage are particularly suitable for long-term therapy of all occlusive diseases.
  • the compounds according to the invention in oral or intravenous administration for the prevention and / or treatment of cerebrovascular diseases such as cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cramps, epilepsy, respiratory arrest, cardiac arrest, Reye syndrome , cerebral thrombosis, embolism, tumors, bleeding, encephalomyelitis, hydroencephalitis,
  • cerebrovascular diseases such as cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cramps, epilepsy, respiratory arrest, cardiac arrest, Reye syndrome , cerebral thrombosis, embolism, tumors, bleeding, encephalomyelitis, hydroencephalitis,
  • Pain such as diabetic neuropathy, post-therapeutic neuralgia, peripheral nerve damage, central pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia and other chronic pain such as lumbago, back pain (lower back pain) or rheumatic pain ,
  • the compounds according to the invention are suitable for the prevention and / or treatment of effects of the genitourinary tract such as urinary incontinence, prostate hypertrophy, stone disorders of the kidney and the urinary tract, erectile dysfunction or sexual dysfunction.
  • CHO cells were stably transfected by electroporation with the human cDNA of the alpha subunit of the BigK channel.
  • the cells were cultivated in MEM alpha medium with 10% FCS.
  • Non-radioactive detection and quantification of rubidium flow through potassium channels ion channel characterization using atomic absorption, cf. DE-A-4433 261.
  • the quantitative detection of rubidium in the extracellular solution can be carried out at different times.
  • the extracellular solution is nominally rubidium-free but contains potassium.
  • Rubidium can get into the supernatant from the loaded cells through unspecific conductivities and active transporters such as sodium / potassium ATPase and thus lead to a certain non-specific background. against this background, the activation of potassium channels with the
  • anesthetized rats After the chest is opened, anesthetized rats have their hearts quickly removed and inserted into a conventional Langendorff apparatus.
  • the coronary arteries are perfused with constant volume (10 ml / min) and the resulting perfusion pressure is registered via a corresponding pressure sensor.
  • a proximal section of the LAD distal to the first diagonal branch is dissected and a calibrated electromagnetic flow measuring head (e.g. Gould Statham, model SP7515) is placed around the vessel and connected to a flow meter (e.g. Statham, model SP-2202).
  • a calibrated electromagnetic flow measuring head e.g. Gould Statham, model SP7515
  • a flow meter e.g. Statham, model SP-2202
  • Blood sampling and substance administration are carried out through a catheter in the femoral vein.
  • a peripheral ECG is derived with hypodermic needles.
  • a microtip pressure gauge e.g. Millar model PC-350
  • the heart rate measurement is triggered by the R wave of the EKG.
  • the hemodynamic parameters and the coronary flow are measured throughout the experiment
  • the animals were housed individually in type III cages, which were positioned on the individual receiving stations, and were adapted to a 12-hour light / dark rhythm. Water and feed were freely available.
  • the blood pressure of each rat was recorded every 5 minutes for 10 seconds.
  • the measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.
  • test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H 2 O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight.
  • the test doses were between 0.3 and 30 mg / kg body weight.
  • mice Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery. The substances to be tested are administered orally in Transcutol, Cremophor EL, H 2 O (10% / 20% / 70%) in a volume of 1 ml / kg.
  • parenterally by inhalation, nasally, buccally, sublingually, rectally or externally, such as, for example, transdermally, particularly preferably orally or parenterally.
  • parenteral administration intravenous, intramuscular, subcutaneous administration should be mentioned in particular, for example as a subcutaneous depot.
  • Oral application is very particularly preferred.
  • the active ingredients can be administered alone or in the form of preparations. Preparations suitable for oral administration include tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. The active ingredient must be present in such an amount that a therapeutic effect is achieved.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the concentration of the active ingredient should be 0.5-90% by weight, ie the active ingredient should be present in amounts which are sufficient to achieve the stated dosage range.
  • the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
  • auxiliary substances are: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), sugar (e.g.
  • non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), sugar (e.g.
  • Milk sugar emulsifiers
  • dispersants e.g. polyvinylpy ⁇ olidone
  • lubricants e.g. magnesium sulfate
  • tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.
  • the amount is about 0.1 to about 10 mg / kg, preferably about 0.5 to about 5 mg / kg body weight.
  • A the first eluting isomer (reversed phase)
  • B the second eluting isomer (reversed phase)
  • DIEA N, N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • EDCI N '- (3-Dimethylamino ⁇ ropyl) -N-ethylcarbodiimide x HC1
  • HOBt 1 -hydroxy-1H-benzotriazole x H 2 O '*
  • HPLC high pressure, high performance liquid chromatography
  • TBTU O- (benzotriazol-l-yl) -N ⁇ JV'-tefra-methyluronium tetrafluoroborate
  • the intermediate is prepared in analogy to the regulation for the racemate (US-A-5 395 840, column 17).
  • the mixture obtained is stirred with diethyl ether or diisopropyl ether.
  • Example XXXVIII (IS, 2_) -2- ⁇ 4 - [(benzyloxy) carbonyl] phenyl ⁇ cyclohexane carboxylic acid
  • the cyclohexane carboxylic acid, PyBOP (1.5 eq.) And 4-dimethylaminopyridine (0.1 eq.) are dissolved in dimethylformamide (0.1 M) at room temperature and N_N-diisopropylethylamine (2 eq.) Is added.
  • the reaction mixture is stirred for 15 min, then the amine (1.5 eq.) Is added and the mixture is stirred at room temperature for 10-16 h.
  • the desired product is purified by means of HPLC chromatography (acetonitrile-water mixtures).
  • Example I from methyl m-methyl cinnamate and butadiene (reaction analog: US-A-5 395 840 Example I and II) with subsequent bromination (analog: US-A-5 395 840 Example IV) is shown.
  • Example LI (IS *, 2S *) - 2- (4-hydroxyphenyl) -7V - [(IS) -l-phenylethyl] cyclohexane carboxamide
  • Example I from ort. O-methoxycinnamic acid methyl ester and butadiene. (Implementation analog: US-A-5 395 840 Example I and II).
  • the compound is synthesized starting from N-phenylpiperidylurea according to general specification [A].
  • the residue is purified by flash chromatography on silica gel (cyclohexane-ethyl acetate 10: 1). 1.4 g (68% yield) of the desired compound are obtained.
  • R f 0.20 (petroleum ether-ethyl acetate 10: 1);
  • the compound is synthesized starting from (IS, 2S) -2- (4 - ⁇ [phenyl (1-pyrrolidinylcarbonyl) - amino] methyl ⁇ phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling. 110 mg (yield 92%) of the desired compound are obtained.
  • the compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis specification [B]. 160 mg (HPLC
  • the compound is synthesized starting from (IS, 2S) -2- (4 - ⁇ [phenyl (l-thiomopholinylcarbonyl) amino] methyl ⁇ phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling.
  • the compound is synthesized starting from N-phenyl- (N-methylpiperazyl) urea according to general instructions [A].
  • the residue is purified by flash chromatography on silica gel (dichloromethane-methanol-triethylamine 10: 1: 0.1).
  • the compound is synthesized starting from _ (IS, 2S) -2- (4 - ⁇ [phenyl (IN-methylpiperazinylcarbonyl) amino] methyl ⁇ phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling , 98 mg (yield 84%) of the desired compound are obtained.
  • reaction mixture is stirred for a further 3 h at room temperature, the resulting solution is washed with cold 10% hydrochloric acid solution, cold saturated sodium bicarbonate solution and cold saturated sodium chloride solution, dried over sodium sulfate and the solvent removed, yield 270 mg.
  • the diastereomers are prepared by preparative HPLC [column: Stability C30; 5 ⁇ m;
  • Phenylcyclopropyl (4 - ⁇ (IS, 2S) -2 - [( ⁇ [(IS) -l-phenylethyl] amino ⁇ carbonyl) amino] - cyclohexyl ⁇ benzyl) carbamate
  • the compound is synthesized based on phenol according to the general procedure [H].
  • the residue is purified by flash chromatography on silica gel (cyclohexane-EtOAc 7: 1). 1.1 g (88% yield) of the desired compound are obtained.
  • the compound is synthesized from (IS, 2S) -2- (4- [phenoxymethyl] phenyl) cyclohexanecarboxylic acid and (S) -phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 130 mg (yield 89%) of the desired compound are obtained.
  • Chlortrityl polystyrene (5.00 g, 4.90 mmol, Rapp polymers) and (R) -Fmoc-Phenylglycinol (2.6 g, 7.3 mmol) are suspended in toluene / pyridine (4: 1) and stirred at 50 ° C for three hours. Methanol (5 ml) is added and the mixture is stirred at 50 ° C. for a further three hours. The reaction mixture is filtered and the resin 1 obtained is washed repeatedly with methanol, dichloromethane and diethyl ether and dried. To determine the load, a resin sample is split off with trifluoroacetic acid / dichloromethane. A loading of 0.98 mm / g (R) -Fmoc-Phenylglycinol is determined by quantitative HPLC. Cleavage of the Fmoc protecting group
  • Resin 1 (100 mg) is shaken in piperidine / dimethylformamide (1: 4, 1 ml) for 20 minutes at room temperature.
  • the resin 2 obtained is filtered and washed repeatedly with methanol, dichloromethane and diethyl ether and dried.
  • the library was produced in MiniKans (IRORI) according to the "mix and split method" [KC Nicolaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, MP Nova, Angew. Chem. Int. Ed. Engl. (1995), 35, 2289-2290].
  • Resin 3 is suspended in dichloromethane / dimefhylformamide (2: 1) in IRORI-
  • MiniKans slurried (about 120 mg / Kan each) and washed repeatedly with dichloromethane and diethyl ether and dried.
  • the resin thus compartmentalized is suspended in separate reaction vessels in dichloromethane / trimethyl orthoformate (1: 1), each with an amine (5 eq, "R-NH 2 ”) at room temperature and shaken for 18 hours.
  • the resin is twice in the separate reaction vessels washed with dimethylformamide, suspended in dimethylformamide and at room temperature with
  • Tetrabutylammonium borohydride (2 eq) added. After shaking for 10 minutes at room temperature, the reaction mixture is cooled to -40 ° C., glacial acetic acid (100 eq) is added and the mixture is warmed to room temperature again. The resin is washed repeatedly with water, methanol, dichloromethane / 10% diisopropylethylamine, methanol, dichloromethane and diethyl ether and dried.
  • Method 1 The again compartmentalized resin is in separate reaction vessels in
  • the again compartmentalized resin is suspended in dioxane, mixed with phenyl isocyanate (10 eq) and dimethylaminopyridine (0.5 eq) and shaken at 50 ° C. overnight.
  • the resin again compartmentalized, is suspended in separate reaction vessels in dichloromethane, mixed with ethyl diisopropylamine (15 eq) and between
  • the substances were detected using a Micromass Quattro LCZ MS, ionization: ESI positive / negative.
  • the retention time is given in minutes.
  • M represents a group -N (-R ! ) - or an oxygen atom -O-,
  • Carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) - alkyl, (dC 6 ) - alkoxy, (-C ö ⁇ alkoxycarbonyl or mono- or di- (C ⁇ - C 6 ) alkylamino may be substituted,
  • R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (-C-C 6 ) - alkyl, optionally benzo-fused (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another Hydroxy, amino, (dC 6 ) - alkoxy, phenyl, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl or mono- or di - (dC 6 ) - alkylamino can be substituted,

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Abstract

The invention relates to substituted cyclohexane derivates of formula (I), a method for the production thereof and the use thereof in medicaments, particularly for preventing and/or treating cardiovascular diseases, diseases of the urogenital tract and cerebrovascular diseases.

Description

SUBSTITUIERTE CYCLOHEXANDERIVATE UND IHRE VERWENDUNG IN ARZNEIMITTELN ZUR BEHANDLUNG VON KARDIOVASKULÄREN ERKRANKUNGENSUBSTITUTED CYCLOHEXANE DERIVATIVES AND THEIR USE IN MEDICINAL PRODUCTS FOR TREATING CARDIOVASCULAR DISEASES
Die vorliegende Erfindung betrifft substituierte Cyclohexandenvate, ein Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln, insbesondere zurThe present invention relates to substituted cyclohexane derivatives, a process for their preparation and their use in medicaments, in particular for
Prävention und/oder Behandlung von kardiovaskulären Erkrankungen, Erkrankungen des Urogenitaltraktes und cerebrovaskulären Erkrankungen.Prevention and / or treatment of cardiovascular diseases, diseases of the genitourinary tract and cerebrovascular diseases.
Koronare Herzerkrankungen stellen noch immer die häufigste Todesursache in den westlichen Industrienationen dar. Obwohl zahlreiche Medikamente wie organischeCoronary artery disease is still the leading cause of death in western industrialized nations. Although numerous medications such as organic
Nitrate, Beta-Blocker, Calciumkanal-Blocker und Kaliumkanal-Öffner zur Behandlung eingesetzt werden, ist die Effektivität dieser Therapien gering. So kann nur eine leichte Verbesserung der Ausdauerleistung des Herzens erzielt werden, die zudem nach Absetzen der Medikamente wieder verschwindet.Nitrates, beta blockers, calcium channel blockers and potassium channel openers are used for treatment, the effectiveness of these therapies is low. Only a slight improvement in the cardiac output can be achieved, which also disappears after the medication is stopped.
Die Wahrscheinlichkeit, dass Kaliumkanäle in der Zellmembran geöffnet sind, bestimmt die Höhe des Ruhemembranpotentials. Mit steigender Wahrscheinlichkeit, dass Kaliumkanäle in der Zellmembran geöffnet sind, wird das Ruhemembranpotential in Richtung des Kalium-Gleichgewichtspotentials verschoben, die Membran wird also hyperpolarisiert. Als Folge hiervon sinkt der Calcium-Einstrom durch sparinungsabhängige Calcium-Kanäle (funktioneller Calcium-Antagonismus). Diese Wirkung ist besonders ausgeprägt in der glatten Muskulatur arterieller Blutgefäße, wo die mit der Hyperpolaiϊsation verbundene Verringerung des intrazellulären Calciums zur Vasorelaxation führt.The probability that potassium channels are open in the cell membrane determines the level of the resting membrane potential. With increasing probability that potassium channels in the cell membrane are open, the resting membrane potential is shifted towards the potassium equilibrium potential, the membrane is thus hyperpolarized. As a result, the calcium influx decreases due to calcium channels that are dependent on savings (functional calcium antagonism). This effect is particularly pronounced in the smooth muscles of arterial blood vessels, where the reduction in intracellular calcium associated with hyperpolasation leads to vasorelaxation.
Der in den kleinen Widerstandsgefäßen exprimierte spannungsabhängige und Calcium-aktivierbare Kaliumkanal großer Leitfähigkeit (Synonyme: BigK, BK, MaxiK, slowpoke) ist unter Ruhebedingungen überwiegend geschlossen. Kommt es jedoch durch eine hohe Aktionspotentialfrequenz zu einem deutlichen Absinken des Membranpotentials und/oder zu einem starken Anstieg der intrazellulären Calcium- konzentration, so öffnet der Kanal und der massive Kaliumausstrom aus der (Muskel)-Zelle bewirkt ein kompensatorisches Schließen der spannungsabhängigen Calciumkanäle. Ein selektiver BigK-Modulator kann daher sowohl zur Behandlung von Angina Pectoris als auch von arteriellen Hypertonie dienen (siehe Brenner et.al., Nature 407, 2000, 870-876).The voltage-dependent and calcium-activatable potassium channel of high conductivity (synonyms: BigK, BK, MaxiK, slowpoke) expressed in the small resistance vessels is mostly closed under resting conditions. However, if there is a significant drop in membrane potential and / or a strong increase in intracellular calcium concentration due to a high action potential frequency, the channel opens and the massive potassium outflow from the (Muscle) cell causes a compensatory closing of the voltage-dependent calcium channels. A selective BigK modulator can therefore be used to treat both angina pectoris and arterial hypertension (see Brenner et.al., Nature 407, 2000, 870-876).
Aufgabe der vorliegenden Erfindung ist nunmehr die Bereitstellung neuer Substanzen zur Prävention und/oder Behandlung von kardiovaskulären Erkrankungen, Erkrankungen des Urogenitaltraktes und cerebrovaskulären Erkrankungen.The object of the present invention is now to provide new substances for the prevention and / or treatment of cardiovascular diseases, diseases of the genitourinary tract and cerebrovascular diseases.
Die vorliegende Erfindung betrifft Verbindungen der Formel (I)The present invention relates to compounds of the formula (I)
woπn embedded image in which
M eine Gruppe -N(-R!)- oder ein Sauerstoffatom -O- bedeutet,M represents a group -N (-R ! ) - or an oxygen atom -O-,
A eine Gruppe -C(=O)- oder -CH2- oder eine chemische Bindung bedeutet,A represents a group -C (= O) - or -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C6)-Alkoxy, (Cι-C6)- Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (-C 6 -C) alkyl, (dC 6 ) alkoxy, (-C -C 6 ) - alkoxycarbonyl or mono- or di- (-C 6 ) alkylamino may be substituted,
R1 Wasserstoff, Benzyl, (C2-C6)-Alkenyl, (C C6)-Alkyl, gegebenenfalls benzokondensiertes (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, Amino, (Cι-C6)-Alkoxy, Phenyl, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, (C3-C8)-Cycloalkyl oder Mono- oder Di-( -C6)- alkylamino substituiert sein können,R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (CC 6 ) alkyl, optionally benzo-fused (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxyl, amino, (-C-C6) alkoxy, phenyl, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl or mono- or di- (-C 6 ) alkylamino can be substituted,
(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Oxo, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (C C6)-Alkyl, (C'ι-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl, N-Acetyl,N-methylamino oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,(C6-Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxy, oxo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CC 6 ) -alkyl, (C ' ι-C 6 ) - Alkoxy, (-CC 6 ) alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (-C6) alkylamino may be substituted,
Wasserstoff, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, (Cι-C6)- Alkoxy, Mono- oder Di^ -Cδ)- alkylamino, gegebenenfalls durch Halogen, Trifluormethyl oder (Ci-C6)- Alkoxy substitiuiertes Phenyl, Biphenyl, Naphtyl, gegebenenfalls durchHydrogen, (-C 6 -C) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, (-C 6 ) alkoxy, mono- or di ^ -Cδ) - alkylamino, optionally substituted by halogen, trifluoromethyl or (Ci-C 6 ) - alkoxy-substituted phenyl, biphenyl, naphthyl, optionally by
Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder gegebenenfalls durch Hydroxy substituiertes 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Phenyl, Benzyl, Morpholinyl, Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)- Alkyl, ( - C6)-Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkyl- amino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 oder -SO2-R4 bedeutet,Halogen substituted 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or optionally substituted by hydroxyl-substituted 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to three heteroatoms of the series N, O and / or S, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by phenyl, benzyl, morpholinyl, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) - Alkyl, (- C 6 ) alkoxy, (-C-C 6 ) alkoxycarbonyl or mono- or di- (-C-C6) alkylamino may be substituted, or a radical of the formula -C (= O) -R 4 or -SO 2 -R 4 means
woπnembedded image in which
R4 Wasserstoff, (d-C6)- Alkyl, das seinerseits durch Hydroxy, Amino, Phenyl, (C6-Cιo)-Aryloxy, (Q- C6)-Alkanoyloxy oder (d-C^-Alkoxy substituiert sein kann, (C6-C1o)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, gegebenenfalls durchR 4 is hydrogen, (dC 6 ) - alkyl, which in turn can be substituted by hydroxy, amino, phenyl, (C6-Cιo) aryloxy, (Q- C 6 ) alkanoyloxy or (dC ^ -alkoxy), (C 6 - C 1 o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, in which aryl, heteroaryl and heterocyclyl in turn up to twice, independently of one another, by halogen, optionally by
Hydroxy substituiertes (Cι-C6)- Alkyl, (Cι-C6)-Alkoxy, (CrC6)- Alkoxycarbonyl, Phenyl oder Cyano substituiert sein können, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxycarbonyl oder einen Rest der Formel -NR5R6 oder -OR7 bedeutet,Hydroxy substituted (-C 6 ) alkyl, (C 6 ) alkoxy, (CrC 6 ) alkoxycarbonyl, phenyl or cyano may be substituted, (C 3 -C 8 ) cycloalkyl, (C 6 ) -Alkoxycarbonyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
woπnembedded image in which
R5 und R6 unabhängig voneinander Wasserstoff, (C6-Cιo)-Aryl, Adamantyl, (Cι-C8)- Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl, (Cι-C6)- Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach durch (Cι-C4)-Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)-Alkyl substituiert ist, bedeuten,R 5 and R 6 independently of one another are hydrogen, (C6-Cιo) aryl, adamantyl, (Cι-C 8 ) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) -cycloalkyl, (-C-C 6 ) - alkoxy, mono- or di- (-C-C 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl with bis can be substituted to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -cycloalkyl, which can be substituted up to three times by (-C-C 4 ) alkyl, hydroxy or oxo, or 5 - or 6-membered heterocyclyl having up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-CC 4 ) -alkyl,
oderor
R5 und R6 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen gesättigten Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O und/oder S ersetzt sind und der durchR 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and by
Hydroxy, Oxo, Aminocarbonyl, (Cι-C6)-Alkyl oder (CrC6)- Alkoxy-(Cι-C6)-alkyl substituiert sein kann,Hydroxy, oxo, aminocarbonyl, (-C 6 -C) alkyl or (CrC 6 ) - alkoxy- (-C 6 ) alkyl may be substituted,
undand
R7 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durch (Q-CÖ)- Alkyl, (Cι-C6)-Alkylthio oder Oxo substituiert sein kann, (C6-C10)-Aryl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (Cι-C6)-Alkoxycarbonyl oder Carboxyl substituiertes (Cι-C6)-Alkyl, (Cι-C6)- Alkoxy, Di-(CrC6)- alkylaminocarbonyl, Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann,R 7 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which can be up to two, independently of one another, by (QC Ö ) - alkyl, (-C-C 6 ) -alkylthio or oxo may be substituted, (C 6 -C 10) -aryl, which up to two times, independently of one another, by optionally substituted by (Cι-C 6) -alkoxycarbonyl or carboxyl substituted (Cι-C6) alkyl, (Cι-C 6 ) - alkoxy, di- (C r C 6 ) - alkylaminocarbonyl, mono- or di- (-C-C 6 ) alkylamino can be substituted,
Adamantyl, Tetrahydronaphtyl, (Cι-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)- Cycloalkyl, (C C6)-Alkoxy, Mono- oder Di-(C1-C6)-alkyl- amino, 5- oder 6-gliedriges Heterocyclyl mit bis zu dreiAdamantyl, tetrahydronaphthyl, (-C-C 8 ) alkyl, whose chain can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) - cycloalkyl, (CC 6 ) -alkoxy, mono- or di- (C 1 -C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three
Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (Cι-C4)-Heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -cycloalkyl, which up to three times, independently of one another, through (Cι-C 4 ) -
Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- bis 10-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)-Alkyl substituiert ist, bedeutet,Alkyl, hydroxy or oxo can be substituted, or 5- to 10-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-C 4 ) alkyl .
oderor
R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 10-gliedrigen gesättigten Heterocyclus mit bis zu zwei weiteren Hetero- atomen aus der Reihe N, O und/oder S bedeuten, der gegebenenfalls bis zu zweifach, unabhängig voneinander, durch Benzyl oder (C6-Cιo)-Aryl, das seinerseits durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (Q-Q)- Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di-(C1-C6)-alkylamino substituiert sein kann, substituiert ist,R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 10-membered saturated heterocycle with up to two further hetero atoms from the series N, O and / or S, which may be up to two , independently of one another, by benzyl or (C 6 -Cιo) aryl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) alkyl, (QQ) - alkoxy, (Cι-C 6 ) -alkoxycarbonyl or mono- or di- (C 1 -C 6 ) -alkylamino can be substituted,
o ™der bedeutet, o ™ which means
woπn Rs für eine Gruppe der Formelembedded image in which Rs for a group of the formula
für (C3-C8)-Cycloalkyl, das durch (Cι-C8)-Alkyl, (C6-Cι0)-Aryl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Heterocyclyl und Heteroaryl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Q-Ce)- Alkyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy, Amino, Mono- oder Di-(Cι-C6)-alkylamino, (Q-C^-Alkoxycarbonyl oder Carboxyl substituiert sein können,for (C 3 -C 8 ) cycloalkyl, which by (-C-C 8 ) alkyl, (C 6 -Cι 0 ) aryl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, where aryl, heterocyclyl and heteroaryl in turn can be substituted up to three times, independently of one another, by halogen, trifluoromethyl, Cyano, nitro, hydroxy, (Q-Ce) - alkyl, (C 3 -C 8 ) cycloalkyl, (Cι-C 6 ) alkoxy, amino, mono- or di- (Cι-C 6 ) alkylamino, ( QC ^ alkoxycarbonyl or carboxyl may be substituted,
oderor
für eine Methylgruppe steht, die bis zu dreifach, unabhängig voneinander, durch Wasserstoff, Trifluormethyl, (C3-C8)-Cycloalkyl, (Cι-C8)-Alkyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO -Gruppe unterbrochen sein kann und das bis zu zweifach, unabhängig voneinander, durch Hydroxy, ( -CÖ)- Alkoxy, (Cι-C6)-Alkoxycarbonyl, Halogen, Cyano, Nitro, Trifluormethoxy, Oxo, Amino, Mono- oder Di-(C1-C6)- alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu dreirepresents a methyl group which is up to three times, independently of one another, by hydrogen, trifluoromethyl, (C 3 -C 8 ) -cycloalkyl, (-C-C 8 ) -alkyl, the chain of which is formed by a sulfur atom or an S (O) - or SO group can be interrupted and that up to two times independently, by hydroxy, (-C Ö ) - alkoxy, (-C-C 6 ) alkoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy, oxo, amino, mono- or Di- (C 1 -C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three
Heteroatomen aus der Reihe N, O und/oder S oder Carboxamid substituiert sein kann, (Cι-C6)-Alkoxycarbonyl, (C6-Cιo)-Aryl, Benzyl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Benzyl, Heterocyclyl und Heteroaryl bis zu dreifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (Cι-C6)- Alkyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy, Amino, Mono- oder Di- (C1-C6)-alkylamino, (Cι-C6)-Alkoxycarbonyl, Carboxyl, (d-C6)- Alkylcarbonylamino, (Cι-C6)-Alkoxycarbonylamino, Aminocarbonyl,Heteroatoms from the series N, O and / or S or carboxamide can be substituted, (-C-C 6 ) alkoxycarbonyl, (C 6 -Cιo) aryl, benzyl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, aryl, benzyl, heterocyclyl and heteroaryl up to three times, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy ( -C-C 6 ) - alkyl, (C 3 -C 8 ) -cycloalkyl, (Cι-C 6 ) -alkoxy, amino, mono- or di- (C 1 -C 6 ) -alkylamino, (Cι-C 6 ) -Alkoxycarbonyl, carboxyl, (dC 6 ) - alkylcarbonylamino, (-C-C 6 ) -alkoxycarbonylamino, aminocarbonyl,
Mono- oder Di-(C1-C6)-alkylaminocarbonyl, das seinerseits durch ( - C6)-Alkoxy substituiert sein kann, Amidosulfon, Mono- öder Di-(Cr C6)-alkylamidosulfon, das seinerseits durch (Cι-C6)- Alkoxy substituiert sein kann, substituiert sein können,Mono- or di- (C 1 -C 6 ) -alkylaminocarbonyl, which in turn can be substituted by (- C 6 ) -alkoxy, amidosulfone, mono- or di- (Cr C 6 ) -alkylamidosulfone, which in turn can be substituted by (Cι- C 6 ) - alkoxy can be substituted, can be substituted,
R »9y Wasserstoff, (d-C6)-Alkoxy, durch (Cι-C6)-Alkyl und/oder Phenyl substituiertes Amino, (d-C6)- Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy oder Mono- oder Di-(Cι-C6)-alkylämino substituiert sein können,R » 9 y hydrogen, (dC 6 ) alkoxy, amino substituted by (-C 6 ) alkyl and / or phenyl, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn, up to three times, independently of one another, can be substituted by hydroxy or mono- or di- (-C 6 ) -alkylamino,
(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, ( -C6)- Alkyl, (Cι-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,(C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-C 6 ) - alkyl, (-C-C 6 ) - alkoxy, (-CC 6 ) alkoxycarbonyl or mono- or di- (-C 6 ) alkylamino may be substituted,
oder R8 und R9 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 10-gliedrigen, gegebenenfalls bicyclischen Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O und/oder S ersetzt sind und der bis zu vierfach, unabhängig voneinander, durch Hydroxy, (d-C6)- Alkyl, (Cι-C6)- Alkoxy, Hydroxy-(d-C6)-alkyl, (C1-C6)-Alkoxy-(C1-C6)-alkyl, Oxo, Amino oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann,or R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- to 10-membered, optionally bicyclic heterocycle, in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and up to fourfold, independently of one another, by hydroxy, (dC 6 ) alkyl, (Cι-C 6 ) alkoxy, hydroxy- (dC 6 ) alkyl, (C 1 -C 6 ) alkoxy- (C 1 - C 6 ) -alkyl, oxo, amino or mono- or di- (-CC-C6) alkylamino can be substituted,
R10 Wasserstoff, (Cι-C6)- Alkoxy, (d-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits, unabhängig voneinander, bis zu dreifach durch Hydroxy oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,R 10 is hydrogen, (-CC 6 ) - alkoxy, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn, independently of one another, up to three times by hydroxy or mono- or di- (-CC 6 ) -alkylamino can be substituted,
(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges(C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered
Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits, unabhängig voneinander, bis zu dreifach durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C6)- Alkoxy,Heterocyclyl with up to three heteroatoms from the series N, O and / or S means, whereby aryl, heteroaryl and heterocyclyl in turn, independently of one another, up to three times by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) Alkyl, (dC 6 ) alkoxy,
(d-C6)-Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,(dC 6 ) -alkoxycarbonyl or mono- or di- (-CC 6 ) alkylamino may be substituted,
R11 einen Rest der Formel -C(0)-R12 oder -SO2-R12 bedeutet,R 11 represents a radical of the formula -C (0) -R 12 or -SO 2 -R 12 ,
woπnembedded image in which
R12 Wasserstoff, (Cι-C6)-Alkyl, das seinerseits durch Hydroxy oder (Cι-C4)-Alkoxy substituiert sein kann, (C6-Cι0)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl und Heteroaryl ihrer- seits, unabhängig voneinander, durch Halogen substituiert sein können, (C3-C8)-Cycloalkyl oder einen Rest der Formel -NR13R14 oder -OR15 bedeutet,R 12 is hydrogen, (Cι-C6) alkyl which (4 Cι-C) alkoxy can in turn be substituted by hydroxyl or (C 6 -Cι 0) -aryl, 5- to 10-membered heteroaryl having up to three Heteroatoms from the series N, O and / or S, in which aryl and heteroaryl are their- on the one hand, independently of one another, can be substituted by halogen, (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR 13 R 14 or -OR 15 ,
woπnembedded image in which
R13 und R14 unabhängig voneinander Wasserstoff, (C6-do)- Aryl, Adamantyl, (Cι-C8)-Alkyl, dessen Kette durch ein oder zwei SauerstoffatomeR 13 and R 14 independently of one another hydrogen, (C 6 -do) - aryl, adamantyl, (Cι-C 8 ) alkyl, the chain through one or two oxygen atoms
10 unterbrochen sein kann und das bis zu dreifach durch10 can be interrupted by up to three times
Hydroxy, gegebenenfalls durch Halogen, (d-Cβ)- Alkoxy oder Amino substituiertes Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-Hydroxy, optionally substituted by halogen, (d-Cβ) - alkoxy or amino-substituted phenyl, trifluoromethyl, (C 3 -C 8 ) cycloalkyl, (Cι-C 6 ) alkoxy, mono- or di- (Cι-C 6 ) -alkylamino, 5- or 6-
15 gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10- gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl,15-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or with 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 3 - C 8 ) cycloalkyl,
20 das bis zu dreifach durch (Cι-C4)- Alkyl, Hydroxy oder20 up to three times through (-C-C 4 ) - alkyl, hydroxy or
Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (d-C4)- Alkyl substituiert ist,May be substituted oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (dC 4 ) alkyl,
25 bedeuten,25 mean
oderor
R13 und R14 gemeinsam mit dem Stickstoffatom, an das sie 30 gebunden sind, einen 4- bis 7-gliedrigen gesättigtenR 13 and R 14 together with the nitrogen atom to which they are attached 30 form a 4- to 7-membered saturated
Heterocyclus bilden, der bis zu zwei weitere Hetero- atome aus der Reihe N, O und/oder S enthalten kann und gegebenenfalls durch Hydroxy, Oxo, (Cι-C6)- Alkyl oder (d-C6)-Alkoxy-(Cι-C6)-alkyl substituiert istForm heterocycle, which can contain up to two further hetero- can contain atoms from the series N, O and / or S and is optionally substituted by hydroxy, oxo, (-C-C 6 ) - alkyl or (dC 6 ) -alkoxy- (-C-C 6 ) alkyl
R15 (C6-Cιo)-Aryl, Adamantyl, (d-C8)- Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl, (d-C6)-Alkoxy, Mono- oder Di-(d-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durchR 15 (C 6 -Cιo) aryl, adamantyl, (dC 8 ) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 - C 8 ) -cycloalkyl, (dC 6 ) -alkoxy, mono- or di- (dC 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5 - Up to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl, which can be substituted up to three times independently
(Cι-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)- Alkyl substituiert ist, bedeutet,(-C-C 4 ) - alkyl, hydroxy or oxo can be substituted, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is hydrogen or (-C-C 4 ) - alkyl is substituted means
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
Salze der erfindungsgemäßen Nerbindungen sind physiologisch unbedenkliche Salze der erfindungsgemäßen Stoffe mit Mineralsäuren, Carbonsäuren oder Sulfonsäuren. Besonders bevorzugt sind z.B. Salze von Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfonsäure, Toluol- sulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Propionsäure,Salts of the inventive compounds are physiologically acceptable salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid,
Milchsäure, Weinsäure, Zitronensäure, Fumarsäure, Maleinsäure oder Benzoesäure. Salze können ebenso physiologisch unbedenkliche Metall- oder Ammoniumsalze der erfindungsgemäßen Nerbindungen sein. Besonders bevorzugt sind Alkalimetallsalze (z.B. Natrium- oder Kaliumsalze), Erdalkalisalze (z.B. Magnesium- oder Calcium- salze), sowie Ammoniumsalze, die abgeleitet sind von Ammoniak oder organischenLactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Salts can also be physiologically acceptable metal or ammonium salts of the Nerbindungen invention. Alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts) and ammonium salts which are derived from ammonia or organic are particularly preferred
Aminen, wie beispielsweise Ethylamin, Di- bzw. Triethylamin, Di- bzw. Triefhanol- amin, Dicyclohexylamin, Dimethylaminoefhanol, Arginin, Lysin, Ethylendiamin oder 2-Phenylethylamin.Amines, such as, for example, ethylamine, di- or triethylamine, di- or triefhanolamine, dicyclohexylamine, dimethylaminoefhanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
Die erfindungsgemäßen Nerbindungen können in Abhängigkeit von dem Substitutionsmuster in stereoisomeren Formen, die sich entweder wie Bild und Spiegelbild (Enantiomere), oder die sich nicht wie Bild und Spiegelbild (Diastereomere) verhalten, existieren. Die Erfindung betrifft sowohl die Enantiomeren oder Diastereomeren oder deren jeweilige Mischungen. Die Racemformen lassen sich ebenso wie die Diastereo- meren in bekannter Weise in die stereoisomer einheitlichen Bestandteile trennen.Depending on the substitution pattern, the Nerbindungen according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
Außerdem umfasst die Erfindung auch Prodrags der erfindungsgemäßen Nerbindungen. Als Prodrugs werden erfindungsgemäß solche Formen der Nerbindungen der Formel (I) bezeichnet, welche selbst biologisch aktiv oder inaktiv sein können, jedoch unter physiologischen Bedingungen in die entsprechende biologisch aktive Form überführt werden können (beispielsweise metabolisch oder solvolytisch).In addition, the invention also includes prodrags of the Nerbindungen invention. According to the invention, prodrugs are those forms of the compound of the formula (I) which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form under physiological conditions (for example metabolically or solvolytically).
Als "Hydrate" bzw. "Solvate" werden erfindungsgemäß solche Formen der Nerbindungen der Formel (I) bezeichnet, welche in festem oder flüssigem Zustand durch Hydratation mit Wasser oder Koordination mit Lösungsmittelmolekülen eineAccording to the invention, “hydrates” or “solvates” are forms of the compounds of the formula (I) which, in the solid or liquid state, are hydrated with water or coordinated with solvent molecules
Molekül-Verbindung bzw. einen Komplex bilden. Beispiele für Hydrate sind Sesquihydrate, Monohydrate, Dihydrate oder Trihydrate. Gleichermaßen kommen auch die Hydrate bzw. Solvate von Salzen der erfindungsgemäßen Verbindungen in Betracht.Form a molecular connection or a complex. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Likewise, the hydrates or solvates of salts of the compounds according to the invention are also suitable.
Halogen steht für Fluor, Chlor, Brom und Iod. Bevorzugt sind Chlor oder Fluor. CCι-C8)-Alkyl steht für einen geradkettigen oder verzweigten Alkylrest mit 1 bis 8 Kohlenstoffatomen. Beispielsweise seien genannt: Methyl, Ethyl, n-Propyl, Isopro- pyl, n-Butyl, Isobutyl, tert.-Butyl, n-Pentyl, n-Hexyl und n-Octyl. Aus dieser Defini- tion leiten sich analog die entsprechenden Alkylgruppen mit weniger Kohlenstoffatomen wie z.B. (Cι-C6)-Alkyl, (Cι-C4)- Alkyl und (Cι-C3)-Alkyl ab. Im allgemeinen gilt, dass (d-C3)- Alkyl bevorzugt ist.Halogen stands for fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred. CCι-C 8 ) alkyl represents a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-octyl. The corresponding alkyl groups with fewer carbon atoms, such as (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkyl and (C 1 -C 3 ) alkyl, are derived analogously from this definition. In general, (dC 3 ) alkyl is preferred.
Aus dieser Definition leitet sich auch die Bedeutung des entsprechenden Bestandteils anderer komplexerer Substituenten ab wie z.B. bei Mono- oder Di-Alkylamino,The meaning of the corresponding constituent of other more complex substituents, e.g. in the case of mono- or di-alkylamino,
Hydroxyalkyl, Alkylc-trbonylamino, Alkylaminocarbonyl, Alkylamidosulfon, Di-(d- C6)-alkylaminocarbonyl oder Alkoxyalkyl.Hydroxyalkyl, alkylc-trbonylamino, alkylaminocarbonyl, alkylamidosulfone, di- (d-C 6 ) -alkylaminocarbonyl or alkoxyalkyl.
(d-C6)-Al anoyloxy steht für einen Alkylrest, der in der 1 -Position ein doppelt gebundenes Sauerstoffatom und ein einfach gebundenes Sauerstoffatom trägt und über das einfach gebundene Sauerstoffatom der 1 -Position verknüpft ist. Beispielsweise seien genannt: Acetoxy, Propionoxy, n-Butyroxy, i-Butyroxy, Pivaloyloxy und n- Hexanoyloxy.(dC 6 ) -Al anoyloxy stands for an alkyl radical which has a double bonded oxygen atom and a single bonded oxygen atom in the 1 position and is linked via the single bonded oxygen atom in the 1 position. Examples include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
(C2-C6)-Alkenyl steht für einen geradkettigen oder verzweigten Alkenylrest mit 2 bis 6(C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6
Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkenylrest mit 2 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt: Vinyl, Allyl, Isopropenyl und n-But-2-en-l-yl.Carbon atoms. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
(C3-C )-Cycloalkyl steht für einen cyclischen Alkylrest mit 3 bis 8 Kohlenstoffatomen.(C 3 -C) Cycloalkyl stands for a cyclic alkyl radical with 3 to 8 carbon atoms.
Beispielsweise seien genannt: Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl. Aus dieser Definition leiten sich analog die entsprechenden Cycloalkylgruppen mit weniger Kohlenstoffatomen wie z.B. (C3-C6)-Cyclo- alkyl ab. Bevorzugt sind Cyclopropyl, Cyclopentyl und Cyclohexyl. (Ci-Cg)- Alkoxy steht für einen geradkettigen oder verzweigten Alkoxyrest mit 1 bis 6 Kohlenstoffatomen. Beispielsweise seien genannt: Mefhoxy, Ethoxy, n-Propoxy, Isopropoxy, n-Butoxy, Isobutoxy, tert-Butoxy, n-Pentoxy und n-Hexoxy. Aus dieser Definition leiten sich analog die entsprechenden Alkoxygruppen mit weniger Koh- lenstoffatomen wie z.B. (d-C )-Alkoxy oder (Cι-C3)-Alkoxy ab. Im allgemeinen gilt, dass (Cι-C3)-Alkoxy bevorzugt ist.Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The corresponding cycloalkyl groups with fewer carbon atoms, such as (C 3 -C 6 ) cycloalkyl, are derived analogously from this definition. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. (Ci-Cg) - Alkoxy stands for a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms. Examples include: mefhoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. The corresponding alkoxy groups with fewer carbon atoms, such as (dC) alkoxy or (C 1 -C 3 ) alkoxy, are derived analogously from this definition. In general, (-C-C 3 ) alkoxy is preferred.
Aus dieser Definition leitet sich auch die Bedeutung des entsprechenden Bestandteils anderer komplexerer Substituenten ab wie z.B. Alkoxycarbonyl, Alkoxyc-trbonylamino oder Alkoxyalkyl.The meaning of the corresponding constituent of other more complex substituents, e.g. Alkoxycarbonyl, alkoxyc-trbonylamino or alkoxyalkyl.
.(C(S-Cιo)-Aryl steht für einen aromatischen Rest mit 6 bis 10 Kohlenstoffatomen. Beispielsweise seien genannt: Phenyl und Naphthyl. , (C ( S -Cιo) aryl represents an aromatic radical having 6 to 10 carbon atoms. Examples include: phenyl and naphthyl.
5- bis 10-gliedriges Heteroaryl mit bis zu 3 Heteroatomen aus der Reihe N, O und/oder5- to 10-membered heteroaryl with up to 3 heteroatoms from the series N, O and / or
S steht für einen mono- oder bicyclischen Heteroaromaten, der über ein Ringkohlenstoffatom des Heteroaromaten, gegebenenfalls auch über ein Ringstickstoffatom des Heteroaromaten, verknüpft ist. Beispielsweise seien genannt: Pyridyl, Pyrimidyl, Pyridazinyl, Pyrazinyl, Thienyl, Furyl, Pyrrolyl, Pyrazolyl, Imidazolyl, Triazolyl, Thiazolyl, Oxazolyl, Oxdiazolyl, Isoxazolyl, Benzofuranyl, Benzothienyl oderS stands for a mono- or bicyclic heteroaromatic which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic. Examples include: pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, oxdiazolyl, isoxazolyl, benzofuranyl, benzothienyl or
Benzimidazolyl. Aus dieser Definition leiten sich analog die entsprechenden Heterocyclen mit wemger Heteroatomen wie z.B. mit bis zu 2 Heteroatomen aus der Reihe N, O und/oder S ab. Im allgemeinen gilt, dass 5- oder 6-gliedrige aromatische Heterocyclen mit bis zu 2 Heteroatomen aus der Reihe N, O und/oder S wie z.B. Pyridyl, Pyrimidyl, Thiazolyl, Oxazolyl und Imidazolyl bevorzugt sind.Benzimidazolyl. The corresponding heterocycles with wemger heteroatoms such as e.g. with up to 2 heteroatoms from the N, O and / or S series. In general, 5- or 6-membered aromatic heterocycles with up to 2 heteroatoms from the series N, O and / or S such as e.g. Pyridyl, pyrimidyl, thiazolyl, oxazolyl and imidazolyl are preferred.
Aus dieser Definition leitet sich auch die Bedeutung des entsprechenden Bestandteils anderer komplexerer Substituenten ab wie z.B. Heteroarylen.The meaning of the corresponding constituent of other more complex substituents, e.g. Heteroarylene.
5- bis 10-gliedriges Heterocyclyl mit bis zu 3 Heteroatomen aus der Reihe N, O und/oder S steht für einen gesättigten oder teilweise ungesättigten, mono- oder bi- cyclischen Heterocyclus, der über ein Ringkohlenstoffatom oder ein Ringstickstoffatom verknüpft ist. Aus dieser Definition leiten sich analog die entsprechenden Heterocyclen mit weniger Ringatomen wie z.B. 5- oder 6-gliedriges Heterocyclyl ab. Beispielsweise seien genannt: Tetrahydrofuryl, Pyrroüdinyl, Pyrrolinyl, Dihydro- pyridinyl, Piperidinyl, Piperazinyl, Mo holinyl, Thiomoφholinyl, Azepinyl. Im allgemeinen gilt, dass 5- oder 6-gliedrige gesättigte Heterocyclen bevorzugt sind, insbesondere Piperidinyl, Piperazinyl, Morpholinyl und Pyrroüdinyl.5- to 10-membered heterocyclyl with up to 3 heteroatoms from the series N, O and / or S represents a saturated or partially unsaturated, mono- or bi- cyclic heterocycle which is linked via a ring carbon atom or a ring nitrogen atom. The corresponding heterocycles with fewer ring atoms, such as 5- or 6-membered heterocyclyl, are derived analogously from this definition. Examples include: tetrahydrofuryl, pyrroüdinyl, pyrrolinyl, dihydropyridinyl, piperidinyl, piperazinyl, mo holinyl, thiomopholinyl, azepinyl. In general, 5- or 6-membered saturated heterocycles are preferred, in particular piperidinyl, piperazinyl, morpholinyl and pyrroüdinyl.
Bevorzugt sind Verbindungen der Formel (I),Compounds of the formula (I) are preferred
woπnembedded image in which
M eine Gruppe -N(-R!)- oder ein Sauerstoffatom -O- bedeutet,M represents a group -N (-R ! ) - or an oxygen atom -O-,
A eine Gruppe -C(=O)- oder -CH - oder eine chemische Bindung bedeutet,A represents a group -C (= O) - or -CH - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)-Alkyl, (d-C6)- Alkoxy, (Cι-C6)-D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to two, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (dC 6 ) alkyl, (dC 6 ) - alkoxy, (Cι-C 6 ) -
Alkoxycarbonyl oder Mono- oder Di-(C1-C6)-alkylamino substituiert sein können,Alkoxycarbonyl or mono- or di- (C 1 -C 6 ) alkylamino can be substituted,
R1 Wasserstoff, Benzyl, (C2-C6)-Alkenyl, (Cι-C6)-Alkyl, wobei Alkyl seinerseits durch (d-C )-Alkoxy, Phenyl, (C3-C8)-Cycloalkyl oder Mono- oder Di-(Cι-C4)-alkylamino substituiert sein kann,R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (-C-C 6 ) alkyl, where alkyl in turn by (dC) alkoxy, phenyl, (C 3 -C 8 ) cycloalkyl or mono- or Di- (-C 4 ) alkylamino can be substituted,
Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Trifluormethoxy, (Cι-C )-Alkyl, (Cι-C4)-Alkoxy, (d-C^-Alkoxycarbonyl, N-Acetyl,N-methylamino oder Mono- oder Di-(C1-C )-alkylamino substituiert sein können,Phenyl or 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S means, phenyl and heteroaryl in turn being up to two, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (Cι-C) alkyl, (-C-C 4 ) alkoxy, (dC ^ alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (C 1 -C) alkylamino may be substituted,
(d-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu zweifach, unabhängig voneinander, durch (Cι-C )-Alkoxy, Mono- oder Di-(d-C6)-allcylarnino, gegebenenfalls durch Halogen, Trifluormethyl oder (d-C6)- Alkoxy substitiuiertes Phenyl, Biphenyl, Naphtyl oder gegebenenfalls durch Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können,(dC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, alkyl and cycloalkyl in turn up to two times, independently of one another, by (-C-C) alkoxy, mono- or di- (dC 6 ) -allcylarnino, optionally substituted by halogen, trifluoromethyl or (dC 6 ) - alkoxy-substituted phenyl, biphenyl, naphthyl or optionally substituted by halogen 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S,
Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Phenyl, Benzyl, Morpholinyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)- Alkyl, (d-C6)-Alkoxy, (Cι-C6)-Phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, with aryl and heteroaryl in turn up to twice, independently of one another, by phenyl, benzyl, morpholinyl, halogen, cyano, nitro, Trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) - alkyl, (dC 6 ) -alkoxy, (Cι-C 6 ) -
Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-all-ylamino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 oder -SO2-R4 bedeutet,Alkoxycarbonyl or mono- or di- (-C 6 ) -all-ylamino can be substituted, or a radical of the formula -C (= O) -R 4 or -SO 2 -R 4 means,
worinwherein
R4 Wasserstoff, Methyl, Ethyl, die ihrerseits durch Hydroxy, Amino, Phenyl, (C6-Cιo)-Aryloxy, (Ci- C6)-Alkanoyloxy oder (d-C4)-Alkoxy substituiert sein können, Phenyl, 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, worin Phenyl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, gegebenenfalls durch Hydroxy substituiertes (Cι-C4)-Alkyl, (d-C4)-Alkoxy, (Cι-C4)-R 4 is hydrogen, methyl, ethyl, which in turn can be substituted by hydroxy, amino, phenyl, (C 6 -Cιo) aryloxy, (Ci- C 6 ) alkanoyloxy or (dC 4 ) alkoxy, phenyl, 5- or 6-membered heteroaryl with up to two heteroatoms from the N, O and / or S series, 5- or 6-membered heterocyclyl with up to two heteroatoms from the N, O and / or S series, in which phenyl, heteroaryl and heterocyclyl in turn up to twice, independently of one another, by halogen, optionally substituted by hydroxy (-CC 4 ) -alkyl, (dC 4 ) -alkoxy, (-C-C 4 ) -
Alkoxycarbonyl, Phenyl oder Cyano substituiert sein können, (C3-C8)-Cycloalkyl oder einen Rest der Formel -NR5R6 oder -OR7 bedeutet,Alkoxycarbonyl, phenyl or cyano can be substituted, Is (C 3 -C 8 ) cycloalkyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
woπnembedded image in which
R5 und R6 unabhängig voneinander Phenyl oder (Cι-C6)-Alkyl bedeuten, dessen Kette durch ein Sauerstoffatom unterbrochen sein kann und das bis zu zweifach durch Phenyl, Trifluormethyl, (C3-C6)- Cycloalkyl oder (Cι-C6)-Alkoxy substituiert sein kann,R 5 and R 6 independently of one another are phenyl or (C 1 -C 6 ) alkyl, the chain of which can be interrupted by an oxygen atom and up to two times by phenyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or (Cι- C 6 ) -alkoxy can be substituted,
oderor
R5 und R6 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 7-gliedrigen gesättigten Heterocyclus bilden, in dem ein Ringkohlenstoffatom durch ein Heteroatom aus der Reihe N, O oder S ersetzt ist und der durch Hydroxy, Oxo, (Cι-C6)-Alkyl oder (Cι-C2)-Alkoxy-(d-C2)-alkyl substituiert sein kann,R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, in which a ring carbon atom is replaced by a hetero atom from the series N, O or S and which is replaced by hydroxyl, oxo , (-C 6 ) alkyl or (-C 2 ) alkoxy- (dC 2 ) alkyl may be substituted,
undand
R7 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durch (d-C6)-R 7 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which is up to two, independently of one another, by (dC 6 ) -
Alkyl, (Cι-C6)-Alkylthio oder Oxo substituiert sein kann, (C6-Cιo)-Aryl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (Cι-C6)-Alkoxy, Di-(d-C6)-alkylamino- carbonyl, Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann, Tetrahydronaphtyl, (d-C4)-Alkyl, dessen Kette durch ein Sauerstoffatom unterbrochen sein kann und das bis zu zweifach, unabhängig voneinander, durch Phenyl, Trifluormethyl, (C3-C6)-Cycloalkyl oder (d-C6)- Alkoxy substituiert sein kann,Alkyl, (-C-C6) -alkylthio or oxo can be substituted, (C 6 -Cιo) -aryl, which is up to two, independently of one another, optionally by (-C-C 6 ) -alkoxy, di- (dC 6 ) alkylamino carbonyl, mono- or di- (-C 6 ) alkylamino can be substituted, Tetrahydronaphthyl, (dC 4 ) alkyl, the chain of which can be interrupted by an oxygen atom and which can be substituted up to twice, independently of one another, by phenyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl or (dC 6 ) alkoxy .
(C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (d-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Hetero- atomen aus der Reihe N, O und/oder S, wobei N durch(C 3 -C 8 ) -cycloalkyl, which can be substituted up to three times, independently of one another, by (dC 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two hetero atoms from the Row N, O and / or S, where N by
Wasserstoff oder (d-C4)- Alkyl substituiert ist, bedeutet,Is hydrogen or (dC 4 ) - alkyl, means
oderor
R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten Heterocyclus mit gegebenenfalls einem weiteren Heteroatom aus der Reihe N, O oder S bedeuten, der gegebenenfalls bis zu zweifach, unabhängig voneinander, durch Benzyl oder Phenyl, das seinerseits durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (d-C4)-Alkyl, (Cι-C )-Alkoxy, (Cι-C4)-Alkoxycarbonyl oder Mono- oderR 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- or 6-membered saturated heterocycle, optionally with a further hetero atom from the series N, O or S, which optionally up to two, independently of one another, by Benzyl or phenyl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (dC 4 ) alkyl, (Cι-C) alkoxy, (Cι-C 4 ) alkoxycarbonyl or mono- or
Di-(Cι-C6)-methylamino substituiert sein kann, substituiert ist,Di- (-C 6 ) methylamino can be substituted, is substituted,
R3 bedeutet, R 3 means
worinwherein
R8 für eine Gruppe der Formel R 8 for a group of the formula
für (C3-C5)-Cycloalkyl, das durch Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)-Alkyl, (C3-C6)-Cycloalkyl, (d-C6)-Alkoxy, Amino, Mono- oder Di-(Cι-C2)-alkylamino, substituiert sein können,for (C 3 -C 5 ) cycloalkyl, which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn up to two times, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxyl, (-CC 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (dC 6 ) -alkoxy, amino, mono- or di- (-Cι- C 2 ) alkylamino, may be substituted,
oderor
für eine Methylgruppe steht,represents a methyl group,
die durch Wasserstoff, durch Trifluormethyl, (C3-C6)-Cycloalkyl oder (d-C4)-Alkyl, das seinerseits durch Hydroxy, (Cι-C4)- Alkoxy, Halogen, Cyano, Trifluormethoxy, Amino, Mono- oder Di-(Cι-C4)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S oder Carboxamid substituiert sein kann, und durch (C6-Cι0)-Aryl oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert ist, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (d-C )-Alkyl, (C3-C6)-by hydrogen, by trifluoromethyl, (C 3 -C 6 ) -cycloalkyl or (dC 4 ) -alkyl, which in turn by hydroxy, (-C-C 4 ) - alkoxy, halogen, cyano, trifluoromethoxy, amino, mono- or di - (-C-C 4 ) alkylamino, 5- or 6-membered heterocyclyl can be substituted with up to two heteroatoms from the series N, O and / or S or carboxamide, and by (C 6 -Cι 0 ) aryl or 5- to 10-membered heteroaryl is substituted with up to three heteroatoms from the series N, O and / or S, with aryl and heteroaryl in turn up to twice, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxyl, optionally by Hydroxy substituted (dC) alkyl, (C 3 -C 6 ) -
Cycloalkyl, (Cι-C4)-Alkoxy, Amino, Mono- oder Di-(d-C4)-alkyl- amino, (Cι-C4)-Alkoxycarbonyl, Carboxyl, (Cι-C )-Alkylcarbonyl- amino, (Cι-C4)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(d-C4)-allcylaminocarbonyl, Amidosulfon, Mono- oder Di-(Cι- C4)-alkylamidosulfon substituiert sein können,Cycloalkyl, (-C-C 4 ) -alkoxy, amino, mono- or di- (dC 4 ) -alkyl-amino, (Cι-C 4 ) -alkoxycarbonyl, carboxyl, (Cι-C) -alkylcarbonyl-amino, (Cι -C 4 ) alkoxycarbonylamino, aminocarbonyl, mono- or Di- (dC 4 ) -allcylaminocarbonyl, amidosulfone, mono- or di- (-C-C 4 ) alkylamido sulfone can be substituted,
R9 Wasserstoff oder durch (d-C2)-Alkyl und Phenyl substituiertes Amino bedeutet,R 9 denotes hydrogen or amino substituted by (dC 2 ) alkyl and phenyl,
R10 Wasserstoffbedeutet,R 10 means hydrogen,
R1 J einen Rest der Formel -C(=O)-R12 bedeutet,R 1 J represents a radical of the formula -C (= O) -R 12 ,
woπnembedded image in which
R12 einen Rest der Formel -NR13R14 bedeutet,R 12 represents a radical of the formula -NR 13 R 14 ,
worinwherein
R » 13 Wasserstoff bedeutet,R »13 means hydrogen,
R14 für eine Methylgruppe steht, die durch Wasserstoff,R 14 represents a methyl group which is formed by hydrogen,
Methyl oder Ethyl und durch Phenyl substituiert ist, das seinerseits durchMethyl or ethyl and substituted by phenyl, which in turn by
Halogen, (Cι-C4)-Alkoxy oder Amino substituiert sein kann,Halogen, (-CC 4 ) alkoxy or amino may be substituted,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
Besonders bevorzugt sind Verbindungen der Formel (I),Compounds of the formula (I) are particularly preferred
worin M eine Gruppe -N^R1)- oder ein Sauerstoffatom -O- bedeutet,wherein M represents a group -N ^ R 1 ) - or an oxygen atom -O-,
A eine Gruppe -CH2- oder eine chemische Bindung bedeutet,A represents a group -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu zwei Heteroatomen aus der ReiheD 5- or 6-membered heteroarylene with up to two heteroatoms from the series
N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Trifluormethoxy, (Cι-C4)-Alkyl oder (Cι-C4)-Alkoxy substituiert sein können,N, O and / or S or phenylene, each of which can be substituted up to twice, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (-CC 4 ) -alkyl or (-C-C 4 ) -alkoxy,
R1 Wasserstoff, Phenyl,(C2-C4)-Alkenyl oder (d-C4)-Alkyl bedeutet, wobei Alkyl seinerseits durch Methoxy, (C3-C6)-Cycloalkyl oder Mono- oder Di-methylamino substituiert sein kann,R 1 is hydrogen, phenyl, (C 2 -C 4 ) alkenyl or (dC 4 ) alkyl, where alkyl in turn can be substituted by methoxy, (C 3 -C 6 ) cycloalkyl or mono- or dimethylamino,
R2 (d-C4)-Alkyl, (C3-C6)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Methoxy, Mono- oder Di-methylamino, gegebenenfalls durch Halogen, Trifluormethyl oder Methoxy substitiuiertes Phenyl, Biphenyl, Naphtyl oder gegebenenfalls durch Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und oder S substituiert sein können,R 2 (dC 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, where alkyl and cycloalkyl in turn up to two times, independently of one another, by methoxy, mono- or dimethylamino, optionally substituted by halogen, trifluoromethyl or methoxy, phenyl , Biphenyl, naphthyl or optionally substituted by halogen substituted 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and or S may be substituted,
Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C4)- Alkyl, (d-C4)- Alkoxy oder Mono- oder Di-methylamino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 bedeutet,Phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, with aryl and heteroaryl in turn up to twice, independently of one another, by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι -C 4 ) - alkyl, (dC 4 ) - alkoxy or mono- or dimethylamino may be substituted, or denotes a radical of the formula -C (= O) -R 4 ,
woπnembedded image in which
R >4 Methyl, das seinerseits durch Phenyl, Phenyloxy oder (C1-C2)-Alkoxy substituiert sein kann,R> 4 methyl, which in turn can be substituted by phenyl, phenyloxy or (C 1 -C 2 ) alkoxy,
Phenyl, 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, worin Phenyl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Methoxy oder (d-C4)-Phenyl, 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, in which phenyl , Heteroaryl and heterocyclyl for their part up to twice, independently of one another, by halogen, methoxy or (dC 4 ) -
Alkoxycarbonyl substituiert sein können,Alkoxycarbonyl can be substituted,
(C3-C4)-Cycloalkyl oder einen Rest der Formel -OR7 bedeutet,Is (C 3 -C 4 ) cycloalkyl or a radical of the formula -OR 7 ,
woπnembedded image in which
R7 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durch (Cι-C )-R 7 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, which is up to two, independently of one another, by (Cι-C) -
Alkyl oder Methylthio substituiert sein kann, Phenyl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (Cι-C4)- Alkoxy, Dimethylaminocarbonyl oder Mono- oder Di-methylamino substituiert sein kann, oder Tetrahydronaphtyl bedeutet,Alkyl or methylthio can be substituted, phenyl which can be substituted up to twice, independently of one another, by optionally substituted by (-C 4 ) alkoxy, dimethylaminocarbonyl or mono- or dimethylamino, or means tetrahydronaphthyl,
eine Gruppe bedeutet, a group means
worinwherein
R8 für (C -C5)-Cycloalkyl, das durch Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch (Cι-C4)-Alkyl oder (Cι-C4)- Alkoxy, substituiert sein können,R 8 represents (C -C 5 ) cycloalkyl, which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, where phenyl and heteroaryl in turn can be substituted up to twice, independently of one another, by (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy,
oderor
für eine Methylgruppe steht,represents a methyl group,
die durch Wasserstoff, durch (Cι-C3)-Alkyl, das seinerseits durch Hydroxy, (d-C2)- Alkoxy,by hydrogen, by (-CC 3 ) -alkyl, which in turn by hydroxy, (dC 2 ) - alkoxy,
Amino oder Mono- oder Di-(Cι-C4)-alkylamino substituiert sein kann, und durch Phenyl oder 5- bis 10-gliedriges Heteroaryl mit 'bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert ist, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (d-C2)- Alkyl, (C3-C6)- Cycloalkyl, (Cι-C4)-Alkoxy, Amino, Mono- oder Di-(Cι-C4)-alkyl- amino, (d-C4)-Alkoxycarbonyl, (Cι-C4)-Alkylcarbonylamino, (d-C4)-AJ-koxyc--rbonylamino, Aminocarbonyl, Mono- oder Di-(d- C4)-alkylaminocarbonyl, Amidosulfon, Mono- oder Di-(Cι-C4)-alkyl- amidosulfon substituiert sein können,Amino or mono- or di- (-C 4 ) alkylamino can be substituted, and by phenyl or 5- to 10-membered heteroaryl with 'up to three heteroatoms from the series N, O and / or S is substituted, wherein Phenyl and heteroaryl for their part up to twice, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy (dC 2 ) - alkyl, (C 3 -C 6 ) - cycloalkyl, (Cι-C 4 ) - Alkoxy, amino, mono- or di- (-C 4 ) alkylamino, (dC 4 ) -alkoxycarbonyl, (Cι-C 4 ) -alkylcarbonylamino, (dC 4 ) -AJ-koxyc - rbonylamino, aminocarbonyl, Mono- or di- (d-C 4 ) -alkylaminocarbonyl, amidosulfone, mono- or di- (-C-C 4 ) -alkyl amidosulfone may be substituted,
R9 Wasserstoff bedeutet,R 9 represents hydrogen,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
Ebenfalls bevorzugt sind Verbindungen der Formel (I),Also preferred are compounds of formula (I)
woπnembedded image in which
M eine Gruppe -N(-R:)- bedeutet, A eine Gruppe -C(=O)- oder -CH2- oder eine chemische Bindung bedeutet,M is a group -N (-R :) - means A represents a group -C (= O) - or -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C^-Alkoxy, (d-C6)- Alkoxycarbonyl oder Mono- oder Di-(C1-C6)-alkylamino substituiert sein können,D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (Cι-C6) alkyl, (dC ^ alkoxy, (dC 6) - alkoxycarbonyl or mono- or di- (C 1 -C 6) alkylamino may be substituted,
R1 Wasserstoff, Benzyl, (C2-C6)-Alkenyl, (d-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Oxo, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C6)-Alkoxy, (Cι-C6)-R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, phenyl or Mono- or di- (-CC 6 ) -alkylamino can be substituted, (C 6 -C -o) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5th - or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn being up to triple, independently of one another, by halogen, hydroxy, oxo, cyano, nitro, trifluoromethyl, Trifluoromethoxy, (-CC 6 ) alkyl, (dC 6 ) -alkoxy, (-C-C 6 ) -
Alkoxycarbonyl oder Mono- oder Di-(C1-C6)-alkylamino substituiert sein können,Alkoxycarbonyl or mono- or di- (C 1 -C 6 ) alkylamino can be substituted,
R2 Wasserstoff, (d-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, (d-C6)- Alkoxy, Mono- oder Di-(Cι-C6)- alkylamino, Phenyl, Biphenyl, Naphtyl oder gegebenenfalls durch Hydroxy substituiertes 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können, (C6-do)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Phenyl, Halogen, Hydroxy, Cyano, Nitro,R 2 is hydrogen, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, (dC 6 ) - alkoxy, mono- or di- (Cι -C 6 ) - alkylamino, phenyl, biphenyl, naphthyl or optionally 5- to 10-membered heterocyclyl substituted by hydroxy may be substituted with up to three heteroatoms from the series N, O and / or S, (C 6 -do) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by phenyl, halogen, hydroxy, cyano, nitro,
Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C6)-Alkoxy, (d-C6)-Trifluoromethyl, trifluoromethoxy, (-C-C 6 ) alkyl, (dC 6 ) alkoxy, (dC 6 ) -
AUcoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können, oder einen Rest der Formel -C(= )-R4 oder -SO2-R4 bedeutet,AUcoxycarbonyl or mono- or di- (-CC 6 ) alkylamino may be substituted, or a radical of the formula -C (=) -R 4 or -SO 2 -R 4 means,
wonnWonn
R4 Wasserstoff, (Cι-C6)- Alkyl, das seinerseits durch Hydroxy oderR 4 is hydrogen, (-CC 6 ) - alkyl, which in turn by hydroxy or
(Cι-C4)-Alkoxy substituiert sein kann, (C6-do)-Aryl, 5- bis 10-glie- driges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl und Heteroaryl ihrerseits, unabhängig voneinander, durch Halogen substituiert sein können, (C3-C8)-Cycloalkyl oder einen Rest der Formel -NR R oder -OR bedeutet,(-C-C 4 ) alkoxy can be substituted, (C 6 -do) aryl, 5- to 10-glazed heteroaryl with up to three heteroatoms from the series N, O and / or S, wherein aryl and heteroaryl in turn, independently of one another, can be substituted by halogen, means (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR R or -OR,
worinwherein
R5 und R6 unabhängig voneinander Wasserstoff, (C6-C1o)-Aryl, Adamantyl, (d-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu drei- fach durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cyclo- alkyl, (d-C6)- Alkoxy, Mono- oder Di-(C1-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-CycloaUcyl, das bis zu dreifach durch (Cι-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6- gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)- Alkyl substituiert ist, bedeuten,R 5 and R 6 are independently hydrogen, (C 6 -C 1 o) aryl, adamantyl, (DC 8) -alkyl, whose chain may be interrupted by one or two oxygen atoms and up to three times by hydroxyl, phenyl , Trifluoromethyl, (C 3 -C 8 ) cycloalkyl, (dC 6 ) - alkoxy, mono- or di- (C 1 -C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms the series N, O and / or S or can be substituted by 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) -CycloaUcyl, which can be substituted up to three times by (-C-C 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-CC 4 ) alkyl,
oderor
R5 und R6 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen gesättigten Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O und/oder S ersetzt sind und der durch Hydroxy, Oxo, Aminocarbonyl, (Cι-C6)- Alkyl oder (Cι-C6)- Alkoxy-(d-C6)-alkyl substituiert sein kann,R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and by Hydroxy, oxo, aminocarbonyl, (-CC 6 ) - alkyl or (-C-C 6 ) - alkoxy- (dC 6 ) -alkyl can be substituted,
undand
R7 (C6-do)-Aryl, Adamantyl, (d-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome ünter- brachen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)- Cycloalkyl, (Cι-C6)-Alkoxy, Mono- oder Di-(Cι-C6)-alkyl- amino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus derR 7 (C 6 -do) -aryl, adamantyl, (dC 8 ) -alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) - Cycloalkyl, (-C-C 6 ) alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl with up to three heteroatoms from the
Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (Cι-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)-Alkyl substituiert ist, bedeutet, oderRow N, O and / or S can be substituted, (C 3 -C 8 ) cycloalkyl, which can be substituted up to three times, independently of one another, by (C 1 -C 4 ) alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-CC 4 ) -alkyl, or
R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 10-gliedrigen gesättigten Heterocyclus mit bis zu zwei weiteren Heteroatomen aus der Reihe N, O und/oder S bedeuten, der gegebenenfalls bis zu zweifach, unabhängig voneinander, durch Benzyl oder (C6-Cιo)-Aryl, das seinerseits durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (d-C6)-Alkoxy, (d-C6)- AUcoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann, substituiert ist,R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 10-membered saturated heterocycle with up to two further heteroatoms from the series N, O and / or S, which may be up to two, independently from each other, by benzyl or (C 6 -Cιo) aryl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) alkyl, (dC 6 ) alkoxy, (dC 6 ) - AUcoxycarbonyl or mono- or di- (-CC 6 ) alkylamino may be substituted, is substituted,
R* eine Gruppe bedeutet, R * means a group
woπnembedded image in which
R8 für eine Gruppe der FormelR 8 for a group of the formula
für (C3-C8)-Cycloalkyl, das durch (d-C8)- Alkyl, (C6-C10)-Aryl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und oder S substituiert sein kann, wobei Aryl, Heterocyclyl und Heteroaryl ihrerseits bis zu dreifach durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)- AUcyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy, Amino, Mono- oder Di- (C1-C6)-alkylamino, (Cι-C6)- AUcoxycarbonyl, Carboxyl, substituiert sein können,for (C 3 -C 8 ) cycloalkyl which is substituted by (dC 8 ) alkyl, (C 6 -C 10 ) aryl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and or S, where aryl, heterocyclyl and heteroaryl in turn can be substituted up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, ( Cι-C 6 ) - AUcyl, (C 3 -C 8 ) cycloalkyl, (Cι-C 6 ) alkoxy, amino, mono- or di- (C 1 -C6) alkylamino, (Cι-C 6 ) - AUcoxycarbonyl, carboxyl, substituted can,
oderor
für eine Methylgruppe steht, die bis zu dreifach, unabhängig voneinander, durch Wasserstoff, (C3-C8)-Cycloalkyl, (d-C8)-AUcyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO - Gruppe unterbrochen sein kann und das bis zu zweifach durchrepresents a methyl group which is up to three times, independently of one another, hydrogen, (C 3 -C 8 ) -cycloalkyl, (dC 8 ) -AUcyl, the chain of which is interrupted by a sulfur atom or an S (O) or SO group can be up to two times
Hydroxy, (d-C6)-Alkoxy, (Cι-C6)- AUcoxycarbonyl, Halogen, Cyano, Nitro, Trifluormethoxy, Oxo, Amino, Mono- oder' Di-(d-C6)- alkylamino oder Carboxamid substituiert sein kann, (d-C^-Alkoxycarbonyl, (C6-Cι0)-Aryl, Benzyl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Benzyl, Heterocyclyl und Heteroaryl bis zu dreifach durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (d-C6)- Alkyl, (C3-C8)-Cycloalkyl, (Cι-C6)- Alkoxy, Amino, Mono- oder Di-Hydroxy, (dC 6 ) alkoxy, (-C-C 6 ) - AUcoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy, oxo, amino, mono- or ' di- (dC 6 ) - alkylamino or carboxamide can be substituted, (dC ^ -Alkoxycarbonyl, (C 6 -Cι 0 ) aryl, benzyl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl with up to three Heteroatoms from the series N, O and / or S can be substituted, aryl, benzyl, heterocyclyl and heteroaryl being substituted up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (dC 6 ) - alkyl, (C 3 -C 8 ) -Cycloalkyl, (-C-C 6 ) - alkoxy, amino, mono- or di-
(Cι-Cö)-alkylamino, (Cι-C6)-Alkoxycarbonyl, Carboxyl, (d-C6)- Alkylcarbonylamino, (Cι-C6)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oderDi-(Cι-C6)-alkylaminocarbonyl, das seinerseits durch (Ci- C6)-Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di-(Cι- C6)-alkylamidosulfon, das seinerseits durch (Cι-C6)-Alkoxy substituiert sein kann, substituiert sein können,(-C-C ö ) alkylamino, (-C-C 6 ) alkoxycarbonyl, carboxyl, (dC 6 ) - alkylcarbonylamino, (Cι-C 6 ) -alkoxycarbonylamino, aminocarbonyl, mono- or di- (Cι-C 6 ) alkylaminocarbonyl , which in turn can be substituted by (C 1 -C 6 ) alkoxy, amidosulfone, mono- or di- (C 1 -C 6 ) alkyl amidosulfone, which in turn can be substituted by (C 1 -C 6 ) alkoxy .
Wasserstoff, (Cι-C6)-Alkoxy, (Cι-C6)- Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy oder Mono- oder Di-(d-C6)-alkylamino substituiert sein können, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)- Alkyl, (d-C6)- Alkoxy, (d-C6)-Alkoxycarbonyl oder Mono- oder Di-(d-C6)-alkylamino substituiert sein können,Hydrogen, (-C 6 -C) alkoxy, (-C -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxyl or mono- or di- (dC 6 ) alkylamino can be substituted, (C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-C-C 6 ) - alkyl, (dC 6 ) - alkoxy, ( dC 6 ) -alkoxycarbonyl or mono- or di- (dC 6 ) -alkylamino can be substituted,
oderor
R8 und R9 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 8-gliedrigen Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O und/oder S ersetzt sind und der bis zu vierfach, unabhängig voneinander, durch Hydroxy, (Cι-C6)-Alkyl, (Cι-C6)- Alkoxy, Hydroxy-(C1- C6)-alkyl, (Cι-C6)-Alkoxy-(Cι-C6)-aUcyl, Oxo, Amino oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann,R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and the up to fourfold, independently of one another, by hydroxy, (-CC 6 ) -alkyl, (-CC 6 ) -alkoxy, hydroxy- (C 1 -C 6 ) -alkyl, (-C-C 6 ) -alkoxy- (Cι- C 6 ) -aUcyl, oxo, amino or mono- or di- (-C-C 6 ) alkylamino may be substituted,
R10 Wasserstoff, (d-C6)- Alkoxy, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits, unabhängig voneinander, bis zu dreifach durch Hydroxy oder Mono- oder Di-(Cι-C6)-alkylammo substituiert sein können, (C6-do)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu dreiR 10 is hydrogen, (dC 6 ) - alkoxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn, independently of one another, up to three times by hydroxy or mono- or di- (-C-C 6 ) alkylammo can be substituted, (C 6 -do) aryl, 5- to 10-membered heteroaryl with up to three
Heteroatomen aus der Reihe N, O und oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits, unabhängig voneinander, bis zu dreifach durch Halogen, Hydroxy, Cyano, Nitro,Heteroatoms from the series N, O and or S or 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn, independently of one another, up to three times Halogen, hydroxy, cyano, nitro,
Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (C C6)-Alkoxy, (C1-C6)-Alkoxycarbonyl oder Mono- oder Di-(d-C6)-alkylamino substituiert sein können,Trifluoromethyl, trifluoromethoxy, (-CC 6 ) alkyl, (CC 6 ) alkoxy, (C 1 -C 6 ) alkoxycarbonyl or mono- or di- (dC 6 ) alkylamino can be substituted,
einen Rest der Formel -C(=O)-R12 oder -SO2-R12 bedeutet,is a radical of the formula -C (= O) -R 12 or -SO 2 -R 12 ,
woπnembedded image in which
R12 Wasserstoff, (Cι-C6)-Alkyl, das seinerseits durch Hydroxy oder (Cι-C4)-Alkoxy substituiert sein kann, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl und Heteroaryl ihrerseits, unabhängig voneinander, durch Halogen substituiert sein können, (C3-C8)-Cycloalkyl oder einen Rest der Formel -NR13R14 oder-OR15 bedeutet,R 12 is hydrogen, (-CC 6 ) alkyl, which in turn may be substituted by hydroxy or (-C-C 4 ) alkoxy, (C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three Heteroatoms from the series N, O and / or S, in which aryl and heteroaryl may in turn, independently of one another, be substituted by halogen, (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR 13 R 14 or -OR 15 means
worinwherein
R13 und R14 unabhängig voneinander Wasserstoff, (C6-Cιo)- Aryl, Adamantyl, (Cι-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl, (d-C6)-Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Hetero- atomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach durch (Cι-C )- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Hetero- atomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (d-C4)-Alkyl substituiert ist, bedeuten,R 13 and R 14 independently of one another hydrogen, (C 6 -Cιo) - aryl, adamantyl, (Cι-C 8 ) alkyl, the chain of which may be interrupted by one or two oxygen atoms and up to three times by hydroxy, phenyl, trifluoromethyl , (C 3 -C 8 ) -cycloalkyl, (dC 6 ) -alkoxy, mono- or di- (-C-C 6 ) -alkylamino, 5- or 6-membered heterocyclyl with up to three hetero atoms from the series N , O and / or S or by 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S can be substituted, (C 3 -C 8 ) -cycloalkyl which can be substituted up to three times by ( Cι-C) - Alkyl, hydroxy or oxo can be substituted, or 5- or 6-membered heterocyclyl with up to two hetero- atoms from the series N, O and / or S, where N is substituted by hydrogen or (dC 4 ) -alkyl,
oderor
R13 und R14 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen gesättigtenR 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated
Heterocyclus bilden, der bis zu zwei weitere Hetero- atome aus der Reihe N, O und/oder S enthalten kann und gegebenenfalls durch Hydroxy, Oxo, (d-C6)- Alkyl oder (Cι-C6)-Alkoxy-(d-C6)-alkyl substituiert istForm heterocycle, which can contain up to two further hetero atoms from the series N, O and / or S and optionally by hydroxy, oxo, (dC 6 ) - alkyl or (-C-C 6 ) alkoxy- (dC 6 ) alkyl is substituted
R15 (C6-Cιo)-Aryl, Adamantyl, (d-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl, (d-C6)-Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus derR 15 (C 6 -Cιo) aryl, adamantyl, (dC 8 ) alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 - C 8 ) -cycloalkyl, (dC 6 ) alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from
Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (Cι-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)- Alkyl substituiert ist, bedeutet,Series N, O and / or S or by 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl which can be up to triple , independently of one another, can be substituted by (-C 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is hydrogen or (-C-C 4 ) - alkyl is substituted means
und ihre Salze, Hydrate, Hydrate der Salze und Solvate. Ebenfalls bevorzugt kann in den Verbindungen der Formel (I) der Restand their salts, hydrates, hydrates of the salts and solvates. The radical in the compounds of the formula (I) can also preferably be used
D Phenylen, Thiophendiyl, Pyridindiyl, Thiazoldiyl, Pyrimidindiyl, Imidazoldiyl, Pyrazoldiyl, Isoxazoldiyl oder Oxazoldiyl bedeuten, die jeweils bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (d-Cö^Alkyl, (Cι-C6)- Alkoxy, (d-C6)-Alkoxycarbonyl oder Mono- oder Di-(C1-C6)-aUcylamino substituiert sein können.D is phenylene, thiophenediyl, pyridinediyl, thiazolediyl, pyrimidinediyl, imidazolediyl, pyrazolediyl, Isoxazoldiyl or oxazolediyl mean that in each case up to three times, independently, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC ö ^ alkyl, (-C-C 6 ) - alkoxy, (dC 6 ) alkoxycarbonyl or mono- or di- (C 1 -C 6 ) -aUcylamino can be substituted.
Besonders bevorzugt kann in den Verbindungen der Formel (I) der RestThe radical in the compounds of the formula (I) can be particularly preferably
D 1,3- oder 1,4-Phenylen; 2,4- oder 2,5-Thiophendiyl oder 2,4- oder 2,5-D 1,3- or 1,4-phenylene; 2,4- or 2,5-thiophene diyl or 2,4- or 2,5-
Pyridindiyl bedeuten, die jeweils bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)-Alkyl, (Cι-C6)-Alkoxy, (Cι-C6)-AUcoxycarbonyl oder Mono- oder Di-(d-C6)-alkylamino substituiert sein können.Pyridindiyl mean, each up to three times, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) -alkyl, (Cι-C 6 ) -alkoxy, (Cι-C 6 ) - AUcoxycarbonyl or mono- or di- (dC 6 ) alkylamino can be substituted.
Ganz besonders bevorzugt kann in den Verbindungen der Formel (I) der RestThe radical in the compounds of the formula (I) can be very particularly preferably
D 1,3- oder 1,4-Phenylen; 2,4- oder 2,5-Thiophendiyl oder 2,4- oder 2,5-D 1,3- or 1,4-phenylene; 2,4- or 2,5-thiophene diyl or 2,4- or 2,5-
Pyridindiyl bedeuten, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (Cι-C6)- Alkoxy, (d-C6)- AUcoxycarbonyl oder Mono- oder Di-(Cι-C6)-aUcylamino substituiert sein können.Pyridinediyl mean, each up to two, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, (-C-C 6 ) -alkyl, (Cι-C 6 ) - alkoxy, (dC 6 ) - AUcoxycarbonyl or mono- or di- (-C-C6) -aUcylamino can be substituted.
insbesondere ganz besonders bevorzugt kann in den Verbindungen der Formel (I) der Restthe radical in the compounds of the formula (I) can be very particularly preferably
D 1,4-Phenylen oder 2,5-Pyridindiyl bedeuten, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)-Alkyl, (Cι-C6)-AUcoxy, (Cι-C6)- AUcoxycarbonyl oder Mono- oder Di-(Cι-C6)-aUcylamino substituiert sein können.D is 1,4-phenylene or 2,5-pyridinediyl, each up to twice, independently of one another, by halogen, hydroxyl, cyano, carboxy, nitro, Trifluoromethyl, trifluoromethoxy, (dC 6 ) alkyl, (-C-C 6 ) -AUcoxy, (Cι-C 6 ) - AUcoxycarbonyl or mono- or di- (Cι-C 6 ) -aUcylamino can be substituted.
Ebenfalls bevorzugt kann in den Verbindungen der Formel (I) der RestThe radical in the compounds of the formula (I) can also preferably be used
R8 für eine Methylgruppe stehen, die als einen Substituenten (C6-Cιo)-Aryl oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S trägt, wobei Aryl und Heteroaryl bis zu dreifach durch Halogen, Trifluormethyl,R 8 represents a methyl group which carries as a substituent (C 6 -Cιo) aryl or 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, with aryl and heteroaryl up to triple through halogen, trifluoromethyl,
Cyano, Nitro, Hydroxy, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy, Amino, Mono- oder Di-(Cι-C6)-alkylamino, (d-C6)- AUcoxycarbonyl, Carboxyl, (d-C^-Alkylcarbonylarnino, (d-C6)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(Cι-C6)-alkylaminocarbonyl, das seinerseits durch (Cι-C6)- Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di-Cyano, nitro, hydroxy, (-C 6 -C) alkyl, (C 3 -C 8 ) cycloalkyl, (-C 6 ) alkoxy, amino, mono- or di- (-C 6) alkylamino, ( dC 6 ) - AUcoxycarbonyl, carboxyl, (dC ^ -alkylcarbonylarnino, (dC 6 ) -alkoxycarbonylamino, aminocarbonyl, mono- or di- (-C-C 6 ) -alkylaminocarbonyl, which in turn may be substituted by (Cι-C 6 ) - alkoxy can, amidosulfone, mono- or di-
(d-C^-alkylamidosulfon, das seinerseits durch (Cι-C6)-Alkoxy substituiert sein kann, substituiert sein können, und außerdem bis zu zweifach, unabhängig voneinander, durch Wasserstoff, (C3-C8)-Cycloalkyl, (Cι-C8)-Alkyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO2-Gruppe unterbrochen sein kann und das bis zu zweifach durch Hydroxy, (Cι-C6)- AUcoxy, (C1-C6)-Alkoxycarbonyl, Halogen, Cyano, Nitro, Trifluormethoxy, Oxo, Amino, Mono- oder Di-(Cι-C6)-alkylamino oder Carboxamid substituiert sein kann, (Cι-C6)-Alkoxycarbonyl, (C6-C10)-Aryl, Benzyl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Benzyl, Heterocyclyl und Heteroaryl bis zu dreifach durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)- Alkyl, (C3-C8)-(dC ^ -alkylamidosulfone, which in turn can be substituted by (-C-C 6 ) alkoxy, can be substituted, and also up to two, independently of one another, by hydrogen, (C 3 -C 8 ) -cycloalkyl, (Cι- C 8 ) -alkyl, the chain of which can be interrupted by a sulfur atom or an S (O) - or SO 2 group and up to two times by hydroxy, (Cι-C 6 ) - AUcoxy, (C 1 -C 6 ) alkoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy, oxo, amino, mono- or di- (Cι-C6) alkylamino, or carboxamide may be substituted (Cι-C6) -alkoxycarbonyl, (C 6 -C 10) Aryl, benzyl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the N, O and / or S series or 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series can be substituted, whereby aryl, benzyl, heterocyclyl and heteroaryl up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (-C-C 6 ) - alkyl, (C 3 -C 8 ) -
Cycloalkyl, (Cι-C6)-Alkoxy, Amino, Mono- oder Di-(d-C6)-alkylamino, (Cι-C6)- AUcoxycarbonyl, Carboxyl, (Cι-C6)-Alkylcarbonylamino, (Cι-C6)- Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(C1-Cö)-alkylamino- carbonyl, das semerseits durch (Cι-C6)-Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di-(Cι-C6)-alkylamidosulfon, das seinerseits durch (d-C6)-Alkoxy substituiert sein kann, substituiert sein können.Cycloalkyl, (-CC 6 ) alkoxy, amino, mono- or di- (dC 6 ) alkylamino, (-C-C 6 ) - AUcoxycarbonyl, carboxyl, (Cι-C 6 ) -alkylcarbonylamino, (Cι-C 6 ) - alkoxycarbonylamino, aminocarbonyl, mono- or di- (C 1 -Cö) -alkylamino-carbonyl, the semester by (-C 6 -C) alkoxy can be substituted, amidosulfone, mono- or di- (-C 6 -C) alkylamido sulfone, which in turn can be substituted by (dC 6 ) alkoxy, can be substituted.
Ebenfalls besonders bevorzugt kann in den Verbindungen der Formel (I) der RestThe rest of the compounds of formula (I) may also be particularly preferred
R8 für eine Methylgruppe stehen, die als einen Substituenten Wasserstoff trägt, als einen weiteren Substituenten (C6-Cιo)-Aryl oder 5- bis 10-gliedrigesR 8 stands for a methyl group which carries hydrogen as a substituent, as a further substituent (C 6 -Cιo) aryl or 5- to 10-membered
Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S trägt, wobei Aryl und Heteroaryl bis zu dreifach durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, (d-C6)-Alkoxy, Amino, Mono- oder Di-(Cι-C6)-alkylamino, (Cι-C6)-Alkoxycarbonyl, Carboxyl, (Cι-C6)-AJkylcarbonylarnino, (d-C6)-Alkoxycarbonylamino,Heteroaryl with up to three heteroatoms from the series N, O and / or S carries, wherein aryl and heteroaryl up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) -Cycloalkyl, (dC 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) alkylamino, (Cι-C 6 ) alkoxycarbonyl, carboxyl, (Cι-C 6 ) -AJkylcarbonylarnino, (dC 6 ) alkoxycarbonylamino,
Aminocarbonyl, Mono- oder Di-(Cι-C6)-alkylaminocarbonyl, das seinerseits durch (C]-C6)-AUcoxy substituiert sein kann, Amidosulfon, Mono- oder Di- (d-C6)-alkylamidosulfc>n, das seinerseits durch (Cι-C6)-Alkoxy substituiert sein kann, substituiert sein können, und außerdem durch Wasserstoff, (C -Cs)-Cycloalkyl, (Cι-Cs)-Alkyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO -Gruppe unterbrochen sein kann und das bis zu zweifach durch Hydroxy, (d-C6)- Alkoxy, (d-C6)-Alkoxycarbonyl, Halogen, Cyano, Nitro, Trifluormethoxy, Oxo, Amino, Mono- oder Di-(Cι-C6)-alkylamino oder Carboxamid substi- tuiert sein kann,Aminocarbonyl, mono- or di- (-C-C 6 ) -alkylaminocarbonyl, which in turn can be substituted by (C] -C 6 ) -AUcoxy, amidosulfone, mono- or di- (dC 6 ) -alkylamidosulfc> n, which in turn can be substituted by (-CC 6 ) alkoxy, may be substituted, and also by hydrogen, (C -Cs) -cycloalkyl, (-C-Cs) -alkyl, the chain of which by a sulfur atom or an S (O) - or SO group can be interrupted and that up to twice by hydroxy, (dC 6 ) - alkoxy, (dC 6 ) -alkoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy, oxo, amino, mono- or di- (Cι-C 6 ) -alkylamino or carboxamide can be substituted,
(d-C6)- AUcoxycarbonyl, (C6-Cι0)-Aryl, Benzyl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert ist, wobei Aryl, Benzyl, Heterocyclyl und Heteroaryl bis zu dreifach durch(dC 6 ) - AUcoxycarbonyl, (C 6 -Cι 0 ) aryl, benzyl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl up to three heteroatoms from the series N, O and / or S is substituted, with aryl, benzyl, heterocyclyl and heteroaryl being substituted up to three times
Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)-Alkyl, (C3-C8)- Cycloalkyl, (Cι-Ce)-Alkoxy, Amino, Mono- oder Di-(C1-C6)-alkylamino, (Cι-C6)-Alkoxycarbonyl, Carboxyl, (Cι-C6)-Alkylcarbonylamino, (d-C6)- AUcoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(C1-C6)-alkylamino- carbonyl, das seinerseits durch (Cι-C6)- Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di-(Cι-C6)-alkylamidosulfon, das seinerseits durchHalogen, trifluoromethyl, cyano, nitro, hydroxy, (-CC 6 ) alkyl, (C 3 -C 8 ) - Cycloalkyl, (-C-Ce) alkoxy, amino, mono- or di- (C 1 -C 6 ) alkylamino, (Cι-C 6 ) alkoxycarbonyl, carboxyl, (Cι-C 6 ) alkylcarbonylamino, (dC 6 ) - AUcoxycarbonylamino, aminocarbonyl, mono- or di- (C 1 -C 6 ) alkylamino-carbonyl, which in turn can be substituted by (Cι-C 6 ) - alkoxy, amidosulfone, mono- or di- (Cι-C 6 ) alkylamido sulfone, which in turn by
(Cι-C6)-Alkoxy substituiert sein kann, substituiert sein können.(-C-C 6 ) alkoxy may be substituted, may be substituted.
Ebenfalls ganz besonders bevorzugt kann in den Verbindungen der Formel (I) der RestThe radical in the compounds of the formula (I) can also be very particularly preferably
R8 für eine Methylgruppe stehen, die als einen Substituenten Wasserstoff trägt, als einen weiteren Substituenten (C6-Cιo)-Aryl oder 5- bis "10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S trägt, wobei Aryl und Heteroaryl bis zu dreifach durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxy,R 8 stands for a methyl group which carries hydrogen as a substituent, as a further substituent (C 6 -Cιo) aryl or 5- to " 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S carries, wherein aryl and heteroaryl up to three times by halogen, trifluoromethyl, cyano, nitro, hydroxy, (-C-C 6 ) alkyl, (C 3 -C 8 ) -cycloalkyl, (-C-C 6 ) alkoxy,
Amino, Mono- oder Di-(Cι-C6)-alkylamino, (C1-C6)-Alkoxycarbonyl, Carboxyl, (d-C6)-Alkylcarbonylamino, (Cι-C6)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(Cι-C6)-alkylaminocarbonyl, das seinerseits durch (Cι-C6)- Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di- (Cι-C6)-alkylamidosulfon, das semerseits durch (d-C6)- Alkoxy substituiert sein kann, substituiert sein können, und außerdem durch Wasserstoff, (C3-C8)-Cycloalkyl oder (d-C8)- Alkyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO2-Gruppe unterbrochen sein kann und das bis zu zweifach durch Hydroxy, (d-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl, Halogen, Cyano, Nitro, Trifluormethoxy,Amino, mono- or di- (-C 6 ) alkylamino, (C 1 -C 6 ) alkoxycarbonyl, carboxyl, (dC 6 ) alkylcarbonylamino, (Cι-C 6 ) alkoxycarbonylamino, aminocarbonyl, mono- or di - (-C-C 6 ) alkylaminocarbonyl, which in turn can be substituted by (Cι-C 6 ) - alkoxy, amidosulfone, mono- or di- (Cι-C 6 ) -alkylamidosulfone, which in turn by (dC 6 ) - alkoxy may be substituted, may be substituted, and also by hydrogen, (C 3 -C 8 ) cycloalkyl or (dC 8 ) alkyl, the chain of which may be interrupted by a sulfur atom or an S (O) or SO 2 group and that up to twice by hydroxy, (dC 6 ) - alkoxy, (-C-C 6 ) alkoxycarbonyl, halogen, cyano, nitro, trifluoromethoxy,
Oxo, Amino, Mono- oder Di-(Cι-C6)-alkylamino oder Carboxamid substituiert sein kann, substituiert ist.Oxo, amino, mono- or di- (-C 6 ) alkylamino or carboxamide may be substituted.
Die erfindungsgemäßen Verbindungen der Formel (I) können über folgendes Verfahren, das drei unterschiedliche Reaktionsfolgen umfasst, hergestellt werden: In einer möglichen Reaktionsfolge werden Verbindungen der Formel (II)The compounds of the formula (I) according to the invention can be prepared by the following process, which comprises three different reaction sequences: In a possible reaction sequence, compounds of the formula (II)
in welchen A und D die oben angegebenen Bedeutungen haben und T für (d-C4)-in which A and D have the meanings given above and T for (dC 4 ) -
Alkyl, vorzugsweise für Methyl oder tert.-Butyl, steht,Alkyl, preferably methyl or tert-butyl,
zunächst in Verbindungen der Formel (TV)initially in compounds of the formula (TV)
in welchen A, D, M, R2 und T die oben angegebenen Bedeutungen haben,in which A, D, M, R 2 and T have the meanings given above,
überführt.transferred.
In Abhängigkeit der Bedeutung von A und M sind hierfür verschiedene Wege möglich.Depending on the meaning of A and M, different ways are possible.
1. Für den Fall, dass A für eine CH2-Gruppe steht, werden die entsprechenden Nerbindungen der Formel (Ha) 1. In the event that A stands for a CH 2 group, the corresponding Nerbindeln of formula (Ha)
in welchen D und T die oben angegebenen Bedeutungen haben,in which D and T have the meanings given above,
mit Nerbindungen der Formel (TTT) oder (lud)with compounds of the formula (TTT) or (loaded)
HΝR!R2 (III) HO-R2 (ffld),HΝR ! R 2 (III) HO-R 2 (ffld),
i o — in welchen R und R die oben angegebenen Bedeutungen haben, ■i o - in which R and R have the meanings given above, ■
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, zu Nerbindungen der Formel (IN) umgesetzt.in a solvent, optionally in the presence of a base, to Nerbindungen of formula (IN).
2. Für den Fall, dass A für eine CO-Gruppe und M für eine Gruppe -Ν^R1)- steht, werden die oben beschriebenen Nerbindungen der Formel (Ila) zunächst durch Umsetzung mit einem Oxidationsmittel in einem Lösungsmittel in die Nerbindungen der Formel (ITb)2. In the event that A stands for a CO group and M for a group -Ν ^ R 1 ) -, the above described Nerbindungen of formula (Ila) are first by reaction with an oxidizing agent in a solvent in the Nerbindungen of Formula (ITb)
in welchen D und T die oben angegebenen Bedeutungen haben,in which D and T have the meanings given above,
überführt und die so erhaltenen Nerbindungen der Formel (Ilb) anschließend mit den oben beschriebenen Nerbindungen der Formel (III) in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kon- densationsmittels, zu den entsprechenden Nerbindungen der Formel (IN) umgesetzt.transferred and the Nerbindungen of formula (IIb) thus obtained then with the above described Nerbindungen of formula (III) in a solvent, optionally in the presence of a base and / or a Kon- sealant, implemented to the corresponding Nerbindungen of formula (IN).
3. Für den Fall, dass A für eine Bindung und M für eine Gruppe -Ν^R1)- steht, werden die oben beschriebenen Nerbindungen der Formel (Ilb) zu Nerbindungen der Formel (IIc)3. In the event that A stands for a bond and M for a group -Ν ^ R 1 ) -, the above described Nerbindungen of formula (Ilb) to Nerbindungen of formula (IIc)
in welchen D und T die oben angegebene Bedeutung haben,in which D and T have the meaning given above,
in einer üblichen Umlagerungsreaktion wie z.B. nach Curtius oder Hofinan umgesetzt und anschließendin a common rearrangement reaction such as implemented according to Curtius or Hofinan and then
entwedereither
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, nacheinander in beliebiger Reihenfolge mit den Nerbindungen der Formel (lila) und (IHb)in a solvent, optionally in the presence of a base, in succession in any order with the Nerbindungen of the formula (purple) and (IHb)
in welchen R1 und R2 die oben angegebenen Bedeutungen haben und N und V für geeignete Abgangsgruppen wie beispielsweise Mesylat, Tosylat oder Halogen, vorzugsweise Chlor oder Brom, stehen,in which R 1 and R 2 have the meanings given above and N and V represent suitable leaving groups such as, for example, mesylate, tosylate or halogen, preferably chlorine or bromine,
oder durch reduktive Aminierung in einem Lösungsmittel unter Verwendung eines geeigneten Reduktionsmittels mit Verbindungen der Formel (IHc)or by reductive amination in a solvent using a suitable reducing agent with compounds of the formula (IHc)
R16-CHO (nie),R 16 -CHO (never),
in welchen R16 Phenyl, (C2-C5)-Alkenyl oder (C1-C5)- Alkyl, das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl oder Mono- oder Di-(d-C6)-alkylamino substituiert sein kann, bedeutet,in which R 16 is phenyl, (C 2 -C 5 ) alkenyl or (C 1 -C 5 ) alkyl, which is up to three times, independently of one another, by hydroxy, phenyl or mono- or di- (dC 6 ) alkylamino can be substituted means
in Verbindungen der Formel (IVa)in compounds of the formula (IVa)
1 ( in welchen A, D, R und T die oben angegebenen Bedeutungen haben,1 (in which A, D, R and T have the meanings given above,
überführt und anschließend in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Nerbindungen der Formel (IHD)transferred and then in a solvent, optionally in the presence of a base, with Nerbindeln of formula (IHD)
R2-V (Illb),R 2 -V (Illb),
in welchen R2 und V die oben angegebenen Bedeutungen haben,in which R 2 and V have the meanings given above,
zu den entsprechenden Nerbindungen der Formel (IN) umgesetzt.implemented to the corresponding Nerbindungen of formula (IN).
Die so hergestellten Verbindungen der Formel (IN) werden dann in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Säure oder Base, in Nerbindungen der Formel (V) The compounds of the formula (IN) thus prepared are then in a solvent, optionally in the presence of an acid or base, in Nerbindungen of the formula (V)
in welchen A, D, M und R die oben angegebenen Bedeutungen haben,in which A, D, M and R have the meanings given above,
überführt.transferred.
Für die weitere Einführung des Restes R3 sind zwei Wege möglich.Two ways are possible for the further introduction of the rest R 3 .
Entweder werden Nerbindungen der Formel (V) mit Nerbindungen der Formel (NT)Either compounds of the formula (V) are combined with compounds of the formula (NT)
in welchen R8 und R9 die oben angegebenen Bedeutungen haben,in which R 8 and R 9 have the meanings given above,
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kondensationsmittels, umgesetzt. In den so erhaltenen Verbindungen der Formel (I) steht der Rest R3 für -COΝR8R9.in a solvent, optionally in the presence of a base and / or a condensing agent. In the compounds of the formula (I) thus obtained, the radical R 3 represents -CO -R 8 R 9 .
Alternativ werden die Verbindungen der Formel (V) in einer üblichen Umlagerungsreaktion wie z.B. nach Curtius oder Hofman umgesetzt. Die so erhaltenen Verbindungen der Formel (VII) Alternatively, the compounds of the formula (V) are reacted in a customary rearrangement reaction, for example according to Curtius or Hofman. The compounds of formula (VII) thus obtained
in welchen A, D, M und R2 die oben angegebenen Bedeutungen haben,in which A, D, M and R 2 have the meanings given above,
werden abschließendwill be final
entwedereither
nacheinander in beliebiger Reihenfolge mit den Nerbindungen der Formel (NITIa) und (VIIIb)successively in any order with the Nerbindungen of formula (NITIa) and (VIIIb)
R10-W (Nrfla) Rπ-W' (Vlllb),R 10 -W (Nrfla) R π -W '(Vlllb),
in welchen R10 und R11 die oben angegebenen Bedeutungen haben und W und W' für geeignete Abgangsgruppen wie beispielsweise Halogen, vorzugsweise Chlor oderin which R 10 and R 11 have the meanings given above and W and W 'for suitable leaving groups such as halogen, preferably chlorine or
Brom, stehen,Bromine standing
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, umgesetztin a solvent, optionally in the presence of a base
oderor
durch reduktive Aminierung in einem Lösungsmittel unter Verwendung eines geeigneten Reduktionsmittels mit Verbindungen der Formel (NTflc)by reductive amination in a solvent using a suitable reducing agent with compounds of the formula (NTflc)
R17-CHO (NIHc),R 17 -CHO (NIHc),
in welchen R17 (C1-C5)- Alkyl bedeutet, das bis zu dreifach, unabhängig voneinander, durch Hydroxy oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein kann, in Nerbindungen der Formel (Ia)in which R 17 denotes (C 1 -C 5 ) alkyl which can be substituted up to three times, independently of one another, by hydroxy or mono- or di- (-C 6 ) alkylamino, in compounds of the formula (Ia)
in welchen A, D, M, R2 und R17 die oben angegebenen Bedeutungen haben,in which A, D, M, R 2 and R 17 have the meanings given above,
überführt und anschließend in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Nerbindungen der Formel (Vlllb)transferred and then in a solvent, optionally in the presence of a base, with Nerbindeln of the formula (VIIIb)
Rn-W (vπib),R n -W (vπib),
in welchen R11 und W' die oben angegebenen Bedeutungen haben,in which R 11 and W 'have the meanings given above,
umgesetzt. In den so erhaltenen Verbindungen der Formel (I) steht der Rest R3 fürimplemented. In the compounds of formula (I) thus obtained, the radical R 3 represents
-ΝR10Rn bzw. -N(CH2-R17)Rπ.-ΝR 10 R n or -N (CH 2 -R 17 ) R π .
In einer zweiten möglichen Reaktionsfolge werden die oben beschriebenen Verbindungen der Formel (Ha) zunächst durch Umsetzung mit einem Oxida- tionsmittel in einem Lösungsmittel in die Verbindungen der Formel (Ild)In a second possible reaction sequence, the compounds of the formula (Ha) described above are first converted into the compounds of the formula (Ild) by reaction with an oxidizing agent in a solvent
in welchen D und T die oben angegebenen Bedeutungen haben, überführt. Anschließend wird in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Säure oder Base, zu Verbindungen der Formel (IX)in which D and T have the meanings given above, transferred. Then in a solvent, optionally in the presence of an acid or base, to give compounds of the formula (IX)
in welchen D die oben angegebene Bedeutung hat,in which D has the meaning given above,
umgesetzt. Die Reaktion in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kondensationsmittels, mit Verbindungen der Formel (VI)implemented. The reaction in a solvent, optionally in the presence of a base and / or a condensing agent, with compounds of the formula (VI)
in welchen R8 und R9 die oben angegebenen Bedeutungen haben,in which R 8 and R 9 have the meanings given above,
liefert dann Nerbindungen der Formel (X)then yields compounds of the formula (X)
in welchen D, R8 und R9 die oben angegebenen Bedeutungen haben. Durch reduktive Aminierung von Nerbindungen der Formel (X) in einem Lösungsmittel unter Nerwendung eines geeigneten Reduktionsmittels mit Nerbindungen der Formel (XI)in which D, R 8 and R 9 have the meanings given above. By reductive amination of Nerbindungen of formula (X) in a solvent using a suitable reducing agent with Nerbindungen of formula (XI)
R!-ΝH2 (XI),R ! -ΝH 2 (XI),
in welchen R1 die oben angegebene Bedeutung hat,in which R 1 has the meaning given above,
werden Nerbindungen der Formel (Xu)compounds of the formula (Xu)
in welchen D, R » 1 , τ R>8 und R die oben angegebenen Bedeutungen haben,in which D, R »1, τ R> 8 and R have the meanings given above,
erhalten.receive.
Alternativ können Nerbindungen der Formel (XII) hergestellt werden, indem zunächst Nerbindungen der Formel (Ila), gegebenenfalls in Gegenwart einer Säure oder Base, zu Verbindungen der Formel (XVI)Alternatively, Nerbindungen of formula (XII) can be prepared by first Nerbindungen of formula (Ila), optionally in the presence of an acid or base, to compounds of formula (XVI)
in welchen D die oben angegebene Bedeutung hat, umgesetzt werden. Die anschließende Reaktion in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kondensationsmittels, mit Verbindungen der Formel (VI)in which D has the meaning given above, be implemented. The subsequent reaction in a solvent, optionally in the presence of a base and / or a condensing agent, with compounds of the formula (VI)
in welchen R und R die oben angegebenen Bedeutungen haben,in which R and R have the meanings given above,
liefert dann Nerbindungen der Formel (XVII)then provides Nerbindungen of formula (XVII)
in welchen D, R8 und R9 die oben angegebenen Bedeutungen haben,in which D, R 8 and R 9 have the meanings given above,
die dann entwederthen either
durch Umsetzung mit Nerbindungen der Formel (XI) in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Baseby reaction with Nerbindungen of formula (XI) in a solvent, optionally in the presence of a base
oderor
durch nukleophile Substitution des Bromids durch Umsetzung mit Natriumazid und anschließende Reduktion der Azidogruppe zur entsprechenden Aminogruppeby nucleophilic substitution of the bromide by reaction with sodium azide and subsequent reduction of the azido group to the corresponding amino group
in Nerbindungen der Formel (XII) überführt werden. Die Einführung des Restes R2 kann abschließend in verschiedener Weise erfolgen, indem man entweder Nerbindungen der Formel (XTI)are converted into compounds of the formula (XII). Finally, the introduction of the radical R 2 can be carried out in various ways by either Nerbindeln of the formula (XTI)
1. durch Reaktion mit einem Phosgenäquivalent wie beispielsweise Trichlormethylchlorformiat in einem Lösungsmittel und anschließende Umsetzung in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Nerbindungen der Formel (XDI)1. by reaction with a phosgene equivalent such as, for example, trichloromethyl chloroformate in a solvent and subsequent reaction in a solvent, if appropriate in the presence of a base, with Nerbindeln of formula (XDI)
HΝR5R6 (xrπ),HΝR 5 R 6 (xrπ),
in welchen R und R die oben angegebenen Bedeutungen haben,in which R and R have the meanings given above,
oderor
2. durch Reaktion in einem Lösungsmittel, gegebenenfalls in Gegenwart einer2. by reaction in a solvent, optionally in the presence of a
Base, mit Nerbindungen der Formel (XIN)Base, with Nerbindungen of the formula (XIN)
in welchen X für eine Abgangsgruppe wie beispielsweise das entsprechende symmetrische Anhydrid oder ein Halogen, vorzugsweise Chlor, steht und R4 die oben angegebene Bedeutung mit Ausnahme von ΝR5R6 hat,in which X represents a leaving group such as, for example, the corresponding symmetrical anhydride or a halogen, preferably chlorine, and R 4 has the meaning given above with the exception of ΝR 5 R 6 ,
oderor
durch Reaktion in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Nerbindungen der Formel (XN) oby reaction in a solvent, optionally in the presence of a base, with Nerbindeln of formula (XN) O
V/ (XV),V / (XV),
^ R4 ^ R 4
in welchen Y für eine Abgangsgruppe wie beispielsweise ein Halogen, vorzugsweise Chlor, steht und R4 die oben angegebene Bedeutung hat,in which Y represents a leaving group such as a halogen, preferably chlorine, and R 4 has the meaning given above,
zu Nerbindungen der Formel (I) umsetzt,converts to compounds of formula (I),
in welchenin which
A für eine CH2-Gruppe, ~ ,A for a CH 2 group, ~ ,
M für eine Gruppe -Ν^R1)-,M for a group -Ν ^ R 1 ) -,
R2 für einen Rest -CO-R4 oder -SO2-R4 undR 2 for a radical -CO-R 4 or -SO 2 -R 4 and
RJ für einen Rest -COΝR8Ry steht.R J stands for a radical -COΝR 8 R y .
In einer dritten möglichen Reaktionsfolge werden Nerbindungen der Formel (XNπi)In a third possible reaction sequence, N compounds of the formula (XNπi)
(XNIII), (XNIII)
in welchen D und T die oben angegebenen Bedeutungen haben,in which D and T have the meanings given above,
zunächst in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Säure oder Base, in Nerbindungen der Formel (XLX) first in a solvent, optionally in the presence of an acid or base, in Nerbindungen of the formula (XLX)
in welchen D die oben angegebenen Bedeutungen hat,in which D has the meanings given above,
überführt, anschließend mit Nerbindungen der Formel (NT)transferred, then with Nerbindungen of formula (NT)
in welchen R8 und R9 die oben angegebenen Bedeutungen haben,in which R 8 and R 9 have the meanings given above,
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kondensationsmittels, zu Verbindungen der Formel (XX)in a solvent, optionally in the presence of a base and / or a condensing agent, to give compounds of the formula (XX)
in welchen D, R und R die oben angegebenen Bedeutungen haben,in which D, R and R have the meanings given above,
umgesetzt. Anschließend wird die Methylschutzgruppe durch Umsetzung mit Bortribromid abgespalten. Durch Umsetzung mit Verbindungen der Formel (Illb)implemented. The methyl protective group is then split off by reaction with boron tribromide. By reaction with compounds of the formula (Illb)
R2-V (fllb),R 2 -V (fllb),
in welchen R2 und V die oben angegebenen Bedeutungen haben, werden Verbindungen der Formel (I) erhalten, in welchenin which R 2 and V have the meanings given above, Compounds of formula (I) are obtained in which
A für eine chemische Bindung undA for a chemical bond and
M für ein Sauerstoffatom -O-M for an oxygen atom -O-
steht.stands.
Die so erhaltenen Verbindungen der Formel (I) können gegebenenfalls anschließend durch Umsetzung z.B. mit einer Säure in die entsprechenden Salze überführt werden.The compounds of formula (I) thus obtained can optionally subsequently be reacted e.g. be converted into the corresponding salts with an acid.
Die Herstellung der Verbindungen der entsprechenden diastereomeren und enantiomeren Formen erfolgt entsprechend, und zwar entweder unter Verwendung enantio- meren- oder diastereomerenreiner Ausgangsstoffe oder aber durch nachträglicheThe compounds of the corresponding diastereomeric and enantiomeric forms are prepared accordingly, either using enantiomerically or diastereomerically pure starting materials, or by means of subsequent ones
Trennung der gebildeten Racemate mit üblichen Methoden (z.B. Racematspaltung, Chromatographie an chiralen Säulen etc.).Separation of the racemates formed using customary methods (e.g. resolution of racemates, chromatography on chiral columns, etc.).
Das erfindungsgemäße Verfahren kann durch folgende Formelschemata beispielhaft erläutert werden: The method according to the invention can be illustrated by the following formula schemes:
R steht für eine Sauerstoffschutzgruppe oder ein Festphasenharz Das erfindungsgemäße Verfahren wird im allgemeinen bei Normaldruck durchgeführt. Es ist aber auch möglich, das Verfahren bei Überdruck oder bei Unterdruck durchzufuhren (z.B. in einem Bereich von 0,5 bis 5 bar).R stands for an oxygen protecting group or a solid phase resin The process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under overpressure or under underpressure (for example in a range from 0.5 to 5 bar).
Die Reaktionen erfolgen im allgemeinen in einem Temperaturbereich zwischenThe reactions generally take place in a temperature range between
-75°C und +150°C, insbesondere zwischen 0°C und +80°C.-75 ° C and + 150 ° C, especially between 0 ° C and + 80 ° C.
Als Lösemittel für das Verfahren eignen sich übliche organische Lösemittel, die sich unter den Reaktionsbedingungen nicht verändern. Hierzu gehören Ether wie Diethyl- ether, Dioxan, Tetrahydrofuran, Glykoldimethy lether, oder Kohlenwasserstoffe wieCustomary organic solvents which do not change under the reaction conditions are suitable as solvents for the process. These include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as
Benzol, Toluol, Xylol, Hexan, Cyclohexan oder Erdölfraktionen, oder Halogenkohlenwasserstoffe wie Dichlormethan, Trichlormethan, Tetrachlormethah, Dichlor- efhylen, Trichlorethylen oder Chlorbenzol, oder sonstige Lösungsmittel wie Essigester, Pyridin, Dimethylsulfoxid, Dimethylformarnid, N,N'-Dimethylpropylen- hamstoff (DMPU), N-Methylpyrrolidon (NMP), Acetonitril, Aceton, Nitromethan oder deren Mischungen.Benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroefethylene, trichlorethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformarnide (N, N'p, DMPU), N-methylpyrrolidone (NMP), acetonitrile, acetone, nitromethane or mixtures thereof.
Als Basen für das erfindungsgemäße Verfahren können im allgemeinen anorganische oder organische Basen eingesetzt werden. Hierzu gehören vorzugsweise Alkalihy- droxide wie zum Beispiel Natriumhydroxid oder Kaliumhydroxid, Erdalkalihy- droxide wie zum Beispiel Bariumhydroxid, Alkalicarbonate wie Natriumcarbonat, Kaliumcarbonat oder Cäsiumcarbonat, Erdalkalicarbonate wie Calciumcarbonat, oder Alkali- oder Erdalkalialkoholate wie Natrium- oder Kaliummethanolat, Natriumoder Kaliumethanolat oder Kalium-tert.-butylat, oder organische Arnine wie Tri- ethylamin, oder Heterocyclen wie l,4-Diazabicyclo[2.2.2]octan (DABCO), 1,8-Di- azabicyclo[5.4.0]undec-7-en (DBU), 1,5-Diazabicyclo [4.3.0]non-5-en (DBN), Pyridin, Diaminopyridin, N-Methylpiperidin oder N-Methyl-morpholin. Es ist auch möglich, als Basen Alkalimetalle wie Natrium oder deren Hydride wie Natrium- hydrid einzusetzen. Als Hilfsstoffe für die Amidbildung werden bevorzugt übliche Kondensationsmittel eingesetzt, wie Carbodiimide z.B. N,N'-Diethyl-, N,N,'-Dipropyl-, N,N'-Diisopro- pyl-, N,N'-Dicyclohexylcarbodiimid, N-(3-Dimefhylaminoisopropyl)-N'-ethylcarbo- diimid-Hydrochlorid (EDC), oder Carbonylverbindungen wie Carbonyldiimidazol oder 1,2-Oxazoliumverbindungen wie 2-Ethyl-5-phenyl-l,2-oxazolium-3-sulfat oderIn general, inorganic or organic bases can be used as bases for the process according to the invention. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium tert .-Butylate, or organic amines such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) , 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), pyridine, diaminopyridine, N-methylpiperidine or N-methylmorpholine. It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases. Conventional condensing agents, such as carbodiimides, for example N, N'-diethyl, N, N, 'dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N-, are preferably used as auxiliaries for the amide formation. (3-Dimefhylaminoisopropyl) -N'-ethylcarbodimide hydrochloride (EDC), or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or
2-tert.-Butyl-5-methyl-isoxazolium-perchlorat, oder Acylaminoverbindungen wie 2- Ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydrochinolin oder Propanphosphonsäureanhydrid oder Isobutylchloroformat oder Bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid oder Benzotriazolyloxy-tri(dimethylamino)phosphoniumhexafluorophosphat oder O- (Benzotriazol- 1 -y -NjNjN'jN'-tetra-methyluronium-hexafluorophosphat (HBTU) oder ©-(Berizotriazol-l-y -NjNjN^N'-tetra-methyluronium-tetrafluoroborat (TBTU) oder 2-(2-Oxo-l-(2H)-ρyridyl)-l,l,3,3-tetramethyluroniumtetrafluoroborat (TPTU) oder O-(7-Azabenzotriazol- 1 -yl)-N,N,N^N'-tetramethyl-urom'umhexafluorophosphat (HATU) oder 1-Hydroxybenztriazol, und als Basen bei der Amidbildung Alkali- carbonate z.B. Natrium- oder Kaliumcarbonat, oder -hydrogencarbonat, oder organische Basen wie Trialkylamine z.B. Triethylaniin, N-Methylmorpholin (NMM), 4-Dimethylaminopyridin (DMAP), N-Methylpiperidin oder Diisopropylethylamin (DIEA) eingesetzt.2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline or propanephosphonic anhydride or isobutylchloroformate or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate or O- (Benzotriazol-1 -y -NjNjN'jN'-tetra-methyluronium hexafluorophosphate (HBTU) or © - (Berizotriazol-ly -NjNjN ^ N'-tetra-methylfluoroborate ) or 2- (2-oxo-l- (2H) -ρyridyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1 -yl) -N, N, N ^ N '-tetramethyl-urom ' umhexafluorophosphate (HATU) or 1-hydroxybenztriazole, and as bases in the amide formation alkali carbonates, for example sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines, for example triethylaniine, N-methylmorpholine (NMM), 4 -Dimethylaminopyridine (DMAP), N-methylpiperidine or diisopropylethylamine (DIEA) used.
Die Umsetzung von Verbindungen (Ila) mit Verbindungen (III) zu VerbindungenThe reaction of compounds (Ila) with compounds (III) to compounds
(IV) erfolgt bevorzugt in Acetonitril als Lösungsmittel unter Nerwendung von Kaliumcarbonat als Base bei einer Reaktionstemperatur zwischen 50°C und 70°C oder in Dimethylformamid als Lösungsmittel unter Nerwendung von Νatriumhydrid als Base bei Raumtemperatur. Die Umsetzung von Nerbindungen (Ila) mit Nerbin- düngen (Illd) erfolgt dagegen bevorzugt in Dimethylformamid oder Tetrahydrofuran als Lösungsmittel unter Nerwendung von Νatriumhydrid als Base.(IV) is preferably carried out in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C. and 70 ° C. or in dimethylformamide as solvent using sodium hydride as base at room temperature. In contrast, the reaction of Nerbindungen (Ila) with Nerbin fertilizers (Illd) is preferably carried out in dimethylformamide or tetrahydrofuran as solvent using sodium hydride as the base.
Die Oxidation von Nerbindungen (Ila) zu Nerbindungen (Ilb) erfolgt bevorzugt in Dimethylsulfoxid als Lösungsmittel unter Nerwendung von Νatriumnitrit/Essigsäure als Oxidationsmittel bei Raumtemperatur. Die Amidbildung bei der Reaktion von Verbindungen (üb) mit Verbindungen (III) zu Verbindungen (IN) erfolgt bevorzugt in Dimethylformamid als Lösungsmittel unter Nerwendung von EDC, HOBT und/oder TBTU als Hilfsstoffe und DMAP, DIEA oder ΝMM als Base bei Raumtemperatur.The oxidation of Nerbindungen (Ila) to Nerbindungen (Ilb) is preferably carried out in dimethyl sulfoxide as a solvent using sodium nitrite / acetic acid as an oxidizing agent at room temperature. The amide formation in the reaction of compounds (above) with compounds (III) to compounds (IN) is preferably carried out in dimethylformamide as solvent using EDC, HOBT and / or TBTU as auxiliaries and DMAP, DIEA or ΝMM as base at room temperature.
Die Umlagerung von Nerbindungen (Ilb) zu Nerbindungen (IIc) erfolgt unter den üblichen Reaktionsbedingungen eines Hofman-, Curtius- oder Lossen-Abbaus. Bevorzugt findet die Reaktion unter Nerwendung von Diphenylphosphorylazid (DPPA) in Dioxan als Lösungsmittel bei Raumtemperatur oder in n-Hexan unter Rückfluss zur Herstellung des intermediär entstehenden Isocyanats statt. Die anschließendeThe rearrangement of Nerbindungen (Ilb) to Nerbindungen (IIc) takes place under the usual reaction conditions of a Hofman, Curtius or Lossen degradation. The reaction preferably takes place using diphenylphosphoryl azide (DPPA) in dioxane as solvent at room temperature or in n-hexane under reflux to produce the intermediate isocyanate. The subsequent one
Hydrolyse des Isocyanats erfolgt bevorzugt mit Kaliumhydroxid als Base in Aceto- nitril als Lösungsmittel bei Raumtemperatur.Hydrolysis of the isocyanate is preferably carried out using potassium hydroxide as the base in acetonitrile as the solvent at room temperature.
Die Umsetzung von Nerbindungen (IIc) mit Nerbindungen (ILTa) und (Ulb) zu Ner- bindungen (IN) kann in beliebiger Reihenfolge erfolgen. Sie erfolgt ebenso wie dieThe conversion of Nerbindungen (IIc) with Nerbindungen (ILTa) and (Ulb) to Nerinkungen (IN) can be done in any order. It takes place just like that
Umsetzung von Nerbindungen (XX) mit Nerbindungen (TTTb) bevorzugt in Acetonitril als Lösungsmittel unter Nerwendung von Kaliumcarbonat als Base bei einer Reaktionstemperatur zwischen 50°C und 70°C oder in Dimethylformamid als Lösungsmittel unter Nerwendung von Νatriumhydrid als Base bei Raumtemperatur.Reaction of Nerbindungen (XX) with Nerbindungen (TTTb) preferably in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C and 70 ° C or in dimethylformamide as solvent using sodium hydride as base at room temperature.
Der erste Schritt der reduktive Aminierung von Nerbindungen (IIc) mit Nerbindungen (Hie) zu Nerbindungen (IVa) erfolgt bevorzugt in einem Gemisch von Trimethylorthoformiat und Dichlormefhan als Lösungsmittel oder in Methanol unter Essigsäurekatalyse bei Raumtemperatur. Die anschließende Reduktion erfolgt be- vorzugt unter Nerwendung von Tetrabutylammoniumborhydrid oder Νatriumcyano- borhydrid als Reduktionsmittel in Dimethylformamid als Lösungsmittel bei Raumtemperatur.The first step of the reductive amination of Nerbindungen (IIc) with Nerbindungen (Hie) to Nerbindungen (IVa) is preferably carried out in a mixture of trimethyl orthoformate and dichloromethane as solvent or in methanol with acetic acid catalysis at room temperature. The subsequent reduction is preferably carried out using tetrabutylammonium borohydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
Die Umsetzung von Verbindungen (IVa) mit Verbindungen (ILIb) zu Verbindungen (IV) erfolgt bevorzugt in Acetonitril als Lösungsmittel unter Verwendung vonThe reaction of compounds (IVa) with compounds (ILIb) to compounds (IV) is preferably carried out in acetonitrile as solvent using
Kaliumcarbonat als Base bei einer Reaktionstemperatur zwischen 50°C und 70°C oder in Dimethylformamid als Lösungsmittel unter Verwendung von Natriumhydrid als Base bei Raumtemperatur.Potassium carbonate as base at a reaction temperature between 50 ° C and 70 ° C or in dimethylformamide as a solvent using sodium hydride as a base at room temperature.
Die Hydrolyse von Verbindungen (IV) zu Nerbindungen (N) bzw. von Nerbindungen (XN-Tf) zu Verbindungen (XIX) erfolgt bevorzugt in Dichlormefhan als Lösungsmittel unter Verwendung von Trifluoressigsäure als Säure bei Raumtemperatur oder in Dioxan als Lösungsmittel unter Verwendung von Salzsäure bei Raumtemperatur.The hydrolysis of compounds (IV) to Nerbindungen (N) or Nerbindungen (XN-Tf) to compounds (XIX) is preferably carried out in dichloromefhan as solvent using trifluoroacetic acid as acid at room temperature or in dioxane as solvent using hydrochloric acid room temperature.
Die Amidbildung bei der Reaktion von Verbindungen (N) bzw. Nerbindungen (XIX) mit Nerbindungen (VT) bzw. Nerbindungen (XX) zu Nerbindungen (I), in denen derThe amide formation in the reaction of compounds (N) or Nerbindungen (XIX) with Nerbindungen (VT) or Nerbindungen (XX) to Nerbindungen (I), in which the
Rest R3 für -COΝR8R9 steht, erfolgt bevorzugt in Dimethylformamid als Lösungsmittel unter Nerwendung von EDC, HOBT und/oder TBTU als HΪlfsstoffe und DMAP, DIEA oder ΝMM als Base bei Raumtemperatur.R 3 stands for -COΝR 8 R 9 , preferably takes place in dimethylformamide as solvent using EDC, HOBT and / or TBTU as excipients and DMAP, DIEA or ΝMM as base at room temperature.
Die Umlagerung von Nerbindungen (V) zu Verbindungen (VII) erfolgt unter den üblichen Reaktionsbedingungen eines Hofinan-, Curtius- oder Lossen-Abbaus. Bevorzugt findet die Reaktion unter Verwendung von Diphenylphosphorylazid (DPPA) in Dioxan als Lösungsmittel bei Raumtemperatur oder in n-Hexan unter Rückfluss zur Herstellung des intermediär entstehenden Isocyanats statt Die anschließende Hydrolyse des Isocyanats erfolgt bevorzugt mit Kaliumhydroxid alsThe rearrangement of Nerbindungen (V) to compounds (VII) takes place under the usual reaction conditions of Hofinan, Curtius or Lossen degradation. The reaction preferably takes place using diphenylphosphoryl azide (DPPA) in dioxane as solvent at room temperature or in n-hexane under reflux to produce the intermediate isocyanate. The subsequent hydrolysis of the isocyanate is preferably carried out with potassium hydroxide
Base in Acetonitril als Lösungsmittel bei Raumtemperatur.Base in acetonitrile as a solvent at room temperature.
Die Umsetzung von Verbindungen (VII) mit Verbindungen (Villa) und (Niπb) zu Nerbindungen (I), in denen Rest R3 für -ΝR10Rπ steht, kann in beliebiger Reihen- folge erfolgen, bevorzugt in Acetonitril als Lösungsmittel unter Nerwendung vonThe reaction of compounds (VII) with compounds (Villa) and (Niπb) to Nerbindungen (I), in which radical R 3 is -ΝR 10 R π , can be carried out in any order, preferably in acetonitrile as a solvent using of
Kaliumcarbonat als Base bei einer Reaktionstemperatur zwischen 50°C und 70°C oder in Dimethylformamid als Lösungsmittel unter Nerwendung von Νatriumhydrid als Base bei Raumtemperatur.Potassium carbonate as a base at a reaction temperature between 50 ° C and 70 ° C or in dimethylformamide as a solvent using sodium hydride as a base at room temperature.
Der erste Schritt der reduktive Aminierung von Nerbindungen (NU) mit Nerbindungen (NIIIc) zu Verbindungen (Ia) erfolgt bevorzugt in einem Gemisch von Tri- methylorthoformiat und Dichlormethan als Lösungsmittel oder in Methanol unter Essigsäurekatalyse bei Raumtemperatur. Die anschließende Reduktion erfolgt bevorzugt unter Verwendung von Tetrabutylammoniumborhydrid oder Natriumcyano- borhydrid als Reduktionsmittel in Dimethylformamid als Lösungsmittel bei Raum- temperatur.The first step of the reductive amination of Nerbindungen (NU) with Nerbindungen (NIIIc) to compounds (Ia) is preferably carried out in a mixture of tri- methyl orthoformate and dichloromethane as solvent or in methanol with acetic acid catalysis at room temperature. The subsequent reduction is preferably carried out using tetrabutylammonium borohydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
Die Umsetzung von Verbindungen (Ia) mit Verbindungen (VTflb) zu Verbindungen (I) erfolgt bevorzugt in Acetonitril als Lösungsmittel unter Verwendung von Kaliumcarbonat als Base bei einer Reaktionstemperatur zwischen 50°C und 70°C oder in Dimethylformamid als Lösungsmittel unter Verwendung von Natriumhydrid als Base bei Raumtemperatur.The reaction of compounds (Ia) with compounds (VTflb) to give compounds (I) is preferably carried out in acetonitrile as solvent using potassium carbonate as base at a reaction temperature between 50 ° C. and 70 ° C. or in dimethylformamide as solvent using sodium hydride as Base at room temperature.
Die Oxidation von Verbindungen (Ila) zu Verbindungen (Ild) erfolgt bevorzugt unter Verwendung von N-Methylmorpholin-N-oxid als Oxidationsmittel in Acetonitril als Lösungsmittel bei Raumtemperatur.The oxidation of compounds (Ila) to compounds (Ild) is preferably carried out using N-methylmorpholine-N-oxide as an oxidizing agent in acetonitrile as a solvent at room temperature.
Die Hydrolyse von Verbindungen (Ild) zu Verbindungen (IX) oder von Verbindungen (Ila) zu Verbindungen (XVI) erfolgt bevorzugt in Dichlormethan als Lösungsmittel unter Verwendung von Trifluoressigsäure als Säure bei Raumtemperatur oder in Dioxan als Lösungsmittel unter Verwendung von Salzsäure bei Raumtemperatur.The hydrolysis of compounds (Ild) to compounds (IX) or of compounds (Ila) to compounds (XVI) is preferably carried out in dichloromethane as solvent using trifluoroacetic acid as acid at room temperature or in dioxane as solvent using hydrochloric acid at room temperature.
Die Amidbildung bei der Reaktion von Verbindungen (IX) bzw. Verbindungen (XVI) mit Verbindungen (VI) bzw. Verbindungen (XVII) zu Verbindungen (X) er- folgt bevorzugt in Dimethylformamid als Lösungsmittel unter Verwendung vonThe amide formation in the reaction of compounds (IX) or compounds (XVI) with compounds (VI) or compounds (XVII) to compounds (X) preferably takes place in dimethylformamide as solvent using
EDC, HOBT und/oder TBTU als Hilfsstoffe und DMAP, DIEA oder NMM als Base bei Raumtemperatur.EDC, HOBT and / or TBTU as auxiliary substances and DMAP, DIEA or NMM as base at room temperature.
Der erste Schritt der reduktive Aminierung von Verbindungen (X) mit Verbindungen (XI) zu Verbindungen (XII) erfolgt bevorzugt in einem Gemisch von Trimefhyl- orthoformiat und Dichlormethan als Lösungsmittel oder in Methanol unter Essig- säurekatalyse bei Raumtemperatur. Die anschließende Reduktion erfolgt bevorzugt unter Verwendung von Tetrabutylammomumborhydrid oder Natriumcyanoborhydrid als Reduktionsmittel in Dimethylformamid als Lösungsmittel bei Raumtemperatur.The first step of the reductive amination of compounds (X) with compounds (XI) to give compounds (XII) is preferably carried out in a mixture of trimethyl orthoformate and dichloromethane as solvent or in methanol with vinegar. acid catalysis at room temperature. The subsequent reduction is preferably carried out using tetrabutylammomumborhydride or sodium cyanoborohydride as a reducing agent in dimethylformamide as a solvent at room temperature.
Die Umsetzung von Verbindungen (XU) mit Phosgenäquivalenten, vorzugsweise mit Trichlormethylchlorformiat, erfolgt bevorzugt in Dichlormethan als Lösungsmittel bei 0°C. Die anschließende Reaktion mit Aminen der Formel (XIII) erfolgt bevorzugt in Dimethylformamid als Lösungsmittel in Gegenwart von Diisopropylethylamin als Base bei Raumtemperatur.The reaction of compounds (XU) with phosgene equivalents, preferably with trichloromethyl chloroformate, is preferably carried out in dichloromethane as solvent at 0 ° C. The subsequent reaction with amines of the formula (XIII) is preferably carried out in dimethylformamide as solvent in the presence of diisopropylethylamine as base at room temperature.
Die Umsetzung von Verbindungen (XII) mit Verbindungen (XIV) oder Nerbindungen (XN) erfolgt bevorzugt in Dichlormethan als Lösungsmittel in* Gegenwart von Diisopropylethylamin als Base zwischen Raumtemperatur und 50°C.The reaction is preferably carried out of compounds (XII) with compounds (XIV) or Nerbindungen (XN) in dichloromethane as a solvent in the presence of diisopropylethylamine as the base * between room temperature and 50 ° C.
Die Verbindungen der Formeln (IT), (Ila), (111), (lila), (Illb), (IIIc), (VI), (Villa),The compounds of the formulas (IT), (Ila), (111), (purple), (Illb), (IIIc), (VI), (Villa),
(VHIb), (XI), (Xπi), (Viπc), (XIN), (XN) und (XNIII) sind bekannt oder nach üblichen Methoden herstellbar (vgl. EP-A-0 725 061, EP-A-0 725 064, EP-A- 0 581 003, EP-A-0 611 767.(VHIb), (XI), (Xπi), (Viπc), (XIN), (XN) and (XNIII) are known or can be prepared by customary methods (cf. EP-A-0 725 061, EP-A-0 725 064, EP-A-0 581 003, EP-A-0 611 767.
Übeπaschenderweise zeigen die erfindungsgemäßen Verbindungen der Formel (I) ein nicht vorhersehbares, wertvolles pharmakologisches Wirkspektrum.Surprisingly, the compounds of the formula (I) according to the invention have an unforeseeable, valuable pharmacological spectrum of action.
Die erfindungsgemäßen Verbindungen wirken als Modulatoren, insbesondere als Öffner von „Big K"-Kanälen. Sie können zur Herstellung von Arzneimitteln zur Prävention und oder Behandlung des Herzkreislaufsystems wie z.B. von Bluthochdruck, Herzinsuffizienz sowie ischämiebedingten peripheren und kardiovaskulären Erkrankungen, insbesondere zur akuten und chronischen Behandlung von ischämischen Erkrankungen des Herz-Kreislauf-Systems, wie z.B. der koronaren Herzkrankheit, der stabilen und instabilen Angina pectoris, von peripheren und arteriellen Verschlusskrankheiten, von thrombotischen Gefäßverschlüssen, desThe compounds according to the invention act as modulators, in particular as openers of “Big K” channels. They can be used to manufacture medicaments for the prevention and or treatment of the cardiovascular system, such as high blood pressure, heart failure and ischemic-related peripheral and cardiovascular diseases, in particular for acute and chronic treatment of ischemic diseases of the cardiovascular system, such as, for example, coronary heart disease, stable and unstable angina pectoris, peripheral and arterial occlusive diseases, thrombotic vascular occlusions, des
Myocardinfarkts und von Reperfusionsschäden, verwendet werden. Außerdem sind sie durch ihr Potential, die Angiogenese zu verstärken, besonders für eine dauerhafte Therapie aller Verschlusskrankheiten geeignet.Myocardial infarction and reperfusion damage. Furthermore, due to their potential to intensify angiogenesis, they are particularly suitable for long-term therapy of all occlusive diseases.
Darüber hinaus können die erfindungsgemäßen Verbindungen allein oder in Kombination mit anderen Arzneimitteln in oraler oder intravenöser Applikation zur Prävention und/oder Behandlung von cerebrovaskulären Erkrankungen wie cerebraler Ischämie, Hirnschlag, Reperfüsionsschäden, Hirntrauma, Ödemen, Krämpfen, Epilepsie, Atemstillstand, Herzstillstand, Reye-Syndrom, zerebraler Thrombose, Embolie, Tumoren, Blutungen, Enzephalomyelitis, Hydroenzephalitis,In addition, the compounds according to the invention, alone or in combination with other drugs, in oral or intravenous administration for the prevention and / or treatment of cerebrovascular diseases such as cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cramps, epilepsy, respiratory arrest, cardiac arrest, Reye syndrome , cerebral thrombosis, embolism, tumors, bleeding, encephalomyelitis, hydroencephalitis,
Rückenmarksverletzungen, post-operative Hirnschäden, Verletzungen der Retina oder des optischen Nervs nach Glaukom, Ischämie, Hypoxie, Ödem oder Trauma sowie in der Behandlung von Schizophrenie, Schlafstörungen und akuten und/oder chronischen Schmerzen sowie neurodegenerativen Erkrankungen, insbesondere zur Behandlung von Krebs-induzierten Schmerzen und chronischen neuropathischenSpinal cord injuries, post-operative brain damage, injuries to the retina or the optical nerve after glaucoma, ischemia, hypoxia, edema or trauma as well as in the treatment of schizophrenia, sleep disorders and acute and / or chronic pain as well as neurodegenerative diseases, in particular for the treatment of cancer-induced Pain and chronic neuropathic
Schmerzen, wie zum Beispiel bei diabetischer Neuropathie, posttherpeutischer Neuralgie, peripheren Nervenbeschädigungen, zentralem Schmerz (beispielsweise als Folge von cerebraler Ischämie) und trigeminaler Neuralgie und anderen chronischen Schmerzen, wie zum Beispiel Lumbago, Rückenschmerz (lower back pain) oder rheumatischen Schmerzen, eingesetzt werden.Pain such as diabetic neuropathy, post-therapeutic neuralgia, peripheral nerve damage, central pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia and other chronic pain such as lumbago, back pain (lower back pain) or rheumatic pain ,
Außerdem sind die erfindungsgemäßen Verbindungen zur Prävention und/oder Behandlung von Erl ankungen des Urogenitaltraktes wie Harninkontinenz, Prostatahypertrophie, Steinleiden der Niere und der ableitenden Harnwege, erektiler Dys- funktion oder sexueller Dysfünktion geeignet. A Bewertung der physiologischen WirksamkeitIn addition, the compounds according to the invention are suitable for the prevention and / or treatment of effects of the genitourinary tract such as urinary incontinence, prostate hypertrophy, stone disorders of the kidney and the urinary tract, erectile dysfunction or sexual dysfunction. A Assessment of physiological effectiveness
In v/ϊro-Testmodelle zur Prüfung von „BigK-Modulatoren"In v / ϊro test models for testing "BigK modulators"
CHO-Zellen wurden mittels Elektroporation stabil mit der humanen cDNA der alpha-Untereinheit des BigK-Kanals transfiziert. Die Kultivierung der Zellen erfolgte in MEM alpha Medium mit 10 % FCS.CHO cells were stably transfected by electroporation with the human cDNA of the alpha subunit of the BigK channel. The cells were cultivated in MEM alpha medium with 10% FCS.
1. Messungen des Rubidiumausstromes Unter physiologischen Bedingungen stellen die meisten Kaliumkanäle sehr selektive1. Measurements of Rubidium Outflow Under physiological conditions, most potassium channels are very selective
Poren für Kalium dar. Diese Kaliumkanäle, so auch BigK, lassen allerdings auch Rubidium in vergleichbarem Ausmaß passieren. Physiologisch ist Rubidium aufgrund seines geringen Vorkommens in diesem Zusammenhang jedoch bedeutungslos. Neben der weit verbreiteten Methode des Nachweises von radioaktivem Rubidium, einem sehr starken ß- und γ-Strahler, gibt es auch die Möglichkeit denPores for potassium. However, these potassium channels, including BigK, also allow rubidium to pass through to a comparable extent. Due to its low occurrence, Rubidium is physiologically meaningless in this context. In addition to the widespread method of detecting radioactive rubidium, a very strong ß and γ emitter, there is also the possibility
Rubidiumfluss durch Kaliumkanäle nicht-radioaktiv nachzuweisen und zu quantifizieren (Ionenkanal-Charakterisierung mittels Atomabsorption, vgl. DE-A- 4433 261). Nach einer Beladung der zu untersuchenden Zellen, bei der das intrazelluläre Kalium weitestgehend durch Rubidium ersetzt wird, kann der quantitative Nachweis von Rubidium in der extrazellulären Lösung zu verschiedenen Zeitpunkten erfolgen. Zu Beginn des Versuches ist die extrazelluläre Lösung nominell Rubidium- frei aber Kalium-haltig. Aus den beladenen Zellen kann Rubidium durch unspezifische Leitfähigkeiten und aktive Transporter wie die Natrium/Kalium-ATPase in den Überstand gelangen und somit zu einem gewissen unspezifischen Hintergrund führen. Vor diesem Hintergrund führt die Aktivierung von Kaliumkanälen mit derNon-radioactive detection and quantification of rubidium flow through potassium channels (ion channel characterization using atomic absorption, cf. DE-A-4433 261). After loading the cells to be examined, in which the intracellular potassium is largely replaced by rubidium, the quantitative detection of rubidium in the extracellular solution can be carried out at different times. At the beginning of the experiment, the extracellular solution is nominally rubidium-free but contains potassium. Rubidium can get into the supernatant from the loaded cells through unspecific conductivities and active transporters such as sodium / potassium ATPase and thus lead to a certain non-specific background. Against this background, the activation of potassium channels with the
Zeit jedoch zu einem deutlichen Anstieg der Rubidiumkonzentration. Die vergleichsweise stärkere Zunahme der Rubidiumkonzentration im Zeilüberstand zeigt ebenso wie die damit einhergehende Abnahme der intrazellulären Rubidiumkonzentration eine quantifizierbare Aktivierung eines Kaliumkanals an. Zur Quantifizierung des intrazellulären Rubidiums werden die Zellen mit einemTime for a significant increase in the rubidium concentration. The comparatively greater increase in the rubidium concentration in the cell supernatant, as well as the associated decrease in the intracellular rubidium concentration, indicate a quantifiable activation of a potassium channel. To quantify the intracellular rubidium, the cells are marked with a
Lysepuffer behandelt. Um BigK-Aktivität unter Hochdurchsatzbedingungen gut nachweisen zu können, wurde eine CHO Zelle mit sehr geringer Kaliumleitfahigkeit ausgewählt und zur stabilen Expression zahlreicher funktioneller BigK-Kanäle gebracht. Die Rubidiumkonzentration der verschiedenen Lösungen wird routinemäßig mit einem Atomabsorptionsspektrometer (Unicam 939, Offenbach, Germany) gemessen.Treated lysis buffer. To keep BigK activity good under high throughput conditions To be able to demonstrate, a CHO cell with very low potassium conductivity was selected and brought to the stable expression of numerous functional BigK channels. The rubidium concentration of the various solutions is routinely measured using an atomic absorption spectrometer (Unicam 939, Offenbach, Germany).
2. Patch-clamp Untersuchungen2. Patch-clamp investigations
48 h nach dem Aussäen der Zellen auf Poly-D-Lysin (100 μg/ml) beschichteten Glasdeckgläschen (30-50 % Konfluenz) erfolgte die Messung der BigK-Kanalströme mittels feuerpolierter Glasmikroelektroden (R = 2 bis 5 MOhm) bei 150 mM intrazellulärer und 5 mM extrazellulärer Kaliumkonzentration. Die Registrierung des Kaliumstromes erfolgte bei Testpotentialen von -100 mV bis + 80 mV (Pulsdauer 100 ms). Die Aktivierung der BigK-Kanalströme durch die Testsubstanz wurde in einem Konzentrationsbereich von 10"8 bis 10"5 M untersucht.48 h after sowing the cells on poly-D-lysine (100 μg / ml) coated glass coverslips (30-50% confluence), the BigK channel currents were measured using fire-polished glass microelectrodes (R = 2 to 5 MOhm) at 150 mM intracellular and 5 mM extracellular potassium concentration. The potassium current was registered at test potentials from -100 mV to + 80 mV (pulse duration 100 ms). The activation of the BigK channel currents by the test substance was examined in a concentration range from 10 "8 to 10 " 5 M.
3. Langendorff-Herz der Ratte3. Langendorff heart of the rat
Narkotisierten Ratten wird nach Eröffnung des Brustkorbes das Herz schnell entnommen und in eine konventionelle Langendorff- Apparatur eingeführt. Die Koronar- arterien werden volumenkonstant (10 ml/min) perfündiert und der dabei auftretende Perfusionsdruck wird über einen entsprechenden Druckaufnehmer registriert. EineAfter the chest is opened, anesthetized rats have their hearts quickly removed and inserted into a conventional Langendorff apparatus. The coronary arteries are perfused with constant volume (10 ml / min) and the resulting perfusion pressure is registered via a corresponding pressure sensor. A
Abnahme des Perfusionsdrucks in dieser Anordnung entspricht einer Relaxation der Koronararterien. Gleichzeitig wird über einen in die linke Herzkammer eingeführten Ballon und einen weiteren Druckaufhehmer der Druck gemessen, der vom Herzen während jeder Kontraktion entwickelt wird. Die Frequenz des isoliert schlagenden Herzens wird rechnerisch aus der Anzahl der Kontraktionen pro Zeiteinheit ermittelt. Tabelle 1: Biologische Aktivität ausgewählter Verbindungen im Langendorff- Herz der RatteDecreasing the perfusion pressure in this arrangement corresponds to relaxation of the coronary arteries. At the same time, the pressure that is developed by the heart during each contraction is measured via a balloon inserted into the left ventricle and another pressure transducer. The frequency of the isolated beating heart is calculated from the number of contractions per unit of time. Table 1: Biological activity of selected compounds in the Langendorff heart of the rat
In vσ-Testmodelle zur Prüfung von „BigK-Modulatoren"In vσ test models for testing "BigK modulators"
4. Hämodynamische Effekte beim Hund4. Hemodynamic effects in dogs
Erwachsene Mischlingshunde (20-30 kg) werden initial mit einer Kombination von Trapanal und Alloferin narkotisiert. Die Narkose wird durch Infusion eines Gemisches von Fentanyl, Alloferin und Dihydrobenzpyridyl erhalten. Die Tiere werden inhibiert mit einem Gemisch aus O2/N2O 1:5 mit einer Atempumpe mit ca. 16 Atemzügen pro min und einem Volumen von 18-24 ml/kg beatmet. Die Körpertemperatur wird bei 38 °C ± 0,1 °C gehalten. Der arterielle Blutdruck wird über einen Katheder in der Femoralarterie gemessen. Es wird eine Thorakotomie auf der linken Seite am fünften Intercostalraum durchgeführt. Die Lunge wird zurückgelegt, fixiert und das Perikard eingeschnitten. Ein proximaler Abschnitt der LAD distal zur ersten diagonalen Verzweigung wird freipräpariert und ein kalibrierter elektromagnetischer Flussmesskopf (z. B. Gould Statham, Modell SP7515) um das Gefäß gelegt und mit einem Flussmessgerät (z.B. Statham, Modell SP-2202) verbunden. Ein mechanischer Occluder wird distal zum Flussmesskopf so angebracht, dass keine Verzweigungen zwischen Flussmesskopf und Occluder liegen.Adult mixed breed dogs (20-30 kg) are initially anesthetized with a combination of Trapanal and Alloferin. Anesthesia is obtained by infusing a mixture of fentanyl, alloferin and dihydrobenzpyridyl. The animals are inhibited with a mixture of O2 / N2O 1: 5 with a breathing pump with about 16 breaths per min and a volume of 18-24 ml / kg. The body temperature is kept at 38 ° C ± 0.1 ° C. Arterial blood pressure is measured via a catheter in the femoral artery. A thoracotomy is performed on the left side of the fifth intercostal space. The lungs are replaced, fixed and the pericardium incised. A proximal section of the LAD distal to the first diagonal branch is dissected and a calibrated electromagnetic flow measuring head (e.g. Gould Statham, model SP7515) is placed around the vessel and connected to a flow meter (e.g. Statham, model SP-2202). A mechanical occluder is attached distal to the flow measuring head so that there are no branches between the flow measuring head and occluder.
Blutentnahmen und Substanzgaben werden durch einen Katheder in der Femoralvene durchgeführt. Ein peripheres EKG wird mit subkutan verankerten Nadeln abgeleitet. Ein Mikrotip-Druckmanometer (z.B. Millarmodell PC-350) wird durch den linken Vorhof geschoben um den linksventrikulären Druck zu messen. Die Messung der Herzfrequenz wird über die R-Zacke des EKGs getriggert. Die hämodynamischen Parameter und der Koronarfluss werden während des gesamten Versuchs über einenBlood sampling and substance administration are carried out through a catheter in the femoral vein. A peripheral ECG is derived with hypodermic needles. A microtip pressure gauge (e.g. Millar model PC-350) is pushed through the left atrium to measure the left ventricular pressure. The heart rate measurement is triggered by the R wave of the EKG. The hemodynamic parameters and the coronary flow are measured throughout the experiment
Vielfachschreiber aufgezeichnet.Multiple writer recorded.
5. Wirkung auf den mittleren Blutdruck von wachen, spontan hypertensi- ven Ratten Kontinuierliche Blutdruckmessungen über 24 Stunden wurden an spontan hyperto- nen 200-250g schweren sich frei bewegenden weiblichen Ratten (M0L:SPRD) durchgeführt. Dazu waren den Tieren chronisch Druckaufhehmer (Data Sciences Inc., St. Paul, MN, USA) in die absteigende Bauchaorta unterhalb der Nierenarterie implantiert und der damit verbundene Sender in der Bauchhöhle fixiert worden.5. Effect on the mean blood pressure of awake, spontaneously hypertensive rats. Continuous blood pressure measurements over 24 hours were made on spontaneously hypertonic 200-250g free-moving female rats (M0L: SPRD) carried out. For this purpose, the animals were chronically implanted with pressure transducers (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta below the renal artery and the associated transmitter was fixed in the abdominal cavity.
Die Tiere wurden einzeln in Typ III Käfigen, die auf den individuellen Empfängerstationen positioniert waren, gehalten und waren an einem 12-Stunden Hell/Dunkel- Rhythmus angepasst. Wasser und Futter standen frei zur Verfügung.The animals were housed individually in type III cages, which were positioned on the individual receiving stations, and were adapted to a 12-hour light / dark rhythm. Water and feed were freely available.
Zur Datenerfassung wurde der Blutdruck jeder Ratte alle 5 Minuten für 10 Sekunden registriert. Die Messpunkte wurden jeweils für eine Periode von 15 Minuten zusam- mengefasst und der Mittelwert aus diesen Werten berechnet.To collect data, the blood pressure of each rat was recorded every 5 minutes for 10 seconds. The measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.
Die Prüfverbindungen wurden in einer Mischung aus Transcutol (10%), Cremophor (20%), H2O (70%) gelöst und mittels Schlundsonde in einem Volumen von 2 ml/kg Körpergewicht oral verabreicht. Die Prüfdosen lagen zwischen 0,3 -30 mg/kg Körpergewicht.The test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H 2 O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight. The test doses were between 0.3 and 30 mg / kg body weight.
6. Blutdruckmessungen an narkotisierten Ratten6. Blood pressure measurements on anesthetized rats
Männliche Wistar-Ratten mit einem Körpergewicht von 300 - 350 g werden mit Thiopental (100 mg/kg i.p.) anästhesiert. Nach Tracheotomie wird in die Femoral- arterie ein Katheter zur Blutdruckmessung eingeführt. Die zu prüfenden Substanzen werden in Transcutol, Cremophor EL, H2O (10%/20%/70%) in einem Volumen von 1 ml/kg oral verabreicht.Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery. The substances to be tested are administered orally in Transcutol, Cremophor EL, H 2 O (10% / 20% / 70%) in a volume of 1 ml / kg.
Für die Applikation der Verbindungen der Formel (I) kommen alle üblichenFor the application of the compounds of formula (I) come all the usual ones
Applikationsformen in Betracht, d.h. also oral, parenteral, inhalativ, nasal, buccal, sublingual, rektal oder äußerlich wie z.B. transdermal, insbesondere bevorzugt oral oder parenteral. Bei der parenteralen Applikation sind insbesondere intravenöse, intramuskuläre, subkutane Applikation zu nennen, z.B. als subkutanes Depot. Ganz besonders bevorzugt ist die orale Applikation. Hierbei können die Wirkstoffe allein oder in Form von Zubereitungen verabreicht werden. Für die orale Applikation eignen sich als Zubereitungen u.a. Tabletten, Kapseln, Pellets, Dragees, Pillen, Granulate, feste und flüssige Aerosole, Sirupe, Emulsionen, Suspensionen und Lösungen. Hierbei muss der Wirkstoff in einer solchen Menge vorliegen, dass eine therapeutische Wirkung erzielt wird. Im allgemeinen kann der Wirkstoff in einer Konzentration von 0,1 bis 100 Gew.-%, insbesondere 0,5 bis 90 Gew.-%, vorzugsweise 5 bis 80 Gew.-%, vorliegen. Insbesondere sollte die Konzentration des Wirkstoffs 0,5 - 90 Gew.-% betragen, d.h. der Wirkstoff sollte in Mengen vorliegen, die ausreichend sind, den angegebenen Dosierungsspiel- räum zu erreichen.Application forms into consideration, that is to say orally, parenterally, by inhalation, nasally, buccally, sublingually, rectally or externally, such as, for example, transdermally, particularly preferably orally or parenterally. In parenteral administration, intravenous, intramuscular, subcutaneous administration should be mentioned in particular, for example as a subcutaneous depot. Oral application is very particularly preferred. The active ingredients can be administered alone or in the form of preparations. Preparations suitable for oral administration include tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. The active ingredient must be present in such an amount that a therapeutic effect is achieved. In general, the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight. In particular, the concentration of the active ingredient should be 0.5-90% by weight, ie the active ingredient should be present in amounts which are sufficient to achieve the stated dosage range.
Zu diesem Zweck können die Wirkstoffe in an sich bekannter Weise in die üblichen Zubereitungen überführt werden. Dies geschieht unter Verwendung inerter, nichttoxischer, pharmazeutisch geeigneter Trägerstoffe, Hilfsstoffe, Lösungsmittel, Vehikel, Emulgatoren und/oder Dispergiermittel.For this purpose, the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
Als Hilfsstoffe seien beispielsweise aufgeführt: Wasser, nichttoxische organische Lösungsmittel wie z.B. Paraffine, pflanzliche Öle (z.B. Sesamöl), Alkohole (z.B. Ethanol, Glycerin), Glykole (z.B. Polyethylenglykol), feste Trägerstoffe wie natür- liehe oder synthetische Gesteinsmehle (z.B. Talkum oder Silikate), Zucker (z.B.Examples of auxiliary substances are: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), sugar (e.g.
Milchzucker), Emulgiermittel, Dispergiermittel (z.B. Polyvinylpyπolidon) und Gleitmittel (z.B. Magnesiumsulfat).Milk sugar), emulsifiers, dispersants (e.g. polyvinylpyπolidone) and lubricants (e.g. magnesium sulfate).
Im Falle der oralen Applikation können Tabletten selbstverständlich auch Zusätze wie Natriumeitrat zusammen mit Zuschlagstoffen wie Stärke, Gelatine und dergleichen enthalten. Wässrige Zubereitungen für die orale Applikation können weiterhin mit Geschmacksaufbesserern oder Farbstoffen versetzt werden.In the case of oral administration, tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like. Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.
Im allgemeinen hat es sich als vorteilhaft erwiesen, bei parenteraler Applikation Mengen von etwa 0,1 bis etwa 10.000 μg/kg, vorzugsweise etwa 1 bis etwaIn general, it has proven to be advantageous in the case of parenteral administration to use amounts of about 0.1 to about 10,000 μg / kg, preferably about 1 to about
1.000 μg/kg, insbesondere etwa 1 μg/kg bis etwa 100 μg/kg Körpergewicht, zur Er- zielung wirksamer Ergebnisse zu verabreichen. Bei oraler Applikation beträgt die Menge etwa 0,1 bis etwa 10 mg/kg, vorzugsweise etwa 0,5 bis etwa 5 mg/kg Körpergewicht.1,000 μg / kg, in particular approximately 1 μg / kg to approximately 100 μg / kg body weight, for to deliver effective results. When administered orally, the amount is about 0.1 to about 10 mg / kg, preferably about 0.5 to about 5 mg / kg body weight.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt.Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application takes place.
Soweit nicht anders angegeben, beziehen sich alle Prozentangaben auf das Gewicht; bei Lösungsmittelgemischen sind Volumenverhältnisse angeführt. Unless otherwise stated, all percentages are by weight; volume ratios are given for solvent mixtures.
B HerstellungsbeispieleB Manufacturing examples
In den Beispielen werden die folgenden Abkürzungen verwendet:The following abbreviations are used in the examples:
A = das zuerst eluierende Isomer (Reversed Phase) B = das als zweites eluierende Isomer (Reversed Phase)A = the first eluting isomer (reversed phase) B = the second eluting isomer (reversed phase)
DIEA = N,N-DiisopropylethylaminDIEA = N, N-diisopropylethylamine
DMAP = 4-DimethylaminopyridinDMAP = 4-dimethylaminopyridine
DMF = DimethylformamidDMF = dimethylformamide
DMSO = Dimefhylsulfoxid EDCI = N'-(3-Dimethylaminoρropyl)-N-ethylcarbodiimid x HC1DMSO = dimethyl sulfoxide EDCI = N '- (3-Dimethylaminoρropyl) -N-ethylcarbodiimide x HC1
EtOH = EthanolEtOH = ethanol
HOBt = 1 -Hydroxy- lH-benzotriazol x H2O ' * HOBt = 1 -hydroxy-1H-benzotriazole x H 2 O '*
HPLC = Hochdruck-, HochleistungsflüssigchromatographieHPLC = high pressure, high performance liquid chromatography
PyBOP® = Benzotriazol-l-yl-oxy-tris-pyπolidino-phosphoniumhexafluorophosphat rt = RetentionszeitPyBOP ® = benzotriazol-l-yl-oxy-tris-pyπolidino-phosphonium hexafluorophosphate rt = retention time
RT = RaumtemperaturRT = room temperature
TBTU = O-(Benzotriazol-l-yl)-N^^JV'-tefra-methyluronium-tetrafluoroboratTBTU = O- (benzotriazol-l-yl) -N ^^ JV'-tefra-methyluronium tetrafluoroborate
TFA = TrifluoressigsäureTFA = trifluoroacetic acid
THF = Tetrahydrofuran Pd-C = Palladium auf Kohle (10%ig)THF = tetrahydrofuran Pd-C = palladium on carbon (10%)
HPLC-Parameter:HPLC parameters:
Methode 1: Säule: Kromasil C18; L-R Temperatur: 30°C; Fluss = 0.75 mimin 1; Eluent: A = 0.01 M HClO4, B = CH3CΝ, Gradient: → 0.5 min 98%A, → 4.5 minMethod 1: Column: Kromasil C18; LR temperature: 30 ° C; Flow = 0.75 min 1 ; Eluent: A = 0.01 M HClO 4 , B = CH 3 CΝ, gradient: → 0.5 min 98% A, → 4.5 min
10%A, -> 6.5 min 10%A.10% A, -> 6.5 min 10% A.
Methode 2: Säule: Kromasil C18 60*2; L-R Temperatur: 30°C; Fluss = 0.75 ml in"1; Eluent: A = 0.01 M H3PO4, B = CH3CN, Gradient: -> 0.5 min 90%A, → 4.5 min 10%A, → 6.5 min 10%A. Methode 3: Säule: Kromasil C18 60*2; L-R Temperatur: 30°C; Fluss = 0.75 mimin *; Eluent: A = 0.005 M HClO4, B = CH3CN, Gradient: → 0.5 min 98%A, -» 4.5 min 10%A, → 6.5 min 10%A.Method 2: Column: Kromasil C18 60 * 2; LR temperature: 30 ° C; Flow = 0.75 ml in "1 ; eluent: A = 0.01 MH 3 PO 4 , B = CH 3 CN, gradient: -> 0.5 min 90% A, → 4.5 min 10% A, → 6.5 min 10% A. Method 3: Column: Kromasil C18 60 * 2; LR temperature: 30 ° C; Flow = 0.75 mimin *; Eluent: A = 0.005 M HClO 4 , B = CH 3 CN, gradient: → 0.5 min 98% A, - »4.5 min 10% A, → 6.5 min 10% A.
Methode 4: Säule: Symmetry C18, 2.1 mm x 150 mm; Säulenofen: 50°C; Fluss = 0 0..66 mmiimmiinn l; EElluueenntt:: AA == 00..66 gg 3300%%iiggee HHOC1// ] 1 Wasser, B = CH3CN, Gradient: 0.0 min 90%A, - 4.0 min 10%A, → 9 min 10%A.Method 4: Column: Symmetry C18, 2.1 mm x 150 mm; Column oven: 50 ° C; Flow = 0 0..66 mmiimmiinn l ; EElluueenntt :: AA == 00..66 gg 3300 %% iiggee HHOC1 //] 1 water, B = CH 3 CN, gradient: 0.0 min 90% A, - 4.0 min 10% A, → 9 min 10% A.
Methode 5: Säule: Kromasil 100 C18, 5 μm, 250 mm x 20 mm, Nr. 1011312; Temperatur: 40°C; Fluss = 1.25 mimin"1 ; Eluent: 50% CH3CN, 50% Wasser.Method 5: Column: Kromasil 100 C18, 5 μm, 250 mm x 20 mm, No. 1011312; Temperature: 40 ° C; Flow = 1.25 mimin "1 ; eluent: 50% CH 3 CN, 50% water.
Methode 6: MHZ-2Q, Instrument Micromass Quattro LCZMethod 6: MHZ-2Q, Micromass Quattro LCZ instrument
Säule Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperatur: 40°C; Fluss = 0.5 mlmm 1; Eluent A = CH3CN + 0.1% Ameisensäure, Eluent B = Wasser + 0.1% Ameisensäure, Gradient: 0.0 min 10%A, - 4 min 90% A, - 6 min 90%A.Column Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperature: 40 ° C; Flow = 0.5 mlmm 1 ; Eluent A = CH 3 CN + 0.1% formic acid, Eluent B = water + 0.1% formic acid, gradient: 0.0 min 10% A, - 4 min 90% A, - 6 min 90% A.
Methode 7: MHZ-2P, Instrument Micromass Platform LCZMethod 7: MHZ-2P, Instrument Micromass Platform LCZ
Säule: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperatur: 40°C; Fluss = 0.5 mimin 1; Eluent A = CH3CN + 0.1% Ameisensäure, Eluent B = Wasser + 0.1% Ameisensäure, Gradient: 0.0 min 10%A, → 4 min 90%A, -» 6 min 90%A.Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperature: 40 ° C; Flow = 0.5 min 1 ; Eluent A = CH 3 CN + 0.1% formic acid, Eluent B = water + 0.1% formic acid, gradient: 0.0 min 10% A, → 4 min 90% A, - »6 min 90% A.
Methode 8: MHZ-7Q, Instrument Micromass Quattro LCZMethod 8: MHZ-7Q, Micromass Quattro LCZ instrument
Säule: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperatur: 40°C; Fluss = 0.5 mlmm 1; Eluent A = CH3CN + 0.1% Ameisensäure, Eluent B = Wasser + 0.1% Ameisensäure, Gradient: 0.0 min 5%A, -> 1 min 5%A, -» 5 min 90%A, -» 6 minColumn: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperature: 40 ° C; Flow = 0.5 mlmm 1 ; Eluent A = CH 3 CN + 0.1% formic acid, Eluent B = water + 0.1% formic acid, gradient: 0.0 min 5% A, -> 1 min 5% A, - »5 min 90% A, -» 6 min
90%A.90% A.
Methode 9: MHZ-1P, Instrument Micromass Platform LCZMethod 9: MHZ-1P, Instrument Micromass Platform LCZ
Säule: Symmetry C18, 150 mm x 2.1 mm, 5 μm; Temperatur: 40°C; Fluss = 0.5 mimin"1; Eluent A = CH3CN + 0.1% Ameisensäure, Eluent B = Wasser + 0.1%Column: Symmetry C18, 150 mm x 2.1 mm, 5 μm; Temperature: 40 ° C; Flux = 0.5 minimin "1 ; eluent A = CH 3 CN + 0.1% formic acid, eluent B = water + 0.1%
Ameisensäure, Gradient: 0.0 min 10%A, → 9 min 90%A, -> 10 min 90%A. Methode 10: Instrument Finnigan MAT 900Formic acid, gradient: 0.0 min 10% A, → 9 min 90% A, -> 10 min 90% A. Method 10: Finnigan MAT 900 instrument
Säule: Symmetry C18, 150 mm x 2.1 mm, 3.5 μm; Temperatur: 40°C; Fluss = 0.9 mimin"1; Eluent A = CH3CN, Eluent B = 0.3g 30%ige HCl/ 1 Wasser, Gradient: 0.0 min 10%A, -> 3 min 90%A, -> 6 min 90%A.Column: Symmetry C18, 150 mm x 2.1 mm, 3.5 μm; Temperature: 40 ° C; Flow = 0.9 min "1 ; eluent A = CH 3 CN, eluent B = 0.3g 30% HCl / 1 water, gradient: 0.0 min 10% A, -> 3 min 90% A, -> 6 min 90% A ,
Methode 11: MHZ-2T, Instrument Micromass TOF-MUX-Interface 4Fach-Parallel- EinspritzungMethod 11: MHZ-2T, Instrument Micromass TOF-MUX-Interface 4-fold parallel injection
Säule: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperatur: 24°C; Fluss = 0.75 mimin"1; Eluent A = CH3CN + 0.1% Ameisensäure, Eluent B = Wasser + 0.1%Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Temperature: 24 ° C; Flux = 0.75 minimin "1 ; eluent A = CH 3 CN + 0.1% formic acid, eluent B = water + 0.1%
Ameisensäure, Gradient: 0.0 min 10%A, - 0.5 min 10 %A, -» 4.0 min 90 %A, →5.5 min 90 %A. " * Formic acid, gradient: 0.0 min 10% A, - 0.5 min 10% A, - »4.0 min 90% A, → 5.5 min 90% A. "*
Methode 12: Säule: Stability C30; 5 μm; 250* 3.0 mm; Temperatur: 25°C; Fluss = 0.60 mimin" Method 12: Pillar: Stability C30; 5 µm; 250 * 3.0 mm; Temperature: 25 ° C; River = 0.60 mimin "
Eluent: A = 0.035 M HClO4, B = CH3CN, isokratisch 55% A und 45% B (v/v) Eluent: A = 0.035 M HClO 4 , B = CH 3 CN, isocratic 55% A and 45% B (v / v)
Ausgangsverbindungenstarting compounds
Beispiel I (lS,2S)-2-(4-Brommethylphenyl)-cyclohexan-l-carbonsäure-t'ert'-butylesterExample I t'ert'-butyl ester (IS, 2S) -2- (4-bromomethylphenyl) cyclohexane-1-carboxylic acid
Das Zwischenprodukt wird in Analogie zur Vorschrift für das Racemat (US-A-5 395 840, Spalte 17) hergestellt. Zur Aufreinigung wird das erhaltene Gemisch mit Diethylether oder Diisopropylether verrührt.The intermediate is prepared in analogy to the regulation for the racemate (US-A-5 395 840, column 17). For the purification, the mixture obtained is stirred with diethyl ether or diisopropyl ether.
Beispiel IIExample II
(lS,2S)-2-(4-Formylphenyl)cyclohexancarbonsäure-ter -butylester(lS, 2S) -2- (4-formylphenyl) cyclohexane carboxylic acid ter-butyl ester
2 g (lS,2S)-2-[4-(Brommethyl)phenyl]cyclohexancarbonsäure-tert-butylester werden mit 1.3 g N-Methylmoφholin-N-oxid und 2 g Molsieb (4Ä) in 40 ml Acetonitril 17 h bei Raumtemperatur gerührt. Man filtriert über Kieselgur und entfernt das Lösungsmittel im Vakuum. Der Rückstand wird in Dichlormethan aufgenommen und die Lösung mit IN wässriger Salzsäure und gesättigter wässriger Νatrium- chloridlösung extrahiert. Die organische Phase wird getrocknet und das Lösungs- mittel im Vakuum entfernt. Man erhält 1.2 g (lS,2S)-2-(4-Formylphenyl)cyclo- hexancarbonsäure-tert-butylester. 1H-NMR (300 MHz, CDC13): 1.14 (s, 9H), 1.45 (m, 4H), 1.84 (m, 4H), 2.51 (m, 1H), 2.81 (m, 1H), 7.38 (d, 2H), 7.80 (d, 2H), 9.97 (s, 1H).2 g (IS, 2S) -2- [4- (bromomethyl) phenyl] cyclohexanecarboxylic acid tert-butyl ester are stirred with 1.3 g of N-methylmoφholin-N-oxide and 2 g of molecular sieve (4Ä) in 40 ml of acetonitrile at room temperature for 17 h , It is filtered through diatomaceous earth and the solvent is removed in vacuo. The residue is taken up in dichloromethane and the solution is extracted with 1N aqueous hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried and the solvent is removed in vacuo. 1.2 g of (IS, 2S) -2- (4-formylphenyl) cyclohexanecarboxylic acid tert-butyl ester are obtained. 1H-NMR (300 MHz, CDC1 3 ): 1.14 (s, 9H), 1.45 (m, 4H), 1.84 (m, 4H), 2.51 (m, 1H), 2.81 (m, 1H), 7.38 (d, 2H), 7.80 (d, 2H), 9.97 (s, 1H).
Beispiel III (lS,2S)-2-(4-Formy!phenyl)cyclohexancarbonsäureExample III (IS, 2S) -2- (4-Formy! Phenyl) cyclohexane carboxylic acid
1.1 g (lS,2S)-2-(4-Formylphenyl)cyclohexancarbonsäure-tert-butylester werden in 20 ml Dichlormethan gelöst und mit 2 ml Trifluoressigsäure versetzt. Man rührt 17 h bei Raumtemperatur und 3 h unter Rückfluss. Das Lösungsmittel wird im Vakuum entfernt und der Rückstand mit Ether verrührt. Man erhält 612 mg (lS,2S)-2-(4- Formylphenyl)cyclohexancarbonsäure (HPLC Reinheit 81%), die ohne weitere Reinigung umgesetzt werden.1.1 g (IS, 2S) -2- (4-formylphenyl) cyclohexanecarboxylic acid tert-butyl ester are dissolved in 20 ml dichloromethane and mixed with 2 ml trifluoroacetic acid. The mixture is stirred at room temperature for 17 h and under reflux for 3 h. The solvent is removed in vacuo and the residue is stirred with ether. 612 mg (IS, 2S) -2- (4-formylphenyl) cyclohexane carboxylic acid (HPLC purity 81%) are obtained, which are reacted without further purification.
1H-NMR (300 MHz, CDC13): 1.43 (m, 4H), 1.88 (m, 4H), 2.65 (m, 1H), 2.87 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 9.96 (s, 1H).1H-NMR (300 MHz, CDC1 3 ): 1.43 (m, 4H), 1.88 (m, 4H), 2.65 (m, 1H), 2.87 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 9.96 (s, 1H).
[A] Allgemeine Vorschrift zur Synthese von Verbindungen des Typs:[A] General instructions for the synthesis of compounds of the type:
4.25 mmol (lS,2S)-2-[4-(Brommethyl)phenyl]cyclohexancarbonsäure-tert-butylester und 4.25 mmol des entsprechenden Harnstoffes werden in 30 ml Dimethylformamid gelöst. Zu dieser Lösung werden 4.46 mmol Natriumhydrid gegeben. Die Reaktion wird 12 h bei Raumtemperatur gerührt. Die Lösung wird dann auf 600 ml Wasser gegossen und mit Diefhylether (dreimal mit je 50 ml) extrahiert. Die vereinigten Extrakte werden mit einer gesättigten wässrigen Kochsalzlösung gewaschen, über Natriumsulfat getrocknet, filtriert und eingeengt.4.25 mmol (1S, 2S) -2- [4- (bromomethyl) phenyl] cyclohexanecarboxylic acid tert-butyl ester and 4.25 mmol of the corresponding urea are dissolved in 30 ml of dimethylformamide. 4.46 mmol of sodium hydride are added to this solution. The reaction is stirred for 12 h at room temperature. The solution is then poured onto 600 ml of water poured and extracted with Diefhylether (three times with 50 ml each). The combined extracts are washed with a saturated aqueous saline solution, dried over sodium sulfate, filtered and concentrated.
[B] Allgemeine Vorschrift zur Hydrolyse des fer/-Butylesters:[B] General instructions for the hydrolysis of the fer / butyl ester:
200 mg des entsprechenden tert-Butylester-Derivates werden in 10 ml einer 4 M Salzsäure-Lösung in Dioxan vorgelegt. Die Reaktion wird 12 h bei Raumtemperatur gerührt, dann eingeengt. Der Rückstand wird fünfmal in Diefhylether (jeweils 10 ml) aufgenommen und zur Trockene eingeengt.200 mg of the corresponding tert-butyl ester derivative are placed in 10 ml of a 4 M hydrochloric acid solution in dioxane. The reaction is stirred for 12 h at room temperature, then concentrated. The residue is taken up five times in diethyl ether (10 ml each) and concentrated to dryness.
[C] Allgemeine Vorschrift zur Amidkupplung:[C] General regulation for the amide coupling:
[C-1J: 0.23 mmol der entsprechenden Carbonsäure werden unter Argon in 5 ml Dimethylformamid gelöst. 0.34 mmol Amin, 0.25 mmol 1-Hydroxy-benzotriazol,[C-1J: 0.23 mmol of the corresponding carboxylic acid are dissolved in 5 ml of dimethylformamide under argon. 0.34 mmol amine, 0.25 mmol 1-hydroxy-benzotriazole,
0.04 mmol 4-Dimethylaminopyridin und 0.26 mmol N-(3-Dimethylaminopropyl)-N'- efhyl-carbodiimid-hydrochlorid werden zugegeben. Die Lösung wird 12 h bei Raumtemperatur gerührt. Der Ansatz wird direkt über präparative HPLC gereinigt.0.04 mmol of 4-dimethylaminopyridine and 0.26 mmol of N- (3-dimethylaminopropyl) -N'-efhyl-carbodiimide hydrochloride are added. The solution is stirred for 12 hours at room temperature. The mixture is purified directly using preparative HPLC.
[C-2]: Die Cyclohexancarbonsäure, PyBOP (1.5 eq.) und 4-Dimethylaminopyridin[C-2]: The cyclohexane carboxylic acid, PyBOP (1.5 eq.) And 4-dimethylaminopyridine
(0.1 eq.) werden bei Raumtemperatur in Dimethylformamid (0.1 M) gelöst und mit NN-Diisopropylethylamin (2 eq.) versetzt. Das Reaktionsgemisch wird für 15 min gerührt, anschließend mit dem Amin (1.5 eq.) versetzt und für 4-24 h bei Raumtemperatur, gegebenenfalls bei 60°C, gerührt. Das gewünschte Produkt wird mittels HPLC-Chromatographie (Acetonitril- Wasser-Gemische) gereinigt. [D] Allgemeine Vorschrift zur Synthese von tertiären Aminen des Typs:(0.1 eq.) Are dissolved in dimethylformamide (0.1 M) at room temperature and NN-diisopropylethylamine (2 eq.) Is added. The reaction mixture is stirred for 15 min, then the amine (1.5 eq.) Is added and the mixture is stirred for 4-24 h at room temperature, if appropriate at 60 ° C. The desired product is purified by means of HPLC chromatography (acetonitrile-water mixtures). [D] General instructions for the synthesis of tertiary amines of the type:
0.57 mmol (lS,2S)-2-[4-(Brommethyl)phenyl]cyclohexancarbonsäure-tert-butylester und 0.57 mmol des entsprechenden sekundären Amins werden in 5 ml Acetonitril gelöst. Dazu werden 5.7 mmol festes Kahumcarbonat zugegeben, und die Suspension wird 4 h bei 60°C gerührt. Die Reaktionslösung wird filtriert und das Filtrat am Rotationsverdampfer zur Trockene eingeengt.0.57 mmol (1S, 2S) -2- [4- (bromomethyl) phenyl] cyclohexanecarboxylic acid tert-butyl ester and 0.57 mmol of the corresponding secondary amine are dissolved in 5 ml of acetonitrile. For this purpose, 5.7 mmol of solid potassium carbonate are added, and the suspension is stirred at 60 ° C. for 4 h. The reaction solution is filtered and the filtrate is evaporated to dryness on a rotary evaporator.
In der folgenden Tabelle sind die für die Umsetzung mit Cyclohexancarbonsäuren eingesetzten Amine aufgeführt The following table shows the amines used for the reaction with cyclohexane carboxylic acids
Beispiel XXVIExample XXVI
(lS,2R)-2-[4-(Brommethyl)phenyl]-7V-[(lS)-l-phenylethyl]cyclohexancarbox- amid(IS, 2R) -2- [4- (bromomethyl) phenyl] -7V - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) 15 g (42.46 mmol) der Verbindung aus Beispiel I werden nach der allgemeinen Vorschrift [B] in die entsprechende Säure überführt (Ausbeute: 13.2 g, quant).a) 15 g (42.46 mmol) of the compound from Example I are converted into the corresponding acid according to the general procedure [B] (yield: 13.2 g, quant).
b) 2.9 g (24.23 mmol) (S)-1-Phenylethylamin werden bei Raumtemperatur zu einer Lösung von 6 g (20.19 mmol) (lS,2R)-2-[4-(Brornmethyl)phenyl]cyclo- hexancarbonsäure, 2.9 g (24.23 mmol) 1,3-Dicyclohexylcarbodiimid und 0.3 g (2.5 mmol) Dimethylaminopyridin in 4.8 ml Dichlormethan gegeben, und das Reaktionsgemisch wird 14 h bei Raumtemperatur gerührt. Zur Aufarbeitung wird vom Niederschlag abfiltriert, das Lösungsmittel im Vakuum entfernt und das Rohprodukt durch Chromatographie (Kieselgel 60, Laufmittel: Cyclohexan-Ethylacetat 8:2) gereinigt; Ausbeute: 3.97 g (49%) der Titelverbindung.b) 2.9 g (24.23 mmol) of (S) -1-phenylethylamine are converted into a solution of 6 g (20.19 mmol) of (IS, 2R) -2- [4- (bromomethyl) phenyl] cyclohexanecarboxylic acid, 2.9 g at room temperature (24.23 mmol) 1,3-dicyclohexylcarbodiimide and 0.3 g (2.5 mmol) dimethylaminopyridine in 4.8 ml dichloromethane, and the reaction mixture is stirred for 14 h at room temperature. For working up, the precipitate is filtered off, the solvent is removed in vacuo and the crude product is purified by chromatography (silica gel 60, mobile phase: cyclohexane-ethyl acetate 8: 2); Yield: 3.97 g (49%) of the title compound.
Rf = 0.33 (Cyclohexan-Ethylacetat 7:3);R f = 0.33 (cyclohexane-ethyl acetate 7: 3);
1H-NMR (200 MHz, DMSO): 1.1-1.9 (m, 10H), 2.4-2.9 (m, 2H), 4.6-4.8 (m, 3H), 1 H-NMR (200 MHz, DMSO): 1.1-1.9 (m, 10H), 2.4-2.9 (m, 2H), 4.6-4.8 (m, 3H),
6.6 (m, 2H), 6.9-7.4 (m, 7H), 8.0 (d, 1H). Beispiel XXVII6.6 (m, 2H), 6.9-7.4 (m, 7H), 8.0 (d, 1H). Example XXVII
(lS,2R)-2-[4-(Aminomethyl)phenyl]-N-[(lS)-l-phenylethyl]cyclohexancarbox- amid(IS, 2R) -2- [4- (aminomethyl) phenyl] -N - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) 770 mg (1.83 mmol) (lS,2R)-2-[4-(Brommethyl)phenyl]-N-[(lS)-l-phenyl- ethyl]cyclohexancarboxamid (Beispiel XXVI) und 131 mg (2.01 mmol) Natriumazid in 60 ml Dimethylformamid werden 16 h bei 80°C gerührt. Das Reaktionsgemisch wird eingeengt, mit Essigsäureethylester versetzt, mit halbgesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Man erhält 600 mg (91%) (lS,2R)-2-[4-(Azidomethyl)ρhenyl]-N- [(lS)-l-phenylefhyl]cyclohexancarboxamid.a) 770 mg (1.83 mmol) (IS, 2R) -2- [4- (bromomethyl) phenyl] -N - [(IS) -l-phenylethyl] cyclohexane carboxamide (Example XXVI) and 131 mg (2.01 mmol) Sodium azide in 60 ml of dimethylformamide are stirred at 80 ° C. for 16 h. The reaction mixture is concentrated, ethyl acetate is added, the mixture is washed with semisaturated sodium chloride solution and dried over sodium sulfate. 600 mg (91%) (IS, 2R) -2- [4- (azidomethyl) ρhenyl] -N- [(IS) -l-phenylefhyl] cyclohexane carboxamide are obtained.
b) 600 mg (1.66 mol) (lS,2R)-2-[4-(Azidomethyl)phenyl]-N-[(lS)-l-phenyl- ethyl]cyclohexancarboxamid und Katalysator (Pd/C, ca. 30 mg) werden 14 h bei Raumtemperatur unter Wasserstoff (1 arm) gerührt. Nach Filtration und Entfernen des Lösungsmittels wird das Rohprodukt über HPLC gereinigt, Ausbeute: 324 mg (58%) der Titelverbindung.b) 600 mg (1.66 mol) (IS, 2R) -2- [4- (azidomethyl) phenyl] -N - [(IS) -l-phenylethyl] cyclohexane carboxamide and catalyst (Pd / C, approx. 30 mg ) are stirred for 14 h at room temperature under hydrogen (1 arm). After filtration and removal of the solvent, the crude product is purified by HPLC, yield: 324 mg (58%) of the title compound.
1H-NMR (200 MHz, DMSO): 1.2 (d, 3H), 1.25-1.6 (m, 4H), 1.6-1.95 (m, ATT), 2.6 (m, IH), 4.0 (bs, 2H), 4.65 (m, IH), 6.6 (m, 2H), 7.0 (m, 3H), 7.15 (d, 2H), 7.25 (d, 2H), 7.95 (d, IH). Beispiel XXVIII1H-NMR (200 MHz, DMSO): 1.2 (d, 3H), 1.25-1.6 (m, 4H), 1.6-1.95 (m, ATT), 2.6 (m, IH), 4.0 (bs, 2H), 4.65 (m, IH), 6.6 (m, 2H), 7.0 (m, 3H), 7.15 (d, 2H), 7.25 (d, 2H), 7.95 (d, IH). Example XXVIII
((lS,2R)-2-{4-[(Cyclopropylamino)methyl]phenyl}-7V-[(lS)-l-phenyIethyl]cyclo- hexancarboxamid((IS, 2R) -2- {4 - [(cyclopropylamino) methyl] phenyl} -7V - [(IS) -l-phenylethyl] cyclohexane carboxamide
Darstellung analog der allgemeinen Arbeitsvorschrift [D] aus 500 mg (1:25 mmol) (lS,2R)-2-[4-(Brommethyl)phenyl]-N-[(lS)-l-phenylethyl]cyclohexancarboxamid und 213.4 mg (3.75 mmol) Cyclopropylamin, Ausbeute: 342 mg (70%).Representation analogous to the general working procedure [D] from 500 mg (1:25 mmol) (lS, 2R) -2- [4- (bromomethyl) phenyl] -N - [(lS) -l-phenylethyl] cyclohexane carboxamide and 213.4 mg ( 3.75 mmol) cyclopropylamine, yield: 342 mg (70%).
1H-ΝMR (200 MHz, CDC13): 0.3-0.7 (m, 4H), 1.25 (d, 3H), 1.3-1.6 (m, 3H), 1.7-2.11H-ΝMR (200 MHz, CDC1 3 ): 0.3-0.7 (m, 4H), 1.25 (d, 3H), 1.3-1.6 (m, 3H), 1.7-2.1
( , 4H), 2.15-2.25 (m, 2H), 2.75 (m, IH), 3.7 (s, 2H), 4.85 (m, IH), 5.2 (d, IH), 6.65 (d, 2H), 7.1 (m, 7H).(, 4H), 2.15-2.25 (m, 2H), 2.75 (m, IH), 3.7 (s, 2H), 4.85 (m, IH), 5.2 (d, IH), 6.65 (d, 2H), 7.1 (m, 7H).
Beispiel XXIX (lS,2R)-2-(4-{[Ethyl(phenoxycarbonyl)amino]methyl}phenyl)cyclohexancarbon- saureExample XXIX (IS, 2R) -2- (4 - {[ethyl (phenoxycarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid
a) 400 mg (1.39 mmol) (lS,2S)-2-(4-Formylphenyl)cyclohexancarbonsäure-tert- butylester (Beispiel II) und 0.05 ml (0.84 mmol) Essigsäure in 8 ml Methanol werden mit 0.69 ml (1.39 mmol) einer 2 M Lösung von Efhylamin in Methanol versetzt. Das Reaktionsgemisch wird 3 h bei Raumtemperatur geriihrt, anschließend mit 105 mg (1.66 mmol) Natriumcyanoborhydrid versetzt und weitere 18 h bei Raumtemperatur gerührt. Das Reaktionsgemisch wird eingeengt und das Rohprodukt zur nächsten Umsetzung direkt eingesetzt.a) 400 mg (1.39 mmol) (lS, 2S) -2- (4-formylphenyl) cyclohexane carboxylic acid tert-butyl ester (Example II) and 0.05 ml (0.84 mmol) acetic acid in 8 ml methanol are mixed with 0.69 ml (1.39 mmol) of a 2 M solution of ethylamine in methanol. The reaction mixture is stirred at room temperature for 3 h, then 105 mg (1.66 mmol) of sodium cyanoborohydride are added and the mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated and the crude product is used directly for the next reaction.
b) 327 mg (lS,2R)-2-{4-[(Ethylamino)mefhyl]phenyl}cyclohexancarbonsäure- tert-butylester (Rohprodukt) in 3 ml Dichlormethan werden mit 0.17 ml (0.136 mmol) Chlorameisensäurephenylester und 0.24 ml (1.36 mmol) N,N-b) 327 mg (IS, 2R) -2- {4 - [(ethylamino) methyl] phenyl} cyclohexanecarboxylic acid tert-butyl ester (crude product) in 3 ml dichloromethane are mixed with 0.17 ml (0.136 mmol) phenyl chloroformate and 0.24 ml (1.36 mmol ) N, N-
Diisopropylethylamin versetzt, und das Reaktionsgemisch wird 14 h bei Raumtemperatur gerührt. Zur Aufarbeitung wird eingeengt und der Rückstand durch Chromatographie (Kieselgel 60, Laufmittel: Cyclohexan-Ethylacetat 8:2) gereinigt; Ausbeute: 327 mg (66%).Diisopropylethylamine added, and the reaction mixture is stirred for 14 h at room temperature. For working up, the mixture is concentrated and the residue is purified by chromatography (silica gel 60, mobile phase: cyclohexane-ethyl acetate 8: 2); Yield: 327 mg (66%).
c) Nach der allgemeinen Arbeitsvorschrift [B] werden aus 296 mg (0.68 mmol) (lS,2R)-2-(4-{[Ethyl(phenoxycarbonyl)amino]methyl}phenyl)cyclohexan- carbonsäure-tert-butylester 264 mg (96%) der Titelverbindung dargestellt.c) According to the general working method [B], 296 mg (0.68 mmol) (IS, 2R) -2- (4 - {[ethyl (phenoxycarbonyl) amino] methyl} phenyl) cyclohexanecarboxylic acid tert-butyl ester are converted into 264 mg ( 96%) of the title compound.
1H-NMR (200 MHz, DMSO): 1.0-1-2 (m, 4H), 1.3-1.6 (m, 4H), 1.6-1.8 (m, 3H), 2.01H-NMR (200 MHz, DMSO): 1.0-1-2 (m, 4H), 1.3-1.6 (m, 4H), 1.6-1.8 (m, 3H), 2.0
(d, IH), 2.55 (m, IH), 2.7 (m, IH), 4.5 (m, IH), 7.0 -7.3 (m, 7H), 7.4 (m, 3H), 11.7 (bs, IH).(d, IH), 2.55 (m, IH), 2.7 (m, IH), 4.5 (m, IH), 7.0 -7.3 (m, 7H), 7.4 (m, 3H), 11.7 (bs, IH).
In Analogie zur Vorschrift des Beispiels XXIX werden die in der folgenden Tabelle aufgeführten Ausgangsverbindungen dargestellt. Beispiel XXXVIII (lS,2_ )-2-{4-[(Benzyloxy)carbonyl]phenyl}cyclohexancarbonsäureThe starting compounds listed in the following table are shown in analogy to the instructions in Example XXIX. Example XXXVIII (IS, 2_) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexane carboxylic acid
a) 4-[(lR,2S)-2-(tert'-Butoxycarbonyl)cyclohexyl]benzoesäure Eine Lösung von (lS,2R)-2-(4-Formylphenyl)cyclohexancarbonsäure-tert-butylestera) 4 - [(lR, 2S) -2- (tert'-butoxycarbonyl) cyclohexyl] benzoic acid A solution of (lS, 2R) -2- (4-formylphenyl) cyclohexane carboxylic acid tert-butyl ester
(35.0 g, 102.0 mmol) in Aceton (500 ml) wird bei Raumtemperatur mit einer Lösung von Kaliumpermanganat (42 g, 265.8 mmol) in Wasser (1 1) versetzt. Das' Reaktionsgemisch wird für 2 h bei 40°C gerührt, mit gesättigter aq. Natriumfhiosulfat-Lösung versetzt, die entstehende Suspension filtriert, der Filterkuchen mit Aceton gewaschen, und die vereinigten Filtrate werden im Vakuum eingeengt. Der Rückstand wird in Ethylacetat- Wasser aufgenommen, und nach Phasentrennung werden die wässrigen Phasen mit Ethylacetat extrahiert. Die vereinigten organischen Phasen werden getrocknet (Natriumsulfat), filtriert und im Vakuum eingeengt. Das gewünschte Produkt wird mittels Flash-Chromatographie (Cyclohexan-Ethylacetat- Gemische) gereinigt. Ausbeute: 15 g, (48%).(35.0 g, 102.0 mmol) in acetone (500 ml) is mixed with a solution of potassium permanganate (42 g, 265.8 mmol) in water (1 1) at room temperature. The reaction mixture is stirred for 2 h at 40 ° C., saturated aq. Sodium fhiosulfate solution is added, the resulting suspension is filtered, the filter cake is washed with acetone, and the combined filtrates are concentrated in vacuo. The residue is taken up in ethyl acetate-water and, after phase separation, the aqueous phases are extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), filtered and concentrated in vacuo. The desired product is purified by means of flash chromatography (cyclohexane / ethyl acetate mixtures). Yield: 15 g, (48%).
MS (DCI, NH3): m/z = 322 [M+NH4]; HPLC (Methode 3): rt = 4.75 min.MS (DCI, NH 3 ): m / z = 322 [M + NH 4 ]; HPLC (method 3): rt = 4.75 min.
b) 4-[(lR,2S)-2-(tert-Butoxycarbonyl)cyclohexyl]benzoesäurebenzyIesterb) 4 - [(IR, 2S) -2- (tert-butoxycarbonyl) cyclohexyl] benzoic acid benzyl ester
Eine Lösung von 4-[(lR,2S)-2-(tert-Butoxycarbonyl)cyclohexyl]benzoesäure (7.00 g, 23.0 mmol) und Cäsiumcarbonat (8.24 g, 25.3 mmol) in Acetonitril (50 ml) wird beiA solution of 4 - [(IR, 2S) -2- (tert-butoxycarbonyl) cyclohexyl] benzoic acid (7.00 g, 23.0 mmol) and cesium carbonate (8.24 g, 25.3 mmol) in acetonitrile (50 ml) is added
Raumtemperatur tropfenweise mit Benzylbromid (4.1 ml, 34.5 mmol) versetzt und 2 h gerührt. Das Reaktionsgemisch wird im Vakuum eingeengt, der Rückstand in Ethylacetat suspendiert, der Niederschlag abfiltriert und gewaschen. Die vereinigten Filtrate werden im Vakuum eingeengt. Das gewünschte Produkt wird mittels Flash- Chromatographie (Cyclohexan-Ethylacetat-Gemische) gereinigt. Ausbeute: 8.63 g,Benzyl bromide (4.1 ml, 34.5 mmol) was added dropwise to the room temperature and the mixture was stirred for 2 h. The reaction mixture is concentrated in vacuo, the residue is suspended in ethyl acetate, the precipitate is filtered off and washed. The combined filtrates are concentrated in vacuo. The desired product is purified by means of flash chromatography (cyclohexane / ethyl acetate mixtures). Yield: 8.63 g,
(95%). MS (DCI, NH3): m/z = 412 [M+NH4 ; HPLC (Methode 3): rt = 6.13 min.(95%). MS (DCI, NH 3 ): m / z = 412 [M + NH 4 ; HPLC (method 3): rt = 6.13 min.
c) (lS,2R)-2-{4-[(Benzyloxy)carbonyl]phenyl}cyclohexancarbonsäurec) (IS, 2R) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexane carboxylic acid
Eine Lösung von 4-[(lR,2S)-2-(tert-Butoxycarbonyl)cyclohexyl]benzoesäurebenzyl- ester (8.63 g, 21.8 mmol) in Dichlormethan (140 ml) wird bei Raumtemperatur mitA solution of 4 - [(IR, 2S) -2- (tert-butoxycarbonyl) cyclohexyl] benzoic acid benzyl ester (8.63 g, 21.8 mmol) in dichloromethane (140 ml) is added at room temperature
Trifluoressigsäure (21.1 ml, 273 mmol) versetzt. Das Reaktionsgemisch wird 4 h bei Raumtemperatur gerührt, im Vakuum eingeengt, dreimal mit Toluol koevaporiert und getrocknet. Das Rohprodukt wird ohne weitere Reinigung in der nächsten Umsetzung eingesetzt. Ausbeute: 7.5 g (100%). MS (DCI, NH3): m/z = 356 [M+NH4 ; HPLC (Methode 3): rt = 4.97 min.Trifluoroacetic acid (21.1 ml, 273 mmol) was added. The reaction mixture is stirred for 4 h at room temperature, concentrated in vacuo, coevaporated three times with toluene and dried. The crude product is used in the next reaction without further purification. Yield: 7.5 g (100%). MS (DCI, NH 3 ): m / z = 356 [M + NH 4 ; HPLC (method 3): rt = 4.97 min.
[E] Allgemeine Vorschrift zur Umsetzung der (lS,2_ )-2-{4-[(Benzyloxy) carbonyl]phenyl}cyclohexancarbonsäureamide zu Benzoesäure-Derivaten[E] General instructions for converting the (IS, 2_) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexanecarboxamides into benzoic acid derivatives
Eine Lösung des (lS,2R)-2-{4-[(Benzyloxy)carbonyl]phenyl}cyclohexancarbon- säureamids in Tetrahydrofuran (0.1 M) wird in Gegenwart von Palladium (10%ig aufA solution of the (IS, 2R) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexane carboxamide in tetrahydrofuran (0.1 M) is in the presence of palladium (10%)
Kohle) für 6-20 h unter Wasserstoff- Atmosphäre gerührt, filtriert und das Filtrat im Vakuum eingeengt. Das gewünschte Produkt kann mittels Flash-Chromatographie (Cyclohexan-Ethylacetat-Gemische) gereinigt werden.Coal) was stirred for 6-20 h under a hydrogen atmosphere, filtered and the filtrate was concentrated in vacuo. The desired product can be purified by means of flash chromatography (cyclohexane / ethyl acetate mixtures).
Die in der folgenden Tabelle aufgeführten Verbindungen werden nach der allgemeinen Vorschrift [E] dargestellt: The compounds listed in the following table are prepared according to the general regulation [E]:
[F] Allgemeine Vorschrift zur Umsetzung der Benzoesäure-Derivate zu Amiden [F] General instructions for converting the benzoic acid derivatives to amides
Die Cyclohexancarbonsäure, PyBOP (1.5 eq.) und 4-Dimethylaminopyridin (0.1 eq.) werden bei Raumtemperatur in Dimethylformamid (0.1 M) gelöst und mit N_N- Diisopropylethylamin (2 eq.) versetzt. Das Reaktionsgemisch wird für 15 min gerührt, anschließend mit dem Amin (1.5 eq.) versetzt und für 10-16 h bei Raumtemperatur gerührt. Das gewünschte Produkt wird mittels HPLC- Chromatographie (Acetonitril- Wasser-Gemische) gereinigt.The cyclohexane carboxylic acid, PyBOP (1.5 eq.) And 4-dimethylaminopyridine (0.1 eq.) Are dissolved in dimethylformamide (0.1 M) at room temperature and N_N-diisopropylethylamine (2 eq.) Is added. The reaction mixture is stirred for 15 min, then the amine (1.5 eq.) Is added and the mixture is stirred at room temperature for 10-16 h. The desired product is purified by means of HPLC chromatography (acetonitrile-water mixtures).
In der folgenden Tabelle sind die für die Umsetzung mit Benzoesäurederivaten eingesetzten A ine aufgeführt: The following table lists the amines used for the reaction with benzoic acid derivatives:
[H] Allgemeine Vorschrift zur Synthese von Verbindungen des Typs:[H] General instructions for the synthesis of compounds of the type:
4.25 mmol (lS,2S)-2-[4-(Broιrιmethyl)phenyl]cyclohexancarbonsäure-tert-butylester und 4.25 mmol des entsprechenden Alkohols werden in Dimethylformamid (30 ml) gelöst. Zu dieser Lösung werden bei 0°C 4.46 mmol Natriumhydrid gegeben. Die Reaktion wird 12 Stunden bei Raumtemperatur gerührt. Die Lösung wird dann auf 300 ml Wasser gegossen und mit Diethy lether (3mal mit 50 ml) extrahiert. Die vereinigten Extrakten werden mit einer gesättigten NaCl Lösung gewaschen, mit Natriumsulfat getrocknet, filtriert und eingeengt.4.25 mmol (IS, 2S) -2- [4- (Broιrιmethyl) phenyl] cyclohexanecarboxylic acid tert-butyl ester and 4.25 mmol of the corresponding alcohol are dissolved in dimethylformamide (30 ml). 4.46 mmol of sodium hydride are added to this solution at 0 ° C. The reaction is stirred for 12 hours at room temperature. The solution is then poured onto 300 ml of water and extracted with diethyl ether (3 times with 50 ml). The combined extracts are washed with a saturated NaCl solution, dried with sodium sulfate, filtered and concentrated.
Beispiel L (15*,2R*)-2-[3-(Brommethyl)phenyl]cyclohexancarbonsäuremethylesterExample L (15 *, 2R *) - 2- [3- (bromomethyl) phenyl] cyclohexanecarboxylic acid methyl ester
Das Zwischenprodukt wird in Analogie zur Synthese der Ausgangsverbindung The intermediate is analogous to the synthesis of the starting compound
Beispiel I aus m-Mefhylzimtsäuremethylester und Butadien (Umsetzung analog: US-A-5 395 840 Example I und II) mit nachfolgender Bromierung (analog: US-A-5 395 840 Example IV) dargestellt. Beispiel LI (lS*,2S*)-2-(4-Hydroxyphenyl)-7V-[(lS)-l-phenylethyl]cyclohexancarboxamidExample I from methyl m-methyl cinnamate and butadiene (reaction analog: US-A-5 395 840 Example I and II) with subsequent bromination (analog: US-A-5 395 840 Example IV) is shown. Example LI (IS *, 2S *) - 2- (4-hydroxyphenyl) -7V - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS*,2S*)-2-(4-Methoxyphenyl)cyclohexancarbonsäuremethylester Das Zwischenprodukt wird in Analogie zur Synthese der Ausgangsverbindunga) (IS *, 2S *) - 2- (4-methoxyphenyl) cyclohexane carboxylic acid methyl ester The intermediate is analogous to the synthesis of the starting compound
Beispiel I aus ort .o-Methoxyzimtsäuremefhylester und Butadien. (Umsetzung analog: US-A-5 395 840 Example I und II) dargestellt.Example I from ort. O-methoxycinnamic acid methyl ester and butadiene. (Implementation analog: US-A-5 395 840 Example I and II).
b) (lS*,2S*)-2-(4-Methoxyphenyl)cycIohexanecarbonsäure Eine Lösung von (lS*,2S*)-2-(4-Methoxyphenyl)cyclohexancarbonsäuremethylesterb) (IS *, 2S *) - 2- (4-methoxyphenyl) cyclohexane carboxylic acid A solution of (IS *, 2S *) - 2- (4-methoxyphenyl) cyclohexane carboxylic acid methyl ester
(1.0 g, 4.0 mmol) und Lit umhydroxid (145 mg, 6.0 mmol) in Methanol- Wasser (3:1, 20 ml) wird 2 d bei 60°C gerührt. Nach Zugabe von Wasser wird Methanol im Vakuum entfernt und der wässrige Rückstand mit 1 N Salzsäure auf pH 1 gebracht. Der dabei ausfallende Niederschlag wird filtriert, mit Wasser gewaschen und im Vakuum getrocknet. Ausbeute: 734 mg (78%) als Diatereomerengemisch.(1.0 g, 4.0 mmol) and lithium hydroxide (145 mg, 6.0 mmol) in methanol-water (3: 1, 20 ml) is stirred at 60 ° C. for 2 d. After adding water, methanol is removed in vacuo and the aqueous residue is brought to pH 1 with 1 N hydrochloric acid. The precipitate is filtered off, washed with water and dried in vacuo. Yield: 734 mg (78%) as a mixture of diatereomers.
MS (ESI): m/z = 217 [M+H-H2O]+; HPLC (Methode 7): rt = 3.90 min.MS (ESI): m / z = 217 [M + HH 2 O] + ; HPLC (method 7): rt = 3.90 min.
c) (lS*,2S*)-2-(4-MethoxyphenyI)-N- [(lS)-l-phenylethyl] cy clohexancarbox- amid (lS*,2S*)-2-(4-Methoxyphenyl)cyclohexanecarbonsäure (710 mg, 3.04 mmol) wird mit (S)-Phenylethylamin (590 μl, 4.56 mmol) nach der allgemeinen Vorschrift [C-2] umgesetzt. Das gewünschte Produkt wird mittels Flash-Chromatographie (Cyclo- hexan-Dichlormethan-Gemische) gereinigt. Ausbeute: 852.1 mg (83%) als Diastereo- merengemisch. MS (ESI): m/z = 338 [M+H]+; HPLC (Methode 3): rt = 4.69 min, 4.75 min. d) (lS*,2S*)-2-(4-Hydroxyρhenyl)-7V-[(lS)-l-phenylethyl]cycIohexan- carboxamidc) (IS *, 2S *) - 2- (4-methoxyphenyl) -N- [(IS) -l-phenylethyl] cy clohexane carboxamide (IS *, 2S *) - 2- (4-methoxyphenyl) cyclohexane carboxylic acid ( 710 mg, 3.04 mmol) is reacted with (S) -phenylethylamine (590 μl, 4.56 mmol) according to the general procedure [C-2]. The desired product is purified by means of flash chromatography (cyclohexane / dichloromethane mixtures). Yield: 852.1 mg (83%) as a mixture of diastereomers. MS (ESI): m / z = 338 [M + H] + ; HPLC (method 3): rt = 4.69 min, 4.75 min. d) (IS *, 2S *) - 2- (4-hydroxyphenyl) -7V - [(IS) -l-phenylethyl] cyclohexane carboxamide
Eine Lösung von (lS*,2S*)-2-(4-Methoxyphenyl)-N-[(lS)-l-phenylethyl]cyclo- hexancarboxamid (772 mg, 2.29 mmol) in Dichlormethan (8 ml) wird bei 0°C tropfenweise mit Bortribromid (1 M in Dichlormethan, 2 eq.) versetzt und 20 h bei Raumtemperatur gerührt. Das Reaktionsgemisch wird auf Eis gegeben und mit gesättigter wässriger Νatriumhydrogencarbonat-Lösung neutralisiert. Die wässrige Phase wird mit 1 Ν Salzsäure angesäuert und mit Ethylacetat extrahiert. Die vereinigten organischen Phasen werden getrocknet (Νatriumsulfat), filtriert und imA solution of (IS *, 2S *) - 2- (4-methoxyphenyl) -N - [(IS) -l-phenylethyl] cyclohexanecarboxamide (772 mg, 2.29 mmol) in dichloromethane (8 ml) is at 0 ° C was added dropwise with boron tribromide (1 M in dichloromethane, 2 eq.) And stirred for 20 h at room temperature. The reaction mixture is poured onto ice and neutralized with saturated aqueous sodium bicarbonate solution. The aqueous phase is acidified with 1 Ν hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), filtered and in
Vakuum eingeengt. Das Rohprodukt wird als Diastereomerengemisch ohne weitere Reinigung die der nächsten Reaktion eingesetzt. ' * Vacuum concentrated. The crude product is used as a mixture of diastereomers without further purification of the next reaction. '*
MS (ESI): m/z = 324 [M+H]+; HPLC (Methode 6): rt = 3.72 min, 3.83 min. MS (ESI): m / z = 324 [M + H] + ; HPLC (method 6): rt = 3.72 min, 3.83 min.
SvnthesebeispieleSvnthesebeispiele
Beispiel 1example 1
N-[4-((lS,2S)-2-{[((li?)-2-Hydroxy-l-phenyIethyl)ammo]carbonyl}cyclohexyl)- benzyl]-N-phenyl-l-piperidincarboxamidN- [4 - ((IS, 2S) -2 - {[((li?) - 2-hydroxy-l-phenylethyl) ammo] carbonyl} cyclohexyl) -benzyl] -N-phenyl-l-piperidinecarboxamide
a) (lS,2S)-2-(4-{[PhenyI(l-pyrrolidinylcarbonyl)amino]methyl}- phenyl)cyclohexancarbonsäure-tert-butylestera) (IS, 2S) -2- (4 - {[PhenyI (l-pyrrolidinylcarbonyl) amino] methyl} - phenyl) cyclohexane carboxylic acid tert-butyl ester
Die Verbindung wird nach der Allgemeinen Vorschrift [A] ausgehend von N-Phenyl- piperidylharnstoff synthetisiert. Der Rückstand wird über Flashchromatographie an Kieselgel (Cyclohexan-Essigester 10:1) gereinigt. Man erhält 1.4 g (68% Ausbeute) der gewünschten Verbindung. Rf = 0.20 (Petrolether-Essigester 10:1);The compound is synthesized starting from N-phenylpiperidylurea according to general specification [A]. The residue is purified by flash chromatography on silica gel (cyclohexane-ethyl acetate 10: 1). 1.4 g (68% yield) of the desired compound are obtained. R f = 0.20 (petroleum ether-ethyl acetate 10: 1);
1H-ΝMR (300 MHz, DMSO): 1.05 (s, 9H), 1.32 (m, 10H), 1.75 (m, 4H), 2.40 (m, 2H), 3.11 (m, 4H), 4.78 (s, 2H), 7.15 (m, 9H).1H-ΝMR (300 MHz, DMSO): 1.05 (s, 9H), 1.32 (m, 10H), 1.75 (m, 4H), 2.40 (m, 2H), 3.11 (m, 4H), 4.78 (s, 2H ), 7.15 (m, 9H).
b) (lS,2S)-2-(4-{[Phenyϊ(l-pyrrolidinylcarbonyl)amino]methyl}phenyl)- cyclohexancarbonsäureb) (IS, 2S) -2- (4 - {[Phenyϊ (l-pyrrolidinylcarbonyl) amino] methyl} phenyl) - cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der Allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 156 mg (HPLC- Reinheit 90%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.80 (Dichlormethan-Methanol 10:1);The compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis specification [B]. 156 mg (HPLC purity 90%) of the desired compound are obtained, which is reacted without further purification. R f = 0.80 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.32 (m, 10H), 1.70 (m, 3H), 1.98 (m, IH), 2.61 (m,1H-NMR (300 MHz, DMSO): 1.32 (m, 10H), 1.70 (m, 3H), 1.98 (m, IH), 2.61 (m,
IH), 3.12 (m, 4H), 4.72 (s, 2H), 7.20 (m, 9H), 11.6 (bs, IH).IH), 3.12 (m, 4H), 4.72 (s, 2H), 7.20 (m, 9H), 11.6 (bs, IH).
c) 7V-[4-((lS,2S)-2-{[((lR)-2-Hydroxy-l-phenylethyl)amino]carbonyl}cyclo- hexyl)benzyl]-iV-phenyl-l-piperidincarboxamidc) 7V- [4 - ((IS, 2S) -2 - {[((IR) -2-hydroxy-l-phenylethyl) amino] carbonyl} cyclohexyl) benzyl] -IV-phenyl-l-piperidinecarboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Phenyl(l-pyrrolidinylcarbonyl)- amino]methyl}phenyl)cyclohexancarbonsäure und (R)-Phenylglycinol nach der Allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 110 mg (Ausbeute 92%) der gewünschten Verbindung.The compound is synthesized starting from (IS, 2S) -2- (4 - {[phenyl (1-pyrrolidinylcarbonyl) - amino] methyl} phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling. 110 mg (yield 92%) of the desired compound are obtained.
Rf = 0.17 (Toluol-Essigester 1:1);R f = 0.17 (toluene-ethyl acetate 1: 1);
1H-NMR (300 MHz, DMSO): 1.35 (m, 10H), 1.74 (m, 4H), 2.65 (m,'2H), 2.31 (m, AT ), 2.63 (m, 2H), 3.18 (m, 4H), 3.45 (m, 2H), 4.61 (m, IH), 4.79 (m, 3H), 6.76 (m, 2H), 7.05 (m, 10H), 7.26 (m, 2H), 7.88 (d, IH).1H-NMR (300 MHz, DMSO): 1.35 (m, 10H), 1.74 (m, 4H), 2.65 (m, ' 2H), 2.31 (m, AT), 2.63 (m, 2H), 3.18 (m, 4H), 3.45 (m, 2H), 4.61 (m, IH), 4.79 (m, 3H), 6.76 (m, 2H), 7.05 (m, 10H), 7.26 (m, 2H), 7.88 (d, IH ).
Beispiel 2Example 2
7V-[4-((lR,2S)-2-{[((li?)-2-Hydroxy-l-phenylethyl)amino]carbonyl}cyclohexyl)- benzyl]-7V-phenyl-l-thiomorpholincarboxamid7V- [4 - ((IR, 2S) -2 - {[((li?) - 2-hydroxy-l-phenylethyl) amino] carbonyl} cyclohexyl) - benzyl] -7V-phenyl-l-thiomorpholine carboxamide
a) (lS,2S)-2-(4-{[Phenyl(l-thiomorpholinylcarbonyl)amino]methyl}- phenyl)cyc!ohexancarbonsäure-tert-butylestera) (IS, 2S) -2- (4 - {[phenyl (l-thiomorpholinylcarbonyl) amino] methyl} - phenyl) cyc! ohexanecarboxylic acid tert-butyl ester
Die Verbindung wird nach der Allgemeinen Vorschrift [A] ausgehend von N-Phenyl- thiomoφholinylharnstoff synthetisiert. Der Rückstand wird über Flashchrornato- graphie an Kieselgel (Cyclohexan-Essigester 10:1) gereinigt. Man erhält 1.6 g (72% Ausbeute) der gewünschten Verbindung. Rf = 0.18 (Petrolether-Essigester 10:1);The compound is synthesized according to the general procedure [A] starting from N-phenylthiomopholinyl urea. The residue is over Flashchrornato- graphite on silica gel (cyclohexane-ethyl acetate 10: 1) cleaned. 1.6 g (72% yield) of the desired compound are obtained. R f = 0.18 (petroleum ether-ethyl acetate 10: 1);
1H-NMR (300 MHz, DMSO): 1.05 (s, 9H), 1.35 (m, 4H), 1.82 (m, ATT), 2.32 (m, 5H), 2.61 (s, IH), 3.41 (m, 4H), 4.78 (s, 2H), 7.20 (m, 9H).1H NMR (300 MHz, DMSO): 1.05 (s, 9H), 1.35 (m, 4H), 1.82 (m, ATT), 2.32 (m, 5H), 2.61 (s, IH), 3.41 (m, 4H) ), 4.78 (s, 2H), 7.20 (m, 9H).
b) (lS,2S)-2-(4-{[Phenyl(l-thiomorpholinylcarbonyl)amino]methyl}phenyl)- cyclohexancarbonsäureb) (IS, 2S) -2- (4 - {[phenyl (l-thiomorpholinylcarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der Allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 160 mg (HPLCThe compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis specification [B]. 160 mg (HPLC
Reinheit 92%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird.Purity 92%) of the desired compound, which is implemented without further purification.
Rf= 0.82 (Dichlormethan-Methanol 10:1);R f = 0.82 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.37 (m, 4H), 1.72 (m, 3H), 1.96 (m, IH), 2.31 (m, 4H), 2.60 (m, IH), 3.34 (m, 4H), 4.71 (s, 2H), 7.25 (m, 9H), 11.8 (bs, IH).1H-NMR (300 MHz, DMSO): 1.37 (m, 4H), 1.72 (m, 3H), 1.96 (m, IH), 2.31 (m, 4H), 2.60 (m, IH), 3.34 (m, 4H) ), 4.71 (s, 2H), 7.25 (m, 9H), 11.8 (bs, IH).
c) JV-[4-((li?,2S)-2-{[((lR)-2-Hydroxy-l-phenylethyl)amino]carbonyI}cyclo- hexyI)benzyl]-iV-phenyl-l-thiomorpholin carboxamidc) JV- [4 - ((li?, 2S) -2 - {[((IR) -2-hydroxy-l-phenylethyl) amino] carbonyI} cyclohexyI) benzyl] -IV-phenyl-l-thiomorpholine carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Phenyl(l-thiomoφholinyl- carbonyl)amino]methyl}phenyl)cyclohexancarbonsäure und (R)-Phenylglycinol nach der Allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhältThe compound is synthesized starting from (IS, 2S) -2- (4 - {[phenyl (l-thiomopholinylcarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling. You get
105 mg (Ausbeute 94%) der gewünschten Verbindung.105 mg (yield 94%) of the desired compound.
Rf = 0.21 (Toluol-Essigester 1:1);R f = 0.21 (toluene-ethyl acetate 1: 1);
1H-NMR (300 MHz, DMSO): 1.47 (m, 11H), 2.32 (m, ATT), 2.61 (m, 2H), 3.45 (m, 6H), 4.59 (m, IH), 4.79 (m, 3H), 6.71 (m, 2H), 7.05 (m, 10H), 7.30 (m, 2H), 7.88 (d,1H-NMR (300 MHz, DMSO): 1.47 (m, 11H), 2.32 (m, ATT), 2.61 (m, 2H), 3.45 (m, 6H), 4.59 (m, IH), 4.79 (m, 3H) ), 6.71 (m, 2H), 7.05 (m, 10H), 7.30 (m, 2H), 7.88 (d,
IH). Beispiel 3IH). Example 3
7V-[4-((lS,2S)-2-{[((lR)-2-Hydroxy-l-phenylethyl)amino]carbonyI}cyclohexyl)- benzyl]-7V-phenyI-l-iV-methylpiperazincarboxamid7V- [4 - ((IS, 2S) -2 - {[((IR) -2-hydroxy-l-phenylethyl) amino] carbonyI} cyclohexyl) benzyl] -7V-phenyI-l-IV-methylpiperazinecarboxamide
a) (lS,2S)-2-(4-{[Phenyl(l-N-methylpiperazinylcarbonyl)amino]methyl- phenyl)cycIohexancarbonsäure-t'-*rt-butylestera) (IS, 2S) -2- (4 - {[phenyl (1-N-methylpiperazinylcarbonyl) amino] methylphenyl) cyclohexanecarboxylic acid t '- * rt-butyl ester
Die Verbindung wird nach der Allgemeinen Vorschrift [A] ausgehend von N-Phenyl- (N-methylpiperazyl)harnstoff synthetisiert. Der Rückstand wird über Flashchromato- graphie an Kieselgel (Dichlormethan-Methanol-Triethylamin 10:1:0.1) gereinigt.The compound is synthesized starting from N-phenyl- (N-methylpiperazyl) urea according to general instructions [A]. The residue is purified by flash chromatography on silica gel (dichloromethane-methanol-triethylamine 10: 1: 0.1).
Man erhält 1.5 g (77% Ausbeute) der gewünschten Verbindung.1.5 g (77% yield) of the desired compound are obtained.
Rf = 0.14 (Dichlormethan-Methanol 10:1);R f = 0.14 (dichloromethane-methanol 10: 1);
1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.41 (m, 4H), 1.85 (m, 3H), 2.70 (m, IH), 3.05 (s, 3H), 3.39 (m, 2H), 3.62 (m, 2H), 4.11 (d, 2H), 4.67 (s, 2H), 7.25 (m,1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.41 (m, 4H), 1.85 (m, 3H), 2.70 (m, IH), 3.05 (s, 3H), 3.39 (m, 2H ), 3.62 (m, 2H), 4.11 (d, 2H), 4.67 (s, 2H), 7.25 (m,
9H), 8.48 (s, IH).9H), 8.48 (s, IH).
b) (lS,2S)-2-(4-{[Phenyl(l-iV-methyIpiperazinylcarbonyl)amino]methyl}- phenyl)cyc!ohexancarbonsäure Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der Allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 165 mg (HPLC- Reinheit 94%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.10 (Dichlormethan-Methanol 10:1); 1H-NMR (300 MHz, DMSO): 1.39 (m, 4H), 1.78 (m, 3H), 1.90 (m, IH), 2.78 (m, IH), 3.05 (s, 3H), 3.39 (m, 2H), 3.62 (m, 2H), 4.12 (d, 2H), 4.61 (s, 2H), 7.25 (m, 9H), 8.91 (s, IH).b) (IS, 2S) -2- (4 - {[phenyl (l-IV-methyipiperazinylcarbonyl) amino] methyl} - phenyl) cyc! ohexanecarboxylic acid The compound is based on the corresponding tert-butyl ester derivative according to the general hydrolysis procedure [B ] synthesized. 165 mg (HPLC purity 94%) of the desired compound are obtained, which is reacted without further purification. R f = 0.10 (dichloromethane-methanol 10: 1); 1H-NMR (300 MHz, DMSO): 1.39 (m, 4H), 1.78 (m, 3H), 1.90 (m, IH), 2.78 (m, IH), 3.05 (s, 3H), 3.39 (m, 2H) ), 3.62 (m, 2H), 4.12 (d, 2H), 4.61 (s, 2H), 7.25 (m, 9H), 8.91 (s, IH).
c) 7V-[4-((lS,2S)-2-{[((lR)-2-Hydroxy-l-phenylethyl)amino]carbonyl}cyclo- hexyl)benzyl]-7V-phenyl-l-iV-methylpiperazmcarboxamidc) 7V- [4 - ((IS, 2S) -2 - {[((IR) -2-hydroxy-l-phenylethyl) amino] carbonyl} cyclohexyl) benzyl] -7V-phenyl-l-IV- methylpiperazmcarboxamid
Die Verbindung wird ausgehend von _(lS,2S)-2-(4-{[Phenyl(l-N-methylpiperazinyl- carbonyl)amino]methyl}phenyl)cyclohexancarbonsäure und (R)-Phenylglycinol nach der Allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 98 mg (Ausbeute 84%) der gewünschten Verbindung.The compound is synthesized starting from _ (IS, 2S) -2- (4 - {[phenyl (IN-methylpiperazinylcarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid and (R) -phenylglycinol according to the general synthesis instructions [C] for the amide coupling , 98 mg (yield 84%) of the desired compound are obtained.
Rf= 0.25 (Dichlormethan-Methanol 10:1);R f = 0.25 (dichloromethane-methanol 10: 1);
1H-ΝMR (300 MHz, DMSO): 1.61 ( , 8H), 2.71 (m, 2H), 3.00 (s, 3H), 3.45 (m, 3H), 4.62 (m, 2H), 4.53 (m, 3H), 6.71 (m, 2H), 7.05 (m, 4H), 7.36 (m, 8H), 8.22 (d, IH).1H-ΝMR (300 MHz, DMSO): 1.61 (, 8H), 2.71 (m, 2H), 3.00 (s, 3H), 3.45 (m, 3H), 4.62 (m, 2H), 4.53 (m, 3H) , 6.71 (m, 2H), 7.05 (m, 4H), 7.36 (m, 8H), 8.22 (d, IH).
Beispiel 4Example 4
(lS,2S)-2-(4-{[MethyI(phenyl)amino]methyI}phenyl)-N-[(lS)-l-phenylethyl]- cyclohexancarboxamid(IS, 2S) -2- (4 - {[methyl (phenyl) amino] methyl} phenyl) -N - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS,2S)-2-(4-{[Methyl(phenyl)amino]methyl}phenyl)- cyclohexancarbonsäure-tert-butylestera) (IS, 2S) -2- (4 - {[methyl (phenyl) amino] methyl} phenyl) - cyclohexane carboxylic acid tert-butyl ester
Die Verbindung wird nach der Allgemeinen Vorschrift [D] ausgehend von N- Methylanilin synthetisiert. Man erhält 201 mg (HPLC-Reinheit 94%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.20 (Cyclohexan-Essigester 1:1); 1H-NMR (300 MHz, DMSO): 1.02 (s, 9H), 1.39 (m, 4H), 1.73 (m, 4H), 2.52 (m, 2H), 2.98 (s, 3H), 4.51 (s, 2H), 6.65 (m, 5H), 7.11 (m, 4H).The compound is synthesized starting from N-methylaniline according to the general specification [D]. 201 mg (HPLC purity 94%) of the desired compound are obtained, which is reacted without further purification. R f = 0.20 (1: 1 cyclohexane-ethyl acetate); 1H NMR (300 MHz, DMSO): 1.02 (s, 9H), 1.39 (m, 4H), 1.73 (m, 4H), 2.52 (m, 2H), 2.98 (s, 3H), 4.51 (s, 2H) ), 6.65 (m, 5H), 7.11 (m, 4H).
b) (lS,2S)-2-(4-{[Methyl(phenyl)amino]methyl}phenyl)cyclohexan- carbonsäureb) (IS, 2S) -2- (4 - {[methyl (phenyl) amino] methyl} phenyl) cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der Allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 170 mg (HPLC- Reinheit 90%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.30 (Dichlormethan-Methanol 10: 1);The compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis specification [B]. 170 mg (HPLC purity 90%) of the desired compound are obtained, which is reacted without further purification. R f = 0.30 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.41 (m, 4H), 1.71 (m, 4H), 2.48 (m, 2H), 2.95 (s, 3H), 4.47 (s, 2H), 6.70 (m, 5H), 7.15 (m, 4H), 11.5 (bs, IH).1H-NMR (300 MHz, DMSO): 1.41 (m, 4H), 1.71 (m, 4H), 2.48 (m, 2H), 2.95 (s, 3H), 4.47 (s, 2H), 6.70 (m, 5H) ), 7.15 (m, 4H), 11.5 (bs, IH).
c) (lS,2S)-2-(4-{[Methyl(phenyl)amino]methyl}phenyl)-7V-[(lS)-l-phenyl- ethyljcyclohexan carboxamidc) (IS, 2S) -2- (4 - {[methyl (phenyl) amino] methyl} phenyl) -7V - [(IS) -l-phenylethyljcyclohexane carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Methyl(phenyl)amino]methyl}- phenyl)cyclohexancarbonsäure und (S)-Phenylethylamin nach der Allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 105 mg (Ausbeute 92%) der gewünschten Verbindung. Rf = 0.51 (Dichlormethan-Methanol 10:1);The compound is synthesized starting from (IS, 2S) -2- (4 - {[methyl (phenyl) amino] methyl} - phenyl) cyclohexanecarboxylic acid and (S) -phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 105 mg (yield 92%) of the desired compound are obtained. R f = 0.51 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 0.85 (d, 3H), 1.35 (m, 4H), 1.71 (m, ATT), 2.28 (m, IH), 2.65 (m, 2H), 2.99 (s, 3H), 4.50 (s, 2H), 4.61 (m, IH), 6.55 (m, IH), 6.70 (d, 2H), 7.15 (m, 11H), 7.80 (d, IH). 1H-NMR (300 MHz, DMSO): 0.85 (d, 3H), 1.35 (m, 4H), 1.71 (m, ATT), 2.28 (m, IH), 2.65 (m, 2H), 2.99 (s, 3H ), 4.50 (s, 2H), 4.61 (m, IH), 6.55 (m, IH), 6.70 (d, 2H), 7.15 (m, 11H), 7.80 (d, IH).
Beispiel 5Example 5
(lS,2S)-2-(4-{[AUyl(phenyl)amino]methyI}phenyl)-iV-[(lS)-l-phenylethyl]cyclo- hexancarboxamid(IS, 2S) -2- (4 - {[AUyl (phenyl) amino] methyl} phenyl) -iV - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS,2S)-2-(4-{[allyl(phenyI)amino]methyl}phenyl)cycIohexancarbon- säure-'eri'-butylestera) (IS, 2S) -2- (4 - {[allyl (phenyl) amino] methyl} phenyl) cyclohexane carboxylic acid 'eri' butyl ester
Die Verbindung wird nach der Allgemeinen Vorschrift [D] ausgehend von N- Allylanilin synthetisiert. Man erhält 220 mg (HPLC Reinheit 96%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.17 (Cyclohexan-Essigester 1:1);The compound is synthesized starting from N-allylaniline according to the general specification [D]. 220 mg (HPLC purity 96%) of the desired compound are obtained, which is reacted without further purification. R f = 0.17 (cyclohexane-ethyl acetate 1: 1);
1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.45 (m, 4H), 1.88 (m, 4H), 2.41 (m, IH), 2.65 ( , IH), 3.99 (d, 2H), 4.50 (s, 2H), 5.18 (m, 2H), 5.91 (m, IH), 6.70 (m, 4H), 7.11 (m, 5H).1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.45 (m, 4H), 1.88 (m, 4H), 2.41 (m, IH), 2.65 (, IH), 3.99 (d, 2H) , 4.50 (s, 2H), 5.18 (m, 2H), 5.91 (m, IH), 6.70 (m, 4H), 7.11 (m, 5H).
b) (lS,2S)-2-(4-{[AHyl(phenyl)amino]methyl}phenyl)cyclohexancarbonsäureb) (IS, 2S) -2- (4 - {[AHyl (phenyl) amino] methyl} phenyl) cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der Allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 180 mg (HPLC- Reinheit 92%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.25 (Dichlormethan-Methanol 10:1);The compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis specification [B]. 180 mg (HPLC purity 92%) of the desired compound are obtained, which is reacted without further purification. R f = 0.25 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.78 (m, 4H), 2.40 (m, IH), 2.47 (m, IH), 4.00 (d, 2H), 4.55 (s, 2H), 5.20 (m, 2H), 5.98 (m, IH), 6.82 (m, 4H), 7.18 (m, 5H), 11.2 (bs, IH). c) (lS,2S)-2-(4-{[Allyl(phenyl)amino]methyl}phenyl)-iV-I(lS)-l-phenyl- ethyl] cyclohexancarboxamid1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.78 (m, 4H), 2.40 (m, IH), 2.47 (m, IH), 4.00 (d, 2H), 4.55 (s, 2H ), 5.20 (m, 2H), 5.98 (m, IH), 6.82 (m, 4H), 7.18 (m, 5H), 11.2 (bs, IH). c) (IS, 2S) -2- (4 - {[allyl (phenyl) amino] methyl} phenyl) -iV-I (IS) -l-phenylethyl] cyclohexane carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Allyl(phenyl)amino]methyl})- cyclohexancarbonsäure und (S)-Phenylethylamin nach der Allgemeinen Synthese- Vorschrift [C] zur Amidkupplung synthetisiert. Man erhält 115 mg (Ausbeute 95%) der gewünschten Verbindung. Rf = 0.53 (Dichlormethan-Methanol 10:1);The compound is synthesized starting from (IS, 2S) -2- (4 - {[allyl (phenyl) amino] methyl}) - cyclohexane carboxylic acid and (S) -phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 115 mg (yield 95%) of the desired compound are obtained. R f = 0.53 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 0.87 (d, 3H), 1.37 (m, 4H), 1.69 (m, 4H), 2.25 (m, IH), 2.65 (m, 2H), 3.99 (d, 2H), 4.51 (s, 2H), 4.62 (m, IH), 5.18 (m, 2H), 5.88 (m, IH), 6.56 (m, IH), 6.70 (d, 2H), 7.16 (m, 1 IH), 7.83 (d, IH).1H-NMR (300 MHz, DMSO): 0.87 (d, 3H), 1.37 (m, 4H), 1.69 (m, 4H), 2.25 (m, IH), 2.65 (m, 2H), 3.99 (d, 2H ), 4.51 (s, 2H), 4.62 (m, IH), 5.18 (m, 2H), 5.88 (m, IH), 6.56 (m, IH), 6.70 (d, 2H), 7.16 (m, 1 IH) ), 7.83 (d, IH).
Die in der folgenden Tabelle aufgeführten Verbindungen wurden in analoger Weise hergestellt: The compounds listed in the following table were prepared in an analogous manner:
Beispiel 123Example 123
(lS,2S)-2-(4-{[Dimethylbenzyl(methyl)amino]methyl}phenyl)-iV-[(lS)-l-phenyl- ethyl] cyclohexancarboxamid(IS, 2S) -2- (4 - {[dimethylbenzyl (methyl) amino] methyl} phenyl) -iV - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS',2S)-2-(4-{[Dimethylbenzyl(methyl)amino]methyl}phenyl)cyclohexan- carbonsaure-fert-butylestera) (IS ', 2S) -2- (4 - {[dimethylbenzyl (methyl) amino] methyl} phenyl) cyclohexane carboxylic acid fert-butyl ester
Die Verbindung wird nach der allgemeinen Vorschrift [D] ausgehend von N- Dimefhylbenzyl-N-Methylamin synthetisiert. Man erhält 280 mg (HPLC-Reinheit 98%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.22 (Cyclohexan-Essigester 1:1);The compound is synthesized according to the general procedure [D] starting from N-dimethylbenzyl-N-methylamine. This gives 280 mg (HPLC purity 98%) of the desired compound, which is reacted without further purification. R f = 0.22 (cyclohexane-ethyl acetate 1: 1);
1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.44 (m, 4H), 1.49 (s, 6TT), 1.88 (m, 4H), 2.05 (s, 3H), 2.40 (m, IH), 2.62 (m, IH), 4.50 (s, 2H), 6.70 (m, ATT), 7.11 (m, 5H).1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.44 (m, 4H), 1.49 (s, 6TT), 1.88 (m, 4H), 2.05 (s, 3H), 2.40 (m, IH ), 2.62 (m, IH), 4.50 (s, 2H), 6.70 (m, ATT), 7.11 (m, 5H).
b) (lS,2S)-2-(4{[Dimethylbenzyl(methyl)amino]methyl}phenyl)cyclohexan- carbonsäureb) (IS, 2S) -2- (4 {[dimethylbenzyl (methyl) amino] methyl} phenyl) cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 210 mg (HPLC- Reinheit 95%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.31 (Dichlormethan-Methanol 10:1);The compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis instructions [B]. 210 mg (HPLC purity 95%) of the desired compound are obtained, which is reacted without further purification. R f = 0.31 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.48 (s, 6H), 1.78 (m, 4H), 2.05 (s, 3H), 2.53 (m, 2H), 3.47 (s, 2H), 6.82 (m, 4H), 7.18 (m, 5H), 11.6 (bs, IH). c) (lS,2S)-2-(4-{[Dimethylbenzyl(methyl)amino]methyl}phenyl)-iV-[(lS)-l- phenylethyljcyclohexancarboxamid1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.48 (s, 6H), 1.78 (m, 4H), 2.05 (s, 3H), 2.53 (m, 2H), 3.47 (s, 2H) ), 6.82 (m, 4H), 7.18 (m, 5H), 11.6 (bs, IH). c) (IS, 2S) -2- (4 - {[dimethylbenzyl (methyl) amino] methyl} phenyl) -iV - [(IS) -l-phenylethylcyclohexane carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Dimethylbenzyl(methyl)amino]- methyl})cyclohexancarbonsäure und (S)-Phenylethylamin nach der allgemeinen Synfhesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 160 mg (Ausbeute 93%) der gewünschten Verbindung. Rf = 0.60 (Dichlormethan-Methanol 10:1);The compound is synthesized starting from (IS, 2S) -2- (4 - {[dimethylbenzyl (methyl) amino] - methyl}) cyclohexanecarboxylic acid and (S) -phenylethylamine according to the general syntax regulation [C] for the amide coupling. 160 mg (yield 93%) of the desired compound are obtained. R f = 0.60 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.10 (d, 3H), 1.37 (m, 4H), 1.49 (s, 6H), 1.72 (m, 4H), 2.05 (s, 3H), 2.65 (m, 2H), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.91 (d, IH).1H-NMR (300 MHz, DMSO): 1.10 (d, 3H), 1.37 (m, 4H), 1.49 (s, 6H), 1.72 (m, 4H), 2.05 (s, 3H), 2.65 (m, 2H) ), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.91 (d, IH).
Beispiel 124Example 124
(lS,2S)-2-(4-{[Dimethylbenzyl(methyl)ammoniumhydrochlorid]methyl}phenyl)-(LS, 2S) -2- (4 - {[dimethyl benzyl (methyl) ammonium hydrochloride] methyl} phenyl) -
7V-[(lS)-l-phenylethyl]cyclohexancarboxamid7V - [(lS) -l-phenylethyl] cyclohexanecarboxamide
200 mg (lS,2S)-2-(4- {[Dimethylbenzyl(methyl)amino]methyl}phenyl)-N-[(lS)-l- phenylethyl]cyclohexancarboxarnid werden in 5ml einer 4M HCL-Lösung in Dioxan gelöst und lyophilisiert. Man erhält 210 mg (Ausbeute 100%) des gewünschten200 mg (IS, 2S) -2- (4- {[dimethylbenzyl (methyl) amino] methyl} phenyl) -N - [(IS) -l-phenylethyl] cyclohexane carboxarnide are dissolved in 5 ml of a 4M HCL solution in dioxane and lyophilized. 210 mg (yield 100%) of the desired are obtained
Produktes als farblosen Feststoff.Product as a colorless solid.
Rf = 0.25 (Dichlormethan-Methanol 10:1);R f = 0.25 (dichloromethane-methanol 10: 1);
1H-NMR (300 MHz, DMSO): 1.11 (d, 3H), 1.37 (m, 4H), 1.53 (s, 6H), 1.72 (m, 4H)1H-NMR (300 MHz, DMSO): 1.11 (d, 3H), 1.37 (m, 4H), 1.53 (s, 6H), 1.72 (m, 4H)
2.20 (s, 3H), 2.65 (m, 2H), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H),2.20 (s, 3H), 2.65 (m, 2H), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H),
7.91 (d, IH), 11.5 (s, IH). Beispiel 1257.91 (d, IH), 11.5 (s, IH). Example 125
(lS,2S)-2-(4-{[Dimethylbenzylamino]methyl}phenyl)-iV-[(lS)-l-phenylethyl]- cyclohexancarboxamid(IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl} phenyl) -iV - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS,2S)-2-(4-{[DimethylbenzyIamino]methyl}phenyl)cyclohexan- carbonsäure-tert'-butylestera) (IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl} phenyl) cyclohexane carboxylic acid tert'-butyl ester
Die Verbindung wird nach der allgemeinen Vorschrift [D] ausgehend von N- Dimethylbenzylamin synthetisiert. Man erhält 280 mg (HPLC Reinheit 96%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf = 0.18 (Cyclohexan-Essigester 1:1)The compound is synthesized according to the general procedure [D] starting from N-dimethylbenzylamine. This gives 280 mg (HPLC purity 96%) of the desired compound, which is reacted without further purification. R f = 0.18 (cyclohexane-ethyl acetate 1: 1)
1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.44 (m, 4H), 1.49 (s, 6H), 1.88 (m, 4H), 2.40 (m, IH), 2.60 (s, IH), 2.62 (m, IH), 4.50 (s, 2H), 6.70 (m, 4H), 7.11 (m, 5H).1H-ΝMR (300 MHz, DMSO): 1.10 (s, 9H), 1.44 (m, 4H), 1.49 (s, 6H), 1.88 (m, 4H), 2.40 (m, IH), 2.60 (s, IH ), 2.62 (m, IH), 4.50 (s, 2H), 6.70 (m, 4H), 7.11 (m, 5H).
b) (lS,2S)-2-(4{[Dimethylbenzyl(methyl)amino]methyl}phenyl)- cyclohexancarbonsäureb) (IS, 2S) -2- (4 {[dimethylbenzyl (methyl) amino] methyl} phenyl) cyclohexane carboxylic acid
Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält.210 mg (HPLC- Reinheit 95%) der gewünschten Verbindung, die ohne weitere Reinigung umgesetzt wird. Rf= 0.23 (Dichlormethan-Methanol 10:1)The compound is synthesized from the corresponding tert-butyl ester derivative according to the general hydrolysis instructions [B]. 210 mg (HPLC purity 95%) of the desired compound are obtained, which is reacted without further purification. R f = 0.23 (dichloromethane-methanol 10: 1)
1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.48 (s, 6H), 1.78 (m, 4H), 2.53 ( , 2H), 2.60 (s, IH), 3.47 (s, 2H), 6.82 (m, 4H), 7.18 (m, 5H), 11.6 (bs, IH). c) (lS,2S)-2-(4-{[DimethylbenzyIamino]methyl}phenyl)-7V-[(lS)-l-phenyl- ethyl] cy clohexancarboxamid1H-NMR (300 MHz, DMSO): 1.46 (m, 4H), 1.48 (s, 6H), 1.78 (m, 4H), 2.53 (, 2H), 2.60 (s, IH), 3.47 (s, 2H) , 6.82 (m, 4H), 7.18 (m, 5H), 11.6 (bs, IH). c) (IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl} phenyl) -7V - [(IS) -l-phenylethyl] cy clohexane carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Dimethylbenzylamino]methyl})- cyclohexancarbonsäure und (S)-Phenylethylamin nach der allgemeinen Synthese- Vorschrift [C] zur Amidkupplung synthetisiert. Man erhält 140 mg (Ausbeute 89%) der gewünschten Verbindung. Rf = 0.60 (Dichlormethan-Methanol 10:1)The compound is synthesized starting from (IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl}) - cyclohexane carboxylic acid and (S) -phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 140 mg (yield 89%) of the desired compound are obtained. R f = 0.60 (dichloromethane-methanol 10: 1)
1H-NMR (300 MHz, DMSO): 1.13 (d, 3H), 1.37 (m, ATT), 1.49 (s, 6H), 1.72 (m, ATT), 2,40 (s, IH), 2.65 (m, 2H), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.90 (d, IH).1H-NMR (300 MHz, DMSO): 1.13 (d, 3H), 1.37 (m, ATT), 1.49 (s, 6H), 1.72 (m, ATT), 2.40 (s, IH), 2.65 (m , 2H), 3.32 (s, 2H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.90 (d, IH).
Beispiel 126Example 126
(lS,2S)-2-(4-{[Dimethylbenzylamino]methyl}phenyl)-iV-methyl-7V-[(lS)-l- phenylethyljcyclohexancarboxamid(IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl} phenyl) -iV-methyl-7V - [(IS) -l-phenylethyljcyclohexane carboxamide
Die Verbindung wird ausgehend von (lS,2S)-2-(4-{[Dimethylbenzylamino]methyl})- cyclohexancarbonsäure und (S)-N-Methyl-N-phenylethylamin nach der allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 89 mg (Ausbeute 62%) der gewünschten Verbindung. Rf = 0.88 (Dichlormethan-Methanol 10:1)The compound is synthesized starting from (IS, 2S) -2- (4 - {[dimethylbenzylamino] methyl}) - cyclohexane carboxylic acid and (S) -N-methyl-N-phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 89 mg (yield 62%) of the desired compound are obtained. R f = 0.88 (dichloromethane-methanol 10: 1)
1H-ΝMR (300 MHz, DMSO): 1.13 (d, 3H), 1.37 (m, 4H), 1.49 (s, 6H), 1.72 (m, 4H), 2.05 (s, 3H), 2.40 (s, IH), 2.65 (m, 2H), 3.32 (s, 2H), 3.50 (s, 3H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.80 (d, IH). Die in der folgenden Tabelle aufgeführten Verbindungen werden in analoger Weise dargestellt: 1H-ΝMR (300 MHz, DMSO): 1.13 (d, 3H), 1.37 (m, 4H), 1.49 (s, 6H), 1.72 (m, 4H), 2.05 (s, 3H), 2.40 (s, IH ), 2.65 (m, 2H), 3.32 (s, 2H), 3.50 (s, 3H), 4.67 (m, IH), 6.56 (m, IH), 7.16 (m, 13H), 7.80 (d, IH) , The compounds listed in the following table are presented in an analogous manner:
Beispiel 145Example 145
3,4-Dimethyl-iV-{4-[(li?,2S)-2-({[(15)-l-phenylethyl]amino}carbonyl)- cyclohexyl]benzyI}benzamid3,4-Dimethyl-iV- {4 - [(li?, 2S) -2 - ({[(15) -l-phenylethyl] amino} carbonyl) - cyclohexyl] benzyI} benzamide
37 mg (0.1 mmol) (lS,2E)-2-{4-[(Aminomethyl]phenyl}-N-[(lS)-l-phenylethyl]- cyclohexancarboxamid (Beispiel XXVH) und 18.5 mg (0.11 - mmol) 3,4- Dimethylbenzoylchlorid in 1 ml Dichlormethan werden mit 0.02 ml (0.11 mmol) NN-Diisopropylethylamin versetzt. Das Reaktionsgemisch wird 1 h bei Raumtemperatur gerührt und direkt über HPLC gereinigt, Ausbeute 38 mg (81%). Rf = 0.42 (Cyclohexan-Ethylacetat 1:1);37 mg (0.1 mmol) (IS, 2E) -2- {4 - [(aminomethyl] phenyl} -N - [(IS) -l-phenylethyl] cyclohexane carboxamide (Example XXVH) and 18.5 mg (0.11 mmol) 3 , 4-Dimethylbenzoyl chloride in 1 ml dichloromethane is mixed with 0.02 ml (0.11 mmol) NN-diisopropylethylamine, the reaction mixture is stirred for 1 h at room temperature and purified directly by HPLC, yield 38 mg (81%). R f = 0.42 (cyclohexane Ethyl acetate 1: 1);
MS (DCI): m/z = 486 (M+ΝH4)+;MS (DCI): m / z = 486 (M + ΝH 4 ) + ;
1H-NMR (200 MHz, DMSO): 1.2 (d, 3H), 1.35-1.9 (m, 8H), 2.25 (s, 6H), 4.4 (d, 2H), 4.7 (m, IH), 6.6 (d, 2H), 7(m, 8H), 7.6 (d, IH), 7.7 (s, IH), 8.0 (d, IH), 8.85 (t, IH).1H-NMR (200 MHz, DMSO): 1.2 (d, 3H), 1.35-1.9 (m, 8H), 2.25 (s, 6H), 4.4 (d, 2H), 4.7 (m, IH), 6.6 (d , 2H), 7 (m, 8H), 7.6 (d, IH), 7.7 (s, IH), 8.0 (d, IH), 8.85 (t, IH).
In Analogie zur Vorschrift des Beispiels 145 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the instructions in Example 145.
Beispiel 154 Example 154
(lS,2-R)-2-(4-{[CyclopropyI(phenoxyacetyl)amino]methyl}phenyl)-N-[(lS)-l- phenylethyl]cyclohexancarboxamid(IS, 2-R) -2- (4 - {[CyclopropyI (phenoxyacetyl) amino] methyl} phenyl) -N - [(IS) -l-phenylethyl] cyclohexane carboxamide
Eine Lösung aus 40 mg (0.11 mmol) (lS,2R)-2-{4-[(Cyclopropylamino)methyl]- phenyl}-N-[(lS)-l-phenylethyl]cyclohexancarboxamid (Beispiel XXVIII) in 2 ml THF wird mit 30 mg (0.15 mmol) Bromacetylbromid und 27.5 mg (0.21 mmol) NN-A solution of 40 mg (0.11 mmol) (IS, 2R) -2- {4 - [(cyclopropylamino) methyl] - phenyl} -N - [(IS) -l-phenylethyl] cyclohexane carboxamide (Example XXVIII) in 2 ml THF is mixed with 30 mg (0.15 mmol) bromoacetyl bromide and 27.5 mg (0.21 mmol) NN-
Diisopropylethylamin versetzt. Das Reaktionsgemisch wird 1 h bei Raumtemperatur gerührt und zu einer Suspension aus 40 mg (0.42 mmol) Phenol und 146.8 mg (1.06 mmol) Kaliumcarbonat in 2 ml THF gegeben. Nach 14 h bei Raumtemperatur wird das Lösungsmittel entfernt und der Rückstand per HPLC gereinigt, Ausbeute: 41 mg (76%).Diisopropylethylamine added. The reaction mixture is stirred for 1 h at room temperature and added to a suspension of 40 mg (0.42 mmol) phenol and 146.8 mg (1.06 mmol) potassium carbonate in 2 ml THF. After 14 h at room temperature, the solvent is removed and the residue is purified by HPLC, yield: 41 mg (76%).
Rf = 0.3 (Cyclohexan-Ethylacetat 1:1);R f = 0.3 (cyclohexane-ethyl acetate 1: 1);
MS (ESIpos): m/z = 511 (M+H)+;MS (ESIpos): m / z = 511 (M + H) + ;
1H-NMR (200 MHz, DMSO): 0.7-0.9 (m, 4H), 1.2 (d, 3H), 1.35-1.6 (m, 4H), 1.7-1H-NMR (200 MHz, DMSO): 0.7-0.9 (m, 4H), 1.2 (d, 3H), 1.35-1.6 (m, 4H), 1.7-
1.95 (m, 4H), 2.5-2.7 (m, 2H), 4.45 (d, IH), 4.6 (d, IH), 4.7 (m, IH), 5.05 (s, 2H), 6.65 (m, 2H), 6.9-7.15 (m, 10H), 7.3 (t, 2H), 7.95 (d, IH).1.95 (m, 4H), 2.5-2.7 (m, 2H), 4.45 (d, IH), 4.6 (d, IH), 4.7 (m, IH), 5.05 (s, 2H), 6.65 (m, 2H) , 6.9-7.15 (m, 10H), 7.3 (t, 2H), 7.95 (d, IH).
In Analogie zur Vorschrift des Beispiels 154 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the instructions in Example 154.
Beispiel 157Example 157
5-(Methylsulfanyl)-l,2,4-thiadiazol-3-yl-cyclopropyl{4-[(lR,2S)-2-({[(lS)-l- phenylethyl] amino}carbonyl)cyc!ohexyl]benzyl}carbamat5- (methylsulfanyl) -l, 2,4-thiadiazol-3-yl-cyclopropyl {4 - [(lR, 2S) -2 - ({[(lS) -l-phenylethyl] amino} carbonyl) cyc! Ohexyl] benzyl} carbamate
a) Zu einer Lösung von 300 mg (0.80 mmol) (lS,2R)-2-{4-[(cyclopropylamino)- methyl]phenyl}-N-[(lS)-l-phenylefhyl]cyclohexancarboxamid (Beispiel XXVTIi) und 120 mg (1.2 mmol) Triethylamin in 3 ml Dichlormethan wird bei 0°C tropfenweise eine Lösung von 102 mg (0.34 mmol) Bis(trichlormethyl)carbonat (Triphosgen) in 1.5 ml Dichlormethan zugegeben. Das Reaktionsgemisch wird weitere 3 h bei Raumtemperatur gerührt, die entstandene Lösung mit kalter 10% Salzsäurelösung, kalter gesättigter Νatriumhydrogencarbonatlösung und kalter gesättigter Νatriumchloridlösung gewaschen, über Νatriumsulfat getrocknet und das Lösungsmittel entfernt, Ausbeute 270 mg. a) To a solution of 300 mg (0.80 mmol) (lS, 2R) -2- {4 - [(cyclopropylamino) - methyl] phenyl} -N - [(lS) -l-phenylefhyl] cyclohexane carboxamide (Example XXVTIi) and A solution of 102 mg (0.34 mmol) of bis (trichloromethyl) carbonate (triphosgene) in 1.5 ml of dichloromethane is added dropwise at 0 ° C. to 120 mg (1.2 mmol) of triethylamine in 3 ml of dichloromethane. The reaction mixture is stirred for a further 3 h at room temperature, the resulting solution is washed with cold 10% hydrochloric acid solution, cold saturated sodium bicarbonate solution and cold saturated sodium chloride solution, dried over sodium sulfate and the solvent removed, yield 270 mg.
b) 90 mg (0.17 mmol) des Rohproduktes in 1 ml Acetonitril werden bei 82°C zu einer Suspension von 44 mg (0.3 mmol) 5-Mefhylthio[1.2.4]thiadiazol-3-ol [JHeterocyclChem. 1979, 16, 961-971] und 370 mg Poly(4-vinylρyridin) und 3 ml Acetonitril gegeben. Das Reaktionsgemisch wird weitere 14 h unter Rückfluss erhitzt. Die Suspension wird filtriert, das Lösungsmittel entfernt und der Rückstand per HPLC gereinigt, Ausbeute: 55 mg (33%) der Titelverbindung.b) 90 mg (0.17 mmol) of the crude product in 1 ml of acetonitrile are at 82 ° C to a suspension of 44 mg (0.3 mmol) of 5-methyl thio [1.2.4] thiadiazol-3-ol [JHeterocyclChem. 1979, 16, 961-971] and 370 mg of poly (4-vinylpyridine) and 3 ml of acetonitrile. The reaction mixture is heated under reflux for a further 14 h. The suspension is filtered, the solvent is removed and the residue is purified by HPLC, yield: 55 mg (33%) of the title compound.
Rf = 0.13 (Cyclohexan-Ethylacetat 1:1);R f = 0.13 (cyclohexane-ethyl acetate 1: 1);
MS (ESIpos): m/z = 551 (M+H)+;MS (ESIpos): m / z = 551 (M + H) + ;
1H-ΝMR (200 MHz, DMSO): 0.7-0.9 (m, 4H), 1.2 (d, 3H), 1.3-1.6 (m, 4H), 1.7-1.9 (m, 4H), 2.5-2.7 (m, 6H), 4.4-4.6 (m, 2H), 4.7 (m, IH), 6.65 (m, 2H), 6.9-7.2 (m,1H-ΝMR (200 MHz, DMSO): 0.7-0.9 (m, 4H), 1.2 (d, 3H), 1.3-1.6 (m, 4H), 1.7-1.9 (m, 4H), 2.5-2.7 (m, 6H), 4.4-4.6 (m, 2H), 4.7 (m, IH), 6.65 (m, 2H), 6.9-7.2 (m,
7H), 8.0 (d, lH). 7H), 8.0 (d, 1H).
Beispiel 158Example 158
2,3-Dimethylphenyl-4-[(li?,2S)-2-({[(lS)-l-(4-aminophenyl)ethyl]amino}carbo- nyl)cyclohexyl]benzyl(cyc!opropyl)carbamat2,3-Dimethylphenyl-4 - [(li?, 2S) -2 - ({[(lS) -l- (4-aminophenyl) ethyl] amino} carbonyl) cyclohexyl] benzyl (cyc! Opropyl) carbamate
270 mg (0.47 mmol) 2,3-Dimethylphenyl-cyclopropyl{4-[(lR,2S)-2-({[(lS)-l-(4- mtrophenyl)ethyl]amino}carbonyl)cyclohexyl]benzyl}carbamate und Pd/C (ca. 20 mg) in 7 mL Essigsäureethylester werden 14 h bei Raumtemperatur unter Wasserstoff (1 atm) gerührt. Nach Filtration und Entfernen des Lösungsmittels wird das Rohprodukt über HPLC gereinigt, Ausbeute: 170 mg (66%). Rf = 0.30 (Cyclohexan-Ethylacetat 1:1); HPLC (Methode 3): rt = 4.59 min; 1H-NMR270 mg (0.47 mmol) 2,3-dimethylphenyl-cyclopropyl {4 - [(IR, 2S) -2 - ({[(IS) -l- (4-mtrophenyl) ethyl] amino} carbonyl) cyclohexyl] benzyl} carbamate and Pd / C (approx. 20 mg) in 7 mL ethyl acetate are stirred for 14 h at room temperature under hydrogen (1 atm). After filtration and removal of the solvent, the crude product is purified by HPLC, yield: 170 mg (66%). R f = 0.30 (cyclohexane-ethyl acetate 1: 1); HPLC (method 3): rt = 4.59 min; 1H-NMR
(200 MHz, DMSO): 0.85 (m, ATT), 1.15 (d, 3H), 1.2-1.6 (m, 4H), 1.7-1.9 (m, 4H), 2.0 (s, 3H), 2.3 (s, 3H), 2.6-2.8 (m, 2H), 4.5 (m, 2H), 4.65 (s, 2H), 6.3 (d, 2H), 6.4 (d, 2H); 6.9 (m, IH); 7.0-7.2 (m, 6H), 7.65 (d, 2H).(200 MHz, DMSO): 0.85 (m, ATT), 1.15 (d, 3H), 1.2-1.6 (m, 4H), 1.7-1.9 (m, 4H), 2.0 (s, 3H), 2.3 (s, 3H), 2.6-2.8 (m, 2H), 4.5 (m, 2H), 4.65 (s, 2H), 6.3 (d, 2H), 6.4 (d, 2H); 6.9 (m, IH); 7.0-7.2 (m, 6H), 7.65 (d, 2H).
Beispiel 159Example 159
2,3-Dimethylphenyl-4-{(lÄ,25)-2-[({(lS)-l-[4-(acetylamino)phenyl]ethyl}amino)- carbonyl]cyclohexyl}benzyl(cyclopropyl)carbamat2,3-Dimethylphenyl-4 - {(LA, 25) -2 - [({(IS) -l- [4- (acetylamino) phenyl] ethyl} amino) carbonyl] cyclohexyl} benzyl (cyclopropyl) carbamate
Eine Lösung aus 50 mg (0.09 mmol) 2,3-Dimethylphenyl 4-[(lR,2S)-2-({[(lS)-l-(4- aminophenyl)ethyl]amino}carbonyl)cyclohexyl]benzyl(cyclopropyl)carbamat, 8.7 mg (0.11 mmol) Acetylchlorid und 14.4 mg (0.11 mmol) Diisopropylethylamin in 2 ml Dichlormethan wird 14 h bei Raumtemperatur gerührt. Das Reaktionsgemisch wird eingeengt und der Rückstand direkt über eine HPLC gereinigt, Ausbeute: 33 mg (61%). A solution of 50 mg (0.09 mmol) 2,3-dimethylphenyl 4 - [(lR, 2S) -2 - ({[(lS) -l- (4-aminophenyl) ethyl] amino} carbonyl) cyclohexyl] benzyl (cyclopropyl ) carbamate, 8.7 mg (0.11 mmol) acetyl chloride and 14.4 mg (0.11 mmol) diisopropylethylamine in 2 ml dichloromethane is stirred for 14 h at room temperature. The reaction mixture is concentrated and the residue is purified directly by HPLC, yield: 33 mg (61%).
HPLC (Methode 3): rt = 4.86 min; 1H-NMR (200 MHz, DMSO): 0.85 (m, 4H), 1.15 (d, 3H), 1.2-1.6 (m, 4H), 1.7-1.9 (m, 4H), 1.95 (s, 3H), 2.05 (s, 2H), 2.25 (s, 3H), 2.5- 2.6 (m, 2H), 2.6-2.8 (m, 2H), 4.5-4.7 (m, 3H), 6.5 (d, 2H), 6.85 (bs, IH), 7.0-7.1 (m, 2H), 7.1-7.3 (m, 6H), 7.8 (d, lH).HPLC (method 3): rt = 4.86 min; 1H-NMR (200 MHz, DMSO): 0.85 (m, 4H), 1.15 (d, 3H), 1.2-1.6 (m, 4H), 1.7-1.9 (m, 4H), 1.95 (s, 3H), 2.05 (s, 2H), 2.25 (s, 3H), 2.5- 2.6 (m, 2H), 2.6-2.8 (m, 2H), 4.5-4.7 (m, 3H), 6.5 (d, 2H), 6.85 (bs , IH), 7.0-7.1 (m, 2H), 7.1-7.3 (m, 6H), 7.8 (d, lH).
In Analogie zur Vorschrift des Beispiels 159 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the specification of Example 159.
Die in der folgenden Tabelle aufgeführten Verbindungen werden nach der allgemeinen Vorschrift [C.2] aus der entsprechenden (lS,2R)-2-(4- {[Cyclopropyl(aryloxycarbonyl)-amino]methyl}phenyl)cyclohexancarbonsäure dargestellt: Beispiel 177The compounds listed in the following table are prepared according to the general procedure [C.2] from the corresponding (IS, 2R) -2- (4- {[cyclopropyl (aryloxycarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid: Example 177
7V-Methyl-N-(l-methyl-l-phenylethyl)-4-[(lR,2S)-2-({[(lS)-lphenylethyl]ammo}- carbonyl)cyclohexyl]benzamid7V-methyl-N- (l-methyl-l-phenylethyl) -4 - [(lR, 2S) -2 - ({[(lS) -lphenylethyl] ammo} - carbonyl) cyclohexyl] benzamide
Zu einer Lösung von 4-[(lR,2S)-2-({[(lS)-l-Phenylethyl]amino}carbonyl)cyclo- hexyl]benzoesäure (70.0 mg, 0.2 mmol), PyBOP (124.4 mg, 0.24 mmol) und 4-Di- methylaminopyridin (2.4 mg, 0.02 mmol) in Dimethylformamid (3 ml) werden bei Raumtemperatur NN-Diisopropylethylamin (42 μl, 0.24 mmol) und N-Methyl-N-(1- methyl-l-phenylethyl)amin [Synthesis 1995, 1534-1538] (44.6 mg, 0.3 mmol) gegeben. Das Reaktionsgemisch wird für 16 h bei Raumtemperatur gerührt. Das gewünschte Produkt wird mittels HPLC-Chromatographie (Acetonitril-Wasser- Gemische) gereinigt. To a solution of 4 - [(IR, 2S) -2 - ({[(IS) -l-phenylethyl] amino} carbonyl) cyclohexyl] benzoic acid (70.0 mg, 0.2 mmol), PyBOP (124.4 mg, 0.24 mmol ) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in dimethylformamide (3 ml) become NN-diisopropylethylamine (42 μl, 0.24 mmol) and N-methyl-N- (1-methyl-l-phenylethyl) amine at room temperature [Synthesis 1995, 1534-1538] (44.6 mg, 0.3 mmol). The reaction mixture is stirred for 16 h at room temperature. The desired product is purified by means of HPLC chromatography (acetonitrile-water mixtures).
MS (DCI, ΝH3): m/z = 484 [M+H]+, 500 [M+NH4]+; HPLC (Methode 3): rt = 4.26 min; 1H-NMR (200 MHz, DMSO): 7.99 (d, IH), 7.49-7.10 (m, 9H), 7.02-6.88 (m, 3H), 6.59 (dd, 2H), 4.76-4.58 (m, IH), 2.95 (s, 3H), 2.82-2.68 (m, IH), 2.64-2.52MS (DCI, ΝH 3 ): m / z = 484 [M + H] + , 500 [M + NH 4 ] + ; HPLC (method 3): rt = 4.26 min; 1H-NMR (200 MHz, DMSO): 7.99 (d, IH), 7.49-7.10 (m, 9H), 7.02-6.88 (m, 3H), 6.59 (dd, 2H), 4.76-4.58 (m, IH) , 2.95 (s, 3H), 2.82-2.68 (m, IH), 2.64-2.52
(m, IH), 1.90-1.28 (m, 14H), 1.20 (d, 3H).(m, IH), 1.90-1.28 (m, 14H), 1.20 (d, 3H).
Analog der allgemeinen Vorschrift [F] werden die folgenden Verbindungen dargestellt: Beispiel 196The following compounds are represented analogously to the general regulation [F]: Example 196
(lS*,2R*)-2-(3-{[Methyl(l-methyl-l-phenylethyl)amino]methyl}phenyl)-N-[(lS)- l-phenylethyl]cyclohexancarboxamid(IS *, 2R *) - 2- (3 - {[methyl (1-methyl-1-phenylethyl) amino] methyl} phenyl) -N - [(IS) - 1-phenylethyl] cyclohexane carboxamide
a) 78 mg (0.52 mmol) N-Mefhyl-2-phenyl-2-propanamin und 200 mg (0.64 mmol) (lS*,2R*)-2-[3-(Brommethyl)phenyl]cyclohexancarbonsäuremethylester (Beispiel L) werden nach der allgemeinen Arbeitsvorschrift [D] zum entsprechenden tertiären Amin umgesetzt, Ausbeute 142 mg (72%).a) 78 mg (0.52 mmol) of N-methyl-2-phenyl-2-propanamine and 200 mg (0.64 mmol) of (IS *, 2R *) - 2- [3- (bromomethyl) phenyl] cyclohexane carboxylic acid methyl ester (Example L) converted to the corresponding tertiary amine according to general working instructions [D], yield 142 mg (72%).
b) 130 mg (0.34 mmol) (lS*,2R*)-2-(3-{[Methyl(l-methyl-l-phenylethyl)amino]- methyl}phenyl)cyclohexancarbonsäuremethylester und 27.4 mg (0.69 mmol) Natriumhydroxid in 2.5 ml Ethanol und 0.25 ml Wasser werden 24 h unter Rückfluss erhitzt. Zur Aufarbeitung wird der Ansatz mit wässriger Salzsäure auf pH 1 gebracht, die Lösungsmittel abgezogen und der Rückstand über eine HPLC gereinigt; Ausbeute: 90 mg (72%).b) 130 mg (0.34 mmol) (IS *, 2R *) - 2- (3 - {[methyl (l-methyl-l-phenylethyl) amino] - methyl} phenyl) cyclohexane carboxylic acid methyl ester and 27.4 mg (0.69 mmol) sodium hydroxide in 2.5 ml of ethanol and 0.25 ml of water are heated under reflux for 24 h. For working up, the mixture is brought to pH 1 with aqueous hydrochloric acid, the solvents are stripped off and the residue is purified by HPLC; Yield: 90 mg (72%).
c) 73 mg (0.20 mmol) (lS*,2R*)-2-(3-{[Methyl(l-methyl-l-phenylethyl)amino]- methyl}phenyl)cyclohexancarbonsäure und 36 mg (0.30 mmol) (S)-Phenylefhylamin werden nach der allgemeinen Arbeitsvorschrift [C] zur Titelverbindung umgesetzt, Ausbeute: 54 mg (58%) als Diastereomerengemisch. Rf = 0.13 (Dichlormethan-Methanol 50:1); MS (DCI): m/z = 469 (M+H)+; 1H-NMR (400 MHz, DMSO): 0.8 (d, 3H), 1.2 (d, 3H), 1.3-1.6 (m, 14H), 1.6-1.9 (m, 8H), 1.95 (s, 3H), 2.1 (s, 3H), 2.5 (m, IH), 2.7 (m, IH), 4.5-4.7 (m, 2H), 6.5 (d, 2H), 6.9-7.4 (m, 18H), 7.6 (d, 4H), 7.8 (d, IH), 7.9 (d, IH).c) 73 mg (0.20 mmol) (IS *, 2R *) - 2- (3 - {[methyl (l-methyl-l-phenylethyl) amino] - methyl} phenyl) cyclohexane carboxylic acid and 36 mg (0.30 mmol) (S ) -Phenylefhylamine are converted to the title compound according to the general procedure [C], yield: 54 mg (58%) as a mixture of diastereomers. R f = 0.13 (dichloromethane-methanol 50: 1); MS (DCI): m / z = 469 (M + H) + ; 1H-NMR (400 MHz, DMSO): 0.8 (d, 3H), 1.2 (d, 3H), 1.3-1.6 (m, 14H), 1.6-1.9 (m, 8H), 1.95 (s, 3H), 2.1 (s, 3H), 2.5 (m, IH), 2.7 (m, IH), 4.5-4.7 (m, 2H), 6.5 (d, 2H), 6.9-7.4 (m, 18H), 7.6 (d, 4H ), 7.8 (d, IH), 7.9 (d, IH).
Die Diastereomere werden mittels präparativer HPLC [Säule: Stability C30; 5 μm;The diastereomers are prepared by preparative HPLC [column: Stability C30; 5 µm;
250* 20 mm; Temperatur: 40°C; Fluss = 25 mimin" 1; Eluentenzusammensetzung: A = 0.2%ige Trifluoressigsäure, B = Acetonitril; isokratisch 55% A und 45% B (v/v)] isoliert:250 * 20 mm; Temperature: 40 ° C; Flow = 25 minimin "1 ; eluent composition: A = 0.2% trifluoroacetic acid, B = acetonitrile; isocratic 55% A and 45% B (v / v)] isolated:
Diastereomer A, Ausbeute 18 mg (43%); HPLC-Retentionszeit (Methode 12): 11.83 min.Diastereomer A, yield 18 mg (43%); HPLC retention time (method 12): 11.83 min.
Diastereomer B, Ausbeute 20 mg (47%); HPLC-Retentionszeit (Methode 12): 14.61 min.Diastereomer B, yield 20 mg (47%); HPLC retention time (method 12): 14.61 min.
In Analogie zur Vorschrift des Beispiels 196 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the instructions in Example 196.
Beispiel 204 Example 204
Phenylcyclopropyl(4-{(lS,2S)-2-[({[(lS)-l-phenylethyl]amino}carbonyl)amino]- cyclohexyl}benzyl)carbamatPhenylcyclopropyl (4 - {(IS, 2S) -2 - [({[(IS) -l-phenylethyl] amino} carbonyl) amino] - cyclohexyl} benzyl) carbamate
a) Zu einer Lösung von 200 mg (0.51 mmol) (lS,2R)-2-(4-{[Cyclopropyl-a) To a solution of 200 mg (0.51 mmol) (IS, 2R) -2- (4 - {[cyclopropyl-
(phenoxycarbonyl)amino]methyl}phenyl)cyclohexancarbonsäure, 61.7 mg (0.61 mmol) Triethylamin in 3 ml Aceton wird bei -10°C eine Lösung von 90 mg (0.66 mmol) Chlorameisensäureisobutylester in 1 ml Aceton zugetropft. Das Reaktionsgemisch wird weitere 1 h bei -10°C gerührt, anschließend mit einer Lösung von 49.6 mg (0.76 mmol) Natriumazid in 0.5 ml Wasser versetzt und weitere 2 h bei(phenoxycarbonyl) amino] methyl} phenyl) cyclohexane carboxylic acid, 61.7 mg (0.61 mmol) triethylamine in 3 ml acetone, a solution of 90 mg (0.66 mmol) isobutyl chloroformate in 1 ml acetone is added dropwise at -10 ° C. The reaction mixture is stirred for a further 1 h at -10 ° C., then a solution of 49.6 mg (0.76 mmol) sodium azide in 0.5 ml water is added and the mixture is stirred for a further 2 h
-10°C gerührt. Das Reaktionsgemisch wird auf Eiswasser gegeben und die wässrige Phase mit Diefhylether extrahiert. Die Etherextrakte werden über Natriumsulfat getrocknet und bei niedriger Temperatur (<30°C) eingeengt. Der Rückstand wird bei 110°C in 2 ml Toluol getropft und das Reaktionsgemisch weitere 2.5 h unter Rückfluss erhitzt.-10 ° C stirred. The reaction mixture is poured onto ice water and the aqueous phase is extracted with dieethyl ether. The ether extracts are dried over sodium sulfate and concentrated at low temperature (<30 ° C). The residue is added dropwise at 110 ° C. in 2 ml of toluene and the reaction mixture is heated under reflux for a further 2.5 h.
b) 1 ml der Toluolösung wird mit 31 mg (0.26) ) (S)-Phenylethylamin versetzt und 14 h bei Raumtemperatur gerührt. Das Reaktionsgemisch wird eingeengt und per HPLC gereinigt, Ausbeute 36 mg (28%). Rf = 0.13 (57 (Cyclohexan-Ethylacetat 7:3);b) 1 ml of the toluene solution is mixed with 31 mg (0.26)) (S) -phenylethylamine and stirred for 14 h at room temperature. The reaction mixture is concentrated and purified by HPLC, yield 36 mg (28%). R f = 0.13 (57 (cyclohexane-ethyl acetate 7: 3);
MS (ESIpos) = 512 (M+H)+;MS (ESIpos) = 512 (M + H) + ;
1H-NMR (200 MHz, DMSO): 0.7 (m, 4H), 1.1 (d, 3H), 1.1-1.6 (m, 4H), 1.6-1.95 (m, 4H), 2.4-2.5 (m, IH), 2.7 (m, IH), 3.6 (m, IH), 4.4-4.6 (m, 3H), 5.5 (d, IH), 5.95 (d, IH), 7.0-7.3 (m, 12H), 7.4-7.5 ( , 2H). In Analogie zur Vorschrift des Beispiels 204 wird folgende Verbindung dargestellt:1H-NMR (200 MHz, DMSO): 0.7 (m, 4H), 1.1 (d, 3H), 1.1-1.6 (m, 4H), 1.6-1.95 (m, 4H), 2.4-2.5 (m, IH) , 2.7 (m, IH), 3.6 (m, IH), 4.4-4.6 (m, 3H), 5.5 (d, IH), 5.95 (d, IH), 7.0-7.3 (m, 12H), 7.4-7.5 (, 2H). The following connection is shown in analogy to the specification of example 204:
Umsetzung von (lS,2R)-2-{4-[(Benzyloxy)carbonyl]phenyl}cyclohexancarbon- säuren zu AmidenConversion of (IS, 2R) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexane carboxylic acids to amides
Die in der folgenden Tabelle aufgeführten Verbindungen werden nach der allgemeinen Vorschrift [C-2] aus den entsprechenden (lS,2R)-2-{4-[(Benzyloxy)- carbonyl]phenyl} cyclohexancarbonsäuren dargestellt. The compounds listed in the following table are prepared according to the general procedure [C-2] from the corresponding (IS, 2R) -2- {4 - [(benzyloxy) carbonyl] phenyl} cyclohexane carboxylic acids.
Beispiel 210 Example 210
(lS,2S)-2-(4-[Phenoxymethyl]phenyl)-N-[(lS)-l-phenylethyl]cyclohexan- carboxamid(IS, 2S) -2- (4- [phenoxymethyl] phenyl) -N - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) (lS,2S)-2-(4-[Phenoxymethyl]phenyl)cyclohexancarbonsäure--'eri'- butylestera) (IS, 2S) -2- (4- [phenoxymethyl] phenyl) cyclohexanecarboxylic acid - 'eri'-butyl ester
Die Verbindung wird nach der allgemeinen Vorschrift [H] ausgehend von Phenol synthetisiert. Der Rückstand wird über Flashchromatographie an Kieselgel (Cyclohexan-EtOAc 7:1) gereinigt. Man erhält 1.1 g (88% Ausbeute) der gewünschten Verbindung.The compound is synthesized based on phenol according to the general procedure [H]. The residue is purified by flash chromatography on silica gel (cyclohexane-EtOAc 7: 1). 1.1 g (88% yield) of the desired compound are obtained.
Rf = 0.20 (Petrolether-Ethylacetat 7:1); 1H-NMR (300MHz, DMSO): 1.08 (s, 9H), 1.42 (m, 4H), 1.78 (m, 4H), 2.62 (m, 2H), 5.08 (s, 2H), 7.15 (m, 14H).R f = 0.20 (petroleum ether-ethyl acetate 7: 1); 1H-NMR (300MHz, DMSO): 1.08 (s, 9H), 1.42 (m, 4H), 1.78 (m, 4H), 2.62 (m, 2H), 5.08 (s, 2H), 7.15 (m, 14H) ,
b) (lS,2S)-2-(4-[PhenoxymethyI]phenyl)cyclohexancarbonsäure Die Verbindung wird ausgehend vom entsprechenden tert-Butylester-Derivat nach der allgemeinen Hydrolysevorschrift [B] synthetisiert. Man erhält 0.8 g (HPLC Reinheit: 97% Ausbeute) der gewünschten Verbindung , die ohne weitere Reinigung umgesetzt wird. Rf = 0.23 (Petrolether-Ethylacetat 1:1); 1H-NMR (300MHz, DMSO): 1.43 (m, 4H), 1.76 (m, 4H), 2.64 (m, 2H), 5.02 (s, 2H), 7.15 (m, 14H), 8.80 (s, IH). c) (lS,2S)-2-(4-[PhenoxymethyI]phenyI)-N-[(lS)-l-phenylethyl]cyclohexan- carboxamid.b) (IS, 2S) -2- (4- [phenoxymethyl] phenyl) cyclohexanecarboxylic acid The compound is synthesized starting from the corresponding tert-butyl ester derivative according to the general hydrolysis instructions [B]. This gives 0.8 g (HPLC purity: 97% yield) of the desired compound, which is reacted without further purification. R f = 0.23 (petroleum ether-ethyl acetate 1: 1); 1H-NMR (300MHz, DMSO): 1.43 (m, 4H), 1.76 (m, 4H), 2.64 (m, 2H), 5.02 (s, 2H), 7.15 (m, 14H), 8.80 (s, IH) , c) (IS, 2S) -2- (4- [phenoxymethyl] phenyI) -N - [(IS) -l-phenylethyl] cyclohexane carboxamide.
Die Verbindung wird ausgehend von (lS,2S)-2-(4-[Phenoxymefhyl]phenyl)cyclo- hexancarbonsäure und (S)-Phenylethylamin nach der allgemeinen Synthesevorschrift [C] zur Amidkupplung synthetisiert. Man erhält 130 mg (Ausbeute 89%) der gewünschten Verbindung.The compound is synthesized from (IS, 2S) -2- (4- [phenoxymethyl] phenyl) cyclohexanecarboxylic acid and (S) -phenylethylamine according to the general synthesis instructions [C] for the amide coupling. 130 mg (yield 89%) of the desired compound are obtained.
Rf = 0.72 (Dichlormethan-Methanol 10:1); 1H-NMR (300MHz, DMSO): 1.20 (d, 3H), 1.37 (m, 4H), 1.76 (m, 4H), 2.65 (m, 2H), 4.68 (m, IH), 5.08 (s, 2H), 7.15 (m, 14H), 8.00 (d, IH).R f = 0.72 (dichloromethane-methanol 10: 1); 1H-NMR (300MHz, DMSO): 1.20 (d, 3H), 1.37 (m, 4H), 1.76 (m, 4H), 2.65 (m, 2H), 4.68 (m, IH), 5.08 (s, 2H) , 7.15 (m, 14H), 8.00 (d, IH).
In Analogie zur Vorschrift des Beispiels 210 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the specification of Example 210.
BeispieI 219 EXAMPLE 219
(lS*,2R*)-2-[3-(Phenoxymethyl)phenyl]-N-[(lS)-l-phenylethyl]cyclohexan- carboxamid(IS *, 2R *) - 2- [3- (phenoxymethyl) phenyl] -N - [(IS) -l-phenylethyl] cyclohexane carboxamide
a) 66.5 mg (0.71 mmol) Phenol und 200 mg (0.64 mmol) (lS*,2R*)-2-[3- (Brommethyl)phenyl]cyclohexancarbonsäuremethylester werden nach der allgemeinen Arbeitsvorschrift [D] zum entsprechenden Ether umgesetzt, Ausbeute 104 mg (78%).a) 66.5 mg (0.71 mmol) phenol and 200 mg (0.64 mmol) (IS *, 2R *) - 2- [3- (bromomethyl) phenyl] cyclohexanecarboxylic acid methyl ester are converted to the corresponding ether according to the general procedure [D], yield 104 mg (78%).
b) 135 mg (0.42 mmol) (lS*,2R*)-2-[3-(Phenoxymethyl)phenyl]cyclohexancarbon- säuremethylester und 33 mg (0.83 mmol) Natriumhydroxid in 2.5 ml Ethanol und 0.25 ml Wasser werden 24 h unter Rückfluss erhitzt. Zur Aufarbeitung wird der Ansatz mit wässriger Salzsäure auf pH 1 gebracht, die Lösungsmittel abgezogen und der Rückstand über eine HPLC gereinigt, Ausbeute; 125 mg (97%).b) 135 mg (0.42 mmol) (IS *, 2R *) - 2- [3- (phenoxymethyl) phenyl] cyclohexane carboxylic acid methyl ester and 33 mg (0.83 mmol) sodium hydroxide in 2.5 ml ethanol and 0.25 ml water are refluxed for 24 h heated. For working up, the mixture is brought to pH 1 with aqueous hydrochloric acid, the solvents are stripped off and the residue is purified by HPLC, yield; 125 mg (97%).
c) 100 mg (0.32 mmol) (lS*,2R*)-2-[3-(Phenoxymethyl)phenyl]cyclohexancarbon- säure und 58 mg (0.48 mmol) (S)-Phenylethylamin werden nach der allgemeinen Arbeitsvorschrift [C] zur Titelverbindung umgesetzt, Ausbeute: 104 mg (79%) als Diastereomerengemisch.c) 100 mg (0.32 mmol) (IS *, 2R *) - 2- [3- (phenoxymethyl) phenyl] cyclohexane carboxylic acid and 58 mg (0.48 mmol) (S) -phenylethylamine become according to the general working procedure [C] Title compound reacted, yield: 104 mg (79%) as a mixture of diastereomers.
Rf = 0.57 (Cyclohexan-Ethylacetat 1:1). MS (DCI): m/z = 431 [M+NH4]+ R f = 0.57 (cyclohexane-ethyl acetate 1: 1). MS (DCI): m / z = 431 [M + NH 4 ] +
1H-NMR (400 MHz, DMSO): 0.9 (d, 3H), 1.2 (d, 3H), 1.3-1-55 ( , 8H), 1.7-1.9 ( , 8H), 2.5-2.65 (m, 2H), 2.75 (t, 2H), 4.6 (g, IH), 4.65 (g, IH), 4.92 (d, IH), 4.95 (d, 1H), 5.0 (d, IH), 5.05 (d, IH), 6.6 (m, 2H), 6.9-7.1 (m, 7H), 7.1-7.2 (m, 5H), 7.2-7.3 (m, 12H), 7.85 (d, IH, 7.95 (d, IH).1H-NMR (400 MHz, DMSO): 0.9 (d, 3H), 1.2 (d, 3H), 1.3-1-55 (, 8H), 1.7-1.9 (, 8H), 2.5-2.65 (m, 2H) , 2.75 (t, 2H), 4.6 (g, IH), 4.65 (g, IH), 4.92 (d, IH), 4.95 (d, 1H), 5.0 (d, IH), 5.05 (d, IH), 6.6 (m, 2H), 6.9-7.1 (m, 7H), 7.1-7.2 (m, 5H), 7.2-7.3 (m, 12H) , 7.85 (d, IH, 7.95 (d, IH).
Die Diastereomere werden mittels präparativer HPLC [Säule: Stability C30; 5 μm; 250* 20 mm; Temperatur: 40°C; Fluss = 25 mhnin"1; Eluentenzusammensetzung: AThe diastereomers are prepared by preparative HPLC [column: Stability C30; 5 µm; 250 * 20 mm; Temperature: 40 ° C; Flow = 25 mhnin "1 ; eluent composition: A
= 0.2%ige Trifluoressigsäure, B = Acetonitril; isokratisch 55% A und 45% B (v/v)] isoliert:= 0.2% trifluoroacetic acid, B = acetonitrile; isocratic 55% A and 45% B (v / v)] isolated:
Diastereomer A, Ausbeute 18 mg (43%); HPLC-Retentionszeit: (Methode 12): 6.67 min.Diastereomer A, yield 18 mg (43%); HPLC retention time: (Method 12): 6.67 min.
Diastereomer B, Ausbeute 20 mg (47%); HPLC-Retentionszeit (Methode 12) : 7.53 min.Diastereomer B, yield 20 mg (47%); HPLC retention time (method 12): 7.53 min.
In Analogie zur Vorschrift des Beispiels 219 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. The compounds listed in the following table are shown in analogy to the instructions in Example 219.
Beispiel 228 (lS*,2R*)-2-[4-(BenzyIoxy)phenyl]-Λ7-[(lS)-lphenylethyl]cyclohexancarboxamid Example 228 (IS *, 2R *) - 2- [4- (benzyloxy) phenyl] -Λ 7 - [(IS) -phenylethyl] cyclohexane carboxamide
Eine Suspension von Natriumhydrid (60%ig in Mineralöl, 8.4 mg, 0.22 mmol) und (lS,2R)-2-(4-Hydroxyphenyl)-N-[(lS)-l-phenylefhyl]cyclohexancarboxamid (65.4 mg, 0.18 mmol) in Tetrahydrofuran (2 ml) wird bei Raumtemperatur mit Benzylbromid (25.7 μl, 0.22 mmol) versetzt. Das Reaktionsgemisch wird 20 h gerührt und mit Wasser und Dichlormethan versetzt. Nach Phasentrennung wird die wässrige Phase mit Dichlormethan extrahiert, die vereinigten organischen Phasen werden getrocknet (Natriumsulfat), filtriert und im Vakuum eingeengt.A suspension of sodium hydride (60% in mineral oil, 8.4 mg, 0.22 mmol) and (lS, 2R) -2- (4-hydroxyphenyl) -N - [(lS) -l-phenylefhyl] cyclohexane carboxamide (65.4 mg, 0.18 mmol ) in tetrahydrofuran (2 ml), benzyl bromide (25.7 μl, 0.22 mmol) is added at room temperature. The reaction mixture is stirred for 20 h and water and dichloromethane are added. After phase separation, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried (sodium sulfate), filtered and concentrated in vacuo.
Das gewünschte Produkt wird mittels HPLC-Chromatographie (Acetonitril- Wasser- Gemische) gereinigt. Ausbeute: 51% als Diastereomerengemisch. MS (ESI): m/z = 414 [M+H]+; HPLC (Methode 3): rt = 5.04 min; 1H-NMR (200 MHz, DMSO): 7.87 (d, IH), 7.78 (d, IH), 7.50-6.98 (m, 22H), 6.91-6.84 (m, 4H), 6.65-6.60 (m, 2H), 5.07 (s, 2H), 5.06 (s, 2H), 4.75-4.56 (m, 2H), 2.70-2.59 (m, 2H), 2.47-2.39 (m, 2H), 1.86-1.67 (m, 8H), 1.59-1.28 (m, 8H), 1.22 (d, 3H), 0.90 (d, 3H).The desired product is purified by means of HPLC chromatography (acetonitrile-water mixtures). Yield: 51% as a mixture of diastereomers. MS (ESI): m / z = 414 [M + H] + ; HPLC (method 3): rt = 5.04 min; 1H-NMR (200 MHz, DMSO): 7.87 (d, IH), 7.78 (d, IH), 7.50-6.98 (m, 22H), 6.91-6.84 (m, 4H), 6.65-6.60 (m, 2H) , 5.07 (s, 2H), 5.06 (s, 2H), 4.75-4.56 (m, 2H), 2.70-2.59 (m, 2H), 2.47-2.39 (m, 2H), 1.86-1.67 (m, 8H) , 1.59-1.28 (m, 8H), 1.22 (d, 3H), 0.90 (d, 3H).
In Analogie zur Vorschrift des Beispiels 228 werden die in der folgenden Tabelle aufgeführten Verbindungen dargestellt. Allgemeine Methode zur Herstellung von substituierten Cyclohexanderivaten der Formel A durch festphasenunterstützte Synthese:The compounds listed in the following table are shown in analogy to the instructions in Example 228. General method for the preparation of substituted cyclohexane derivatives of the formula A by solid-phase-assisted synthesis:
Anbindung von (R)-Fmoc-PhenyIgIycinol an ChlortritylpolystyrolharzAttachment of (R) -Fmoc-PhenyIgIycinol to chlortritylpolystyrene resin
Chlortritylpolystyrol (5.00 g, 4.90 mmol, Rapp Polymere) und (R)-Fmoc-Phenyl- glycinol (2.6 g, 7.3 mmol) werden in Toluol/Pyridin (4:1) suspendiert und drei Stunden bei 50°C gerührt. Methanol (5 ml) wird zugegeben und weitere drei Stunden bei 50°C gerührt. Das Reaktionsgemisch wird filtriert und das erhaltene Harz 1 wird wiederholt mit Methanol, Dichlormethan und Diethylether gewaschen und getrocknet. Zur Bestimmung der Beladung wird eine Harzprobe mit Trifluor- essigsäure/Dichlormethan abgespalten. Durch quantitative HPLC wird eine Beladung von 0,98 mm/g (R)-Fmoc-Phenylglycinol bestimmt. Spaltung der Fmoc-SchutzgruppeChlortrityl polystyrene (5.00 g, 4.90 mmol, Rapp polymers) and (R) -Fmoc-Phenylglycinol (2.6 g, 7.3 mmol) are suspended in toluene / pyridine (4: 1) and stirred at 50 ° C for three hours. Methanol (5 ml) is added and the mixture is stirred at 50 ° C. for a further three hours. The reaction mixture is filtered and the resin 1 obtained is washed repeatedly with methanol, dichloromethane and diethyl ether and dried. To determine the load, a resin sample is split off with trifluoroacetic acid / dichloromethane. A loading of 0.98 mm / g (R) -Fmoc-Phenylglycinol is determined by quantitative HPLC. Cleavage of the Fmoc protecting group
Harz 2Resin 2
Harz 1 (100 mg) wird in Piperidin/Dimethylformamid (1:4, 1 ml) 20 Minuten bei Raumtemperatur geschüttelt. Das erhaltene Harz 2 wird filtriert und wiederholt mit Methanol, Dichlormethan und Diethylether gewaschen und getrocknet.Resin 1 (100 mg) is shaken in piperidine / dimethylformamide (1: 4, 1 ml) for 20 minutes at room temperature. The resin 2 obtained is filtered and washed repeatedly with methanol, dichloromethane and diethyl ether and dried.
Amidbildungamide formation
[lS,2S]-2-(4-Formylphenyl)cyclohexancarbonsäure (8.88 g, 38.2 mmol), Ethyldiiso- propylamin (19.8 g, 153 mmol) und TBTU (24.5 g, 76.4 mmol) werden in 250 ml[IS, 2S] -2- (4-formylphenyl) cyclohexane carboxylic acid (8.88 g, 38.2 mmol), ethyldiisopropylamine (19.8 g, 153 mmol) and TBTU (24.5 g, 76.4 mmol) are dissolved in 250 ml
Dichlormethan 10 Minuten gerührt. Diese Lösung wird im Eisbad gekühlt und mit Harz 2 (26.0 g) versetzt. Das Reaktionsgemisch wird mit Dimethylacetamid (100 ml) versetzt, auf Raumtemperatur erwärmt und 3 Stunden geschüttelt. Das Reaktionsgemisch wird filtriert und das erhaltenen Harz 3 wird wiederholt mit Dimethylformamid, Methanol, Dichlormethan und Diethylether gewaschen und getrocknet. Herstellung einer Bibliothek von substituierten Cyclohexanderivaten der Formel ADichloromethane stirred for 10 minutes. This solution is cooled in an ice bath and resin 2 (26.0 g) is added. The reaction mixture is mixed with dimethylacetamide (100 ml), warmed to room temperature and shaken for 3 hours. The reaction mixture is filtered and the resin 3 obtained is washed repeatedly with dimethylformamide, methanol, dichloromethane and diethyl ether and dried. Preparation of a library of substituted cyclohexane derivatives of the formula A.
Die Bibliothek wurde in MiniKans (IRORI) nach der „Mix- und Split Methode" hergestellt [K. C. Nicolaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, M. P. Nova, Angew. Chem. Int. Ed. Engl. (1995), 35, 2289-2290]. The library was produced in MiniKans (IRORI) according to the "mix and split method" [KC Nicolaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, MP Nova, Angew. Chem. Int. Ed. Engl. (1995), 35, 2289-2290].
Harz 3 wird als Suspension in Dichlormethan/Dimefhylformamid (2:1) in IRORI-Resin 3 is suspended in dichloromethane / dimefhylformamide (2: 1) in IRORI-
MiniKans eingeschlämmt (jeweils etwa 120 mg/Kan) und wiederholt mit Dichlormethan und Diethylether gewaschen und getrocknet.MiniKans slurried (about 120 mg / Kan each) and washed repeatedly with dichloromethane and diethyl ether and dried.
Reduktive AminierungReductive amination
Das so kompartimentierte Harz wird in getrennten Reaktionsgefäßen in Dichlormethan/Trimethylorthoformiat (1:1) suspendiert, mit jeweils einem Amin (5 eq, „R-NH2") bei Raumtemperatur versetzt und 18 Stunden geschüttelt. Das Harz wird in den getrennten Reaktionsgefäßen zweimal mit Dimethylformamid gewaschen, in Dimethylformamid suspendiert und bei Raumtemperatur mitThe resin thus compartmentalized is suspended in separate reaction vessels in dichloromethane / trimethyl orthoformate (1: 1), each with an amine (5 eq, "R-NH 2 ") at room temperature and shaken for 18 hours. The resin is twice in the separate reaction vessels washed with dimethylformamide, suspended in dimethylformamide and at room temperature with
Tetrabutylammoniumborhydrid (2 eq) versetzt. Nach 10 Minuten Schütteln bei Raumtemperatur wird das Reaktionsgemisch auf -40°C gekühlt, mit Eisessig (100 eq) versetzt und wieder auf Raumtemperatur erwärmt. Das Harz wird wiederholt mit Wasser, Methanol, Dichlormethan/ 10 %Diisopropylethylamin, Methanol, Dichlor- methan und Diethylether gewaschen und getrocknet.Tetrabutylammonium borohydride (2 eq) added. After shaking for 10 minutes at room temperature, the reaction mixture is cooled to -40 ° C., glacial acetic acid (100 eq) is added and the mixture is warmed to room temperature again. The resin is washed repeatedly with water, methanol, dichloromethane / 10% diisopropylethylamine, methanol, dichloromethane and diethyl ether and dried.
Synthese von HarnstoffenSynthesis of ureas
Methode 1: Das wiederum kompartimentierte Harz wird in getrennten Reaktionsgefäßen inMethod 1: The again compartmentalized resin is in separate reaction vessels in
Dichlormethan suspendiert, mit Diisopropylethylamin (15 eq) versetzt und im Eisbad gekühlt. Trichlormethylchlorformiat (5 eq) wird zugegeben und 30 Minuten gerührt. Die Reaktionslösung wird dekantiert, das Harz wird einmal mit Dichlormethan gewaschen, anschließend wird eine Lösung von primären oder sekundären Aminen (jeweils 10 eq, „R"-NH2") und Ethyldiisopropylamin (10 eq) in Dimethylformamid zugegeben und über Nacht bei Raumtemperatur geschüttelt. Methode 2:Suspended dichloromethane, mixed with diisopropylethylamine (15 eq) and cooled in an ice bath. Trichloromethyl chloroformate (5 eq) is added and the mixture is stirred for 30 minutes. The reaction solution is decanted, the resin is washed once with dichloromethane, then a solution of primary or secondary amines (each 10 eq, "R" -NH 2 ") and ethyldiisopropylamine (10 eq) in dimethylformamide is added and shaken overnight at room temperature , Method 2:
Das wiederum kompartimentierte Harz wird in Dioxan suspendiert, mit Phenylisocyanat (10 eq) und Dimethylaminopyridin (0,5 eq) versetzt und bei 50°C über Nacht geschüttelt.The again compartmentalized resin is suspended in dioxane, mixed with phenyl isocyanate (10 eq) and dimethylaminopyridine (0.5 eq) and shaken at 50 ° C. overnight.
Synthese von Sulfonsäureamiden, Carbamaten und SäureamidenSynthesis of sulfonic acid amides, carbamates and acid amides
Das wiederum kompartimentierte Harz wird in getrennten Reaktionsgefäßen in Dichlormethan suspendiert, mit Efhyldiisopropylamin (15 eq) versetzt und zwischenThe resin, again compartmentalized, is suspended in separate reaction vessels in dichloromethane, mixed with ethyl diisopropylamine (15 eq) and between
0°C und Raumtemperatur werden Säurechloride, Chlorameisensäureester oder Sulfonsäurechloride (jeweils 5 eq) zugegeben und über Nacht bei 50°C geschüttelt.At 0 ° C and room temperature, acid chlorides, chloroformate or sulfonic acid chlorides (5 eq each) are added and shaken at 50 ° C overnight.
Die so erhaltenen Harzintermediate werden abschließend wiederholt mit Methanol, Dimethylformamid, Wasser, Dimethylformamid, Methanol, Dichlomethan undThe resin intermediates thus obtained are then repeated with methanol, dimethylformamide, water, dimethylformamide, methanol, dichlomethane and
Diethylether gewaschen und getrocknet. Die Produkte werden anschließend mit Trifluoressigsäure/Dichlomethan (1:1) von der festen Phase gespalten, das Harz wird abfiltriert und die Reaktionslösungen werden eingedampft.Washed and dried diethyl ether. The products are then cleaved from the solid phase using trifluoroacetic acid / dichloromethane (1: 1), the resin is filtered off and the reaction solutions are evaporated.
Die auf diese Weise erhaltenen Verbindungen sind in der folgenden Tabelle aufgeführt: The compounds obtained in this way are listed in the following table:
Die in der vorstehenden Tabelle aufgeführten Verbindungen wurden wie folgt charakterisiert:The compounds listed in the table above were characterized as follows:
Analysenparameteranalysis parameters
Alle Produkte wurden mittels LC-MS charakterisiert. Dazu wurde standardmäßig folgendes Trennsystem verwendet: HP 1100 mit UV-Detektor (208 - 400 nm), 40°C Ofentemperatur, Waters-Symmetry C18 Säule (50 mm x 2.1 mm, 3,5 μm), Laufmittel A: 99.9 %o Acetonitril/0.1 % Ameisensäure, Laufmittel B: 99.9 % Wasser/ 0,1 % Ameisensäure; Gradient:All products were characterized using LC-MS. The following separation system was used as standard: HP 1100 with UV detector (208 - 400 nm), 40 ° C oven temperature, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3.5 μm), solvent A: 99.9% o acetonitrile /0.1% formic acid, mobile phase B: 99.9% water / 0.1% formic acid; Gradient:
Der Nachweis der Substanzen erfolgte mittels eines Micromass Quattro LCZ MS, Ionisierung: ESI positiv/negativ. Die Retentionszeit ist in Minuten angegeben.The substances were detected using a Micromass Quattro LCZ MS, ionization: ESI positive / negative. The retention time is given in minutes.
Weiterhin wurden die in der folgenden Tabelle aufgeführten Verbindungen in analoger Weise hergestellt: Furthermore, the compounds listed in the following table were prepared in an analogous manner:
LC- Retentions¬LC retention¬
Beispiel Struktur Masse Methode zeit [min]Example structure mass method time [min]
237 512,3 Methode 6 4,28 237 512.3 Method 6 4.28
238 528,3 Methode 6 4,72238 528.3 Method 6 4.72
239 576,3 Methode 6 4,76239 576.3 Method 6 4.76
240 526,3 Methode 6 4,54240 526.3 Method 6 4.54
241 578,3 Methode 6 4,45241,578.3 Method 6 4.45
LC- Retentions¬ LC retention¬
Beispiel Struktur MasseExample structure mass
Methode zeit [min]Method time [min]
242 528,3 Methode 6 3,92242 528.3 Method 6 3.92
243 512,3 Methode 6 4,41 243 512.3 Method 6 4.41
244 619,3 Methode 6 3,93244 619.3 Method 6 3.93
245 585,3 Methode 6 2,89245 585.3 Method 6 2.89
246 556,3 Methode 6 4,28246 556.3 Method 6 4.28
LC- Retentions¬ LC retention¬
Beispiel Struktur MasseExample structure mass
Methode zeit [min]Method time [min]
263 544,29 Methode 6 4,15 263 544.29 Method 6 4.15
264 510,27 Methode 6 3,7 264 510.27 Method 6 3.7
265 410,26 Methode 6 2,11265 410.26 Method 6 2.11
266 558,31 Methode 6 4,37266 558.31 Method 6 4.37
267 573,32 Methode 6 3,97267,573.32 Method 6 3.97
PatentansprtichePatentansprtiche
1. Verbindungen der Formel (I),1. Compounds of formula (I)
woπn embedded image in which
M eine Gruppe -N(-R!)- oder ein Sauerstoffatom -O- bedeutet,M represents a group -N (-R ! ) - or an oxygen atom -O-,
A eine Gruppe -C(=O)- oder -CH2- oder eine chemische Bindung bedeutet,A represents a group -C (= O) - or -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu drei Heteroatomen aus derD 5- or 6-membered heteroarylene with up to three heteroatoms from the
Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano,Series N, O and / or S or phenylene, each up to three times, independently of one another, by halogen, hydroxy, cyano,
Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)- Alkyl, (d-C6)- Alkoxy, ( -Cö^Alkoxycarbonyl oder Mono- oder Di-(Cι- C6)-alkylamino substituiert sein können,Carboxy, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) - alkyl, (dC 6 ) - alkoxy, (-C ö ^ alkoxycarbonyl or mono- or di- (Cι- C 6 ) alkylamino may be substituted,
R1 Wasserstoff, Benzyl, (C2-C6)-Alkenyl, (Cι-C6)- Alkyl, gegebenenfalls benzokondensiertes (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, Amino, (d-C6)- Alkoxy, Phenyl, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, (C3-C8)-Cycloalkyl oder Mono- oder Di-(d-C6)- alkylamino substituiert sein können, R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (-C-C 6 ) - alkyl, optionally benzo-fused (C 3 -C 8 ) cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another Hydroxy, amino, (dC 6 ) - alkoxy, phenyl, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl or mono- or di - (dC 6 ) - alkylamino can be substituted,

Claims

(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Oxo, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)- Alkyl, (Cι-Cδ)-Alkoxy, (d-Cö^Alkoxycarbonyl, N-Acetyl,N-methylamino oder Mono- oder Di-(Cι-C6)-alkylamino substituiert sein können,(C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and / or S, where aryl, heteroaryl and heterocyclyl for their part up to trisubstituted, independently, by halogen, hydroxy, oxo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C6) - alkyl, (Cι-C δ) -Alkoxy, (dC ö ^ alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (-C-C 6 ) alkylamino may be substituted,
R >2^ Wasserstoff, (Cι-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Hydroxy, (Cι-C6)-Alkoxy, Mono- oder Di-(d- C6)-alkylamino, gegebenenfalls durch Halogen, Trifluormethyl oder (Cι-C6)-Alkoxy substitiuiertes Phenyl, Biphenyl, Naphtyl, gegebenenfalls durch Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und oder S oder gegebenenfalls durch Hydroxy substituiertes 5- bis 10- gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können,R> 2 ^ hydrogen, (-C-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy, (-C-C 6 ) alkoxy, mono - Or di- (d- C 6 ) alkylamino, optionally substituted by halogen, trifluoromethyl or (-C-C 6 ) alkoxy-substituted phenyl, biphenyl, naphthyl, optionally substituted by halogen 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and or S or optionally substituted by hydroxy substituted 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S can be substituted,
(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und oder S, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Phenyl, Benzyl, Morpholinyl, Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (Cι-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di-(d-C6)-allcylamino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 oder -SO2-R4 bedeutet, worin(C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the N, O and / or S series or 5- or 6-membered heterocyclyl with up to three heteroatoms from the N, O series and or S, where aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by phenyl, benzyl, morpholinyl, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) - Alkoxy, (-C-C6) alkoxycarbonyl or mono- or di- (dC 6 ) -allcylamino can be substituted, or a radical of the formula -C (= O) -R 4 or -SO 2 -R 4 means . wherein
R4 Wasserstoff, (Cι-C6)-Alkyl, das seinerseits durch Hydroxy, Amino, Phenyl, (C6-Cιo)- Aryloxy, (d-C6)-Alkanoyloxy oder (Cι-C4)-Alkoxy substituiert sein kann,R 4 is hydrogen, (-CC 6 ) -alkyl, which in turn can be substituted by hydroxy, amino, phenyl, (C 6 -C -o) aryloxy, (dC 6 ) -alkanoyloxy or (-C-C 4 ) -alkoxy,
(C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, 5- bis 10- gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, gegebenenfalls durch Hydroxy substituiertes (d-C6)- Alkyl, (Cι-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl, Phenyl oder Cyano substituiert sein können,(C6-Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S, in which aryl, heteroaryl and heterocyclyl in turn up to twice, independently of one another, substituted by halogen, optionally substituted by hydroxy (dC 6 ) - alkyl, (-C-C 6 ) - alkoxy, (-C-C 6 ) -alkoxycarbonyl, Phenyl or cyano can be substituted,
(C3-C8)-Cycloalkyl, (Cι-C6)-Alkoxycarbonyl oder einen Rest der Formel -NR5R6 oder -OR7 bedeutet,(C 3 -C 8 ) cycloalkyl, (-C-C 6 ) alkoxycarbonyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
woπnembedded image in which
R und R unabhängig voneinander Wasserstoff, (C6-C1o)-Aryl, Adamantyl, (d-C8)-Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach durch Hydroxy, Phenyl, Trifluormethyl, (C3-C8)-Cycloalkyl,R and R are independently hydrogen, (C 6 -C 1 o) aryl, adamantyl, (DC 8) -alkyl, whose chain may be interrupted by one or two oxygen atoms and up to three times by hydroxyl, phenyl, trifluoromethyl, ( C 3 -C 8 ) cycloalkyl,
(d-C6)- Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Hetero- atomen aus der Reihe N, O und/oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach durch (d-C4)-Alkyl, Hydroxy oder(dC 6 ) - alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10- membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, (C 3 -C 8 ) cycloalkyl, which can be up to triple by (dC 4 ) alkyl, hydroxy or
Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zweiMay be substituted oxo, or 5- or 6-membered heterocyclyl with up to two
Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)-Alkyl substituiert ist, bedeuten,Heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (C 1 -C 4 ) -alkyl,
oderor
1010
R5 und R6 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen gesättigten Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O 15 und/oder S ersetzt sind und der durch Hydroxy, Oxo,R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O 15 and / or S and the through hydroxy, oxo,
Aminocarbonyl, (Cι-C6)-Alkyl oder (Cι-C6)-Alkoxy- (Cι-C6)-alkyl substituiert sein kann,Aminocarbonyl, (-CC 6 ) -alkyl or (-C-C 6 ) -alkoxy- (-C-C 6 ) -alkyl may be substituted,
undand
2020
R7 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durch (Ci-Cβ)- Alkyl, (Cι-C6)-Alkylthio oder Oxo substituiertR 7 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which can be up to two, independently of one another, by (Ci-Cβ) alkyl, (Cι-C 6 ) alkylthio or substituted oxo
25 sein kann,Can be 25
(C6-Cιo)-Aryl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (d-C6)-Alkoxycarbonyl oder Carboxyl substituiertes (Cι-C6)- Alkyl, (d-C^-Alkoxy,(C 6 -Cιo) aryl, which is up to two, independently of one another, optionally substituted by (dC 6 ) alkoxycarbonyl or carboxyl (Cι-C 6 ) alkyl, (dC ^ alkoxy,
30 Di-(Cι-C6)-alkylaminocarbonyl, Mono- oder Di-(Cι-30 di- (-C 6 ) -alkylaminocarbonyl, mono- or di- (Cι-
C6)-alkylamino substituiert sein kann, Adamantyl, Tetrahydronaphtyl, (Ci -Cg)- Alkyl, dessen Kette durch ein oder zwei Sauerstoffatome unterbrochen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluor- mefhyl, (C3-C8)-Cycloalkyl, (Cι-C6)- Alkoxy, Mono- oder Di-(Cι-C6)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann,C 6 ) alkylamino can be substituted, Adamantyl, tetrahydronaphthyl, (Ci -Cg) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C 3 -C 8 ) cycloalkyl, (-C-C 6 ) - alkoxy, mono- or di- (-C-C 6 ) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or by 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S,
(C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (Cι-C4)-Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- bis 10-gliedriges Heterocyclyl mit bis zu zwei(C 3 -C 8 ) Cycloalkyl, which can be substituted up to three times, independently of one another, by (-C 4 ) alkyl, hydroxy or oxo, or 5- to 10-membered heterocyclyl with up to two
Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (Cι-C4)-Alkyl substituiert ist, bedeutet,Heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (-CC 4 ) -alkyl,
oderor
R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 10-gliedrigen gesättigten Heterocyclus mit bis zu zwei weiteren Heteroatomen aus der Reihe N, O und/oder S bedeuten, der gegebenenfalls bis zu zweifach, unabhängig voneinander, durchR 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 10-membered saturated heterocycle with up to two further heteroatoms from the series N, O and / or S, which may be up to two, independently from each other, by
Benzyl oder (C6-Cιo)-Aryl, das seinerseits durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (C C6)-Alkoxy, (d-C6)-Alkoxycarbonyl oder Mono- oder Di-(C C6)- alkylamino substituiert sein kann, substituiert ist, bedeutet, Benzyl or (C 6 -Cιo) aryl, which in turn by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (Cι-C 6 ) alkyl, (CC 6 ) alkoxy, (dC 6 ) alkoxycarbonyl or mono - or di- (CC 6 ) - alkylamino can be substituted, is substituted, means
woπnembedded image in which
R für eine Gruppe der FormelR for a group of the formula
für (C3-C8)-Cycloalkyl, das durch (Cι-C8)-Alkyl, (C6-C10)- Aryl, 5- bis 10-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Heterocyclyl und Heteroaryl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (Cι-C6)- Alkyl, (C3-C8)- Cycloalkyl, (Cι-C6)- Alkoxy, Amino, Mono- oder Di-(Cι-C6)- alkylamino, (d-C6)-Alkoxycarbonyl oder Carboxyl substituiert sein können,for (C 3 -C 8 ) cycloalkyl, which by (-C-C 8 ) alkyl, (C 6 -C 10 ) aryl, 5- to 10-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, where aryl, heterocyclyl and heteroaryl in turn can be substituted up to three times, independently of one another, by halogen, trifluoromethyl, Cyano, nitro, hydroxy, (-C-C 6 ) - alkyl, (C 3 -C 8 ) - cycloalkyl, (Cι-C 6 ) - alkoxy, amino, mono- or di- (Cι-C 6 ) - alkylamino, (dC 6 ) -alkoxycarbonyl or carboxyl can be substituted,
oderor
für eine Methylgruppe steht, die bis zu dreifach, unabhängig voneinander, durchrepresents a methyl group which is up to three times independent of one another
Wasserstoff, Trifluormethyl, (C3-C8)-Cycloalkyl, (Cι-C8)- Alkyl, dessen Kette durch ein Schwefelatom oder eine S(O)- oder SO2-Gruppe unterbrochen sein kann und das bis zu zweifach, unabhängig voneinander, durch Hydroxy, (d-C6)- Alkoxy, (Cι-C6)-Alkoxycarbonyl, Halogen, Cyano, Nitro, Trifluormefhoxy, Oxo, Amino, Mono- oder Di-(Cι-Cö)- alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder Carboxamid substituiert sein kann, (Cι-C6)-Alkoxycarbonyl, (C6-C1o)-Aryl, Benzyl, 5- bis 10-glie- driges Heterocyclyl mit bis zu drei Heteroatomen aus derHydrogen, trifluoromethyl, (C 3 -C 8 ) cycloalkyl, (Cι-C 8 ) - Alkyl, the chain of which can be interrupted by a sulfur atom or an S (O) or SO 2 group and up to twice, independently of one another, by hydroxy, (dC 6 ) alkoxy, (C 1 -C 6 ) alkoxycarbonyl, Halogen, cyano, nitro, trifluoromefhoxy, oxo, amino, mono- or di- (-C-C ö ) - alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S or carboxamide can be substituted, (-CC 6 ) alkoxycarbonyl, (C 6 -C 1 o) aryl, benzyl, 5- to 10-glazed heterocyclyl with up to three heteroatoms from
Reihe N, O und/oder S oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Aryl, Benzyl, Heterocyclyl und Heteroaryl bis zu drei- fach, unabhängig voneinander, durch Halogen, Trifluormethyl,Series N, O and / or S or 5- to 10-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, aryl, benzyl, heterocyclyl and heteroaryl being up to three times independent one another, by halogen, trifluoromethyl,
Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (Cι-C6 Alkyl, (C3-C8)-Cycloalkyl, (d-C6)- Alkoxy, Amino, Mono- oder Di-(d-C6)-alkylamino, (d-C6)- Alkoxycarbonyl, Carboxyl, (Cι-C6)-Alkylcarbonylamino, (d-C6)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oderCyano, nitro, hydroxy, optionally substituted by hydroxy (-CC 6 alkyl, (C 3 -C 8 ) cycloalkyl, (dC 6 ) - alkoxy, amino, mono- or di- (d-C6) alkylamino, ( dC 6 ) - alkoxycarbonyl, carboxyl, (-C-C 6 ) alkylcarbonylamino, (dC 6 ) alkoxycarbonylamino, aminocarbonyl, mono- or
Di-(Cι-C6)-alkylaminocarbonyl, das seinerseits durch (d-C6)- Alkoxy substituiert sein kann, Amidosulfon, Mono- oder Di- (d-C6)-allcylanιidosulfon, das seinerseits durch (Cι-C6)- Alkoxy substituiert sein kann, substituiert sein können,Di- (-C-C 6 ) alkylaminocarbonyl, which in turn can be substituted by (dC 6 ) - alkoxy, amidosulfone, mono- or di- (dC 6 ) -allcylanιidosulfone, which in turn is substituted by (Cι-C 6 ) - alkoxy can be, can be substituted,
R >9y Wasserstoff, (Cι-C6)-Alkoxy, durch (Cι-C6)-Alkyl und/oder Phenyl substituiertes Amino, (d-C6)- Alkyl, (C3-C8)-Cyclo- alkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu dreifach, unab- hängig voneinander, durch Hydroxy oder Mono- oder Di-(Cι-R > 9 y hydrogen, (-CC 6 ) alkoxy, amino substituted by (-C 6 ) -alkyl and / or phenyl, (dC 6 ) - alkyl, (C 3 -C 8 ) -cycloalkyl, alkyl and cycloalkyl in turn up to three times, independently of one another, by hydroxy or mono- or di- (Cι-
C6)-alkylamino substituiert sein können, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6- gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits bis zu dreifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormefhoxy, (d-C6)- Alkyl, (Cι-C6)-Alkoxy, oder Mono- oder Di- (Cι-C6)-alkylamino substituiert sein können,C 6 ) alkylamino can be substituted, (C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to three heteroatoms from the series N, O and / or S means, aryl, heteroaryl and heterocyclyl in turn up to three times, independently of one another, by halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromefhoxy, (dC 6 ) alkyl, (C 1 -C 6 ) alkoxy, or mono- or di- (-C 6 ) alkylamino can be substituted,
oderor
R8 und R9 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 10-gliedrigen, gegebenenfalls bicyclischen Heterocyclus bilden, in dem bis zu zwei Ringkohlenstoffatome durch Heteroatome aus der Reihe N, O und/oder S ersetzt sind und der bis zu vierfach, unabhängig voneinander, durch Hydroxy, (Cι-C6)-Alkyl, (d-C6)-Alkoxy, Hydroxy-(d-C6)- alkyl, (Cι-C6)-Alkoxy-(d-C6)-alkyl, Oxo, Amino oder Mono- oder Di-(C1-C6)-alkylamino substituiert sein kann,R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- to 10-membered, optionally bicyclic heterocycle, in which up to two ring carbon atoms are replaced by heteroatoms from the series N, O and / or S and the up to fourfold, independently of one another, by hydroxy, (-CC 6 ) -alkyl, (dC 6 ) -alkoxy, hydroxy- (dC 6 ) -alkyl, (-C-C 6 ) -alkoxy- (dC 6 ) - alkyl, oxo, amino or mono- or di- (C 1 -C 6 ) alkylamino can be substituted,
R10 Wasserstoff, (d-C6)-Alkoxy, (d-C6)- Alkyl, (C3-C8)-Cyclo- alkyl, wobei Alkyl und Cycloalkyl ihrerseits, unabhängig vonein- ander, bis zu dreifach durch Hydroxy oder Mono- oder Di-(Cι-R 10 is hydrogen, (dC 6) alkoxy, (dC 6) - alkyl, (C 3 -C 8) -cycloalkyl, where alkyl and cycloalkyl for their part, independently of each other, up to three times by hydroxyl or mono- or di- (Cι-
C6)-alkylamino substituiert sein können, (C6-Cιo)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder 5- oder 6- gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Aryl, Heteroaryl und Heterocyclyl ihrerseits, unabhängig voneinander, bis zu dreifach durch Halogen, Hydroxy, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)-Alkyl, (Cι-C6)-Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di- (Cι-C6)-alkylammo substituiert sein können,C6) alkylamino can be substituted, (C 6 -Cιo) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S or 5- or 6-membered heterocyclyl with up to means three heteroatoms from the series N, O and / or S, where aryl, heteroaryl and heterocyclyl in turn, independently of one another, up to three times through halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) -alkyl, (Cι-C 6 ) -alkoxy, (Cι-C 6 ) - Alkoxycarbonyl or mono- or di- (-CC 6 ) alkylammo can be substituted,
R11 einen Rest der Formel -C(=O)-R12 oder -SO2-R12 bedeutet,R 11 represents a radical of the formula -C (= O) -R 12 or -SO 2 -R 12 ,
woπnembedded image in which
R12 Wasserstoff, (Cι-C6)-Alkyl, das semerseits durchR 12 is hydrogen, (-C-C 6 ) alkyl, the semi-side by
Hydroxy oder (Cι-C4)-Alkoxy substituiert sein kann,Hydroxy or (-CC 4 ) alkoxy may be substituted,
(C6-do)-Aryl, 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, worin Aryl und Heteroaryl ihrerseits, unabhängig voneinander, durch Halogen substituiert sein können, (C3-C8)-Cycloalkyl oder einen Rest der Formel -NR13R14 oder -OR15 bedeutet,(C 6 -do) aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, in which aryl and heteroaryl in turn, independently of one another, can be substituted by halogen, (C 3 -C 8 ) -cycloalkyl or a radical of the formula -NR 13 R 14 or -OR 15 ,
worinwherein
R13 und R14 unabhängig voneinander Wasserstoff, (C6- Cιo)-Aryl, Adamantyl, (d-C8)- Alkyl, dessen Kette durch ein oder zwei Sauer- stoffatome unterbrochen sein kann und das bis zu dreifach durch Hydroxy, gegebenenfalls durch Halogen, (Cι-C6)- Alkoxy oder Amino substituiertes Phenyl, Trifluormethyl, (C3-C8)- Cycloalkyl, (Cι-C6)- Alkoxy, Mono- oder Di- (Cι-Cö)-alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10- gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, 5 (C3-C8)-Cycloalkyl, das bis zu dreifach durch (Cι-C4)-Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O 10 und/oder S, wobei N durch Wasserstoff oderR 13 and R 14 independently of one another are hydrogen, (C 6 -Cιo) aryl, adamantyl, (dC 8 ) - alkyl, the chain of which can be interrupted by one or two oxygen atoms and up to three times by hydroxy, optionally by halogen , (-CC 6 ) - alkoxy or amino substituted phenyl, trifluoromethyl, (C 3 -C 8 ) - cycloalkyl, (-C-C 6 ) - alkoxy, mono- or di- (-C-Cö) alkylamino, 5- or 6-membered heterocyclyl with up to three heteroatoms from the Series N, O and / or S or by 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S can be substituted, 5 (C 3 -C 8 ) cycloalkyl, which is up to can be substituted three times by (-CC 4 ) -alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O 10 and / or S, where N is hydrogen or
(d-C4)- Alkyl substituiert ist, bedeuten,(dC 4 ) - alkyl is substituted mean
oderor
15 R13 und R14 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen gesättigten Heterocyclus bilden, der bis zu zwei weitere Heteroatome aus der Reihe N, O und/oder S enthalten kann und gegebenenfalls15 R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which can contain up to two further heteroatoms from the series N, O and / or S and, if appropriate
20 durch Hydroxy, Oxo, (d-C6)-Alkyl oder (d-20 by hydroxy, oxo, (d-C6) -alkyl or (d-
C6)-Alkoxy-(Cι-C6)-alkyl substituiert istC 6 ) -alkoxy- (-C-C 6 ) alkyl is substituted
R15 (C6-Cιo)-Aryl, Adamantyl, (d-C8)- Alkyl, dessen Kette durch ein oder zweiR 15 (C 6 -Cιo) aryl, adamantyl, (dC 8 ) - alkyl, the chain through one or two
25 Sauerstoffatome unterbrochen sein kann und das bis zu dreifach, unabhängig voneinander, durch Hydroxy, Phenyl, Trifluormethyl, (C -C8)- Cycloalkyl, (Cι-C6)-Alkoxy, Mono- oder Di- (d-C6)-alkylamino, 5- oder 6-gliedriges25 oxygen atoms can be interrupted and up to three times, independently of one another, by hydroxy, phenyl, trifluoromethyl, (C -C 8 ) - cycloalkyl, (-C-C 6 ) alkoxy, mono- or di- (dC 6 ) alkylamino , 5- or 6-membered
30 Heterocyclyl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder durch 5- bis 10- gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und oder S substituiert sein kann, (C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (Cι-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder30 heterocyclyl with up to three heteroatoms from the series N, O and / or S or through 5- to 10- membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and or S, (C 3 -C 8 ) cycloalkyl, which can be up to three times, independently of one another, by (C 1 -C 4 ) - alkyl, hydroxy or May be substituted oxo, or 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and / or S, where N is hydrogen or
(Cι-C4)-Alkyl substituiert ist, bedeutet,(-C-C 4 ) alkyl is substituted means
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
Verbindungen der Formel (I) nach Anspruch 1 ,Compounds of formula (I) according to claim 1,
woπnembedded image in which
M eine Gruppe -N(-R!)- oder ein Sauerstoffatom -O- bedeutet,M represents a group -N (-R ! ) - or an oxygen atom -O-,
A eine Gruppe -C(=O)- oder -CH2- oder eine chemische Bindung bedeutet,A represents a group -C (= O) - or -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Hydroxy, Cyano, Carboxy, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C6)-Alkyl, (Cι-C6)-Alkoxy, (Cι-C6)-Alkoxycarbonyl oder Mono- oder Di-(Cι- C6)-alkylamino substituiert sein können,D is 5- or 6-membered heteroarylene with up to three heteroatoms from the series N, O and / or S or phenylene, each up to two, independently of one another, by halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy , (Cι-C6) alkyl, (Cι-C6) alkoxy, (Cι-C6) -alkoxycarbonyl or mono- or di- (Cι- C6) alkylamino can be substituted,
R1 Wasserstoff, Benzyl, (C2-C6)-Alkenyl, (Cι-C6)-Alkyl, wobei Alkyl seinerseits durch (d-C4)-Alkoxy, Phenyl, (C3-C8)-Cyclo- alkyl oder Mono- oder Di-(Cι-C4)-alkylamino substituiert sein kann, Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S bedeutet, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Trifluormethoxy, (Ci- C4)-Alkyl, (d-C4)-Alkoxy, (d-C4)-Alkoxycarbonyl, N-Acetyl,N- methylamino oder Mono- oder Di-(Cι-C )-alkylamino substituiert sein können,R 1 is hydrogen, benzyl, (C 2 -C 6 ) alkenyl, (-C-C 6 ) alkyl, where alkyl in turn can be substituted by (dC 4 ) alkoxy, phenyl, (C 3 -C 8 ) cycloalkyl or mono- or di- (-C 4 ) alkylamino, phenyl or 5- or 6-membered Heteroaryl with up to three heteroatoms from the series N, O and / or S means, phenyl and heteroaryl in turn up to two times, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (Ci-C 4 ) -alkyl, (dC 4 ) -Alkoxy, (dC 4 ) -alkoxycarbonyl, N-acetyl, N-methylamino or mono- or di- (-C-C) alkylamino may be substituted,
R .R.
2^ (d-C6)-Alkyl, (C3-C8)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu zweifach, unabhängig voneinander, durch (d-C4)- Alkoxy, Mono- oder Di-(Cι-C6)- alkylamino, gegebenenfalls durch Halogen, Trifluormethyl oder (d- C6)-Alkoxy substitiuiertes Phenyl, Biphenyl, Naphtyl oder gegebenenfalls durch Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können, Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu drei Hetero- atomen aus der Reihe N, O und/oder S, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Phenyl, Benzyl, Mo holinyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (d-C6)- Alkyl, (Cι-C6)- Alkoxy, (C1-C6)-Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)-alkyl- amino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 oder -SO2-R4 bedeutet,2 ^ (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, where alkyl and cycloalkyl in turn up to twice, independently of one another, by (dC 4 ) alkoxy, mono- or di- (-C-C 6 ) - alkylamino, optionally substituted by halogen, trifluoromethyl or (d- C 6 ) alkoxy-substituted phenyl, biphenyl, naphthyl or optionally substituted by halogen 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S. Can be substituted, phenyl or 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, with aryl and heteroaryl in turn up to two, independently of one another, by phenyl, benzyl, mo holinyl , Halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (dC 6 ) - alkyl, (Cι-C 6 ) - alkoxy, (C 1 -C 6 ) alkoxycarbonyl or mono- or di- (Cι-C 6 ) alkyl - can be amino substituted, or a radical of the formula -C (= O) -R 4 or -SO 2 -R 4 ,
woπnembedded image in which
R4 Wasserstoff, Methyl, Ethyl, die ihrerseits durch Hydroxy, Amino, Phenyl, (C6-Cιo)- Aryloxy, (Cι-C6)-Alkanoyloxy oder (Cι-C )-Alkoxy substituiert sein können,R 4 is hydrogen, methyl, ethyl, which in turn can be substituted by hydroxy, amino, phenyl, (C 6 -Cιo) aryloxy, (Cι-C 6 ) alkanoyloxy or (Cι-C) alkoxy,
Phenyl, 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Hetero- 5 atomen aus der Reihe N, O und/oder S, 5- oder 6-gliedrigesPhenyl, 5- or 6-membered heteroaryl with up to two hetero-atoms from the series N, O and / or S, 5- or 6-membered
Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, worin Phenyl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen,Heterocyclyl with up to two heteroatoms from the series N, O and / or S, in which phenyl, heteroaryl and heterocyclyl in turn up to two times, independently of one another, by halogen,
10 gegebenenfalls durch Hydroxy substituiertes (d-C4)-Alkyl,10 optionally substituted by hydroxy (dC 4 ) alkyl,
(d-C4)-Alkoxy, (Cι-C4)-Alkoxycarbonyl, Phenyl oder Cyano substituiert sein können,(dC 4 ) alkoxy, (-CC 4 ) alkoxycarbonyl, phenyl or cyano may be substituted,
(C3-C8)-Cycloalkyl oder einen Rest der Formel -NR5R6 oder -OR7 bedeutet,Is (C 3 -C 8 ) cycloalkyl or a radical of the formula -NR 5 R 6 or -OR 7 ,
15 woπn15 weeks
R5 und R6 unabhängig voneinander Phenyl oder (Cι-C6)- Alkyl bedeuten, 20 dessen Kette durch ein Sauerstoffatom unterbrochen sein kann und das bis zu zweifach durch Phenyl, Trifluormethyl, (C3-C6)-Cycloalkyl oder (d-C6)- Alkoxy substituiert sein kann,R 5 and R 6 independently of one another are phenyl or (-CC 6 ) - alkyl, 20 the chain of which may be interrupted by an oxygen atom and up to twice by phenyl, trifluoromethyl, (C 3 -C 6 ) -cycloalkyl or (dC 6 ) - alkoxy can be substituted,
25 oder25 or
R5 und R6 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- bis 7-gliedrigen gesättigtenR 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated
Heterocyclus bilden, in dem ein RingkohlenstoffatomForm heterocycle, in which a ring carbon atom
30 durch ein Heteroatom aus der Reihe N, O oder S ersetzt ist und der durch Hydroxy, Oxo, (Cι-C6)- Alkyl oder (Cι-C2)-Alkoxy-(Cι-C2)-alkyl substituiert sein kann,30 replaced by a heteroatom from the series N, O or S. is and which can be substituted by hydroxy, oxo, (C 1 -C 6 ) alkyl or (C 1 -C 2 ) alkoxy- (C 1 -C 2 ) alkyl,
undand
R7 5- oder 6-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durch (Cι-C6)-Alkyl, (C C6)-Alkylfhio oder Oxo substituiert sein kann,R 7 5- or 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which can be up to two, independently of one another, by (-C 6 ) -alkyl, (CC 6 ) -alkylfhio or Oxo may be substituted
(C6-C10)-Aryl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (d-C6)- Alkoxy, Di-(Cι-C6)- alkylaminocarbonyl, Mono- oder Di-(C1-C6)-alkyl- amino substituiert sein kann,(C 6 -C 10 ) aryl, which is up to two, independently of one another, optionally by (dC 6 ) - alkoxy, di- (-C-C 6 ) - alkylaminocarbonyl, mono- or di- (C 1 -C 6 ) alkylamino may be substituted,
Tetrahydronaphtyl, (Cι-C4)-Alkyl, dessen Kette durch ein Sauerstoffatom unterbrochen sein kann und das bis zu zweifach, unabhängig voneinander, durch Phenyl, Trifluormethyl, (C3-C6)- Cycloalkyl oder (Cι-C6)- Alkoxy substituiert sein kann,Tetrahydronaphtyl, (-CC 4 ) alkyl, the chain of which can be interrupted by an oxygen atom and up to two, independently of one another, by phenyl, trifluoromethyl, (C 3 -C 6 ) - cycloalkyl or (-C-C 6 ) - Alkoxy can be substituted,
(C3-C8)-Cycloalkyl, das bis zu dreifach, unabhängig voneinander, durch (d-C4)- Alkyl, Hydroxy oder Oxo substituiert sein kann, oder 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei(C 3 -C 8 ) cycloalkyl, which can be substituted up to three times, independently of one another, by (dC 4 ) - alkyl, hydroxy or oxo, or 5- or 6-membered heterocyclyl with up to two
Heteroatomen aus der Reihe N, O und/oder S, wobei N durch Wasserstoff oder (d-C4)-Alkyl substituiert ist, bedeutet,Heteroatoms from the series N, O and / or S, where N is substituted by hydrogen or (dC 4 ) -alkyl,
oder R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten Heterocyclus mit bis zu einem weiteren Heteroatomen aus der Reihe N, O oder S bedeuten, der gegebenenfalls bis zu zweifach, unabhängig voneinander, durch Benzyl oder Phenyl, das seinerseits durch Halogen, Hydroxy, Cyano,or R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- or 6-membered saturated heterocycle with up to one further hetero atom from the series N, O or S, which may optionally be up to two, independently of one another, by benzyl or phenyl, which in turn is halogen, hydroxy, cyano,
Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C4)-Alkyl, (d-C4)- Alkoxy, (Cι-C4)-Alkoxycarbonyl oder Mono- oder Di-(Cι-C6)- methylamino substituiert sein kann, substituiert ist,Nitro, trifluoromethyl, trifluoromethoxy, (-C 4 -C) alkyl, (dC 4 ) - alkoxy, (-C 4 -C) alkoxycarbonyl or mono- or di- (-C 6 ) - methylamino may be substituted .
Rj eine Gruppe bedeutet, R j represents a group
woπnembedded image in which
R )» für eine Gruppe der FormelR) »for a group of the formula
ür (C3-C5)-Cycloalkyl, das durch Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, (d-C6)- Alkyl, (C3-C6)-Cycloalkyl, (Cι-C6)- Alkoxy, Amino, Mono- oder Di-(Cι-C )-alkylamino, substituiert sein können, oderfor (C 3 -C 5 ) cycloalkyl, which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn up to two times, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, (dC 6 ) - alkyl, (C 3 -C 6 ) -cycloalkyl, (Cι-C 6 ) - alkoxy, amino, mono- or di- (Cι- C) alkylamino, may be substituted, or
für eine Methylgruppe steht,represents a methyl group,
die durch Wasserstoff, durch Trifluormethyl, (C3-C6)-Cycloalkyl oder (Cι-C4)-Alkyl, das seinerseits durch Hydroxy, (d-C4)-Alkoxy, Halogen, Cyano, Trifluormethoxy, Amino, Mono- oder Di-(Cι-C4)- alkylamino, 5- oder 6-gliedriges Heterocyclyl mit bis zu zweiby hydrogen, by trifluoromethyl, (C 3 -C 6 ) cycloalkyl or (Cι-C 4 ) alkyl, which in turn by hydroxy, (dC 4 ) alkoxy, halogen, cyano, trifluoromethoxy, amino, mono- or di - (-C-C 4 ) - alkylamino, 5- or 6-membered heterocyclyl with up to two
Heteroatomen aus der Reihe N, O und/oder S oder Carboxamid substituiert sein kann, und durch (C6-Cιo)-Aryl oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert ist, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (d-C4)-Alkyl, (C3-C6)-Cycloalkyl, (Cι-C4)- Alkoxy, Amino, Mono- oder Di-(d-C4)-alkylamino, (d-C )-Heteroatoms from the series N, O and / or S or carboxamide can be substituted, and by (C 6 -Cιo) aryl or 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S is substituted, aryl and heteroaryl in turn up to twice, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy (dC 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, (Cι- C 4 ) - alkoxy, amino, mono- or di- (dC 4 ) alkylamino, (dC) -
Alkoxycarbonyl, Carboxyl, (d-C4)-Alkylcarbonyl-ιmino, (d-C4)-Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(Cι-C4)-alkylaminocarbonyl, Amidosulfon, Mono- oder Di- (Cι-C )-alkylamidosulfon substituiert sein können,Alkoxycarbonyl, carboxyl, (dC 4 ) -alkylcarbonyl-imino, (dC 4 ) -alkoxycarbonylamino, aminocarbonyl, mono- or di- (-C-C 4 ) -alkylaminocarbonyl, amidosulfone, mono- or di- (Cι-C) -alkylamidosulfone can be substituted
R >9y Wasserstoff oder durch (Cι-C2)-Alkyl und Phenyl substituiertes Amino bedeutet,R > 9 y is hydrogen or amino substituted by (-C 2 ) alkyl and phenyl,
R10 Wasserstoff bedeutet,R 10 means hydrogen,
R11 einen Rest der Formel -C(=O)-R12 bedeutet, woπnR 11 represents a radical of the formula -C (= O) -R 12 , embedded image in which
R12 einen Rest der Formel -NR13R14 bedeutet,R 12 represents a radical of the formula -NR 13 R 14 ,
worinwherein
R13 Wasserstoffbedeutet,R 13 means hydrogen,
R14 für eine Methylgruppe steht, die durch Wasserstoff,R 14 represents a methyl group which is formed by hydrogen,
Methyl oder Ethyl und durch Phenyl substituiert ist, das seinerseits durch Halogen, (Cι-C4)- Alkoxy oder Amino substituiert sein kann,Methyl or ethyl and substituted by phenyl, which in turn can be substituted by halogen, (-CC 4 ) - alkoxy or amino,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
3. Verbindungen der Formel (I) nach Anspruch 1 ,3. Compounds of formula (I) according to claim 1,
woπnembedded image in which
M eine Gruppe -N(-R!)- oder ein Sauerstoffatom -O- bedeutet,M represents a group -N (-R ! ) - or an oxygen atom -O-,
A eine Gruppe -CH2- oder eine chemische Bindung bedeutet,A represents a group -CH 2 - or a chemical bond,
D 5- oder 6-gliedriges Heteroarylen mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S oder Phenylen bedeutet, die jeweils bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Trifluormethoxy, (d-C4)-Alkyl oder (d-C )- Alkoxy substituiert sein können, R1 Wasserstoff, Phenyl,(C2-C4)-Alkenyl oder (Cι-C4)-Alkyl bedeutet, wobei Alkylsemerseits durch Methoxy, (C3-C6)-Cycloalkyl oder Mono- oder Di-methylamino substituiert sein kann,D is 5- or 6-membered heteroarylene with up to two heteroatoms from the series N, O and / or S or phenylene, each up to two, independently of one another, by halogen, trifluoromethyl, trifluoromethoxy, (dC 4 ) -alkyl or (dC) - alkoxy can be substituted, R 1 is hydrogen, phenyl, (C 2 -C 4) -alkenyl or (Cι-C 4) -alkyl, it being possible Alkylsemerseits by methoxy, (C 3 -C 6) -cycloalkyl or mono- or di-substituted methylamino,
R2 (d-C4)-Alkyl, (C3-C6)-Cycloalkyl, wobei Alkyl und Cycloalkyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Methoxy, Mono- oder Di-methylamino, gegebenenfalls durch Halogen, Trifluormethyl oder Methoxy substitiuiertes Phenyl, Biphenyl, Naphtyl oder gegebenenfalls durchR 2 (dC 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, where alkyl and cycloalkyl in turn up to two times, independently of one another, by methoxy, mono- or dimethylamino, optionally substituted by halogen, trifluoromethyl or methoxy-phenyl , Biphenyl, naphthyl or optionally by
Halogen substituiertes 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S substituiert sein können, Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, wobei Aryl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (Cι-C4)-Alkyl, (Cι-C4)-Alkoxy oder Mono- oder Di- methylamino substituiert sein können, oder einen Rest der Formel -C(=O)-R4 bedeutet,Halogen-substituted 5- or 6-membered heteroaryl can be substituted with up to two heteroatoms from the series N, O and / or S, phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, wherein aryl and heteroaryl in turn up to twice, independently of one another, by halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-C-C 4 ) -alkyl, (C-C 4 ) -alkoxy or mono- or dimethylamino may be substituted, or denotes a radical of the formula -C (= O) -R 4 ,
woπnembedded image in which
R4 Methyl, das seinerseits durch Phenyl, Phenyloxy oder (d-C2)-Alkoxy substituiert sein kann,R 4 is methyl, which in turn can be substituted by phenyl, phenyloxy or (dC 2 ) alkoxy,
Phenyl, 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und oder S, 5- oder 6-gliedriges Heterocyclyl mit bis zu zwei Heteroatomen aus der Reihe N, O und oder S, worin Phenyl, Heteroaryl und Heterocyclyl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Methoxy oder (Cι-C )-Alkoxycarbonyl substituiert sein können, (C3-C )-Cycloalkyl oder einen Rest der Formel -OR7 bedeutet,Phenyl, 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and or S, 5- or 6-membered heterocyclyl with up to two heteroatoms from the series N, O and or or S, in which phenyl, heteroaryl and heterocyclyl in turn can be substituted up to twice, independently of one another, by halogen, methoxy or (-CC) alkoxycarbonyl, (C 3 -C) -cycloalkyl or a radical of the formula -OR 7 ,
woπnembedded image in which
R 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S, das bis zu zweifach, unabhängig voneinander, durchR 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, which is up to two, independently of one another
(d-C4)-Alkyl oder Methylthio substituiert sein kann, Phenyl, das bis zu zweifach, unabhängig voneinander, durch gegebenenfalls durch (Cι-C4)-Alkoxy, Dimefhylamino- carbonyl oder Mono- oder Di-methylamino substituiert sein kann, oder Tetrahydronaphtyl bedeutet,(dC 4 ) -Alkyl or methylthio can be substituted, phenyl, which can be substituted up to twice, independently of one another, optionally by (-C-C 4 ) -alkoxy, dimefhylamino-carbonyl or mono- or dimethylamino, or tetrahydronaphtyl means
eine Gruppe bedeutet, a group means
woπnembedded image in which
R für (C3-C5)-Cycloalkyl, das durch Phenyl oder 5- oder 6-gliedriges Heteroaryl mit bis zu zwei Heteroatomen aus der Reihe N, O und/oder S substituiert sein kann, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch (Cι-C )-Alkyl oder (Cι-C4)- Alkoxy, substituiert sein können, oderR is (C 3 -C 5 ) cycloalkyl, which can be substituted by phenyl or 5- or 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn up to two times , independently of one another, can be substituted by (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy, or
für eine Methylgruppe steht,represents a methyl group,
die durch Wasserstoff, durch (d-C3)- Alkyl, das seinerseits durch Hydroxy, (Cι-C2)- Alkoxy, Amino oder Mono- oder Di-(Cι-C )-alkylamino substituiert sein kann, und durch Phenyl oder 5- bis 10-gliedriges Heteroaryl mit bis zu drei Heteroatomen aus der Reihe N, O und/oder S substituiert ist, wobei Phenyl und Heteroaryl ihrerseits bis zu zweifach, unabhängig voneinander, durch Halogen, Trifluormethyl, Cyano, Nitro, Hydroxy, gegebenenfalls durch Hydroxy substituiertes (Cι-C2)-Alkyl, (C3-C6)-Cycloalkyl, (Cι-C4)-which can be substituted by hydrogen, by (dC 3 ) - alkyl, which in turn can be substituted by hydroxy, (Cι-C 2 ) alkoxy, amino or mono- or di- (Cι-C) alkylamino, and by phenyl or 5- up to 10-membered heteroaryl is substituted with up to three heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn being substituted up to twice, independently of one another, by halogen, trifluoromethyl, cyano, nitro, hydroxy, optionally substituted by hydroxy (-C-C 2 ) alkyl, (C 3 -C 6 ) cycloalkyl, (Cι-C 4 ) -
Alkoxy, Amino, Mono- oder Di-(C1-C4)-alkylamino, (d-C4)- Alkoxycarbonyl, (Cι-C4)-Alkylcarbonylamino, (Cι-C4)- Alkoxycarbonylamino, Aminocarbonyl, Mono- oder Di-(d~ C4)-alkylaminocarbonyl, Amidosulfon, Mono- oder Di-(d- C4)-alkylamidosulfon substituiert sein können,Alkoxy, amino, mono- or di- (C 1 -C 4 ) alkylamino, (dC 4 ) - alkoxycarbonyl, (Cι-C 4 ) alkylcarbonylamino, (Cι-C 4 ) - alkoxycarbonylamino, aminocarbonyl, mono- or di - (d ~ C 4 ) alkylaminocarbonyl, amidosulfone, mono- or di- (d- C 4 ) alkylamidosulfone can be substituted,
R9 Wasserstoff bedeutet,R 9 represents hydrogen,
und ihre Salze, Hydrate, Hydrate der Salze und Solvate.and their salts, hydrates, hydrates of the salts and solvates.
4. Verfahren zur Herstellung der Verbindungen der Formel (I), wie in Anspruch 1 definiert, dadurch gekennzeichnet, dass man entweder4. A process for the preparation of the compounds of formula (I) as defined in claim 1, characterized in that either
[A] Verbindungen der Formel (V) [A] Compounds of Formula (V)
in welchen A, D, M und R die in Anspruch 1 angegebenen Bedeutungen haben,in which A, D, M and R have the meanings given in claim 1,
mit Verbindungen der Formel (VI)with compounds of the formula (VI)
in welchen R8 und R9 die in Anspruch 1 angegebenen Bedeutungen haben,in which R 8 and R 9 have the meanings given in Claim 1,
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base und/oder eines Kondensationsmittels umsetztin a solvent, optionally in the presence of a base and / or a condensing agent
oderor
[B] Nerbindungen der Formel (VII)[B] compounds of the formula (VII)
in welchen A, D, M und R2 die in Anspruch 1 angegebenen Bedeutungen haben, nacheinander in beliebiger Reihenfolge mit den Nerbindungen der Formel (NIHa) und (NHIb)in which A, D, M and R 2 have the meanings given in Claim 1, successively in any order with the Nerbindungen of the formula (NIHa) and (NHIb)
R10-W (Viπa) Rn-W' (VHIb),R 10 -W (Viπa) R n -W '(VHIb),
in welchen R10 und R11 die in Anspruch 1 angegebenen Bedeutungen haben und W und W' für geeignete Abgangsgruppen wie beispielsweise Halogen, vorzugsweise Chlor oder Brom, stehen,in which R 10 and R 11 have the meanings given in Claim 1 and W and W 'represent suitable leaving groups such as, for example, halogen, preferably chlorine or bromine,
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, umsetztin a solvent, optionally in the presence of a base
oderor
[C] Verbindungen der Formel (Ia)[C] Compounds of Formula (Ia)
in welchen A, D, M, R2 und R17 die in Anspruch 1 angegebenen Bedeutungen haben,in which A, D, M, R 2 and R 17 have the meanings given in Claim 1,
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Verbindungen der Formel (VHIb)in a solvent, optionally in the presence of a base, with compounds of the formula (VHIb)
Rπ-W' (VHIb),R π -W '(VHIb),
in welchen R11 und W' die in Anspruch 1 angegebenen Bedeutungen haben, umsetztin which R 11 and W 'have the meanings given in Claim 1, implements
oderor
[D] Verbindungen der Formel (XII)[D] Compounds of Formula (XII)
in welchen D, R1, R8 und R9 die in Anspruch 1 angegebenen Bedeutungen haben,in which D, R 1 , R 8 and R 9 have the meanings given in claim 1,
entweder mit einem Phosgenäquivalent wie beispielsweise Trichlormethyl- chlorformiat in einem Lösungsmittel und anschließend in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Verbindungen der Formel (XIII)either with a phosgene equivalent such as trichloromethyl chloroformate in a solvent and then in a solvent, optionally in the presence of a base, with compounds of the formula (XIII)
in welchen R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben,in which R 5 and R 6 have the meanings given in claim 1,
oderor
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Verbindungen der Formel (XIV) in a solvent, optionally in the presence of a base, with compounds of the formula (XIV)
in welchenin which
X für eine Abgangsgruppe wie beispielsweise das entsprechende symmetrische Anhydrid oder ein Halogen, vorzugsweise Chlor, steht undX represents a leaving group such as the corresponding symmetrical anhydride or a halogen, preferably chlorine, and
R4 die in Anspruch 1 angegebene Bedeutung mit Ausnahme von NR5R6 hat,R 4 has the meaning given in claim 1 with the exception of NR 5 R 6 ,
oderor
in einem Lösungsmittel, gegebenenfalls in Gegenwart einer Base, mit Nerbin- düngen der Formel (XN)in a solvent, optionally in the presence of a base, with Nerbin fertilizers of the formula (XN)
O PO P
(XV), γ"s (XV), γ " s
in welchenin which
Y für eine Abgangsgruppe wie beispielsweise ein Halogen, vorzugsweise Chlor, steht undY represents a leaving group such as a halogen, preferably chlorine, and
R4 die oben angegebene Bedeutung hat,R 4 has the meaning given above,
oderor
[E] Nerbindungen der Formel (XX) [E] compounds of formula (XX)
in welchen D, R und R die m Anspruch 1 angegebenen Bedeutungen haben,in which D, R and R have the meanings given in claim 1,
nach Abspaltung der Methylschutzgruppe mit Nerbindungen der Formel (TTTb)after splitting off the methyl protective group with Nerbindungen of the formula (TTTb)
R2_y (Ulb),R 2 _y (Ulb),
in welchen R2 und V die in Anspruch 1 angegebenen Bedeutungen haben,in which R 2 and V have the meanings given in claim 1,
umsetzt.implements.
5. Verbindungen der Formel (I), wie in Anspruch 1 definiert, zur Bekämpfung von Erl ankungen.5. Compounds of formula (I), as defined in claim 1, for combating Erl restrictions.
6. Arzneimittel, enthaltend mindestens eine Verbindung der Formel (I), wie in Anspruch 1 definiert, und mindestens einen weiteren Wirkstoff.6. Medicament containing at least one compound of formula (I) as defined in claim 1 and at least one further active ingredient.
7. Arzneimittel, enthaltend mindestens eine Verbindung der Formel (I), wie in Anspruch 1 definiert, und mindestens einen weiteren Hilfsstoff.7. Medicament containing at least one compound of formula (I) as defined in claim 1 and at least one further auxiliary.
8. Verwendung von Verbindungen der Formel (I), wie in Anspruch 1 definiert, zur Herstellung von Arzneimitteln zur Prävention und/oder Behandlung von kardiovaskulären Erkrankungen. 8. Use of compounds of formula (I), as defined in claim 1, for the manufacture of medicaments for the prevention and / or treatment of cardiovascular diseases.
9. Nerwendung von Nerbindungen der Formel (I), wie in Anspruch 1 definiert, zur Herstellung von Arzneimitteln zur Prävention und/oder Behandlung von Erkrankungen des Urogenitaltraktes.9. Use of compounds of the formula (I) as defined in claim 1 for the manufacture of medicaments for the prevention and / or treatment of diseases of the genitourinary tract.
i 10. Nerwendung von Nerbindungen der Formel (I), wie in Anspruch 1 definiert, zur Herstellung von Arzneimitteln zur Prävention und/oder Behandlung von cerebrovaskulären Erkrankungen. 10. Use of compounds of the formula (I) as defined in claim 1 for the manufacture of medicaments for the prevention and / or treatment of cerebrovascular diseases.
EP01994647A 2000-11-24 2001-11-12 Substituted cyclohexane derivates and the use thereof in medicaments for treating cardiovascular diseases Withdrawn EP1339670A1 (en)

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