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WO2005085221A1 - Composes de cetoamides beta a action antagoniste et medicaments comprenant ledit compose - Google Patents

Composes de cetoamides beta a action antagoniste et medicaments comprenant ledit compose Download PDF

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Publication number
WO2005085221A1
WO2005085221A1 PCT/EP2005/002132 EP2005002132W WO2005085221A1 WO 2005085221 A1 WO2005085221 A1 WO 2005085221A1 EP 2005002132 W EP2005002132 W EP 2005002132W WO 2005085221 A1 WO2005085221 A1 WO 2005085221A1
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Prior art keywords
alkyl
group
amino
cycloalkyl
phenyl
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PCT/EP2005/002132
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German (de)
English (en)
Inventor
Gerald-Juergen Roth
Philipp Lustenberger
Marcus Schindler
Leo Thomas
Dirk Stenkamp
Stephan Georg Mueller
Thorsten Lehmann-Lintz
Marco Santagostino
Ralf Richard Hermann Lotz
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to CA002552907A priority Critical patent/CA2552907A1/fr
Priority to EP05715624A priority patent/EP1730130A1/fr
Priority to JP2007501195A priority patent/JP2007527424A/ja
Publication of WO2005085221A1 publication Critical patent/WO2005085221A1/fr

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
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Definitions

  • the present invention relates to novel /? - Ketoamid compounds, their physiologically acceptable salts and their use as MCH antagonists and their use for the manufacture of a medicament, which for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or be in a different causal relationship with MCH.
  • Another object of this invention relates to the use of a compound according to the invention for influencing the eating behavior as well as for reducing the body weight and / or for preventing an increase in the body weight of a mammal.
  • compositions and pharmaceutical compositions, each containing a compound of the invention, as well as processes for their preparation are the subject of this invention. Further objects of this invention relate to processes for the preparation of the compounds according to the invention.
  • the term obesity refers to an excess of adipose tissue in the body.
  • obesity is basically considered to be any elevated level of body fat, leading to a health risk.
  • BMI body mass index
  • the individuals having a body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared are above the value of 25, especially above 30, as being obese considered suffering.
  • MCH antagonists inter alia WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • MCH-1 R G ⁇ s -coupled MCH-1 R in rodents [3-6], since in contrast to primates, ferrets and dogs, no second MCH receptor has been detected in rodents.
  • Loss of the MCH-1 R leads to lower fat mass, an increased level, in "knock out” mice Energy expenditure and in high-fat diet no weight increase compared to control animals.
  • Another indication of the importance of the MCH system in the regulation of the energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term experiments, the animals treated with this antagonist lose significant weight.
  • the MCH-1 R antagonist SNAP-7941 provides further anxiolytic and antidepressant effects in behavioral experiments with rats [3].
  • the MCH-MCH-1 R system is involved not only in the regulation of the energy balance but also the affectivity.
  • WO 01/82925 also compounds of the formula in which Ar 1 is a cyclic group, X and Y spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R 1 and R 2 are independently H or a hydrocarbon group, wherein R 1 and R 2 together with the adjacent N Atom can form an N-containing heterocyclic ring and R 2 together with the adjacent N-atom and Y can form an N-containing hetero ring, described as MCH antagonists for the treatment of, inter alia, obesity.
  • an object of the present invention to provide novel medicaments suitable for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • Further objects of the present invention relate to the demonstration of advantageous uses of the compounds of the invention.
  • It is also an object of this invention to provide a process for preparing the amide compounds of the present invention.
  • Other objects of the present invention will become apparent to those skilled in the art directly from the foregoing and following embodiments. Subject of the invention
  • a first object of the present invention are? -Ketoamide compounds of general formula I.
  • R 1, R 2 are independently H, an optionally mono- or with the radical R 11 multiply substituted C ⁇ alkyl or C. 3 7 -Cycloalkyl group, wherein a -CH 2 - group in position 3 or 4 of a 5, 6 or 7-membered Cydoalkyl distr by -O-, -S- or -NR 13 - may be replaced, or optionally with the remainder R 20 mono- or polysubstituted and / or nitro-substituted phenyl or pyridinyl, or
  • R 3 H C ⁇ . 6- alkyl, C 3 . 7 -cycloalkyl, C 3 . 7 -cycloalkyl-C M -alkyl- or phenyl-C ⁇ -alkyl,
  • Z is a single bond or -CR 7a R 7b -CR 7c R 7d -,
  • Y is one of the meanings given for Cy, where R 1 is Y, including the group X and the N-atom joined to R 1 and X, to form a heterocyclic group fused to Y. and / or wherein X may be linked to Y to form a carbamoyl or heterocyclic group fused to Y, and
  • b is the value 0 or 1, -
  • Cy is a carbo or heterocyclic group selected from one of the following meanings. - a saturated 3- to 7-membered carbocyclic group, - a unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group an N, O or S atom as a heteroatom, a saturated or unsaturated 5- to 7-membered heterocyclic group having two or more N atoms or having one or two N atoms and an O or S atom as Heteroatoms, - an aromatic heterocyclic 5- or 6-membered group having one or more identical or different heteroatoms selected from N, O and / or S, wherein the above-mentioned 4-, 5-, 6- or 7-membered groups on two common adjacent carbon atoms may be fused to a phenyl or pyridine ring, and wherein in the aforementioned 5, 6 or 7 membere
  • R 4 is one of the meanings given for R 17 , C 3 . 6 alkenyl or C 3 . 6- alkynyl,
  • R 5a , R 5b are independently H, C 1-4 alkyl, C 3 . 7 -cycloalkyl, C 3 - 7 -cycloalkyl-C. 3 -alkyl, CF 3 , F or Cl, where R 5a and R 5b in the meaning of alkyl can be linked together in such a way that, together with the carbon atom to which R 5a and R 5b are bonded, a C 3 . 7- cycloalkyl group is formed,
  • R 7a , R 7c independently of one another are H, F, Cl, C 1-4 -alkyl or CF 3 ,
  • R 7b , R 7d independently H, F, C ⁇ . 4- alkyl, C 3 . Cycloalkyl, C 3-7 -CycIoalkyl-C. 1 3 - alkyl or CF 3 , where R 7a and R 7b, in the meaning of alkyl, can be linked to one another in such a way that they are bound by the CC - AAttoomm, which are bonded to RR 7a and R 7b , a C 3 . 7 cycloalkyl group is formed, wherein R may be connected 7c and R 7d in the meaning alkyl in such a manner that, together with the carbon atom, are bonded to the R 7d and R 7c, C 3 and / or.
  • R 7 cycloalkyl group is formed, or wherein R 7b, and R 7d, may be connected in the meaning of alkyl each other such that together with the two carbon atoms are bonded to the R 7d and 7b, R, C. 3 7 -cycloalkyl group is formed;
  • R 10 is hydroxy, hydroxy-C 1-4 -alkyl, C 1-4 -alkoxy, (C 1 -alkoxy) -C 1 . 3- alkyl, carboxy, C ⁇ - alkoxycarbonyl, amino, C ⁇ -alkyl-amino, di- (C 1 ⁇ -alkyl) -amino, cyclo-C 3 . 6 -alkylenimino, amino-C 1 .
  • R 11 is C 1-3 -alkyl, C 2 . 6 alkenyl, C 2 . 6- alkynyl, R 15 -O-, R 15 -Od. 3 -alkyl-, R 15 -O-CO-, R 15 -CO-O-, cyano, R 16 R 7 N-, R 18 R 19 N-CO- or cy-,
  • R 3 is one of the meanings given for R 17 ,
  • R 14 halogen, d. 6- alkyl, C 2 . 6 alkenyl, C 2 . 6- alkynyl, R 15 -O-, R 5 -O-CO-, R 15 -CO-, R 15 -CO-O-, R 16 R 17 N-, R 18 R 19 N-CO-, R 15 -od.
  • R 15 is H, C 1-4 -alkyl, C 3 . 7 -cycloalkyl, C 3 . 7 -cycloalkyl-d. 3 -alkyl, phenyl, phenyl-C 1 . 3- alkyl, pyridinyl or pyridinyl-d .. 3- alkyl,
  • R 16 H d. 6- alkyl, C 3 . 7- cycloalkyl, C 3 - cycloo [kyl-d. 3- alkyl, C 4 . 7 cycloalkenyl, C 4 . 7 - cycloalkenyl-d. 3 -alkyl-, hydroxy-C 2 . 3 -alkyl-, C ⁇ ⁇ -Alkoxy-C 2 . 3- alkyl, amino-C 2 . 6 -alkyl, C ⁇ . 4- alkyl-amino-C 2 _ 6 -alkyl-, di- (C M -alkyl) -amino-C 2 . 6 -alkyl- or cyclo-C 3 . 6 -alkylenimino-C 2 . 6- alkyl,
  • R 17 is one of the meanings given for R 16 or phenyl, phenyl-d. 3 alkyl, pyridinyl, dioxolan-2-yl, d ⁇ alkylcarbonyl, hydroxy-carbonyl-3 C ⁇ _ alkyl, C ⁇ alkoxycarbonyl, C ⁇ _ -AIkoxycarbonyl 4-C. 1 3 alkyl, d_ 4 alkylcarbonylamino-C. 2 3- alkyl-, N- (C 1 -alkylcarbonyl) -N- (C 1 -alkyl) -amino-C 2 . 3- alkyl- : d ⁇ -alkylsulfonyl, d.
  • R 18 , R 19 are independently H or d. 6- alkyl
  • R 20 is halogen, hydroxy, cyano, C- ,. 6 -alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3-7 cycloalkyl, C. 3 7 - cycloalkyl-d. 3- alkyl, hydroxy-d ⁇ -alkyl, R 22 -d. 3- alkyl or one of the meanings given for R 22 ,
  • R 21 C ⁇ _ 4 alkyl, hydroxy-C 2 . 3- alkyl, C ⁇ alkoxy-C ⁇ e-alkyl, C M alkyl-amino-C 2 . 6 alkyl, di (d ⁇ -alky amino-de-alkyl, cyclo-C 3. 6 -alkylenimino-C 2. 6 alkyl, phenyl-d. 3 alkyl, Cp 4 alkyl carbonyl, C ⁇ alkoxy-carbonyl or d. 4 alkylsulfonyl, R 22 is phenyl-d. 3 -alkoxy, cyclo-C 3 .
  • the H atom of an existing carboxy group or an H atom bound to an N atom can each be replaced by an in-vivo leaving group
  • the compounds of the present invention have particular activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies.
  • the compounds of the invention have a high to very high selectivity with respect to the MCH receptor.
  • the compounds according to the invention have a low toxicity, a good oral absorbability and intracerebral transitivity, in particular brain clearance.
  • the invention also relates to the respective compounds in the form of the individual optical isomers, mixtures of the individual diastereomers, enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
  • the compounds of the invention including their salts, in which one or more hydrogen atoms are replaced by deuterium.
  • physiologically acceptable salts of the above-described and hereinafter described? -Ketoamide compounds are also an object of this invention.
  • compositions comprising at least one inventive? -Ketoamide compound and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • medicaments containing at least one .alpha.-ketoamide compound and / or an inventive salt in addition to optionally one or more inert carriers and / or diluents are the subject of the present invention.
  • an object of this invention is the use of at least one ⁇ -ketoamide compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • an object of the present invention is the use of at least one /? - ketoamide compound and / or a salt according to the invention for the production of a medicament with MCH receptor antagonistic activity, in particular with MCH-1 receptor antagonistic activity.
  • an object of this invention is the use of at least one ketoamide compound according to the invention and / or a salt according to the invention for the manufacture of a medicament, which for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or with MCH in another causal relationship is appropriate.
  • Another object of this invention is the use of at least one inventive? -Ketoamide compound and / or a salt according to the invention for the manufacture of a medicament, which for the prophylaxis and / or treatment of metabolic disorders and / or eating disorders, in particular obesity, bulimia, bulimia nervosa , Cachexia, anorexia, anorexia nervosa and hyperphagia.
  • an object of this invention is the use of at least one .alpha.-ketoamide compound and / or a salt according to the invention for the preparation of a medicament which is particularly suitable for the prophylaxis and / or treatment of obesity-related diseases and / or disorders, in particular diabetes Type II diabetes, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • diabetes Type II diabetes diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, especially arteriosclerosis and hypertension, arthritis and gonitis.
  • the present invention has the use of at least one ketoamide compound according to the invention and / or a salt according to the invention for the manufacture of a medicament which is used for the prophylaxis and / or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders , Depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders is the subject.
  • a further subject matter of this invention is the use of at least one .alpha.-ketoamide compound and / or a salt according to the invention for the manufacture of a medicament which is used for the prophylaxis and / or treatment of voiding disorders, such as urinary incontinence, overactive bladder, urinary urgency, nocturia and enuresis, suitable is.
  • the present invention relates to the use of at least one ketoamide compound according to the invention and / or a salt according to the invention for the production of a medicament which is suitable for the prophylaxis and / or treatment of dependencies and / or withdrawal symptoms.
  • an object of this invention relates to processes for the preparation of a medicament according to the invention, characterized in that at least one inventive /? - Ketoamide compound and / or a salt according to the invention is incorporated into one or more inert carriers and / or diluents non-chemically ,
  • a further subject of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient selected from the ⁇ -ketoamide compounds and / or the corresponding salts according to the invention and a second active ingredient selected from the group consisting of active ingredients for the treatment of diabetes , Drugs for the treatment of diabetic complications, drugs for the treatment of obesity, preferably other than MCH antagonists, drugs for the treatment of hypertension, drugs for the treatment of Dyslipidemia or Hyperlipidemia, including arteriosclerosis, drugs for the treatment of arthritis, drugs for the treatment of anxiety and drugs for the treatment of depression, besides optionally one or more inert carriers and / or diluents.
  • an object of this invention is a process for the preparation of? -Ketoamide compounds of the formula I.
  • A, B, b, R 5a and R 5b have the meanings given above, and the radical M OH, Cl, d. 6- alkoxy, d. 6- alkylthio or d. 6 alkyl COO means
  • Another object of this invention relates to a process for the preparation of ß-ketoamide compounds of the formula I.
  • radicals and / or substituents in a compound may each have the same or different meanings given.
  • R 5b is an H atom
  • the following compounds are included, wherein the formula I (keto) indicates the keto form and the formula I (enol) the corresponding enol form:
  • keto form is explicitly indicated; the corresponding enol form which can be readily derived by the person skilled in the art is included according to the invention in each individual case.
  • R 5a , R 5b are each independently H, F, Cl, CF 3 , methyl, ethyl, in particular H, F, methyl, ethyl, particularly preferably H, F, methyl.
  • R 5a and R 5 are connected in is methyl another such that bound 5b together with the carbon atom to which R 5a and R, a cyclopropyl group is formed.
  • R 5a , R 5b are H.
  • R 3 are H, C 1-4 alkyl, C 3 . 6 -cycloalkyl or C 3 . 6 -cycloalkyl-d. 3 -alkyl; in particular H or d. 3- alkyl.
  • R 3 particularly preferably denotes H or methyl, in particular H.
  • the substituents R 1 and R 2 may have a meaning as defined above and below as separate radicals or as a bridge connected to one another.
  • the preferred meanings of R 1 and R 2 are described below as separate radicals and then the preferred meanings of interconnected, bridging radicals R 1 and R 2 .
  • Preferred compounds according to the invention therefore have one of the preferred meanings of R 1 and R 2 described below as separate radicals combined with one of the preferred meanings of R 1 and R 2 described below as interconnected radicals forming a bridge.
  • R 1 and R 2 are not linked to one another via an alkylene bridge, then R 1 and R 2, independently of one another, preferably represent an optionally monosubstituted or polysubstituted with the radical R 1 . 8 alkyl or C 3 . 7 -Cycloalkyl group, wherein a -CH 2 group in position 3 or 4 of a 5, 6 or 7-membered Cydoalkyl distr by -O-, -S- or -NR 13 - may be replaced, or optionally with the rest R 20 mono- or polysubstituted and / or nitro single substituted phenyl or pyridinyl, and wherein one of the radicals R 1 and R 2 may also be H.
  • one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another with Cl, Br or CN.
  • Preferred meanings of the radical R 11 are d. 3- alkyl, C 2 . 6 alkenyl, C 2 . 6- alkynyl, R 5 -O-, cyano, R 16 R 17 N-, C 3 . 7 -cycloalkyl, cyclo-C 3 .
  • R 11 is one of the meanings R 15 -O-, cyano, R 16 R 17 N- or Cydo-C 3 . 6 -alkylenimino-, preferably the R 11 substituted C atom of the alkyl or cycloalkyl group is not directly connected to a heteroatom, such as the group -NX- connected.
  • the radicals R 1, R 2 are independently H, d_ 6 alkyl, C 3rd 5 alkenyl, C 3 . 5- alkynyl, C 3 . 7 -cycloalkyl, hydroxy-C 3 . 7 cycloalkyl, C 3 _ 7 cycloalkyl-3 C ⁇ _ alkyl, (hydroxy-C 3 H 7 -, cycloalkyl) -C- ⁇ _ 3 -alkyl, hydroxy-C ⁇ alkyl-, NC-C 2.
  • the C ⁇ alkyl may bridges in the meanings hydroxy-C. 2 4- alkyl and Ci. 4 -alkoxy-C M -alkyl- additionally be simply substituted with hydroxy, hydroxy-d_ 3 -alkyl, d_ 3 alkyl or C ⁇ - alkoxy, in particular hydroxy, hydroxymethyl, methyl or methoxy.
  • Preferred substituents of the abovementioned phenyl or pyridyl radicals are selected from the group F, Cl, Br, I, cyano, C, M- alkyl, C 1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, d. 3 alkylamino, di (C 1.
  • radicals R 1 and / or R 2 are selected from the group consisting of H, C- ,. 6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-d_ 3 alkyl,
  • 3- alkyloxy especially hydroxy, hydroxymethyl, methyl and methoxy may be substituted, and wherein C ⁇ alkyl bridges in the meanings hydroxy-C ⁇ -alkyl and C ⁇ alkoxy-C ⁇ -alkyl- additionally simple with hydroxy, Hydroxide. 3 -alkyl, d.
  • 3- alkyl or C ⁇ alkyloxy, in particular hydroxy, hydroxymethyl, methyl or methoxy may be substituted, and wherein alkyl groups may be mono- or polysubstituted by F and / or simply substituted with Cl.
  • radicals R 1 and / or R 2 are selected from the group consisting of H, C- M- alkyl, C 3 . 5 alkenyl, C 3 . 5- alkynyl, C 3 . 7 -cycloalkyl, C 3 . 7 - cycloalkyl-d. 3 -alkyl-, C- ⁇ ⁇ -alkoxy-C 2 .
  • alkyl, cycloalkyl or Cycldalkylalkyl may be mono- or disubstituted by hydroxy, mono- or polysubstituted by F or simply Br, Cl or CN, and wherein one of the radicals R 1 and R 2 can also mean H
  • R 1 and / or R 2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, propen-3-yl, propyne-3 yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl, phenylmethyl, Pyridylmethy ⁇ , tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, piperidin-4-yl, N- (C ⁇ ⁇ alkyl ) -piperidin-4-yl, piperidin-4-yl-methyl, N- (C 1 -C 4) -alkyl) -piperidin-4-yl-methyl, where the said ethyl,
  • radicals R 1 and / or R 2 are methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2- methyl-propyl, 2-methoxyethyl, 3-aminopropyl, propen-3-yl, propyn-3-yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl , Pyridylmethyl, tetrahydropyran-4-yl, N-methyl-piperidin-4-yl, N- (methylcarbonyl) -piperidin-4-yl and N- (tert-butyloxycarbonyl) -piperidin-4-yl, with hydroxyalkyl groups in
  • the substituent R 1 has one of the meanings given above as preferred, but not H
  • the substituent R 2 very particularly preferably denotes H, methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl or 2-methoxyethyl.
  • At least one of the radicals R, R 2 has a meaning other than H.
  • one or more H atoms may be replaced by R 14 , and
  • R 13 is preferably H, d. 6 alkyl, C ⁇ alkylcarbonyl or d ⁇ alkyloxycarbonyl. More preferably R 13 is H or d- ⁇ -alkyl, in particular H, methyl, ethyl or propyl.
  • R and R 2 form such an alkylene bridge that R 1 R 2 N- is a group selected from azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1 H-pyrrole, 1, 2,3,6 Tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6J-tetrahydro-1H-azepine, piperazine, in which the free imine function is substituted with R 13 , piperidine-4 on, morpholine and thiomorpholine means
  • one or more H atoms may be replaced by R 14 , and / or the abovementioned groups in a manner given by the general definition of R 1 and R 2 with one or two identical or different carbo- or heterocyclic groups Cy may be substituted.
  • Particularly preferred groups Cy are phenyl, C 3 . 7 -cycloalkyl, aza-C 4 . 7 -cycloalkyl-, in particular phenyl, C 3 . 6 -cycloalkyl, cyclo-C 3 . 5 -alkylenimino-, and NC 1 ⁇ alkyl- (C aza-4. 6 - cycloalkyl) -, where the cyclic groups Cy may be substituted as indicated.
  • the C formed by R 1 and R 2. 2 The 8- alkylene bridge in which -CH 2 groups may be replaced as indicated may be substituted as described with one or two identical or different carbo- or heterocyclic groups Cy, which may be substituted as defined above.
  • Cy is preferably selected from the group consisting of C 3 . 7 -cycloalkyl, cyclo-C 3 " 6 -alky] enimino, piperazinyl, 1 H-imidazole, thienyl and phenyl, in particular C 3 . 6 - cycloalkyl, pyrrolidinyl, piperidinyl and piperazinyl, which may be substituted as indicated, in particular wherein the N atoms may each be substituted by C- M- alkyl.
  • Cy is preferably selected from the group consisting of C 3 . 7 -cycloalkyl, aza-C 4 . 8 -cycloalky-, oxa-C 4 . 8 - cycloalkyl, 2,3-dihydro-1H-quinazolin-4-one, in particular cyclopentyl and cyclohexyl, the may be substituted as indicated, in particular wherein the N atoms in each case with C -, ⁇ - may be substituted alkyl.
  • Cy is preferably selected from the group consisting of C 4 to C 7 cycloalkyl, aza -C 4 . 7 -cycloalky-, phenyl, thienyl, in particular phenyl and pyrrolidinyl, which may be substituted as indicated, in particular wherein the N atoms may each be substituted by C- M - alkyl.
  • Cy is preferably C 4 . 8 -cycloalkyl or aza-C. 8 -cycloalkyl.
  • the group has a meaning according to one of the following sub-formulas
  • H atoms of the heterocycle formed by the group R 1 R 2 N- by R 14 and / or an H atom by Cy in the meaning C 3 . 7 -cycloalkyl which is mono- or polysubstituted with R 20 , in particular with F, hydroxy, d. Alkyl, CF 3 , d. 3 alkyloxy, OCF 3 or Hydroxy-C ⁇ _3-alkyl may be substituted, and wherein the ring connected to the heterocycle formed by the group R 1 R 2 N- one or more times at one or more C atoms with R 20 , in the case of a phenyl Rings can also be substituted in addition simply with Nitro and
  • 3 -alkyl) - or -O- can mean, wherein in the above for X ', X" meanings each a C Atom with R 10 , preferably with a hydroxy, ⁇ -hydroxy-C ⁇ _ 3 -alkyl, ⁇ - (C 1 ⁇ alkoxy) - d_ 3 alkyl and / or C ⁇ alkoxy radical, and / or one or two carbon atoms, each having one or two identical or different substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 . 7 cycloalkyl-C ,.
  • C 4 7 -.. cycloalkenyl, and C 4 7 cycloalkenyl can be substituted C ⁇ 3 alkyl, wherein two alkyl and / or alkenyl substituents forming a carbocyclic ring system.
  • X ', X "independently of one another in each case one or more C atoms one or more times with F and / or each one or two C atoms independently of one another may be substituted by Cl or Br, and
  • R 2 , R 10 , R 13 , R 14 , R 18 , R 20 , R 21 and X are those given above and below
  • X ', X means "are each independently a single bond or d_ 3 - alkylene and in the event that the group Y via a carbon atom where X' or X" is connected, also -d 3 alkylene-O-.
  • X also denotes -NH-, -N (D- 3- alkyl) - or -O-.
  • X ", X" independently of one another denote a single bond or methylene and in the case that the group Y is connected to X 'or X "via a C atom, also -CH 2 -O-, -CH 2 - NH- or -CH 2 -N (d 3 -alkyl) -, and in the case that the group Y is connected to X "via a C atom, X” also denotes -NH-, -N (C-) ⁇ _ 3 - alkyl) - or -O-.
  • R 14 the following definitions of the substituent R 14 are preferred: F, Cl, Br, d 1-4 -alkyl, C 2 . -Alkenyl, C 2 - 4 alkynyl, Cs ⁇ -cycloalkyl-C ⁇ s-alkyl, hydroxy, hydroxy-C ⁇ _ 3 -alkyl, C ⁇ alkoxy, ⁇ - (-C-4-alkoxy) -C 1 . 3- alkyl, C 1-4 alkyl-carbonyl, carboxy, d.
  • one or more C atoms may or may not be present repeatedly with F and / or one or two C atoms independently be substituted with Cl or Br, in particular alkyl radicals may be monosubstituted or polysubstituted by fluorine.
  • Very particularly preferred meanings of the substituent R 14 are F, Cl, C ⁇ alkyl, C 3 _ 6 cycloalkyl-C ⁇ .. 3 alkyl, hydroxy, hydroxy-3 C ⁇ _ alkyl, d. Alkoxy, C ⁇ . 4- alkoxy-C. 3 -alkyl, amino-C ⁇ . 3- alkyl, C 3 . 7 -cycloalkyl-amino-C. 3 alkyl, N- (C 3 7 -. Cycloalkyl) -N- (C 1 ⁇ .- alkyl) amino-C 1. 3 alkyl, di (C 1. 4, alkyl) amino-C. 1 3 -alkyl, cyclo-C 3 .
  • R 14 Alkylenimino-C- ⁇ . 3 -alkyl, aminocarbonyl and pyridylamino.
  • R 14 may be a "barren more C atoms, in particular alkyl radicals mono- or polysubstituted with fluorine.
  • preferred meanings of R 14 include, for example, -CF 3 and -OCF 3 .
  • Cy are C 3 . 6 -cycloalkyl and 1-hydroxy-C 3 . 5 -cycloalkyl.
  • the group has a meaning according to one of the following sub-formulas
  • R 14 are each independently F, Cl, C ⁇ alkyl, de-cycloalkyl-d-alkyl, hydroxy, hydroxy-d_ 3 alkyl, d ⁇ alkyloxy, C M alkoxy-ds-alkyl, pyridylamino or aminocarbonyl in each case one or more C atoms, in particular alkyl radicals may be additionally mono- or polysubstituted by F; most preferably methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methyl-ethyl, 1-hydroxycyclopropyl, methoxy, ethoxy, methoxymethyl, pyridylamino or aminocarbonyl; and
  • R is as defined above, in particular H or C ⁇ _ 3 alkyl.
  • R 4 may be linked together with Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group
  • a -CH 2 group immediately adjacent to the group R 1 R 2 N- is not denoted by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 - replaced.
  • group X one or two -CH 2 groups are independently replaced by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 -, these are Preferably, groups are spaced from the group R 1 R 2 N- by an alkylene bridge having at least 2 C atoms.
  • two -CH 2 groups are independently replaced by -O-, -S-, - (SO) -, - (SO 2 ) -, -CO- or -NR 4 -, these groups are preferred separated by an alkylene bridge with at least 2 C atoms.
  • this -CH 2 group is preferably not directly linked to a heteroatom, a double bond or a triple bond.
  • the alkylene bridge X, X 'or X has no or at most one imino group
  • the position of the imino group within the alkylene bridge X, X' or X" is preferably chosen such that together with the amino group NR 1 R 2 or another adjacent amino group no aminal function is formed or two N atoms are not directly connected.
  • X is an unbranched d ⁇ -alkylene bridge
  • R 4 may be linked together with Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group, and wherein in X is a C atom with R 10 and / or one or two C atoms each having one or two identical or different substituents selected from d. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 - alkynyl, C 3 . 7 -cycloalkyl, C 3 . 7 -cycloalkyl-C- ,. 3- alkyl, C 4 . 7 cycloalkenyl and C 4 . 7 cycloalkenyl d. 3 alkyl, in particular d_ 4 alkyl, may be substituted, wherein two alkyl and / or alkenyl substituents may be joined together to form a carbocydischen ring system, and
  • one or more C atoms may be mono- or polysubstituted with F and / or one or two C atoms independently of one another and may be substituted simply by Cl or Br, and
  • R 1 , R 4 and R 10 are as defined above and below.
  • -CH 2 -CH CH-, -CH 2 -C ⁇ C-, -CH 2 -CH 2 -O -, CH 2 -CH 2 -CH 2 -O- or
  • R 4 may be linked together with Y to form a heterocyclic ring system
  • bridge X may be connected to R 1 including the N atom connected to R 1 and X to form a heterocyclic group
  • X is a C atom with R 10 , preferably a hydroxy, ⁇ -hydroxy-d. 3 alkyl, ⁇ - (C 1. 4 alkoxy) -d. 3 -alkyl and / or C-alkoxy radical, and / or one or two C atoms independently of one another each with one or two identical or different may be substituted, wherein two alkyl radicals may be connected together to form a carbocyclic ring system, and
  • the group Y is connected to X via a C atom (the group Y), -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, CH 2 -CH 2 -O-, -CH 2 -CH 2 - CH 2 -O-, -CH 2 -CH 2 -NR 4 - or -CH 2 -CH 2 -CH 2 -NR 4 -, which may be unsubstituted or substituted as indicated.
  • R 4 has one of the meanings given for R 17 , preferably one of R 16 .
  • R 4 Particularly preferred meanings of the substituent R 4 are H, C ⁇ " 6 alkyl and C 3 . 6 - Alkenyl. Most preferably, R 4 is H, methyl or ethyl. If R 4 is linked to Y to form a heterocyclic ring system, particularly preferred meanings of R 4 are C 2 . 6- alkyl and C 2 . 6- alkenyl.
  • Y preferably has the meaning phenyl and R 4 preferably has the meaning C 2 . 6- alkyl or C 2 . 6- alkenyl.
  • Heterocyclic ring systems which are preferably formed here are indole, dihydroindole, quinoline, dihydroquinoline, tetrahydroquinoline and benzoxazole.
  • the radical R 4 preferably has the meaning vinyl only if R 4 is bonded to Y to form a heterocyclic ring system.
  • the substituent R 10 is preferably hydroxy, ⁇ -hydroxy-d_3-alkyl, d. Alkoxy or ⁇ - (C 1-4 alkoxy) -C. 3 -alkyl, especially hydroxy, hydroxymethyl or methoxy.
  • the group X preferably has no carbonyl group.
  • substituents are selected from the group consisting of d ⁇ - ⁇ lkyl-, C2 ⁇ alkenyl, C ⁇ 2 alkynyl, C 3. 7, cycloalkyl , C 3 7 cycloalkyl-C ⁇ 3 -... (. C 1 -C 4 alkoxy) alkyl, hydroxy, ⁇ -hydroxy-C ⁇ -C3 alkyl, -C 1 alkyl ⁇ - 3 and d ⁇ .
  • one C atom may be monosubstituted and / or disubstituted by one C atom and / or one or two C atoms, preferred substituents being selected from the group consisting of C 1 -C 4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 3 .
  • Very particularly preferred substituents of one or two C atoms in X, X 'or X are selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, where two alkyl substituents on a C atom also form a Carbocyclic ring can be connected to each other.
  • one or more carbon atoms can additionally be mono- or polysubstituted by F and / or in each case one or two C atoms, independently of one another, may additionally be monosubstituted by Cl or Br.
  • Y denotes a fused bicyclic ring system
  • a preferred meaning of the group X is -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -, in particular -CH 2 - or -CH 2 -CH 2 -, which may be substituted as indicated.
  • the group Y preferably has a meaning selected from the group of bivalent cyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl , Chromen-4-onyl, thienyl, benzothienyl, pyrimidinyl or benzofuranyl, wherein the aforementioned cyclic groups one or more times to one or more carbon atoms with R 20 , in the case of a phenyl ring also additionally simply with nitro, and / or one or more N atoms may be substituted with R 21 .
  • R 1 may
  • the bridges X and Z are preferably connected in para-position with the group Y.
  • Y has one of the following meanings
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , in the case of a phenyl ring also additionally being monosubstituted by nitro, and / or one or more NH groups by R 21 .
  • the group Y meaning phenyl may be linked to the group X to form a carbo or heterocyclic group fused to Y.
  • preferred meanings of the interconnected groups -XY- are selected from the list consisting of
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , in the case of a phenyl ring additionally also simply with nitro.
  • the group Y is preferably unsubstituted or monosubstituted or disubstituted.
  • substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, d " 4- alkyl, C 2 . 6 alkenyl, hydroxy, hydroxy-d. 3 -alkyl, d. 4 -alkoxy, trifluoromethyl, trifluoromethoxy, C 2 .
  • Very particularly preferred substituents R 20 of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, d. 3- alkyl, C ⁇ _ 3 -alkoxy, d. 4 - alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, amino, in the case of a phenyl ring also nitro.
  • the group Y represents substituted phenylene Partial formula in which L 1 is one of the previously for R 2 0
  • the bridge Z represents a single bond or -CR 7a R 7b -CR 7c R 7d - wherein R 7a, R 7b, R 7c, R 7d independently preferably H, F, CH 3 or CF mean. 3
  • bridge Z is selected from:
  • bridge Z is a single bond and -CH 2 -CH 2 - Most preferably, Z is a single bond.
  • a preferred meaning of group A is aryl or heteroaryl.
  • the group A is selected from the group of cyclic groups phenyl, pyridinyl or naphthyl, which may be mono- or polysubstituted to one or more C atoms with R 20 , in the case of a phenyl ring also additionally simply with nitro.
  • the group A is preferably monosubstituted, disubstituted or trisubstituted. If b has the value 1, the group A is preferably unsubstituted or monosubstituted or disubstituted. If b has the value 1 and the group A is monosubstituted, then the substituent is preferably in the ortho position relative to the ⁇ -ketoamide group.
  • A is one of the groups listed below
  • substituents R 20 of group A are selected from the group consisting of fluorine, chlorine, bromine, cyano, C ⁇ -alkyl, C 2 . 6 alkenyl, hydroxy, hydroxy -C. 3 -alkyl, d. 4 -alkoxy, trifluoromethyl, trifluoromethoxy, C 2 . 4 alkynyl, carboxy, d- 4 alkoxycarbonyl, d ⁇ alkoxy-d- 3- alkyl, C ⁇ alkoxy-carbonylamino, amino, C lJr alkylamino , di (C 1 ⁇ -alkyl ) -amino-, cyclo-C 3 . 6 -alkylenimino-, aminocarbonyl, -C. 4 alkyl-amino-carbonyl and di- (C 1. 4 alkyl) amino-carbonyl.
  • R 20 of the group A are selected from the group consisting of fluorine, chlorine, bromine, cyano, d ⁇ alkyl, C M alkoxy, trifluoromethyl, trifluoromethoxy, carboxy, C ⁇ alkoxycarbonyl, C ⁇ alkyl amino and di (C 1 -C 4 alkyl) amino
  • L 2 has one of the meanings given for R 20 or H, preferably F, Cl, Br, I, CH 3 , CF 3 , OCH 3 , OCF 3 , CN or NO 2 ,
  • L 3 has one of the meanings given for R 20 or H, preferably F, Cl, Br, I, CF 3 , OCF 3 , CN, NO 2 , d ⁇ alkyl, C 3 . 7 -cycloalkyl, C 3 . 7 -cycloalkyl-d. 3 -alkyl, C ⁇ _ 4 -alkoxy, C 3 . 7 -cycloalkyl-O-, C 3 . 7 -cycloalkyl-d .. 3 -alkoxy, -COO-C ⁇ -alkyl or -COOH; particularly preferably F, Cl, Br, d. 4- alkyl, CF 3 , methoxy, OCF 3 , CN or NO 2 ; most preferably Cl, Br, CF 3 or NO 2 ;
  • q has the value 0, 1 or 2.
  • A is particularly preferably substituted phenyl according to the above sub-formula in which q is 1 or 2 and / or at least one substituent L 2 is in the meta position to the substituent L 3 .
  • substituent L 3 is Cl, methoxy and CF 3 .
  • the group A is preferably unsubstituted or substituted with L 2 phenyl, wherein L 2 is preferably in the ortho position to the? -Ketoamid- group.
  • L 2 has the meanings given above.
  • b has the value 1
  • a preferred meaning of the group B is aryl or heteroaryl, which may be substituted as indicated.
  • group B are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl. Most preferably, the group B is phenyl.
  • the group B in the meanings given may be monosubstituted or polysubstituted by R 20 , a phenyl group may additionally also be monosubstituted by nitro.
  • the group B is unsubstituted or mono-, di- or trisubstituted, in particular unsubstituted or monosubstituted or disubstituted. In the case of a single substitution, the substituent is preferably in ortho or para position, in particular para position to group A.
  • Preferred substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, d ⁇ -alkyl, hydroxy, hydroxy-C. 3 -alkyl, C- M alkoxy, trifluoromethyl, trifluoromethoxy, C 2 . 4 alkynyl, carboxy, d ⁇ alkoxycarbonyl, C ⁇ alkoxy C ⁇ - 3 alkyl, d ⁇ alkoxy-carbonylamino, amino, d .. amino-4 alkyl, di- (C 1 4- alkyl) amino, cyclo-C 3 . 6 -alkylenimino, aminocarbonyl, C ⁇ ⁇ alkyl-amino-carbonyl and di- (C M -alkyl) - amino-carbonyl-.
  • substituents R 20 of group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF 3 , C 1-4 alkyl, d. 4- alkoxy, trifluoromethoxy and nitro; in particular fluorine, chlorine, bromine, methoxy, CF 3 and trifluoromethoxy.
  • Very particularly preferred substituents R 20 of group B are selected from the group consisting of chlorine and methoxy.
  • R 13 preferably has one of the meanings given for R 16 . More preferably, R 13 is H, C 1-4 alkyl, C 3 . -Cycloalkyl, C 3 . 7 -cycloalkyl-d_ 3 -alkyl-, ⁇ -hydroxy-C 2 . 3- alkyl, ⁇ - (C 1 ⁇ alkoxy) -C 2 . 3 -alkyl. Most preferably, R 13 is H or The above-mentioned alkyl groups may be monosubstituted by Cl or mono- or polysubstituted by F.
  • R 15 are H, C 3 . 7 -cycloalkyl, C 3 . 7 - cycloalkyl-d. 3 -alkyl-, where, as defined above, in each case one or more C atoms additionally mono- or polysubstituted with F and / or in each case one or two C atoms independently may additionally be additionally substituted simply with Cl or Br. More preferably R 15 is H, methyl, ethyl, propyl or butyl.
  • the substituent R 16 is preferably H, C 1-4 alkyl, C 3 . 7 -cycloalkyl, C 3 . 7 -Cydoalkyl -C ⁇ _ 3 - alkyl, ⁇ -hydroxy-C 2 " 3 -alkyl- or ⁇ - (C 1. 4 -alkoxy) -C 2 - 3 -alkyl-, where, as defined above, in each case one or several C atoms additionally one or more times with F and / or in each case one or two C-atoms independently of each other additionally simply with Cl or Br can be substituted. More preferably R 16 is H, d. 3- alkyl, C 3 . 6 -cycloalkyl or C 3 .
  • R 17 preferably has one of the meanings given for R 16 as being preferred or denotes phenyl, phenyl-d. 3 -alkyl, pyridinyl or d. 4- alkylcarbonyl. R 17 particularly preferably has one of the meanings given for R 16 as being preferred.
  • the substituent R 20 is preferably halogen, hydroxy, cyano, d. 4- alkyl, C 2 -
  • R 20 are halogen, hydroxy, cyano, d ⁇ - alkyl, C 3 . 7 -cycloalkyl and d ⁇ alkoxy, where, as defined above, in each case one or more C atoms additionally mono- or polysubstituted with F and / or in each case one or two C-atoms independently can additionally be additionally substituted simply with Cl or Br , Most preferably R 20 is F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, iso-propoxy, Methoxycarbonyl, ethoxycarbonyl or amino.
  • the substituent R 22 is preferably d. Alkoxy, C 1-4 alkylthio, carboxy,
  • Preferred meanings of the group R 21 are C ⁇ "4 alkyl, alkylcarbonyl, d_ 4 - alkylsulfonyl, -SO 2 -NH 2, -SO 2 -NH-d. 3 alkyl, -SO 2 -N (d. 3 alkyl) 2 and cyclo-C 3. 6 - alkylenimino-sulfonyl-, where, as defined above, in each case one or more C atoms may additionally be mono- or polysubstituted with F and / or in each case one or two C atoms independently additionally simply substituted with Cl or Br.
  • R 21 are H, d ⁇ alkyl, d ⁇ alkylcarbonyl, C - - alkoxycarbonyl, in particular H and C- ⁇ . 3- alkyl.
  • Cy is preferably a C 3 . 7 -cycloalkyl, in particular a C 3 . 6- cycloalkyl group, a C 5 . 7 -Cycloalkenyi group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, a phenyl ring on which a C 5 . 7 -cycloalkyl- or aza-C 4 .
  • aryl or heteroaryl is preferably a monocyclic or fused bicydisches ring system, and wherein the aforementioned cyclic groups one or more times to one or more C atoms with R 20 , in the case of Phenyl group may additionally be additionally substituted with nitro, and / or one or more NH groups with R 21 .
  • aryl is preferably phenyl or naphthyl, in particular phenyl.
  • heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.
  • cyclic groups may be monosubstituted or polysubstituted by one or more C atoms with R 20 , and in the case of a phenyl ring may additionally be additionally substituted by nitro, and / or
  • Phenyl or pyridyl which may be mono- or polysubstituted by R 20 , and additionally in addition simply with nitro
  • / or B is phenyl which may be monosubstituted or polysubstituted by R 20 , and additionally simply by nitro, and / or
  • b has the value 0 or 1.
  • L 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 5a , R 5b and R 20 have the meanings given above and multiply occurring substituents may have the same or different meanings; in particular
  • R 1 , R 2 are independently H, C ⁇ . 6- alkyl, C 3 . Cycloalkyl, C 3 _ 7 cycloalkyl-d_ 3 alkyl, tetrahydropyran-3 or -4-yl, tetrahydropyranyl-d ..
  • R 1 , R 2 are independently methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl, 2-hydroxy- ⁇ ropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 2-methoxyethyl, 3-amino propyl, propen-3-yl, propyn-3-yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, (1-hydroxycyclopropyl) methyl, phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N- Methyl-piperidin-4-yl, N
  • R 3 is preferably H or methyl
  • R 14 are each independently of one another F, Cl, d-alkyl, C 3 . 6 -cycloalkyl-C ⁇ _ 3 -alkyl-, hydroxy, hydroxy-d. 3- alkyl, d ⁇ -Alkyloxy, C ⁇ _ 4 -alkoxy-C ⁇ .
  • R 13 is H, C 1-4 alkyl, C 1-4 alkylcarbonyl or C 1-4 alkyloxycarbonyl; particularly preferably H or d ⁇ -alkyl;
  • Q is CH or N, in particular CH, where CH may be substituted by R 20 ,
  • L 1 , L 2 , L 3 each independently of one another has one of the meanings given above for R 20 , preferably fluorine, chlorine, bromine, cyano, d. 3- alkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy or nitro,
  • p has the value 0 or 1
  • r, s are each independently 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1, and
  • Z is a single bond or -CH 2 -CH 2 -, more preferably a single bond means
  • R 5a , R 5 independently of one another are H, F, Cl, methyl or ethyl, particularly preferably H, R 2 0 each independently preferably fluorine, chlorine, bromine, cyano, C ⁇ - alkyl, C 2 . 6 alkenyl, hydroxy, hydroxy-d. 3- alkyl, C ⁇ alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ alkynyl, carboxy, C-alkoxycarbonyl, C ⁇ alkoxy C ⁇ . 3- alkyl, C ⁇ alkoxy-carbonylamino, amino, C M alkylamino, di (C ⁇ alkyl) amino, cyclo C 3 .
  • R 20 is selected from fluorine, chlorine, bromine, cyano, nitro , d. 4- alkyl, hydroxy, ⁇ -hydroxy-d. 3- alkyl, C ⁇ alkoxy, trifluoromethyl, trifluoromethoxy, C ⁇ alkynyl, carboxy, C ⁇ alkoxycarbonyl and C ⁇ alkoxy C- ⁇ . 3 -alkyl.
  • halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.
  • C ⁇ . n- alkyl wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 1 to n carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
  • C 1 . n -Alkylen where n can have a value of 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge having 1 to n carbon atoms.
  • groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), 1-methyl-ethylene (-CH (CH 3 ) -CH 2 -), 1, 1-dimethyl-ethylene (- C (CH 3 ) 2 -CH 2 -), n -prop-1, 3-ylene (-CH 2 -CH 2 - CH 2 -), 1-methylprop-1, 3-ylene (-CH (CH 3 ) -CH 2 -CH 2 -), 2-methylprop-1, 3-ylene (-CH 2 -CH (CH 3 ) -CH 2 -), etc., as well as the corresponding mirror-image forms.
  • groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
  • C 2 The term C 2 .
  • n- alkynyl wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and a C ⁇ C triple bond.
  • groups include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
  • C,. n- alkoxy denotes a d. n- alkyl-O-group, in which C ⁇ . n- alkyl is as defined above.
  • groups include methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- Hexoxy, iso-hexoxy etc.
  • n -Alkylthio denotes a C ⁇ . n-alkyl-S-group wherein n d_ alkyl is as defined above.
  • groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, tert-pentylthio, n-butylthio Hexylthio, iso-hexylthio, etc.
  • groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso -propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-butyl Hexylcarbonyl, iso-hexylcarbonyl, etc.
  • n- Cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group having 3 to n C atoms.
  • groups include cydopropyl, cydobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc.
  • C 5 . n -Cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group having 5 to n carbon atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
  • aryl refers to a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.
  • a particularly preferred meaning of "aryl” is phenyl.
  • cyclo-C 3 . 7 -alkyleneimino- refers to a 4- to 7-membered ring having from 3 to 7 methylene units and an imino group, the bond to the rest of the molecule being via the imino group.
  • cyclo-C 3 . 7 -alkylenimino-carbonyl denotes a previously defined, .Cyclo-C 3 . 7 - Alkylenimino ring which is connected via the imino group with a carbonyl group.
  • heteroaryl used in this application denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, comprises one or more heteroatoms selected from N, O and / or S. Examples of such groups are
  • heteroaryl also encompasses the partially hydrogenated heterocyclic aromatic ring systems, in particular the ring systems listed above.
  • partially hydrogenated heterocycles are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
  • Heteroaryl particularly preferably denotes a heteroaromatic mono- or bicydic ring system.
  • the H atom of an existing carboxy group or an H atom bound to an N atom (imino or amino group) can each be replaced by a residue which can be split off in vivo.
  • a cleavable by a N-atom in vivo radical is understood to mean, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C t e alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C ⁇ _ 16 alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, Pentoxycarbonyl-, hexyloxycarbonyl, octyloxycarbonyl
  • Phenylpropoxycarbonyl group a C 1 . 3- alkylsulfonyl-C 2 _ -alkoxycarbonyl, -C. Alkoxy C 2 . -alkoxy-C 2 - alkoxycarbonyl or R e CO-O- (R f CR g ) -O-CO- group in which R e a d. 8 alkyl, C 5 . 7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,
  • R f is a hydrogen atom, a C
  • R g represents a hydrogen atom, a C 1-4 alkyl or R e CO-O- (R f CR g ) -O- group, in which R e to R g are defined as mentioned above,
  • the phthalimido group is contemplated, wherein the above-mentioned ester groups can also be used as in vivo into a carboxy group convertible group.
  • radicals and substituents described above may be mono- or polysubstituted by fluorine in the manner described.
  • Preferred fluorinated alkyl radicals are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy radicals are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.
  • the compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, e.g.
  • Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid)
  • pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethy
  • the compounds according to the invention can be obtained using synthesis methods known in principle.
  • the compounds are preferably obtained in analogous application to the production process explained in more detail below, which also form the subject of this invention.
  • the abbreviations used below are defined in the introduction to the experimental part or are familiar to the person skilled in the art as such.
  • radicals R 1 , R 2 , R 3 , X, Y, Z, A or B with amine functions these are preferably in protected form, for example, with a Boc, Fmoc or Cbz protecting group used and released at the end of the reactions according to standard methods.
  • compounds of the formula I according to the invention are prepared by reacting an amine of the formula A1 with a carboxylic acid or a carboxylic acid derivative of the formula A2 using amide derivatives known to the person skilled in the art.
  • the radical M preferably has a meaning selected from OH, Cl, d. 6- alkoxy, -C. 6- alkylthio, C ⁇ . 6- alkyl-COO-, etc.
  • the peptide coupling reagent such as TBTU, is used advantageously in equimolar amounts or in excess, preferably equimolar to 50 mol%, excess relative to the carboxylic acid A2.
  • the reaction can also be carried out in the presence of an equimolar amount of HOBt to the TBTU.
  • carboxylic acid and the corresponding activated carboxylic acid derivatives, such as esters, ortho-esters, carboxylic acid chlorides or anhydrides, are used.
  • Suitable bases are especially tertiary amines such as triethylamine or Hünigbase and alkali metal carbonates, such as potassium carbonate.
  • the reactions are carried out in a suitable solvent or solvent mixture, preference being given to using DMF and / or THF.
  • the carboxylic acid or the carboxylic acid derivative (A2) and the amine (A1) are preferably used in a molar ratio of 1, 5: 1 to 1: 1.5.
  • the reaction is advantageously carried out in a period of 1 to 24 hours in a temperature range from 0 ° C to 120 ° C, preferably from 20 ° C to 80 ° C.
  • the mixed anhydride of the respective carboxylic acid A2 is preferably prepared by reaction of the carboxylic acid with an excess of alkyl chloroformate, preferably isopropyl chloroformate, in a molar ratio of 1: 1 to 1: 1.2.
  • the bases used are preferably tertiary amines, for example N-methylmorpholine, which are used in equimolar amounts to the respective alkyl chloroformate.
  • the reaction is carried out in a suitable solvent such as THF at temperatures between -20 ° C and 20 ° C, in particular from -15 to 0 ° C, and takes place in a period of 10 to 2400 minutes.
  • a suitable solvent such as THF
  • the mixed anhydride thus obtained is preferably "reacted without further purification with an amine compound (A1).
  • the amine compound (A1) is in excess of the respective carboxylic acid derivative (A2), preferably 5-10 mol% excess, is used.
  • the reaction is carried out, for example, at 0 ° C to 60 ° C in a period of 1 to 4 hours.
  • compounds of the formula I according to the invention are obtained by hydrolysis of the triple bond of the propionic acid amide of the formula B1.
  • the hydrolysis of the propionic acid amide to the corresponding ⁇ -ketoamide is carried out by adding an acid or base and optionally in the presence of an activating nucleophile.
  • Suitable acids for this purpose are, in particular, strong inorganic or organic acids, such as, for example, hydrochloric acid, sulfuric acid, acetic acid,
  • Suitable bases are in particular alkali metal hydroxides, carbonates or acetates, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium acetate or potassium carbonate, or aqueous solutions of secondary or tertiary amines, such as triethylamine, piperidine, morpholine, diisopropylethylamine or diethylamine.
  • the acid or base is advantageously used in molar excess in comparison to propoxide.
  • an activating nucleophile come ' especially secondary amines, such as piperidine, morpholine or diethylamine or thiols, such as ethanethiol or
  • phosphines such as triphenylphosphine or tributylphosphine in question.
  • the reaction is advantageously carried out in a suitable solvent or solvent mixture, for example in alcohols, for example in ethanol, or in acetone, dimethylformamide, dimethyl sulfoxide or acetonitrile, if appropriate in each case with the addition of small amounts of water, in particular less than or equal to 10% by volume, based on the volume Solvent, at temperatures between 20 and 120 ° C, preferably in the range Boiling temperature of the solvent, carried out. Suitable reaction times are usually in the range of 1 to 24 hours.
  • Compounds of formula B1 may be prepared by reaction of an amine compound of general formula B2 with a propynoic acid compound of general formula B3 in an organic solvent such as DMF, THF, dioxane, acetonitrile or toluene in the presence of a base such as triethylamine and activating reagents such as for example, CDI, TBTU or DCC.
  • a base such as triethylamine
  • activating reagents such as for example, CDI, TBTU or DCC.
  • the carboxylic acid chloride or a mixed anhydride of the compound B3 may also be used.
  • the amide linkage methods described in connection with Synthetic Scheme A can also be used here.
  • a compound of general formula B3 may also be prepared by reacting a compound of general formula B5 in an organic solvent such as dioxane, ethanol or THF with or without addition of water with a base such as potassium tertiarybutylate, sodium hydroxide or sodium ethylate at temperatures of 0 ° C to 150 ° C converts. But it is also possible to bring for this reaction, a compound of general formula B5 with pyridine or quinoline at temperatures of 0 ° C to 150 ° C to the reaction.
  • a compound of general formula B5 is obtained by bromination of a compound of general formula B4 in a solvent such as carbon tetrachloride at temperatures between -20 ° C to 100 ° C, preferably at temperatures between 0 ° C and room temperature.
  • stereoisomeric compounds of the formula (I) can be separated by customary methods.
  • the separation of the respective diastereomers is possible due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • racemates covered by the general formula (I) succeeds, for example, by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be resolved via the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or ⁇ () - tartaric acid, (+) - or ⁇ ( ) -Diacetyltartaric acid, (+) - or " () -Monomethyltartrat or (+) - camphorsulfonic acid, or an optically active base, for example, with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -brucine arise.
  • an optically active acid for example (+) - or ⁇ () - tartaric acid, (+) - or ⁇ ( ) -Diacetyltartaric acid, (+)
  • the racemate of a compound of the general formula (I) is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts taking advantage of their different solubility separated.
  • This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in the solubility of the salts.
  • methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid for example, with dilute hydrochloric acid or aqueous methanesulfonic acid
  • the compounds of the formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids.
  • the compound of formula (I) in the case of acidically bound hydrogen by reaction with inorganic bases, can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion. Hydrochloric acid, hydrobromic acid, for example, can be used to prepare the acid addition salts.
  • alkali metal and alkaline earth metal salts of the compound of formula (I) with acidic hydrogen are preferably the alkali and alkaline earth metal hydroxides and hydrides into consideration, wherein the hydroxides and hydrides of Alkali metals, especially of sodium and potassium are preferred, sodium and potassium hydroxide are particularly preferred.
  • the compounds of the present invention have activity as antagonists of the MCH receptor, particularly the MCH-1 receptor, and show good affinities in MCH receptor binding studies.
  • Pharmacological test systems for MCH antagonistic properties are described in the experimental section below.
  • the compounds of the invention are advantageously useful as pharmaceutical agents for the prophylaxis and / or treatment of phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • the compounds according to the invention have low toxicity, good oral absorbability and intracerebral transitivity, in particular cerebral activity.
  • MCH antagonists which have at least one compound of the invention, especially in mammals, such as rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and / or prophylaxis of Phenomena and / or diseases caused by MCH or in another causal relationship with MCH.
  • Obesity, and eating disorders such as bulimia, including bulimia nervosa.
  • the indications of obesity include especially exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal
  • compounds of the invention may be useful in reducing hunger, curbing appetite, controlling eating behavior, and / or inducing satiety.
  • diseases caused by MCH or otherwise causally related to MCH may also include hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders is suitable.
  • Compounds of the invention are also useful as agents for the prophylaxis and / or treatment of other diseases and / or disorders, in particular those with
  • obesity such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications, including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, heart failure , Cardiovascular diseases, in particular
  • MCH antagonists and formulations according to the invention can advantageously be used in combination with an alimentary therapy, such as, for example, an alimentary diabetes therapy, and exercise.
  • an alimentary therapy such as, for example, an alimentary diabetes therapy, and exercise.
  • Another indication for which the compounds of the invention are advantageously useful is the prophylaxis and / or treatment of voiding disorders such as urinary incontinence, hyperactive urinary bladder, urinary urgency, nocturia, enuresis, with overactive bladder and urinary urgency with or without benign Need to communicate with prostate hyperplasia.
  • the compounds of the invention are potentially useful to prevent and / or treat dependencies such as alcohol and / or nicotine addiction, and / or withdrawal symptoms, such as weight gain in nicotine withdrawal from smokers.
  • dependencies is here generally an irresistible urge to take an addictive substance and / or perform certain acts, in particular either to achieve a feeling of well-being or to eliminate discomfort understood.
  • an addictive dependency is understood here as “dependency”.
  • withdrawal symptoms is meant generally symptoms which occur or may occur in the withdrawal of addictive substances in patients dependent on one or more such addictive agents.
  • the compounds of the invention are in particular potentially as active ingredients for To reduce or stop the consumption of tobacco, to treat or prevent nicotine dependence and / or to treat or prevent nicotine withdrawal symptoms, to reduce cravings for tobacco and / or nicotine and generally as anti-smoking agents. Furthermore, the compounds of the invention may be useful to prevent or at least reduce the weight gain typical of smoking cessation of smoking.
  • the substances can furthermore be suitable as active ingredients which prevent or at least reduce the craving for and / or relapse into dependence on addictive substances.
  • Addictive substances are understood to mean in particular but not exclusively psycho-motor active substances, such as narcotics or intoxicants, in particular alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.
  • the dosage required to achieve a corresponding effect is expediently from 0.001 to 30 mg / kg body weight, preferably from 0.01 to 5 mg / kg body weight, by intravenous or subcutaneous administration, and from 0.01 to 50 mg / kg by oral, nasal or inhalative administration Body weight, preferably 0.1 to 30 mg / kg body weight, once to three times daily.
  • the compounds of general formula I according to the invention optionally in combination with other active substances, as described in more detail below, together with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures , in common pharmaceutical preparations such as tablets, dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories incorporate.
  • compositions comprising at least one amide compound according to the invention and / or a salt according to the invention in addition to optionally one or more physiologically acceptable excipients.
  • Such compositions may, for example, also be foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.
  • suitable further active substances are, in particular, those which, for example, have the therapeutic efficacy of a reinforce MCH antagonists according to the invention with respect to one of the above indications and / or allow a reduction in the dosage of a MCH antagonist of the invention.
  • one or more further active substances are selected from the group consisting of - active ingredients for the treatment of diabetes,
  • drugs for the treatment of obesity preferably other than MCH antagonists, drugs for the treatment of hypertension,
  • - active substances for the treatment of hyperiipidemia including arteriosclerosis
  • - active substances for the treatment of dyslipidemia including arteriosclerosis
  • Examples of drugs for the treatment of diabetes are insulin sensitizers, insulin secretion accelerators, biguanides, insulins, glucosidase inhibitors, ⁇ 3 adreno receptor agonists.
  • Insulin sensitizers include glitazones, especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13 1258, KRP-297, R-119702, GW-1929.
  • glitazones especially pioglitazones and its salts (preferably hydrochlorides), troglitazones, rosiglitazones and its salts (preferably maleates), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13 1258, KRP-297, R-119702, GW-1929.
  • Insulin secretion enhancers include sulfonylureas such as tolbutamide, chlorpropamide, tolzamide, acetohexamide, glyclopytamide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608.
  • Biguanides include metformin, buformin, phenformin.
  • Insulins include insulins derived from animals, particularly cattle or swine, semi-synthetic human insulins which are synthesized enzymatically from animal-derived insulin, human insulin genetically engineered, e.g. Escherichia coli or yeasts. Further, insulin is understood as meaning insulin zinc (containing 0.45 to 0.9% by weight of zinc) and protamine insulin zinc available from zinc chloride, protamine sulfate and insulin. In addition, insulin can be obtained from insulin fragments or derivatives (e.g., INS-1, etc.).
  • Insulin may also include different types, for example, with regard to the time of onset and duration of action ("ultra-immediate action type”, “immediate action type”, “two-phase type”, “intermediate type”, “extended action type”, etc.), which are selected depending on the pathological condition of the patients.
  • ⁇ -glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
  • ⁇ 3 adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • drugs for the treatment of diabetes include ergoset, pramlintide, leptin, BAY-27-9955 and glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipizide, glyburide.
  • Agents for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-1 analogs, SGLT-2 inhibitors.
  • Aldose reductase inhibitors are, for example, Tolrestat, Epalrestat, Imirestat, Zenarestat, SNK-860, Zopolrestat, ARI-50 ⁇ , AS-3201.
  • Protein kinase C inhibitors are, for example, NGF, LY-333531.
  • DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541, 823093 and 825964 (all GlaxoSmithkline).
  • GLP-1 analogs are for example Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amlyin).
  • SGLT-2 inhibitors are AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson).
  • Agents for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • Examples of preferred anorectic agents are phentermine, mazindol, fluoxetine, sibutramine, baiamine, (S) -sibutramine, SR-141716, NGD-95-1.
  • anorectics are also counted for the purposes of this application to the drug group of anti-obesity drugs, the ß 3 agonists, thyromimetic agents and NPY antagonists are highlighted.
  • the scope of the substances which may be considered as preferred anti-adiposity or anorectic agents is exemplified by the following list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake ( reuptake) inhibitor (such as sibutramine), a sympathomimetic drug, a serotonergic drug (such as dexfenfluramine, fenfluramine, a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine agonist (such as bromocriptine or pramipexole
  • anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein Antagonists, agonists of the glucagon-like peptide-1 receptor, such as exendin, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neutrophotropic factors, such as axokines.
  • therapies should be mentioned in this context, which lead to weight loss by increasing the fatty acid oxidation in peripheral tissue, such as inhibitors of acetyl-CoA carboxylase.
  • Agents for the treatment of hypertension include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers, angiotensin II antagonists.
  • Inhibitors of the angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).
  • calcium antagonists examples include nifedipine, amlodipine, efonidipine, nicardipine.
  • Potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121.
  • Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.
  • Agents for the treatment of hyperlipidemia include arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and their salts.
  • Fibrate compounds include bezafibrates, clinofibrates, clofibrates, simfibrates.
  • Agents for the treatment of dyslipidemia, including arteriosclerosis include e.g. Drugs that increase HDL spotting, such as Nicotinic acid and its derivatives or preparations, such as Niaspan, and agonists of the nicotinic acid receptor.
  • Drugs that increase HDL spotting such as Nicotinic acid and its derivatives or preparations, such as Niaspan, and agonists of the nicotinic acid receptor.
  • Agents for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), in particular COX2 inhibitors such as meloxicam or ibuprofen.
  • Agents for the treatment of anxiety include chlordiazepoxides, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Agents for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage.
  • the invention also relates to the use of at least one amide compound according to the invention and / or a salt according to the invention for influencing the eating behavior of a mammal.
  • This use is based in particular on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and / or inducing satiety.
  • the eating behavior is favorably influenced so that the food intake is reduced. Therefore, the compounds of the invention find advantageous application for reducing body weight.
  • Another use of the invention is to prevent an increase in body weight, for example, in people who have previously taken weight-loss measures and are subsequently interested in maintaining the reduced body weight. In accordance with this embodiment, it is preferably a non-therapeutic use.
  • Such a non-therapeutic use may be a cosmetic application, for example, for altering the appearance or an application for improving the general condition.
  • the compounds according to the invention are preferably used non-therapeutically for mammals, in particular humans, who have no diagnosed disorders of eating behavior, no diagnosed obesity, bulimia, diabetes and / or no diagnosed micturition disorders, in particular urinary incontinence.
  • the compounds of the invention are suitable for non-therapeutic use in humans whose body mass index (BMI), defined as the kilogram of body weight divided by height (in meters) squared, is below the value of 30, in particular below 25, lies.
  • BMI body mass index
  • Chamber saturation determined.
  • the R r values determined under the name Alox are determined using TLC plates alumina 60 F254 (E. Merck, Darmstadt, Article No. 1.05713) without chamber saturation.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • the indicated volume units at NH 3 refer to a concentrated solution of NH 3 in water.
  • silica gel from Millipore MATREX TM, 35-70 my
  • Alox E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 microns, item no: 1.01097.9050
  • Methyl-piperidine are dissolved in 100 ml of methylene chloride and 12 hours at
  • Patent application WO 01/27081 or can be carried out at least analogously to the method described therein: (X.1) 4- (piperidin-1-yl-methyl) -phenylamine
  • N-methyl-4- (2-diethylamino-ethoxy) -phenylamine 10.7 g (280 mmol) of lithium aluminum hydride are initially charged in 600 ml of THF and 30.0 g (113 mmol) of N-methoxycarbonyl-4- (2-diethylamino) ethoxy) -phenylamine (Compound XI.l .a) in 300 ml of THF at 0 ° C carefully added dropwise. The mixture is stirred for 12 hours at room temperature. After this time, a further 7.00 g (183 mmol) of lithium aluminum hydride are added and the mixture is stirred for a further 24 hours at room temperature. After this time, carefully neutralize with sodium hydroxide solution. The mixture is filtered, the filtrate over
  • Example 1.0 Analogously to Example 1.0, the following compounds of the general formula 1-1 are prepared, the starting materials to be used being indicated in the column "starting materials":
  • Example 1.0 Analogously to Example 1.0, the following compounds of the general formula 11-1 are prepared, the starting materials to be used being indicated in the column "starting materials":
  • Example 4 Analogously to Example 1.0, the following compounds of the general formula IV-1 are prepared, the starting materials to be employed being indicated in the column "starting materials":
  • Example 5 Analogously to Example 1.0, the following compounds of the general formula V-1 are prepared, the starting materials to be employed being indicated in the column "starting materials":
  • Example 6 Analogously to Example 1.0, the following compounds of the general formula VI-1 are prepared, the starting materials to be used being indicated in the column "starting materials":
  • N- ⁇ 4-r2- (4-Amino-piperidin-1-yl-ethyll-3-chloro-phenyl) -3-biphenyl-4-yl-3-oxo-propionamide 0.19 g (0.33 mmol) of N- ⁇ 4- [2- (4-tert-butoxycarbonylaminopiperidin-1-yl) ethyl] -3-chlorophenyl ⁇ -3-biphenyl-4-yl 3-oxo-propionamide (compound 1.41) are dissolved in 7 ml of methylene chloride, 500 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 12 hours.
  • test methods for determining MCH receptor antagonist activity are described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and the biosensing measurement of the binding of MCH to the MCH receptor in the presence of plasmon resonance antagonistic substances, as described by Karlsson OP and Lofas S. in Flow Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors ", Anal. Biochem. 300 (2002), 132-138. Further test methods for MCH receptor antagonist activity are contained in the cited references and patent documents whose description of the test methods is hereby incorporated in this application.
  • MCH-1 Receptor Binding Test Method MCH binding to hMCH-1 R transfected cells
  • Human test cell hMCH-1 R stably transfected into CHO / Galpha16 cells
  • Membranes from human hMCH-1R stably transfected CHO / Galpha16 cells are resuspended by syringe (0.6 x 25 mm needle) and assay buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00, 0.1% bovine serum Albumin (protease-free), 0.021% Bacitracin, 1 ⁇ g / ml aprotinin, 1 ⁇ g / ml leupeptin and 1 ⁇ M phosphoramidone) to one
  • assay buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00, 0.1% bovine serum Albumin (protease-free), 0.021% Bacitracin, 1 ⁇ g / ml aprotinin, 1 ⁇ g / ml leupeptin and 1 ⁇ M phosphoramidone
  • Non-specific binding is defined as bound radioactivity in the presence of 1
  • Unlabeled MCH competes with labeled 125 I-MCH for receptor binding with an IC50 value between 0.06 and 0.15 nM.
  • the KD value of the radioligand is 0.156 nM.
  • Test Cells Stably-transfected CHO / Galpha 16 cells with hMCH-R1
  • HBSS (10x) (GIBCO) HEPES buffer (1M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) Probenseed (Sigma) MCH (Bachern) Bovine serum albumin (Serva) (Protease free ) DMSO (Serva) Ham's F12 (BioWhittaker) FCS (BioWhittaker) L-Glutamine (GIBCO) Hygromycin B (GIBCO) PENStrep (BioWhittaker) Zeocin (Invitrogen)
  • Clonal CHO / Galpha16 hMCH-R1 cells are cultured in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat. No .: BE12-615F). This contains per mL mL 10% FCS, 1% PENStrep, 5 mL L-Glutamine (200 mM stock solution), 3 mL Hygromycin B (50 mg / mL in PBS) and 1.25 mL Zeocin (100 ⁇ g / mL stock solution).
  • the cells are plated on 384-well microtiter plate (black-walled with transparent bottom, manufacturer: Costar) at a density of 2500 cells per well and in the above-described medium overnight at 37 ° C, 5% CO 2 and 95% relative humidity cultured.
  • the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid are added at 37 ° C for 45 minutes. After loading with fluorescent dye, the cells are washed four times with Hanks buffer solution (1 ⁇ HBSS, 20 mM HEPES) supplemented with 0.07% Probenicid.
  • the test substances are diluted in Hanks buffer solution, mixed with 2.5% DMSO.
  • the background fluorescence of unstimulated cells is measured in the presence of substance in the 384-well microtiter plate five minutes after the last wash in the FLIPR 384 instrument (Molecular Devices, excitation wavelength: 488 nm, emission wavelength: bandpass 510 to 570 nm).
  • MCH is diluted in Hanks buffer with 0.1% BSA, pipetted 35 minutes after the last wash step to the 384-well cell culture plate and the MCH-stimulated fluorescence subsequently measured in the FLIPR 384 device.
  • D o cellular Ca 2+ mobilization is as a peak of the relative fluorescence minus the background and expressed as percentage of the maximum signal of the reference (MCH 10 "6 M) This measurement serves to identify any possible agonistic effect of a test substance.
  • the compounds according to the invention exhibit an MCH receptor antagonistic action in the abovementioned tests.
  • MCH-1 receptor binding test described above is "to 10 9" 6 M, obtain an antagonistic activity in a dose range of about 10 "10 to 10" 5 M, in particular of 10 degrees.
  • active compound 1 denotes one or more compounds according to the invention, including their salts.
  • Composition 1 capsule for powder inhalation contains: Active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg
  • Active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg
  • Method of preparation The active substance is ground to the particle size required for inhalants. The ground active substance is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.
  • 1 hub contains:
  • the active substance and benzalkonium chloride are dissolved in water and filled into Respimat® cartridges.
  • composition 1 vial contains:
  • Active substance sodium chloride and benzalkonium chloride are dissolved in water.
  • Composition 1 stroke contains:
  • Active ingredient 1.0 mg lecithin 0.1%
  • micronized drug is homogeneously suspended in the mixture of lecithin and propellant.
  • the suspension is filled into a pressure vessel with metering valve.
  • composition active ingredient 1.0 mg
  • the active substance and the excipients are dissolved in water and in a corresponding
  • Glykofurol and glucose in water for injection dissolve (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; Fill into ampoules under nitrogen fumigation.
  • Disodium hydrogenphosphate Na 2 HPO 4-2H 2 O 2 mg
  • Dissolve polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; fill in ampoules.
  • Dissolve mannitol in water for injections Wfl
  • Wfl water for injections
  • Human serum albumin Dissolve active ingredient with heating
  • fill with Wfl to batch volume to fill in vials; freeze-dry.
  • Polysorbate 80 Tween 80 20 mg
  • composition Active substance 20 mg
  • Preparation Mix active substance, lactose and corn starch homogeneously; granulate with an aqueous solution of povidone; mix with magnesium stearate; press on a tablet press; Tablet weight 200 mg.
  • composition active substance 20 mg corn starch 80 mg
  • Preparation Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill mixture on a capsule filling machine into hard gelatin capsules size 3.
  • Dissolve mannitol in water for injections Wfl
  • Wfl water for injections
  • Human serum albumin Dissolve active ingredient with heating
  • fill with Wfl to batch volume Fill into ampoules under nitrogen fumigation.

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Abstract

L'invention concerne des composés de cétoamides B de formule (I), dans laquelle les groupes et les restes A, B, b, X, Y, Z, R1, R2, R3, R5a et R5b sont spécifiés dans la revendication 1. L'invention concerne, de plus, des médicaments comprenant au moins un amide de l'invention. Les médicaments de l'invention conviennent pour le traitement de troubles du métabolisme et/ou des troubles de l'appétit, en particulier l'adiposité, la boulimie, l'anorexie, l'hyperphagie et le diabète, grâce à l'activité antagoniste du récepteur de MCH.
PCT/EP2005/002132 2004-03-06 2005-03-01 Composes de cetoamides beta a action antagoniste et medicaments comprenant ledit compose WO2005085221A1 (fr)

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CA002552907A CA2552907A1 (fr) 2004-03-06 2005-03-01 Composes de cetoamides beta a action antagoniste et medicaments comprenant ledit compose
EP05715624A EP1730130A1 (fr) 2004-03-06 2005-03-01 Composes de cetoamides beta a action antagoniste et medicaments comprenant ledit compose
JP2007501195A JP2007527424A (ja) 2004-03-06 2005-03-01 ＭＣＨ拮抗作用を有するβ−ケトアミド化合物及びこれを含む医薬

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DE102004010893A DE102004010893A1 (de) 2004-03-06 2004-03-06 Neue ß-Ketoamid-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092416A3 (fr) * 2006-02-06 2007-11-01 Bristol Myers Squibb Co Antagonistes de recepteur-1 de l'hormone de concentration de la melanine
WO2008022979A1 (fr) 2006-08-25 2008-02-28 Boehringer Ingelheim International Gmbh NOUVEAUX DÉRIVÉS DE LA PYRIDONE PRÉSENTANT UNE ACTIVITÉ ANTAGONISTE de MCH ET MÉDICAMENTS COMPRENANT CES COMPOSÉS
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
WO2008071646A1 (fr) 2006-12-11 2008-06-19 Boehringer Ingelheim International Gmbh Nouveaux dérivés pyridazines à activité antagoniste du récepteur mch et médicaments comprenant ces composés
WO2008135448A1 (fr) * 2007-05-03 2008-11-13 Neurosearch A/S Nouveaux dérivés de béta-céto-amide servant de modulateurs de canaux ioniques
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
WO2012007560A1 (fr) * 2010-07-16 2012-01-19 Merz Pharma Gmbh & Co. Kgaa Utilisation d'un médicament amphiphile cationique pour la préparation d'une formulation destinée à la réduction du tissu adipeux sous-cutané

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WO2001021577A2 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2002010146A1 (fr) * 2000-07-31 2002-02-07 Smithkline Beecham P.L.C. Composes du carboxamide et leur utilisation comme antagonistes d'un recepteur 11cby humain
EP1285651A1 (fr) * 2000-04-28 2003-02-26 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone concentrant la melanine
WO2003033476A1 (fr) * 2001-10-15 2003-04-24 Smithkline Beecham Plc Pyrimidinones en tant que recepteur 1 de l'hormone de concentration de la melanine

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WO2001021577A2 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
EP1285651A1 (fr) * 2000-04-28 2003-02-26 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone concentrant la melanine
WO2002010146A1 (fr) * 2000-07-31 2002-02-07 Smithkline Beecham P.L.C. Composes du carboxamide et leur utilisation comme antagonistes d'un recepteur 11cby humain
WO2003033476A1 (fr) * 2001-10-15 2003-04-24 Smithkline Beecham Plc Pyrimidinones en tant que recepteur 1 de l'hormone de concentration de la melanine

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
WO2007092416A3 (fr) * 2006-02-06 2007-11-01 Bristol Myers Squibb Co Antagonistes de recepteur-1 de l'hormone de concentration de la melanine
US7553836B2 (en) 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US7956049B2 (en) 2006-02-06 2011-06-07 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
WO2008022979A1 (fr) 2006-08-25 2008-02-28 Boehringer Ingelheim International Gmbh NOUVEAUX DÉRIVÉS DE LA PYRIDONE PRÉSENTANT UNE ACTIVITÉ ANTAGONISTE de MCH ET MÉDICAMENTS COMPRENANT CES COMPOSÉS
EP2383259A1 (fr) 2006-08-25 2011-11-02 Boehringer Ingelheim International GmbH Nouveaux dérivés de pyridone avec activité antagoniste MCH et médicaments comportant des composants
WO2008071646A1 (fr) 2006-12-11 2008-06-19 Boehringer Ingelheim International Gmbh Nouveaux dérivés pyridazines à activité antagoniste du récepteur mch et médicaments comprenant ces composés
WO2008135448A1 (fr) * 2007-05-03 2008-11-13 Neurosearch A/S Nouveaux dérivés de béta-céto-amide servant de modulateurs de canaux ioniques
WO2012007560A1 (fr) * 2010-07-16 2012-01-19 Merz Pharma Gmbh & Co. Kgaa Utilisation d'un médicament amphiphile cationique pour la préparation d'une formulation destinée à la réduction du tissu adipeux sous-cutané

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AR048254A1 (es) 2006-04-12
CA2552907A1 (fr) 2005-09-15
TW200540142A (en) 2005-12-16
EP1730130A1 (fr) 2006-12-13

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