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WO2005075458A1 - Pyrimidine derivatives as orexin receptors antagonists - Google Patents

Pyrimidine derivatives as orexin receptors antagonists Download PDF

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Publication number
WO2005075458A1
WO2005075458A1 PCT/HU2005/000010 HU2005000010W WO2005075458A1 WO 2005075458 A1 WO2005075458 A1 WO 2005075458A1 HU 2005000010 W HU2005000010 W HU 2005000010W WO 2005075458 A1 WO2005075458 A1 WO 2005075458A1
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group
alkyl
hydroxy
carboxylic acid
phenyl
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WO2005075458A8 (en
Inventor
Péter ARÁNYI
Mária BALOGH
Sándor BÁTORI
Judit Bence
Michel Finet
Zoltán Kapui
Christophe Philippo
Tibor SZABÓ
Zoltán SZLÁVIK
Zsuzsanna TÖMÖSKÖZI
Katalin URBÁN-SZABÓ
Olivier Venier
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Sanofi Aventis France
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Sanofi Aventis France
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Priority to EP05708501A priority Critical patent/EP1718632B1/en
Priority to JP2006552698A priority patent/JP4825686B2/en
Priority to DE602005014086T priority patent/DE602005014086D1/en
Priority to AT05708501T priority patent/ATE429427T1/en
Publication of WO2005075458A1 publication Critical patent/WO2005075458A1/en
Publication of WO2005075458A8 publication Critical patent/WO2005075458A8/en
Priority to US11/463,825 priority patent/US7812031B2/en
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to the orexin receptor antagonist compounds of the general formula (I), as well as their isomers, salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic application thereof.
  • hypocretin neuropeptides in other name hypocretin neuropeptides and their receptors were discovered in
  • the orexinergic neuropeptides are formed in large amount in the neurons of the lateral hypothalamus, but via axonal transport processes, they also reach numerous remote areas of the nervous system. On the basis of experimental observations the orexinergic system seems to plays crutial role in the feeding, in the sleep-wake cycle and in the regulation of the autonomic nervous system processes.
  • the orexin A and orexin B proteins are formed by the enzymatic cleavage of their only common precursor, the preproorexin protein molecule.
  • Orexin A consists of 33 aminoacid residues with two intramolecular disulphide bridges.
  • Orexin B is a linear protein consisting of 28 aminoacid residues.
  • the aminoacid sequence of the orexin peptides has largely been conserved.
  • the aminoacid sequences of the orexin A peptides are fully identical, whereas the aminoacid sequences of the orexin B proteins differ only in a few aminoacids.
  • the orexin-producing neurons of the brain form a heterogenous cell population: one part of them exhibits leptin sensitivity, whereas the other part glucose sensitivity.
  • orexinergic neurones are capable to express galanine, neuropeptide Y or dinorfme, in addition to the orexines.
  • the orexin A and orexin B bind to specific receptors on the surface of the target cells: i.e. the orexin- 1 and orexin-2 receptors.
  • the orexin- 1 receptors consist of 425, whereas the orexin-2 receptors of 444 aminoacid residues, and their aminoacid sequences are in 64% identical. Between the variants of the two orexin receptor types occuring in the different mammal species (man, pig, dog, mouse, rat) a considerable sequence-homology (of 91-98%) can be found.
  • the aminoacid sequence of the human orexin- 1 receptor is in 94% identical with the aminoacid sequence of the rat, whereas the sequences of the human and rat orexin-2 receptors are in
  • orexin A and B peptides bind with high affinity to both receptor types. Orexin affinities of the two receptor types were determined by intracellular Ca 2+ concentration measurements in recombinant systems (on CHO cells) and on hypothalamic neurons.
  • the orexin A peptide was shown to be 10-50-fold more effective on the orexin- 1 receptors, demonstrating that this receptor type is selective towards orexin A.
  • both neuropeptides exhibited similar, high activities, i.e. the orexin-2 receptors are not selective towards the orexin peptides.
  • the orexin- 1 receptors -via the G q/ n sub-class G- proteins- may activate the phospholipase ⁇ (PLC ⁇ ) enzyme, whereas the orexin-2 receptors are supposed to bind also to the G q/ n and G; /0 or G s sub-classess of the G-proteins, thus beside the PLC ⁇ path, they may also influence the cAMP path.
  • PLC ⁇ phospholipase ⁇
  • the orexin- 1 and 2 receptor types are most frequent in the central nervous system (brain, spinal marrow), but they can also be found in numerous peripherical tissue types (as for instance in the hypophysis, in the adrenal glands, in the gastro-intestinal tract, in the pancreas and in the kidney).
  • Orexines play important role in the regulation of the eating behizate, the sleeping-wake cycle, the neuroendocrinological processes and in the complex regulation of the energy consumption. Orexines in the central nervous system get in interaction with a number of specific neuron-nuclea, as for instance with the feeding centres of the hypothalamus, with the sleep-wake centres in the brain stam, with the symphatic and parasymphatic neuron nuclea and with the limbic system. After ventricular administration, orexines enhance in a dose-dependent manner the food-intake, the length of the time of wakefullness, the motoric activity, the speed of the metabolic processes, the heart rhythm and the blood pressure.
  • Orexins and their receptors can also be found in the peripheric tissues. Orexins exert a direct effect on the hypophysis and on the hormon secretion of the adrenal glands and they influence considerably the digestion and absorbtion processes acting locally, along the gastro-intestinal tract.
  • the orexin- A can effectively increase both in vitro and in vivo the insuline secretion of the pancrease and the leptin secretion of the lipides.
  • X stands for CM-alkyl group; amino group -optionally substituted with one or two C M alkyl group, C ⁇ _ 4 -alkyl-S-group; saturated or partially saturated mono- or bicyclic moiety containing 1 or 2 or 3 heteroatoms (N, O or S) and connected to the pyrimidine ring through the nitrogen atom; or benzylamino-, phenylethylamino, N-C M alkylbenzylamino-, N-C M alkylphenylethylamino-, N-C M -hydroxyalkylbenzylamino-, N-C ⁇ .
  • Z represents hydroxyl group, halogen atom, C ⁇ . 4 -alkoxy group, amino-group, C ⁇ . 4 -alkyl- amino-group, -NHCOC ⁇ . 4 -alkyl group;
  • R + Y may mean -together with the included nitrogen and carbon atom- a
  • Z + W together may mean an oxo group
  • Q is a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms, optionally substituted with one or more identical or different C ⁇ . 4 -alkyl-, C ⁇ - -alkoxy- or hydroxyl group, or halogen atom, or a
  • R is hydrogen atom, halogen atom, hydroxyl-, cyano-, C ⁇ . 4 - alkoxy- or C ⁇ . 4 -alkyl- group;
  • R 3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, cyano-, C ⁇ . 4 -alkylamino-, di(C ⁇ . 4 )alkylamino-, benzylamino-, benzyl-(Cj.
  • R 7 is C M alkyl group, benzyl group or a phenyl group -optionally mono- or polysubstituted with halogen atom, C M alkoxy group, C M alkyl group or trihalogenomethyl group
  • R 4 stands for hydrogen atom, halogen atom, hydroxyl group, cyano-group, C M alkoxy group or C alkyl group
  • R 3 and R 4 together mean a -O-CH 2 -O-group; with the proviso that, if Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different C M alkyl-, C M alkoxy-, hydroxyl- group or halogen atom, W represents hydrogen atom, Z represents hydroxyl group, R + Y may form together with the included nitrogen and carbon atom a
  • A represents NH- or NC ⁇ . 4 -alkyl or -CH 2 - group, and the meaning of Ar is as defined above, then the meaning X is different from C M alkyl- group or from an amino group -optionally substituted with one or two d. 4 alkyl group.
  • W means hydrogen atom or C ⁇ . 4 -alkyl- group
  • Z stands for hydroxyl group, halogen atom, C ⁇ . 4 -alkoxy group, amino group, Ci ⁇ -alkylamino group, -NHCOCM alkyl group
  • Z + W form together an oxo-group
  • R + Y form together with the included nitrogen and carbon atom a
  • A stands for oxygen atom, -CH 2 -, -NH-, group and the value of n is 0, 1 or 2;
  • Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different C M alkyl-, C M alkoxy-, hydroxyl- group or halogen atom, with the proviso that, if if W represents hydrogen atom, Z represents hydroxyl group, n is 1,
  • A represents -NH-, or -NC M alkyl- or -CH 2 - group, then the meaning of X is different from C ⁇ . 4 alkyl group and different from an amino group -optionally substituted with one or more C M alkyl- group;
  • a further group of the compounds of the general formula (I) are those where
  • X and Ar have the meaning as defined in claim 1.
  • W represents hydrogen atom or C ⁇ . 4 alkyl group
  • Z stands for hydroxyl group, halogen atom, C M -alkoxy group, amino group, Ci. ⁇ alkylamino group, -NHCOC ⁇ . 4 -alkyl group; or Z + W form together an oxo-group; R + Y may form together with the included nitrogen and carbon atom a
  • A stands for oxygen atom, -CH2-, -NH-, -NC M -alkyl- group and the value of n is 0, 1 or 2;
  • Q represents - group where R 2 stands for hydrogen atom, halogen atom, hydroxyl group, Cj. 4 alkoxy group or C M alkyl group;
  • R 3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, C ⁇ . 4 -alkylamino-, di(C ⁇ )alkylamino-, benzylamino-, benzyl-(Cj. 4 )alkylamino- group, nitro group, benzyl group, phenylethyl group or C ⁇ .
  • R 4 represents hydrogen atom, halogen atom, hydroxyl group, Ci ⁇ -alkoxy group or C M alkyl group; or
  • Y represents hydrogen atom or C M alkyl group
  • W represents hydrogen atom or C M alkyl group
  • Z stands for hydroxyl group, halogen atom, C ⁇ . 4 -alkoxy group, amino group, Cj. ⁇ alkylamino group, -NHCOC ⁇ _ 4 -alkyl group; or
  • R + Z form together a -(CH 2 ) m -G-group, where the value of m is 1, 2 or 3 and G represents oxygen atom, -CH 2 -, -NH- or -NC ⁇ _ 4 -alkyl- group;
  • Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different C ⁇ . 4 alkyl-, C ⁇ . 4 alkoxy-, hydroxyl-group or halogen atom, or a group wherein R 2 represents hydrogen atom, halogen atom, hydroxyl group, Cj. 4 alkoxy group or
  • R 3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, C ⁇ . 4 -alkylamino-, di(C ⁇ . 4 )alkylamino-, benzylamino-, benzyl-(C ⁇ _ 4 )alkylamino- group, nitro group, benzyl group, phenylethyl group or C ⁇ . 4 -alkyl group,
  • R 5 represents a Cj. 4 -alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group, or
  • R 4 stands for hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or C M alkyl group;
  • a further group of the compounds of the general formula (I) are those where
  • R represents hydrogen atom or C M alkyl group
  • Y represents hydrogen atom or CM alkyl group
  • W represents hydrogen atom or C M alkyl group
  • Z stands for hydroxyl group, halogen atom, CM-alkoxy group, amino group, CM-alkyl- amino group, -NHCOC ⁇ . 4 -alkyl group; or
  • Q represents group wherein R 2 represents hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or
  • R 3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, C ⁇ . 4 -alkylamino-, di(C ⁇ . 4 )alkylamino-, benzylamino-, benzyl-(C ⁇ - 4 )alkylamino- group, nitro group, benzyl group, phenylethyl group, d. 4 -alkyl group or
  • R 5 represents a C ⁇ _ 4 -alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group-;
  • R 4 stands for hydrogen atom, halogen atom, hydroxyl group, C M alkoxy group or C M alkyl group;
  • a further group of the compounds of the general formula (I) are those where
  • R represents hydrogen atom or C ⁇ . 4 alkyl group
  • Y represents hydrogen atom or C M alkyl group
  • W represents hydrogen atom or C alkyl group
  • Z stands for hydroxyl group, halogen atom, C ⁇ . 4 -alkoxy group, amino group, Cj. 4 - alkylamino group, -NHCOC ⁇ . 4 -alkyl group; or
  • Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different C M alkyl-, alkoxy-, hydroxyl-group or halogen atom.
  • a further group of the compounds of the general formula (I) are those where X represents benzylamino group, -N-C ⁇ . 4 -alkyl-benzyl-amino group - where the aromatic ring of the benzyl group may optionally be substituted with one or more identical or different C ⁇ . 4 -alkyl group, Cj ⁇ -alkoxy group, halogen atom or hydroxyl group;
  • Ar means phenyl group -optionally substituted with one or more identical or different C M - alkyl group, Cj. 4 -alkoxy group, halogen atom trihalogenomethyl group or hydroxyl group;
  • R+Y may form together with the included nitrogen atom and carbon atom a
  • n 0, 1 or
  • W represents hydrogen atom
  • Z represents hydroxyl group
  • Q represents a phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatom -optionally substituted with one or more identical or different halogen atom, Cj. 4 alkyl-, C M alkoxy-, hydroxyl-group.
  • the denomination faced5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms may mean for example a 2-, 3- or 4-pyridyl or 2-thienyl or 3- thienyl group.
  • the denomination arrivingsaturated or partially saturated mono- or bicycle containing 1-3 heteroatoms may mean for example pyrrolidinyl, morpholinyl, piperidinyl or tetrahydroisoquinolinyl moiety.
  • the denomination spentHet means a heterocyclic moiety containing 1 or 2 identical or different heteroatoms (N, O or S), as for example a furanyl-, pyridyl-, thienyl- or morpholinyl group.
  • the ,,4-7-membered cycloalkyl group may mean for example a cyclobutyl, cyclopentyl or cyclohexyl group.
  • C M alkyl group we mean groups with straight or branched carbon chains, for instance a n-propyl, ethyl, n-butyl or tert.-butyl groups.
  • C M alkoxy group we mean groups with straight or branched carbon chains, for instance a methoxy, ethoxy, isopropoxy or secondary butyloxy group.
  • bicyclic ring optionally containing heteroatoms we mean for example a quinoline, isoquinoline, quinoxaline, benzotriazine or benzthiazole ring.
  • halogen atom we mean fluoro, chloro, bromo or iodo atom.
  • trihalogenomethyl group we mean for example trifluoromethyl-, trichloromethyl- or tribromomethyl- group.
  • Orex-1 IC 50 22 nM
  • Orex-2 IC 50 5800 nM
  • Orex-1 IC 50 30 nM
  • Orex-2 IC 50 3600 nM
  • Orex-1 IC 50 12 nM
  • Orex-2 IC 50 5400 nM
  • Orex-1 IC 50 15 nM
  • Orex-2 IC 50 320 nM
  • Orex-1 IC 50 11 nM
  • Orex-2 IC 50 6700 nM III
  • Figure 1 shows the method of preparation of the compounds of the general formula (I).
  • the acid of the general formula (II) wherein the meaning of Ar and X is as defined above- is transformed with an acid halogenide forming reagents, preferably with thionyl chloride, into the acid chloride, which is then reacted with the amine of the general formula (III) - wherein in the formula the meaning of R, Y, Z, W, Q is as defined above- in an inert solvent, (e.g. in dchloromethane or chloroform) in the presence of a base (e.g. triethylamine) or in pyridine, at room temperature or at reflux temperature.
  • a base e.g. triethylamine
  • the activating agent may be benzotriazol-1-yloxy- tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or benzotriazol-1-yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) or 4-(4,6-dimethoxy- 1,3,5- triazin-2-yl)-4-methylmo holinium chloride (DMTMM) or l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (EDC) with 1-hydroxybenzotriazole or 2,3,4,5,6-pentafluorophenol.
  • PyBOP benzotriazol-1-yloxy- tris(pyrrolidino)phosphonium hexafluorophosphate
  • BOP benzotriazol-1-yloxy-tris- (dimethylamino)phosphonium hexafluor
  • the reaction is carried out in an inert sovent (e.g. in N,N- dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile or in the mixture of thereof) at room temperature or under reflux conditions.
  • an inert sovent e.g. in N,N- dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile or in the mixture of thereof
  • the compounds of the general formula (I) can also be prepared by using tetrafluorophenol bound to a solid phase polymeric support (for instance polystyrol-divinylbenzene-resin (J. M. Salvino et al. J. Comb. Chem. 2000, 2, 691) to activate the carboxylic acid.
  • Functional groups of the compounds of the general formula (I) can be transformed into other functional groups (for example the substituents Q, R 2 , R 3 , R 4 , Z, W can be transformed into other Q, R 2 , R 3 , R 4 , Z, W substituents).
  • the carboxylic acids of the general formula (II) -wherein the meaning of Ar and X is as defined above- are in part known from the literature or they can be prepared by methods known from the literature ( Figure 2.).
  • the ⁇ -keto-esters of the general formula (IN) are available from the market or they can be synthesized by known methods (Gilman H. et al., J. Am. Chem. Soc. 1948, 70, 2755, Sicker D. et al., Coll. Czech. Chem. Commun. 1988, 53, 839-850, Wierenga W. et al., J. Org. Chem. 1979, 44, 310-311). Reaction of the compounds of the general formula (IN) with NN-dimethylformamide dimethyl acetale can be performed in the presence of solvent (for example in toluene at 60 °C; Herrero M.T.
  • the enaminoesters of the general formula (N) with ⁇ -C- ⁇ dinucleofils for example with guanidine (VI), amidines (VI), S-methylisothiocarbamide (Nil), O-methylisocarbamide (NM) can be transformed into 2-substituted-pyrimidinecarboxylic acid esters (IX, X, XI) Breaux E. J. et al., J. Heterocyclic Chem. 1981, 18, 183, WO 00/73279).
  • Ring closure can be effected in the presence of base (sodium ethylate or sodium hydrogen carbonate) in ethanol, NN-dimethylformamide or ⁇ -methylpyrrolidinone, at room temperature or at elevated temperature (80-100°C).
  • base sodium ethylate or sodium hydrogen carbonate
  • the 2-methylsulphanyl group of the compound of the general formula (X) can be oxidized with an oxidating agent (e.g. with 3-chloro-perbenzoic acid) into 2-methylsulphonyl group.
  • the compounds of the general formula (XII) by reacting with a primary or secondary amine, in the presence of a solvent (e.g.
  • esters of the general formula (IX) can be transformed into the esters of the general formula (IX) -where in the formula X represents a dialkylamino group, alkylamino group, arylamino group, arylalkylamino group, alkyl-arylalkylamino group, hetarylalkylamino group (for example hetarylmethylamino group), alkyl-hetarylalkylamino group (for example methyl- hetarylmethylamino group), amino group, 3,4-dihydro-lH-isoquinolin-2-yl group; the aryl group is a phenyl group optionally containing one or more substituents (e.g.
  • halogen atom C ⁇ . 4 -alkyl group, C ⁇ . 4 -alkoxy group
  • the hetaryl group is a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms (nitrogen, oxygen or sulphur atom) (for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl group).
  • esters of the general formula (IX) where in the formula X represents a dialkylamino group, alkylamino group, arylamino group, arylalkylamino group, alkyl-arylalkylamino group, hetarylalkylamino group (for example hetarylmethylamino group), alkyl-hetarylalkylamino group (for example methyl-hetarylmethylamino group), amino group, 3,4-dihydro-lH- isoquinolin-2-yl group; the aryl group is a phenyl group optionally containing one or more substituents (e.g. halogen atom, C ⁇ .
  • substituents e.g. halogen atom, C ⁇ .
  • the hetaryl group is a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms (nitrogen, oxygen or sulphur atom)
  • 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl group can also be prepared by reacting the ester of the formula (XI) with a primary or secondary amine at elevated temperature (up to 170 °C) in the presence of a solvent or without solvent.
  • esters of the general formula (IX) -where in the formula the meanings of Ar and X are as defined above- can be hydrolyzed under acidic or basic conditions into the acids of the general formula (II) -where in the formula the meaning of Ar and X is as defined above.
  • acid e.g. hydrochloric acid
  • base e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
  • base e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
  • the acids of the general formula (II) can also be prepared by a novel method, as shown in Figure 3.
  • the compounds of the general formula (XIII) can be synthesized by known methods, by the base-catalysed condensation of amidines with diethyl ethoxymethylenemalonate. The resulting compounds give with phosphoryl chloride the chloro-compounds of the general formula (XIV) (Dostert P. et al., Eur. J. Med. Chem. Chim. Ther. 1982, 17, 437-444).
  • the chloro-compounds of the general formula (XIV) are transformed with aryl-boronic acids in dimethoxyethane, in the presence of tetrakis(triphenylphosphino)palladium catalyst into the compounds of the general formula (IX) -where in the formula Ar and X have the meanings as defined above.
  • the esters of the general formula (IX) are hydrolyzed under acidic or basic conditions, preferably in the presence of base.
  • the amines of the general formula (III) where in the formula the meanings of R, Y, Z, W and Q are defined above- can be purchased on the market or can be synthesized by methods known in the literature.
  • the compounds of the general formula (XV), where in the formula A represents a CH, NH, N-Boc, N-(C ⁇ . 4 )-alkyl group, n 1, 2, 3 and PG means a protecting group (e.g.
  • the compounds of the general formula (XVI) are those - wherein in the formula M represents a metal atom (e.g. lithium or magnesium atom), B represents a CH group, or a nitrogen atom, R 5 means hydrogen atom, hydroxyl group, halogen atom, C ⁇ . 4 -alkyl group, C ⁇ . 4 -alkoxy group.
  • the substituent R 5 may take o-, m-, or p-position.
  • the reaction of compounds (XV) with compounds (XVI) is performed in an inert solvent, for example in tetrahydrofuran or in ether, at low temperature (between 0 °C and -78 °C ).
  • the protecting group (e.g. the t-butyloxycarbonyl-, trifluoroacetyl-, benzyloxycarbonyl group) of the compounds of the general formula (XVII) can be removed under acidic conditions (for example with trifluoroacetic acid in dichloromethane, with hydrochloric acid in dioxane or in dichloromethane), under basic conditions (for example with sodium hydroxide in aqueous methanol) or by catalytic hydrogenolysis (e.g. with palladium-on- charcoal catalyst in alcohol or in ethyl acetate).
  • acidic conditions for example with trifluoroacetic acid in dichloromethane, with hydrochloric acid in dioxane or in dichloromethane
  • basic conditions for example with sodium hydroxide in aqueous methanol
  • catalytic hydrogenolysis e.g. with palladium-on- charcoal catalyst in alcohol or in ethyl acetate.
  • the pharmaceutically acceptable salts of the compounds of the general formula (I) can be prepared by reacting the bases with the appropriate acids.
  • solvates of the compounds of the general formula (I) we also mean the hydrates.
  • the compounds of the general formula (I), as well as their pharmaceutically acceptable derivatives can be used for the treatment of diseases where human orexin receptors play a role, and for the treatment of which orexin receptor antagonists are needed.
  • the orexin receptor antagonistic compounds of the general formula (I), and their pharmaceutically acceptable derivatives may be appropriate for the treatment of obesity and type-II diabetes (non-insuline dependent diabetes), furthermore for the treatment of sleeping disorders, narcolepsy, insomnia, jet-lag syndrome, for the treatment of sleeping disorders connected to neurological disorders, depression, anxiety, behavioral disorders, sexual disorders, neuropathic pain, pains connected to infections (like HIV), phantome pains, post-operative pains.
  • the compounds of the general formula (I), and their pharmaceutically acceptable derivatives may be used for the treatment of stroke, heart- and lung diseases.
  • the compounds of the general formula (I), as well as their pharmaceutically acceptable derivatives can be used for the treatment and prevention of diseases where human orexin receptor antagonists are needed for the treatment.
  • the compounds according to the invention are used in the form of pharmaceutical composition.
  • compositions contain the compounds of the general formula (I) or their derivatives together with pharmaceutically acceptable carriers and excipients.
  • the compounds of the general formula (I), and their pharmaceutically acceptable derivatives can be administered by any of the traditional routes, e.g. by oral, parentheral, sublingual, nasal, rectal, or transdermal routes.
  • the compounds of the general formula (I) and their pharmaceutically acceptable derivatives may be administered orally, in the forms of solid or liquide formulations, as for instance sirups, suspensions, emulsions, tablets or capsules.
  • Liquid formulations contain the active component beside an appropriate liquid vehicle (e.g. water, ethanol, glycerine, polyethyleneglycole, oil) in the form of a solution or suspension.
  • an appropriate liquid vehicle e.g. water, ethanol, glycerine, polyethyleneglycole, oil
  • They may also contain colouring and odour agents.
  • Tablets may contain the usual additives, e.g. magnesium stearate, starch, lactose, sucrose and cellulose.
  • Hard and soft gelatine capsules can be prepared by the standard operations.
  • Parenteral formulations contain the active ingredient in the form of a solution or suspension, prepared with a sterile aqueous carrier or with an appropriate oil, as for instance polyethylene glycol, polyvinylpyrrolidone, sesame oil or lecitine.
  • an appropriate oil as for instance polyethylene glycol, polyvinylpyrrolidone, sesame oil or lecitine.
  • Aerosols For nasal application aerosols, drops, gels or powders can be applied. Aerosols contain the active ingredient in the form of an aqueous or non-aqueous solution or suspension, in a closed container, in single or multiple doses.
  • suppositories may be used which contain the usual excipients (e.g. cacao-butter or coconut-butter).
  • excipients e.g. cacao-butter or coconut-butter.
  • gels or dermal paches may be used.
  • the doses of the compounds of the general formula (I) and their pharmaceutically acceptable derivatives used for the treatment or prevention of the above diseases depend on the nature of the disease and in general, a single dose is between 0.05 mg and 1000 mg and the daily dose is between 0.01 mg/kg and 100 mg/kg.
  • 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.22 g, 5 mmol) is dissolved in tefrahydrofuran (60 ml). After 5 minutes of stirring to the solution are added: L- phenylephrine hydrochloride (1.22 g, 6 mmol) in tefrahydrofuran (50 ml), after another 5 minutes of stirring the N-methylmorpholine (1.21 g, 12 mmol) and after 2 minutes of stirring the 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.66 g, 6 mmol).
  • the reaction mixture is stirred for 2 hours at room temperature, then heated at reflux temperature for 2 hours.
  • the solvent is removed in vacuum.
  • To the residue water (50 ml) is added, and the mixture is extracted with chloroform (75 ml), the exfract is washed with 10 % sodium carbonate solution (35 ml), with water (35 ml), dried over sodium sulphate and evaporated.
  • the residue is chromatographed on silicagel using chloroform-methanol 100/1-100/5 mixture eluent. 0.36 g of the title compound is obtained, m.p.: 79-81 °C.
  • Example 1 According to the process described in Example 1. are prepared the compounds of Tables 1. and 2.
  • Example 17 4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethylJmethylamide (I) a) Ethyl 4-phenyl-2-methylsulphanylpyrimidine-5-carboxylate The mixture of ethyl benzoylacetate (9.61 g, 50 mmol) and NN-dimethylformamide dimethyl acetal (6.55 g, 55 mmol) was heated in microwave reactor for 10 minutes (30 W, — » 130 °C).
  • Tetrakis(triphenylphosphino)palladium catalyst (0.25 g, 0.22 mmol) is dissolved under nitrogen atmosphere in dimethoxyethane (20 ml) and to this solution the solution of ethyl- 2-(benzylmethylamino)-4-chloropyrimidine-5-carboxylate (2.75 g, 9.0 mmol) in dimethoxyethane (20 ml) is added.
  • 2-chlorophenylboronic acid (1.55 g, 9.9 mmol
  • sodium carbonate (2.43 g, 23 mmol)
  • dimethoxyethane (20 ml) and water 40 ml
  • the material is prepared according to the method described in Example 17. Starting from 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid and L- phenylephrine hydrochloride.M.p.:139 °C. Table 3.
  • Example 41 White crystals 145-146
  • Example 44 52-57 Yellow crystals 1.5 mol H 2 O
  • Example 59 2-Dimethylamino-4-(3,4-dichIorophenyl)pyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-hydroxyethyl]methylamide
  • Example 74 4-Phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy-l- methyl-2-phenylethyl)methylamide
  • Method B Starting from 4-phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.48 g, 1.5 mmol) and (lR,2S)-2-methylamino-l -phenyl- 1-propanol [(-)-ephedrine] (0.25 g, 1.5 mmol) according to the method described in Example 17. the title amide 0.42 g (58 %) is obtained as white crystalline matrerial; m.p.: 82 °C; [M+HJ + 468.
  • the mixture is srirred at room temperature for 20 hours.
  • the resin is filtered off, washed with NN-dimethylformamide, with tefrahydrofuran and finally with dichloromethane (3 x 10-10 ml).
  • the reagent resin is then swelled in 2 ml of NN-dimethylformamide for 5 minutes under stirring, then 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-aminophenyl)- 2-hydroxyethyl]methylamide (39 mg, 0.10 mmol) is added to it.
  • the mixture is srirred at room temperature for 20 hours.
  • Ar phenyl
  • X Me(C 6 H 5 CH 2 )N
  • R 2 H
  • R 3 OH
  • hr- 125 I-orexin-A radioligand competition (displacement) experiments a fixed concentration of hr- 125 I-orexin-A is incubated with increasing concentrations of unlabeled test compound in the presence of highly purified plasmamembranes bearing either the human recombinant orexin- 1 (hr-OX-1) or the human recombinant orexin-2 (hr- OX-2) receptors.
  • hr-OX-1 human recombinant orexin- 1
  • hr- OX-2 human recombinant orexin-2
  • Culturing the Chinese hamster ovarian cells expressing human recombinant orexin -1 or orexin-2 receptor proteins (CHO-hr-OX- 1 or CHO-hr-OX-2 cells) was carried out in cell culture medium (MEM medium, supplemented with 40 mg/1 prolin, 20 mg/1 gentamycin, 300 mg/1 geneticin, 10% dialysed fetal calf serum).
  • Adherent cells were plated into Greiner flasks (175 cm 2 ). 4-6 days later culture medium was removed and cells were scarped in calcium- and magnesium-free phosphate buffered saline (PBS, 20 ml/flask). The cell suspension was cenfrifuged at 1,000 g for 5 minutes (4°C). The resulting pellet was resuspended and homogenized with a teflon pestle (4°C), then layered onto a discontinous sucrose gradient and cenfrifuged at 105,000 g. Plasmamembrane fraction accumulated in the interface between 14 and 34% sucrose layers was separated and pelleted by a further centrifugation step at 105,000 g for 60 min (4°C). The final pellet was resuspended in binding assay buffer and stored at -80°C up to the day of radioligand binding experiment. In vitro 125 I-orexin-A binding
  • Test compounds were dissolved at a concentration of 1 mM in dimethylsulfoxide (DMSO).
  • Serial dilution series were prepared from stock solutions (100% DMSO) with binding assay buffer in such a way that each samples contained a final concentration of 1% of DMSO in the receptor binding reaction mixture.
  • samples were filtered through Whatman GF/C glass fibre filters using a SKATRON cell harvester, and the filters were washed with 5 ml of ice-cold buffer. The radioactivity remained on the filter was counted in a gamma counter (Wallac Automatic Gamma Counter 1470 Wizard).

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Abstract

The present invention relates to the orexin receptor antagonists of the general formula (I), which are selective to orexin I receptors. (I) -wherein Ar stands for phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms or methylenedioxyphenyl group -these groups may optionally be substituted with one or more identical or different C1.4 alkyl group, halogen atom, hydroxyl group, C1-4 alkoxy group, trihalogenomethyl group, NHC1.4 alkyl, -N(CI-4 alkyl)2 or -NHC(=0)-C1-4 alkyl group,

Description

PYRIMIDINE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
The present invention relates to the orexin receptor antagonist compounds of the general formula (I), as well as their isomers, salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic application thereof.
Further subjects of the invention are the methods of preparation of the compounds of the general formula (I) and the new intermediates of these processes.
Orexines, in other name hypocretin neuropeptides and their receptors were discovered in
1998 by molecular biological methods.
The orexinergic neuropeptides are formed in large amount in the neurons of the lateral hypothalamus, but via axonal transport processes, they also reach numerous remote areas of the nervous system. On the basis of experimental observations the orexinergic system seems to plays crutial role in the feeding, in the sleep-wake cycle and in the regulation of the autonomic nervous system processes.
The orexin A and orexin B proteins are formed by the enzymatic cleavage of their only common precursor, the preproorexin protein molecule. Orexin A consists of 33 aminoacid residues with two intramolecular disulphide bridges. Orexin B is a linear protein consisting of 28 aminoacid residues. During the evolution of mammals the aminoacid sequence of the orexin peptides has largely been conserved. In man, pig, dog, mouse and rat species the aminoacid sequences of the orexin A peptides are fully identical, whereas the aminoacid sequences of the orexin B proteins differ only in a few aminoacids. The orexin-producing neurons of the brain form a heterogenous cell population: one part of them exhibits leptin sensitivity, whereas the other part glucose sensitivity.
Further sub-groups of the orexinergic neurones are capable to express galanine, neuropeptide Y or dinorfme, in addition to the orexines.
The orexin A and orexin B bind to specific receptors on the surface of the target cells: i.e. the orexin- 1 and orexin-2 receptors.
In men, the orexin- 1 receptors consist of 425, whereas the orexin-2 receptors of 444 aminoacid residues, and their aminoacid sequences are in 64% identical. Between the variants of the two orexin receptor types occuring in the different mammal species (man, pig, dog, mouse, rat) a considerable sequence-homology (of 91-98%) can be found. The aminoacid sequence of the human orexin- 1 receptor is in 94% identical with the aminoacid sequence of the rat, whereas the sequences of the human and rat orexin-2 receptors are in
95% identical.
The orexin A and B peptides bind with high affinity to both receptor types. Orexin affinities of the two receptor types were determined by intracellular Ca2+ concentration measurements in recombinant systems (on CHO cells) and on hypothalamic neurons.
Compared to the orexin B, the orexin A peptide was shown to be 10-50-fold more effective on the orexin- 1 receptors, demonstrating that this receptor type is selective towards orexin A. On the orexin-2 receptors both neuropeptides exhibited similar, high activities, i.e. the orexin-2 receptors are not selective towards the orexin peptides.
According to experimental results, the orexin- 1 receptors -via the Gq/n sub-class G- proteins- may activate the phospholipase β (PLCβ) enzyme, whereas the orexin-2 receptors are supposed to bind also to the Gq/n and G;/0 or Gs sub-classess of the G-proteins, thus beside the PLCβ path, they may also influence the cAMP path. In the synaptic activity stimulating effect of the orexines a significant role may be played by their capability to evoke phosphorylation of the ion channels. The orexin- 1 and 2 receptor types are most frequent in the central nervous system (brain, spinal marrow), but they can also be found in numerous peripherical tissue types (as for instance in the hypophysis, in the adrenal glands, in the gastro-intestinal tract, in the pancreas and in the kidney).
Orexines play important role in the regulation of the eating behavoir, the sleeping-wake cycle, the neuroendocrinological processes and in the complex regulation of the energy consumption. Orexines in the central nervous system get in interaction with a number of specific neuron-nuclea, as for instance with the feeding centres of the hypothalamus, with the sleep-wake centres in the brain stam, with the symphatic and parasymphatic neuron nuclea and with the limbic system. After ventricular administration, orexines enhance in a dose-dependent manner the food-intake, the length of the time of wakefullness, the motoric activity, the speed of the metabolic processes, the heart rhythm and the blood pressure.
Latest electrophysiological studies have demonstrated that in the regulation of the functions of the orexin-producing neurons important mediators of the metabolic processes take part, such as the leptin, the glucose, the grelin, the monoamines and the acetylcholine, which means that the orexin-producing neurones develop functional connections with the feeding-centres, with monoaminerg-acetylcholinerg centres in the brain stam and with the factors reflecting the supply with food.
Orexins and their receptors can also be found in the peripheric tissues. Orexins exert a direct effect on the hypophysis and on the hormon secretion of the adrenal glands and they influence considerably the digestion and absorbtion processes acting locally, along the gastro-intestinal tract.
The orexin- A can effectively increase both in vitro and in vivo the insuline secretion of the pancrease and the leptin secretion of the lipides.
These observations prove that the orexinergic neuropeptides and their receptors play important role in the energy intake - expenditure balance and in the higher regulation of the adaptive behavioral processes.
Based on the above, we can expect that compounds exerting antagonistic effect on the orexin- 1 and orexin-2 receptors are suitable -among others- to treat diseases like obesity, including obesity of the non-insuline-dependent diabetes patients, for the treatment of sleeping disorders, stroke, nausea and vomiting.
We aimed to prepare novel compounds suitable for drug development, exerting strong antagonistic effect on the orexin- 1 and orexin-2 receptors, first of all on the orexin- 1 receptors.
We have found that the compounds of the general formula (I) wherein
X stands for CM-alkyl group; amino group -optionally substituted with one or two CM alkyl group, Cι_4-alkyl-S-group; saturated or partially saturated mono- or bicyclic moiety containing 1 or 2 or 3 heteroatoms (N, O or S) and connected to the pyrimidine ring through the nitrogen atom; or benzylamino-, phenylethylamino, N-CM alkylbenzylamino-, N-CM alkylphenylethylamino-, N-CM-hydroxyalkylbenzylamino-, N-Cι.4- hydroxyalkylphenylethylamino-, cyclohexylmethylamino-, N-(Cι_4-cyclohexyl- methyl)amino-group - where the aromatic ring is optionally substituted with one or two of the same or different Cι_4 alkyl- or C alkoxy group or hydroxy group or halogen atom; or X stands for a Het-Cι.4 alkyl-N(R')-group, where the meaning of Het is a saturated or unsaturated heterocyclic ring containing one or two identical or different heteroatoms (N, O vagy S), optionally substituted with one or more identical or different C alkyl-, C alkoxy group or halogen atom and R1 means CM alkyl-group or a Cι_4-hydroxyalkyl group.
Ar stands for phenyl group or a 5- or 6-memebered heterocyclic ring containing 1-3 identical or different heteroatoms or a methylenedioxyphenyl group-optionally substituted with one or more identical or different CM alkyl group, halogen atom, hydroxyl group, Cι.4 alkoxy group, trihalogenomethyl group, -NHCM alkyl, -N(CM alkyl)2 or -NHC(=O)-Cι.4 alkyl group; R represents hydrogen atom or Cι.4-alkyl group; Y represents hydrogen atom or Cι_4-alkyl group; W represents hydrogen atom or Cι-4-alkyl group;
Z represents hydroxyl group, halogen atom, Cι.4-alkoxy group, amino-group, Cι.4-alkyl- amino-group, -NHCOCι.4-alkyl group; R + Y may mean -together with the included nitrogen and carbon atom- a
-group
Figure imgf000005_0001
- wherein A stands for CH2 group, oxygen atom, NH, NCj-4-alkyl group; n = 0, 1 , 2
R + Z together may mean a -(CH2)m-G-group, wherein m = 1, 2, 3, G means oxygen atom, CH2, NH,
Figure imgf000005_0002
group;
Z + W together may mean an oxo group;
The meaning of Q is a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms, optionally substituted with one or more identical or different Cι.4-alkyl-, Cι- -alkoxy- or hydroxyl group, or halogen atom, or a
group
Figure imgf000005_0003
wherein the meaning of R is hydrogen atom, halogen atom, hydroxyl-, cyano-, Cι.4- alkoxy- or Cι.4-alkyl- group; R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, cyano-, Cι.4-alkylamino-, di(Cι.4)alkylamino-, benzylamino-, benzyl-(Cj. 4)alkylamino- group, nitro group, benzyl group, phenylethyl group or
Figure imgf000005_0004
group, -OR5 group - wherein R5 represents a group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group-; or -NH-C(=O)-R6 group, wherein R6 stands for phenyl group or 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, optionally substituted with halogen atom, Cι.4- alkyl group, Cj. -alkoxy group; or a -NH-C(=O)-NH-R7 group wherein the meaning of R7 is CM alkyl group, benzyl group or a phenyl group -optionally mono- or polysubstituted with halogen atom, CM alkoxy group, CM alkyl group or trihalogenomethyl group; R4 stands for hydrogen atom, halogen atom, hydroxyl group, cyano-group, CM alkoxy group or C alkyl group; or R3 and R4 together mean a -O-CH2-O-group; with the proviso that, if Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different CM alkyl-, CM alkoxy-, hydroxyl- group or halogen atom, W represents hydrogen atom, Z represents hydroxyl group, R + Y may form together with the included nitrogen and carbon atom a
-group
Figure imgf000006_0001
where n = l,
A represents NH- or NCι.4-alkyl or -CH2- group, and the meaning of Ar is as defined above, then the meaning X is different from CMalkyl- group or from an amino group -optionally substituted with one or two d.4 alkyl group.
- and their salts, isomers and solvates exert significant orexin- 1 and orexin-2 receptor antagonistic activity, first of all orexin- 1 antagonistic activity and they are suitable for drug development.
One group of the above family is formed by those compounds of the general formula (I) where the meaning of X and Ar is defined in claim 1.,
W means hydrogen atom or Cι.4-alkyl- group; Z stands for hydroxyl group, halogen atom, Cι.4-alkoxy group, amino group, Ci ^-alkylamino group, -NHCOCM alkyl group; or Z + W form together an oxo-group; R + Y form together with the included nitrogen and carbon atom a
-group
Figure imgf000007_0001
A stands for oxygen atom, -CH2-, -NH-,
Figure imgf000007_0002
group and the value of n is 0, 1 or 2; Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different CM alkyl-, CM alkoxy-, hydroxyl- group or halogen atom, with the proviso that, if if W represents hydrogen atom, Z represents hydroxyl group, n is 1,
A represents -NH-, or -NCM alkyl- or -CH2- group, then the meaning of X is different from Cι.4 alkyl group and different from an amino group -optionally substituted with one or more CM alkyl- group; A further group of the compounds of the general formula (I) are those where
X and Ar have the meaning as defined in claim 1., W represents hydrogen atom or Cι.4 alkyl group;
Z stands for hydroxyl group, halogen atom, CM-alkoxy group, amino group, Ci. ^alkylamino group, -NHCOCι.4-alkyl group; or Z + W form together an oxo-group; R + Y may form together with the included nitrogen and carbon atom a
-group
Figure imgf000007_0003
A stands for oxygen atom, -CH2-, -NH-, -NCM-alkyl- group and the value of n is 0, 1 or 2; Q represents - group
Figure imgf000008_0001
where R2 stands for hydrogen atom, halogen atom, hydroxyl group, Cj.4 alkoxy group or CM alkyl group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι.4-alkylamino-, di(Cι^)alkylamino-, benzylamino-, benzyl-(Cj.4)alkylamino- group, nitro group, benzyl group, phenylethyl group or Cι.4-alkyl group, -OR5 group- wherein R5 represents a Cι_4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group, or -NH-C(=O)-R6 group, wherein R6 stands for phenyl group -optionally substituted with one or more halogen atom, CM alkyl group, CM alkoxy group; or a 4-7-membered cycloalkyl group, methylenedioxyphenyl group, Cι_4 alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, or -NH-C(=O)-NH-R7 group where R7 stands for Cι.4-alkyl group, benzyl group, or phenyl group, optionally mono- or polysubstituted with halogen atom, Ci ^-alkoxy group, Cι.4-alkyl group or trihalogenomethyl group,
R4 represents hydrogen atom, halogen atom, hydroxyl group, Ci ^-alkoxy group or CM alkyl group; or where
X and Ar have the meaning as defined in claim 1.,
Y represents hydrogen atom or CM alkyl group;
W represents hydrogen atom or CM alkyl group;
Z stands for hydroxyl group, halogen atom, Cι.4-alkoxy group, amino group, Cj. ^alkylamino group, -NHCOCι_4-alkyl group; or
R + Z form together a -(CH2)m-G-group, where the value of m is 1, 2 or 3 and G represents oxygen atom, -CH2-, -NH- or -NCι_4-alkyl- group;
Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different Cι.4 alkyl-, Cι.4 alkoxy-, hydroxyl-group or halogen atom, or a group
Figure imgf000009_0001
wherein R2 represents hydrogen atom, halogen atom, hydroxyl group, Cj.4 alkoxy group or
CM alkyl group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι.4-alkylamino-, di(Cι.4)alkylamino-, benzylamino-, benzyl-(Cι_4)alkylamino- group, nitro group, benzyl group, phenylethyl group or Cι.4-alkyl group,
-OR5 group - wherein R5 represents a Cj.4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group, or
-NH-C(=O)-R6 group, wherein R6 stands for phenyl group -optionally substituted with halogen atom, CM alkyl group, CM alkoxy group; or a 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, or -NH-C(=O)-NH-R7 group wherein R7 means C alkyl group, benzyl group or a phenyl group -optionally substituted with halogen atom, C alkoxy group, C alkyl group or trihalogenomethyl group,
R4 stands for hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or CM alkyl group;
A further group of the compounds of the general formula (I) are those where
X and Ar have the meaning as defined in claim 1.,
R represents hydrogen atom or CM alkyl group;
Y represents hydrogen atom or CM alkyl group;
W represents hydrogen atom or CM alkyl group;
Z stands for hydroxyl group, halogen atom, CM-alkoxy group, amino group, CM-alkyl- amino group, -NHCOCι.4-alkyl group; or
Z + W form together an oxo-group;
Q represents group
Figure imgf000010_0001
wherein R2 represents hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or
C alkyl group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι.4-alkylamino-, di(Cι.4)alkylamino-, benzylamino-, benzyl-(Cι-4)alkylamino- group, nitro group, benzyl group, phenylethyl group, d.4-alkyl group or
-OR5 group - wherein R5 represents a Cι_4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group-; or
-NH-C(=O)-R6 group, wherein R6 stands for phenyl group -optionally substituted with halogen atom, CM alkyl group, CM alkoxy group, 4-7-membered cycloalkyl group, methylenedioxyphenyl group, C alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, or -NH-C(=O)-NH-R7 group wherein R7 means Cj.4 alkyl group, benzyl group or a phenyl group -optionally substituted with one or more halogen atom, CM alkoxy group, CM alkyl group or trihalogenomethyl group,
R4 stands for hydrogen atom, halogen atom, hydroxyl group, CM alkoxy group or CM alkyl group;
A further group of the compounds of the general formula (I) are those where
X and Ar have the meaning as defined in claim 1.,
R represents hydrogen atom or Cι.4 alkyl group;
Y represents hydrogen atom or CM alkyl group;
W represents hydrogen atom or C alkyl group;
Z stands for hydroxyl group, halogen atom, Cι.4-alkoxy group, amino group, Cj.4- alkylamino group, -NHCOCι.4-alkyl group; or
Z + W form together an oxo-group;
Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different CM alkyl-,
Figure imgf000010_0002
alkoxy-, hydroxyl-group or halogen atom.
A further group of the compounds of the general formula (I) are those where X represents benzylamino group, -N-Cι.4-alkyl-benzyl-amino group - where the aromatic ring of the benzyl group may optionally be substituted with one or more identical or different Cι.4-alkyl group, Cj ^-alkoxy group, halogen atom or hydroxyl group; Ar means phenyl group -optionally substituted with one or more identical or different CM- alkyl group, Cj.4-alkoxy group, halogen atom trihalogenomethyl group or hydroxyl group; R+Y may form together with the included nitrogen atom and carbon atom a
-group
Figure imgf000011_0001
wherein
- A means oxygen atom, -CH2-, -NH- or -N-CM-alkyl- group and the value of n is 0, 1 or
2;
W represents hydrogen atom;
Z represents hydroxyl group;
Q represents a phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatom -optionally substituted with one or more identical or different halogen atom, Cj.4 alkyl-, CM alkoxy-, hydroxyl-group. The denomination „5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms" may mean for example a 2-, 3- or 4-pyridyl or 2-thienyl or 3- thienyl group. The denomination „saturated or partially saturated mono- or bicycle containing 1-3 heteroatoms" may mean for example pyrrolidinyl, morpholinyl, piperidinyl or tetrahydroisoquinolinyl moiety.
The denomination „Het" means a heterocyclic moiety containing 1 or 2 identical or different heteroatoms (N, O or S), as for example a furanyl-, pyridyl-, thienyl- or morpholinyl group.
The ,,4-7-membered cycloalkyl group" may mean for example a cyclobutyl, cyclopentyl or cyclohexyl group.
By CM alkyl group we mean groups with straight or branched carbon chains, for instance a n-propyl, ethyl, n-butyl or tert.-butyl groups. By CM alkoxy group we mean groups with straight or branched carbon chains, for instance a methoxy, ethoxy, isopropoxy or secondary butyloxy group.
By a bicyclic ring optionally containing heteroatoms we mean for example a quinoline, isoquinoline, quinoxaline, benzotriazine or benzthiazole ring. By halogen atom we mean fluoro, chloro, bromo or iodo atom.
By trihalogenomethyl group we mean for example trifluoromethyl-, trichloromethyl- or tribromomethyl- group.
Far from beeing complete, hereby we list some of the very active compounds of the general formula (I) according to our invention:
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxyphenyl) ethyl] methyl amide;
2-Dimethylamino-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
4-Phenyl-2-[(thiophen-2-yl-methyl)amino]pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5 -carboxylic acid [2-hydroxy-2-(3 -hydroxy- phenyl)ethyl] methyl amide;
2-Benzylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxyphenyl) ethyl]methyl amide;
2-[Benzyl-(2-hydroxyethyl)amino]-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-methylphenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-(2-methoxyphenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethyl]methyl amide;
2-(2-Chlorobenzylamino)-4-phenylpyrimidine-5- carboxylic acid [2-hydroxy-2-(3-hydroxy phenyl)ethyl] methyl amide;
4-Phenyl-2-[methyl-(pyridin-2-ylmethyl)amino]pirimidine-5-carboxylic acid [2-hydroxy- 2-(3-hydroxyphenyl)ethyl]methyl amide; 2-(Benzylmethylamino)-4-(2-iodophenyl)pyrimidine-5- carboxylic acid [2-hydroxy-2-(3- hydroxypheny l)ethy 1] methyl amide ;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-phenylpyrimidine-5-carbonyl) methylamino]- 1 -hydroxyethyl }phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-thiophen-3-yl-pyrimidine-5- carbonyl)methylamino] - 1 -hydroxyethyl } phenyl ester;
2 ,2-Dimethylpropionic acid 3 - { 2-[(2-dimethylamino-4-thiophen-2-yl-pyrimidine-5 - carbonyl)methylamino] - 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(2-chlorophenyl)pyrimidine-5- carbonyl)methylamino]-l -hydroxyethyl} phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(3-chlorophenyl)pyrimidine-5- carbony l)methy lamino] - 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(3-fluorophenyl)pyrimidine-5- carbonyl)methylamino]- 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(4-methoxyphenyl)pyrimidine-5- carbonyl)methylamino]- 1 -hydroxyethyl }phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino- 4-(3,4-methylenedioxyphenyl) pyrimidine-5-carbonyl)methylamino]-l-hydroxyethyl}phenyl ester;
2-Dimethylamino-4-phenylpirimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- hydroxy ethyl] methyl amide
2-Dimethylamino-4-(2-fluorophenyl)pyrimidine-5-carboxylic acid [2-(3-benzyloxy phenyl)-2-hydroxyethyl]methyl amide;
2-Dimethylamino-4-(2-chlorophenyl)pyrimidine-5- carboxylic acid [2-(3-benzyloxy phenyl)-2-hydroxyethyl]methyl amide;
4-Phenyl-2- [(pyridin-2-yl-methyl)amino]pyrimidine-5 -carboxylic acid (2-hydroxy- 1 - methyl-2-phenylethyl)methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy- 1 -methyl-2- phenylethyl)methyl amide;
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidin-5-carboxylic acid (2-hydroxy- 1 - methyl-2-phenylethyl)methyl amide;
2-Benzylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy- l-methyl-2- phenylethyl)methyl amide; 4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy-l- methyl-2-phenylethyl)methyl amide;
4-Phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy- 1- methyl-2-phenylethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-2- carbonyl)amino]phenyl} ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzoylaminophenyl)-2- hydroxy ethyl] methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-hydroxy-2-[3-(2-methoxy benzoylamino)phenyl]ethyl}methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-hydroxy-2-[3-(3-methoxy benzoylamino)phenyl] ethyl } methyl amide ;
2-Dimethylamino-4-phenylpyrimidine-5 -carboxylic acid (2-hydroxy-2- { 3 - [(thiophen-2- carbonyl)amino]phenyl}ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2-{3-[(thiofen-3- carbonyl)amino]phenyl } ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-{3-[(furan-3-carbonyl)amino] phenyl } -2-hydroxyethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-3- carbonyl)amino]phenyl } ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-4- carbonyl)amino]phenyl}ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(2,2-dimethylpropionyl amino)phenyl] -2-hydroxyethyl } methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(cyclopentanecarbonyl amino)phenyl]-2-hydroxyethyl }methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-hydroxx-2-[3-(3-chloro benzoylamino)phenyl]ethyl}methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(3-tert-butylureido) phenyl]-2-hydroxyethyl} methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(4-hydroxy- phenyl)ethyl]methyl amide; 2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-fluoro phenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(4-fluoro phenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-methoxy- phenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(4-methoxy- phenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-phenyl-2-hydroxyethyl)- methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-(3-aminophenyl)-2- hydroxyethyl]methyl amide;
2-Benzylamino-4-phenylpyrimidine-5 -carboxylic acid [2-(3,4-dihydroxyphenyl)-2- hydroxy ethyl] methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5- carboxylic acid [2-(3-benzyloxyphenyl)-2- fluoroethyl]methyl amide;
(±) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxyphenylmethyl)- piperidin- 1 -yl]methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- methoxyphenyl)methyl]piperidin-l-yl}methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- hydroxyphenyl)methyl]piperidin-l-yl}methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-fluorophenyl) hydroxymethyl]piperidin-l-yl}methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyiridin-3-yl- methyl)piperidin- 1 -yl]methanone;
(±) Anti-[2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidin-5-yl]-[2-(hydroxyphenyl- methyl)piperidin- 1 -yl] methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-2- ylmethyl)piperidin- 1 -yl]methanone
2-(Benzylmethylamino)-4-(2-bromophenyl)pyrimidine-5-carboxylic acid [2-(3,4- dihydroxyphenyl)-2-hydroxyethyl]methyl amide 2-(Benzylmethylamino)-4-(2-bromophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide
2-(Benzylmethylamino)-4-(2-fluorophenyl)pyrimidine-5 -carboxylic acid [2-(4-chloro- phenyl)-2-hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-(4-chlorophenyl)-2- hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-benzo[l,3]dioxol-5-yl-2- hydroxyethyl)methyl amide
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-(3,4- dihydroxyphenyl)-2-hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-(4-cyanophenyl)-2- hydroxyethyl]methyl amide
4-(2-Chlorophenyl)-2-dimethylaminopyrimidine-5-carboxylic acid (2-hydroxy-2- {3-
[(pyridine-4-carbonyl)amino]phenyl} ethyl)methyl amide
2-(Ethyl-pyridin-3-ylmethyl-amino)-4-(2-fluorophenyl)pyrimidine-5-carboxylic acid [2- hydroxy-2-(3-hydroxyphenyl)ethyl]methyl amide
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(4-fluorophenyl)- hydroxymethyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- ?-tolyl- methyl)piperidin- 1 -yl]methanone
(±)Anti-[2-(hydroxyphenylmethyl)piperidin-l-yl]-[2-(3-methoxybenzylamino)-4- phenylpyrimidin-5-yl]methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-chlorophenyl)- hydroxymethyl]piperidin- 1 -yl } methanone
(±)Anti-{2-[(4-chlorobenzyl)methylamino]-4-phenylpyrimidin-5-yl}-[2-(hydroxy- phenylmethyl)piperidin- 1 -yl]methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- -tolyl- methyl)piperidin- 1 -yljmethanone
(±) Anti- { 2 - [(4-fluorobenzy l)methy lamino] -4-phenylpyrimidin-5 -yl } - [2 -(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy-o-tolyl- methyl)piperidin- 1 -yljmethanone (±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(2-fluorophenyl)- hydroxymefhyljpiperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(4-methoxy- phenyl)methyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(4-fluorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-chloro-4- fluorophenyl)hydroxymethyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3,4-difluorophenyl)- hydroxymethyljpiperidin- 1 -yl } methanone
(±)Anti-[2-(3-chlorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-(2-chlorophenyl)-pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-4-yl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-(2-fluorophenyl)pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-2-[(3-chlorobenzyl)methylamino]-4-phenylpyrimidin-5-yl}-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(2-chlorophenyl)- hydroxymethyl Jpiperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy-thiophen-3-yl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(3-chloro-4-fluorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-{2-[(3-chloro-4-fluorobenzyl)methylamino]-4-phenylpyrimidin-5-yl}-[2- (hydroxyphenylmethyl)-piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-(4-chlorophenyl)pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(3-chloro-4-fluorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- thiophen-3-yl-methyl)piperidin-l-yl]methanone. IC50 values of the compounds of the general formula (I) are usually smaller than 1000 nM, the favourable compounds exhibit IC50 values smaller than 100 nM. For demonstration herebelow we give IC50 values of some of our compounds of the general formula (I):
2-(Benzylmethylamino)-4-(2-methylphenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methylamide
Orex-1 IC5022 nM, Orex-2 IC505800 nM
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(2-chlorophenyl)pyrimidine-5- carbonyl)methylamino] - 1 -hydroxyethyl } phenyl ester Orex-1 IC5030 nM, Orex-2 IC502900 nM
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- hydroxyethyjmethylamide
Orex-1 IC5030 nM, Orex-2 IC503600 nM
4-Phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-5 -carboxylic acid (2-hydroxy- 1-methyl-
2-phenylethyl)methylamide
Orex-1 IC50 12 nM, Orex-2 IC505400 nM
2-Dimethylamino-4-phenylpyrimidin-5 -carboxylic acid { 2-hydroxy-2- [3 -(2-methoxy- benzoylamino)phenyl]ethyl } methylamide
Orex-1 IC50 15 nM, Orex-2 IC50320 nM
(±) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxyphenylmethyl) piperidin- 1 -yljmethanone
Orex-1 IC50 11 nM, Orex-2 IC506700 nM
Figure imgf000019_0001
III
Figure 1.
Figure 1. shows the method of preparation of the compounds of the general formula (I). According to one of the processes the acid of the general formula (II) -wherein the meaning of Ar and X is as defined above- is transformed with an acid halogenide forming reagents, preferably with thionyl chloride, into the acid chloride, which is then reacted with the amine of the general formula (III) - wherein in the formula the meaning of R, Y, Z, W, Q is as defined above- in an inert solvent, (e.g. in dchloromethane or chloroform) in the presence of a base (e.g. triethylamine) or in pyridine, at room temperature or at reflux temperature.
According to the other process the acid of the general formula (II) -wherein the meaning of Ar and X is as defined above- is reacted with the amine of the general formula (III) - wherein in the formula the meaning of R, Y, Z, W, Q is as defined above- in the presence of an activating agent. The activating agent may be benzotriazol-1-yloxy- tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or benzotriazol-1-yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) or 4-(4,6-dimethoxy- 1,3,5- triazin-2-yl)-4-methylmo holinium chloride (DMTMM) or l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (EDC) with 1-hydroxybenzotriazole or 2,3,4,5,6-pentafluorophenol. The reaction is carried out in an inert sovent (e.g. in N,N- dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile or in the mixture of thereof) at room temperature or under reflux conditions. The compounds of the general formula (I) can also be prepared by using tetrafluorophenol bound to a solid phase polymeric support (for instance polystyrol-divinylbenzene-resin (J. M. Salvino et al. J. Comb. Chem. 2000, 2, 691) to activate the carboxylic acid.
Functional groups of the compounds of the general formula (I) can be transformed into other functional groups (for example the substituents Q, R2, R3, R4, Z, W can be transformed into other Q, R2, R3, R4, Z, W substituents). The carboxylic acids of the general formula (II) -wherein the meaning of Ar and X is as defined above- are in part known from the literature or they can be prepared by methods known from the literature (Figure 2.).
The β-keto-esters of the general formula (IN) are available from the market or they can be synthesized by known methods (Gilman H. et al., J. Am. Chem. Soc. 1948, 70, 2755, Sicker D. et al., Coll. Czech. Chem. Commun. 1988, 53, 839-850, Wierenga W. et al., J. Org. Chem. 1979, 44, 310-311). Reaction of the compounds of the general formula (IN) with NN-dimethylformamide dimethyl acetale can be performed in the presence of solvent (for example in toluene at 60 °C; Herrero M.T. et al., Tetrahedron 2002, 58, 8581), or without solvent at 100-120 °C, or in microwave reactor (10 - 30 W). The enaminoesters of the general formula (N) with Ν-C-Ν dinucleofils, for example with guanidine (VI), amidines (VI), S-methylisothiocarbamide (Nil), O-methylisocarbamide (NM) can be transformed into 2-substituted-pyrimidinecarboxylic acid esters (IX, X, XI) Breaux E. J. et al., J. Heterocyclic Chem. 1981, 18, 183, WO 00/73279). Ring closure can be effected in the presence of base (sodium ethylate or sodium hydrogen carbonate) in ethanol, NN-dimethylformamide or Ν-methylpyrrolidinone, at room temperature or at elevated temperature (80-100°C). The 2-methylsulphanyl group of the compound of the general formula (X) can be oxidized with an oxidating agent (e.g. with 3-chloro-perbenzoic acid) into 2-methylsulphonyl group. The compounds of the general formula (XII) by reacting with a primary or secondary amine, in the presence of a solvent (e.g. in dioxane) can be transformed into the esters of the general formula (IX) -where in the formula X represents a dialkylamino group, alkylamino group, arylamino group, arylalkylamino group, alkyl-arylalkylamino group, hetarylalkylamino group (for example hetarylmethylamino group), alkyl-hetarylalkylamino group (for example methyl- hetarylmethylamino group), amino group, 3,4-dihydro-lH-isoquinolin-2-yl group; the aryl group is a phenyl group optionally containing one or more substituents (e.g. halogen atom, Cι.4-alkyl group, Cι.4-alkoxy group); the hetaryl group is a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms (nitrogen, oxygen or sulphur atom) (for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl group). The esters of the general formula (IX) -where in the formula X represents a dialkylamino group, alkylamino group, arylamino group, arylalkylamino group, alkyl-arylalkylamino group, hetarylalkylamino group (for example hetarylmethylamino group), alkyl-hetarylalkylamino group (for example methyl-hetarylmethylamino group), amino group, 3,4-dihydro-lH- isoquinolin-2-yl group; the aryl group is a phenyl group optionally containing one or more substituents (e.g. halogen atom, Cι.4-alkyl group, Cι.4-alkoxy group); the hetaryl group is a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms (nitrogen, oxygen or sulphur atom) (for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl group) can also be prepared by reacting the ester of the formula (XI) with a primary or secondary amine at elevated temperature (up to 170 °C) in the presence of a solvent or without solvent.
The esters of the general formula (IX) -where in the formula the meanings of Ar and X are as defined above- can be hydrolyzed under acidic or basic conditions into the acids of the general formula (II) -where in the formula the meaning of Ar and X is as defined above.
As for acid e.g. hydrochloric acid, as for base e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate can be used in aqueous ethanol or aqueous methanol.
Figure imgf000022_0001
IX KOH '
Figure imgf000022_0002
II 7igure 2.
The acids of the general formula (II) can also be prepared by a novel method, as shown in Figure 3. The compounds of the general formula (XIII) can be synthesized by known methods, by the base-catalysed condensation of amidines with diethyl ethoxymethylenemalonate. The resulting compounds give with phosphoryl chloride the chloro-compounds of the general formula (XIV) (Dostert P. et al., Eur. J. Med. Chem. Chim. Ther. 1982, 17, 437-444). In the novel process the chloro-compounds of the general formula (XIV) are transformed with aryl-boronic acids in dimethoxyethane, in the presence of tetrakis(triphenylphosphino)palladium catalyst into the compounds of the general formula (IX) -where in the formula Ar and X have the meanings as defined above. The esters of the general formula (IX) are hydrolyzed under acidic or basic conditions, preferably in the presence of base.
Figure imgf000023_0001
XIII XIV
Figure imgf000023_0002
IX Figure 3.
The amines of the general formula (III) -where in the formula the meanings of R, Y, Z, W and Q are defined above- can be purchased on the market or can be synthesized by methods known in the literature. The compounds of the general formula (III) wherein R and Y, together with the nitrogen atom and the carbon atom to which they are attached, form a ring, i.e.xompounds (Ilia), can be prepared according to Figure 4. The compounds of the general formula (XV), where in the formula A represents a CH, NH, N-Boc, N-(Cι. 4)-alkyl group, n = 1, 2, 3 and PG means a protecting group (e.g. a t-butyloxycarbonyl-, trifluoroacetyl-, benzyloxycarbonyl- group, or an other protecting group, see Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc., New York)- can be purchased on the market or can be synthesized by methods known in the literature. (Beak P. et al., J. Org. Chem. 1993, 58, 1109-1117, Brosius A.D. et al., J. Am. Chem. Soc. 1999, 121, 700-709, WO 98/33793, WO 01/00213). The compounds of the general formula (XVI) are those - wherein in the formula M represents a metal atom (e.g. lithium or magnesium atom), B represents a CH group, or a nitrogen atom, R5 means hydrogen atom, hydroxyl group, halogen atom, Cι.4-alkyl group, Cι.4-alkoxy group. The substituent R5 may take o-, m-, or p-position. The reaction of compounds (XV) with compounds (XVI) is performed in an inert solvent, for example in tetrahydrofuran or in ether, at low temperature (between 0 °C and -78 °C ).
Figure imgf000024_0001
Figure 4. The protecting group (e.g. the t-butyloxycarbonyl-, trifluoroacetyl-, benzyloxycarbonyl group) of the compounds of the general formula (XVII) can be removed under acidic conditions (for example with trifluoroacetic acid in dichloromethane, with hydrochloric acid in dioxane or in dichloromethane), under basic conditions (for example with sodium hydroxide in aqueous methanol) or by catalytic hydrogenolysis (e.g. with palladium-on- charcoal catalyst in alcohol or in ethyl acetate).
The pharmaceutically acceptable salts of the compounds of the general formula (I) can be prepared by reacting the bases with the appropriate acids. By solvates of the compounds of the general formula (I) we also mean the hydrates.
The compounds of the general formula (I), as well as their pharmaceutically acceptable derivatives can be used for the treatment of diseases where human orexin receptors play a role, and for the treatment of which orexin receptor antagonists are needed. The orexin receptor antagonistic compounds of the general formula (I), and their pharmaceutically acceptable derivatives may be appropriate for the treatment of obesity and type-II diabetes (non-insuline dependent diabetes), furthermore for the treatment of sleeping disorders, narcolepsy, insomnia, jet-lag syndrome, for the treatment of sleeping disorders connected to neurological disorders, depression, anxiety, behavioral disorders, sexual disorders, neuropathic pain, pains connected to infections (like HIV), phantome pains, post-operative pains. The compounds of the general formula (I), and their pharmaceutically acceptable derivatives may be used for the treatment of stroke, heart- and lung diseases. The compounds of the general formula (I), as well as their pharmaceutically acceptable derivatives can be used for the treatment and prevention of diseases where human orexin receptor antagonists are needed for the treatment. In the course of the therapy the compounds according to the invention are used in the form of pharmaceutical composition.
The pharmaceutical compositions contain the compounds of the general formula (I) or their derivatives together with pharmaceutically acceptable carriers and excipients.
The compounds of the general formula (I), and their pharmaceutically acceptable derivatives can be administered by any of the traditional routes, e.g. by oral, parentheral, sublingual, nasal, rectal, or transdermal routes.
The compounds of the general formula (I) and their pharmaceutically acceptable derivatives may be administered orally, in the forms of solid or liquide formulations, as for instance sirups, suspensions, emulsions, tablets or capsules.
Liquid formulations contain the active component beside an appropriate liquid vehicle (e.g. water, ethanol, glycerine, polyethyleneglycole, oil) in the form of a solution or suspension.
They may also contain colouring and odour agents.
Tablets may contain the usual additives, e.g. magnesium stearate, starch, lactose, sucrose and cellulose.
Hard and soft gelatine capsules can be prepared by the standard operations.
Parenteral formulations contain the active ingredient in the form of a solution or suspension, prepared with a sterile aqueous carrier or with an appropriate oil, as for instance polyethylene glycol, polyvinylpyrrolidone, sesame oil or lecitine.
For nasal application aerosols, drops, gels or powders can be applied. Aerosols contain the active ingredient in the form of an aqueous or non-aqueous solution or suspension, in a closed container, in single or multiple doses.
For rectal application suppositories may be used which contain the usual excipients (e.g. cacao-butter or coconut-butter).
For transdermal application ointments, gels or dermal paches may be used.
The doses of the compounds of the general formula (I) and their pharmaceutically acceptable derivatives used for the treatment or prevention of the above diseases depend on the nature of the disease and in general, a single dose is between 0.05 mg and 1000 mg and the daily dose is between 0.01 mg/kg and 100 mg/kg.
In the above dose regimens the compounds of the general formula (I) are not expected to cause toxic side effects. Chemical Examples
Example 1.
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxy- phenyl)ethyl]methyl amide (L-isomer)
Method A
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.22 g, 5 mmol) is dissolved in tefrahydrofuran (60 ml). After 5 minutes of stirring to the solution are added: L- phenylephrine hydrochloride (1.22 g, 6 mmol) in tefrahydrofuran (50 ml), after another 5 minutes of stirring the N-methylmorpholine (1.21 g, 12 mmol) and after 2 minutes of stirring the 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.66 g, 6 mmol). The reaction mixture is stirred for 2 hours at room temperature, then heated at reflux temperature for 2 hours. The solvent is removed in vacuum. To the residue water (50 ml) is added, and the mixture is extracted with chloroform (75 ml), the exfract is washed with 10 % sodium carbonate solution (35 ml), with water (35 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using chloroform-methanol 100/1-100/5 mixture eluent. 0.36 g of the title compound is obtained, m.p.: 79-81 °C.
According to the process described in Example 1. are prepared the compounds of Tables 1. and 2.
Table 1.
Figure imgf000026_0001
X = Me2Ν, R = Me, Y = H, Z = OH, W = H, Q = m-phenylene, R2 = H, R3 = OH, R4 = H
Figure imgf000027_0001
Figure imgf000028_0001
Table 2.
Figure imgf000028_0002
I Ar = Phenyl, X = Me2N, Y = H, Z = OH, W = H, Q = m-phenylene, R = H, RJ= OH, R =H
Figure imgf000029_0001
Example 17. 4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethylJmethylamide (I) a) Ethyl 4-phenyl-2-methylsulphanylpyrimidine-5-carboxylate The mixture of ethyl benzoylacetate (9.61 g, 50 mmol) and NN-dimethylformamide dimethyl acetal (6.55 g, 55 mmol) was heated in microwave reactor for 10 minutes (30 W, — » 130 °C). To the resulting orange coloured oil ethanol (100 ml), S-methylisothiuronium sulphate (6.96 g, 25 mmol) and sodium ethylate (3.40 g, 50 mmol) were added and the reaction mixture was boiled for 2.5 hours. Ethanol was removed in vacuum, to the residue water (200 ml) was added. The mixture was exfracted with ethyl acetate (3 x 100 ml), the organic phase was dried over sodium sulphate and evaporated. 11.41 g (83 %) yellow oil was obtained. [M+HJ+ 275. b) Ethyl 4-phenyl-2-methanesulphonylpyrimidine-5-carboxylate Ethyl 4-phenyl-2-methylsulphanylpyrimidine-5-carboxylate (6.4 g, 23.3 mmol) was dissolved in dichloromethane (250 ml) and under stirring at 0-5 °C, in a period of 15 minutes, 70% 3-chloroperbenzoic acid (14.36 g, 58.2 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 4 hours; extracted with saturated sodium hydrogencarbonate solution (2 x 250 ml), then with water (2 x 250 ml), dried over sodium sulphate and evaporated. The residue was crystallized with diisopropyl ether (15 ml). 4.57 g (64 %) of the title ester was obtained as white crystals, mp.: 85-86 °C; [M+HJ+ 307 c) Ethyl 4-phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylate The mixture of ethyl 4-phenyl-2-methanesulphonylpyrimidine-5-carboxylate (2.30 g, 7.5 mmol), 2-thienylmethylamine (2.12 g, 18.75 mmol) and dioxane (30 ml) were stirred at room temperature for 16 hours, the solvent was removed in vacuum. To the residue ethanol
(10 ml) was added, the resulting crystals were filtered off in vacuum, washed with ethanol
(5 ml) to obtain 1.99 g (78 %) of the title ester in the form of white crystals, m.p.: 123-124
°C; [M+H]+ 340
d) 4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid
Ethyl 4-phenyl-2-[(thiophen-2-ylmethyl)aminoJpyrimidine-5-carboxylate (1.70 g, 5 mmol) was dissolved in ethanol (10 ml). To the solution potassium hydroxide (0.56 g, 10 mmol) dissolved in 10 ml of water was added and the mixture was refluxed for 3 hours. The solvent was distilled off in vacuum, the residue was dissolved in water (35 ml), acidified to pH = 3 with 10 % hydrochloric acid. The precipitated white crystals were filtered off, washed with water (2 x 20 ml) and dried. 1.52 g (92 %) of the title acid was obtained, m.p.: 212-213 °C; [M+H]+ 312.
e) 4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid [2-hydroxy-
2-(3-hydroxyphenyl)ethylJmethylamide (I)
Method B
4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.49 g, 1.5 mmol) was dissolved in dioxane (35 ml) and to the solution benzotriazol-1-yloxy- tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (0.78 g, 1.5 mmol), D,L- phenylephrine hydrochloride (0.305 g, 1.5 mmol) and ethyldiisopropylamine (0.53 g, 4.1 mmol) were added. The solution was stirred at room temperature for 16 hours, evaporated in vacuum, to the residue water (50 ml) was added, the mixture was exfracted with dichloromethane (50 ml), the organic phase was washed with 10 % sodium hydrogencarbonate solution (15 ml), then with water (3 x 25 ml), dried over sodium sulphate, evaporated, chromatographed on silicagel using ethyl acetate eluent. 0.51 g (74 %) of the title amide was obtained in the form of white crystals, containing 1 mol of water as solvate. M.p.: 85-87 °C; [M+H]+ 461. Example 28.
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-
2-(3-hydroxyphenyl)ethyl]methylamide (L-isomer)(I)
a) 2-(Benzylmethylamino)-4-(2-chlorophenyI)pyrimidine-5-carboxylic acid (II)
Ar = 2-Cl-C6H4, X = Me(C6H5CH2)N
Tetrakis(triphenylphosphino)palladium catalyst (0.25 g, 0.22 mmol) is dissolved under nitrogen atmosphere in dimethoxyethane (20 ml) and to this solution the solution of ethyl- 2-(benzylmethylamino)-4-chloropyrimidine-5-carboxylate (2.75 g, 9.0 mmol) in dimethoxyethane (20 ml) is added. To the resulting mixture 2-chlorophenylboronic acid (1.55 g, 9.9 mmol), sodium carbonate (2.43 g, 23 mmol), dimethoxyethane (20 ml) and water (40 ml) are added. The mixture is stirred at 100°C for 16 hours, cooled to room temperature and after the addition of dichloroethane (100 ml) it is washed with water (100 ml), dried over sodium sulphate and evaporated. The palladium impurities precipitating on the addition of ether, are filtered off, the filtrate is evaporated. 3.13 g of the ester is obtained which is hydrolyzed to the acid without further purification. To the solution of the ester in 95% alcohol (25 ml) the solution of potassium hydroxide (1.12 g, 20.0 mmol) in 95% alcohol (25 ml) is added. The mixture is heated at 80°C for 3 hours, evaporated in vacuum. To the residue water (50 ml) and then 10% hydrochloric acid is added until pH = 5, the mixture is exfracted with dichloromethane (50 ml), the organic phase is dried over sodium sulphate and evaporaetd. 2.77 g (87 %) white coloured title acid is obtained, m.p.: 92 °C; purity by HPLC-MS: 95 %.
b) 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2- hydroxy-2-(3-hydroxyphenyl)ethyl]methylamide (L-isomer) (I)
Method B
The material is prepared according to the method described in Example 17. starting from 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid and L- phenylephrine hydrochloride.M.p.:139 °C. Table 3.
Figure imgf000032_0001
R = Me,Y = H, Z = OH, W = H, Q = m-Phenylene, R2 = H, R3 = OH, R4 = H
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000034_0001
Example 41. 2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-phenylpyrimidine-5-carbonyl) methylaminoj-l -hydroxyethyl} phenyl ester (L-isomer)
The mixture of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methylamide (L-isomer) (0.52 g, 1.32 mmol), pyvaloyl chloride (0.16 g, 1.32 mmol), triethylamine (0.145 g, 1.43 mmol) and dichloromethane (20 ml) is boiled under stirring for 4 hours. The reaction mixture is cooled to room temperature, dichloromethane (15 ml) is added to it, washed with water (3 x 25 ml), dried over sodium sulphate, evaporated and the residie is chromatographed on silica, using ethyl acetate as eluent. 0.36 g (57 %) of white title compound is obtained , m.p.: 145-146 °C; [M+H]+ 477.
The compounds of Table 4. are prepared according to the method described in Example 41. Table 4.
Figure imgf000035_0001
X = Me2N, R = Me, Y = H, Z = OH, W = H, Q = m-phenylene, R2 = H, R3 = (CH3)3CCOO, R4 = H Ar Mp (°C) 76-77
Example 41. White crystals 145-146
Example 42. 79-83 Pale-yellow crystals 2 mol H2O
Example 43. 116-118 Yellow crystals 1 mol H2O
Example 44. 52-57 Yellow crystals 1.5 mol H2O
Example 45. 123-124 White crystals
Example 46. 72 Pale-yellow crystals ( HCl-salt
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000037_0003
Example 59. 2-Dimethylamino-4-(3,4-dichIorophenyl)pyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-hydroxyethyl]methylamide (I) The mixture of 2-dimethylamino-4-(3,4-dichlorophenyl)pyrimidine-5-carboxylic acid [2- hydroxy-2-(3-hydroxyphenyl)ethyl]methylamide (0.92 g, 2 mmol), benzylbromide (1.71 g, 10 mmol), cesium carbonate (1.30 g, 4 mmol) and acetonitrile (25 ml) are boiled under stirring for 5 hours. The reaction mixture is evaporated in vacuum, dichloromethane (50 ml) is added to it, washed with water (3 x 50 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel, using dichloromethane - methanol 100/1 mixture as eluent. 0.50 g (45.4 %) of pale-yellow crystalline material is obtained , m.p.: 68-70 °C; [M+HJ+ 551.
The compounds of Tables 5 and 6. are prepared according to the method described in Example 59. Table 5.
Figure imgf000037_0002
R = Me,Y = H, Z = OH, W = H, Q = m-phenylene, R2 = H, R3 = OCH2Ph, R4 = H
Figure imgf000037_0004
Figure imgf000038_0001
Table 6.
Figure imgf000038_0002
I Ar = 4-Pyridyl, X = Me2N, Y = H, Z = OH, W = H, Q = m-phenylene, R2 = H, R4 = H
Figure imgf000039_0001
Example 74. 4-Phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy-l- methyl-2-phenylethyl)methylamide (I) Method B Starting from 4-phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.48 g, 1.5 mmol) and (lR,2S)-2-methylamino-l -phenyl- 1-propanol [(-)-ephedrine] (0.25 g, 1.5 mmol) according to the method described in Example 17. the title amide 0.42 g (58 %) is obtained as white crystalline matrerial; m.p.: 82 °C; [M+HJ+ 468.
The compounds of Table 7. are prepared according to the process described in Example 74. Table 7.
Figure imgf000040_0001
I R = Me, Y = Me, Z = OH, W = H, Q = Phenyl, R2 = H, R3 = H, R4 = H
Figure imgf000040_0002
Figure imgf000041_0001
Example 85. 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2-{3-[(pyridine- 2-carbonyl)amino] phenyl} ethyl)methylamide (I) Ar = Phenyl, X = Me2N, R = Me, Y = H, Z = OH, W = H, R2 = H, R3 = 2-Pyridyl-CONH, R4= H Method C (Table 8.) 300 mg PS-TFP resin (0.39 mmol, 1.30 mmol/g) is swelled in NN-dimethylformamide (3 ml) at room temperature for 5 minutes, then 2-picolinic acid (99 mg, 0.80 mmol), 4- (dimethylamino)pyridine (15 mg, 0.12 mmol) and diisopropyl carbodiimide (125 μl, 0.80 mmol) are added to it. The mixture is srirred at room temperature for 20 hours. The resin is filtered off, washed with NN-dimethylformamide, with tefrahydrofuran and finally with dichloromethane (3 x 10-10 ml). The reagent resin is then swelled in 2 ml of NN-dimethylformamide for 5 minutes under stirring, then 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-aminophenyl)- 2-hydroxyethyl]methylamide (39 mg, 0.10 mmol) is added to it. The mixture is srirred at room temperature for 20 hours. The resin is filtered off, washed with NN- dimethylformamide (2 x 1 ml). To the resulting solution ethyl acetate (15 ml) is added and the mixture is extracted with 5% citric acid (3 x 7 ml), then with water (7 ml). The organic phase is dried over sodium sulphate and evaporated. The resulting solid material is digerated with a small amount of water and the resulting white crystalline material is filtered off. 26 mg (52%) of the title compound is obtained, m. p.: 111°C. Purity by HPLC- MS: 97%.
The compounds of Table 8. are prepared according to the process described in Example 85. Table 8.
Figure imgf000042_0001
I X = Me2N, R = Me, Y = H, Z OH, W = H, Q = m-phenylene, R2 = H, R3 = NHCOR6, R4 = H
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
Example 107. 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2- [3-(3-te«'-butylureido) phenyl]-2-hydroxyethyl} methylamide (I) Ar = Phenyl, X = Me2N, R = Me, Y = H, Z = OH, W = H, R2 = H, R3 = t-BuNHCONH, R4 = H (Table 9.) To the solution made of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3- aminophenyl)-2-hydroxyethylJmethylamide (200 mg, 0.51 mmol) and NN- dimethylformamide (2 ml), at room temperature tert-butyl isocyanate (60 μl, 0.52 mmol) is added. The reaction mixture is stirred at 60°C for 20 hours, then ethyl acetate (15 ml) is added and the mixture is extracted with 5% citric acid solution (3 x 7 ml) and with water (7 ml). The organic phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using ethyl acetate as eluent. 0.15 g (60%) of the title carbamide is obtained in the form of white crystals; m.p.: 139°C; purity by HPLC-MS: 99%.
The compounds of Table 9. are prepared according to the process described in Example 107. Table 9.
Figure imgf000045_0001
X = Me2N, R = Me, Y = H, Z = OH, W = H, Q = m-phenylene, R2 = H, R3 = NHCONHR7, R4 = H
Figure imgf000045_0002
Figure imgf000046_0002
The compounds of Table 10. are prepared according to method B (PyBOP). Table 10.
Figure imgf000046_0001
I Ar = Phenyl, R = Me, Y = H, Z = OH, W = H, Q = m-phenylene
Figure imgf000046_0003
Figure imgf000047_0001
Figure imgf000048_0001
Example 139. 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- fluoroethyl]methylamide (I) Ar = Phenyl, X = Me2N, R = Me, Y = H, Z = F, W = H, R2 = H, R3 = OCH2C6H5, R4 = H (Table 11.) To the solution of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-hydroxyethyl]methylamide (0.30 g, 0.62 mmol) in dichloromethane (2 ml) under nitrogen atmosphere at -78°C the solution of (diethylamino)sulphur frifluoride
(DAST) (132 μl, 1.0 mmol) in dichloromethane (2ml) is added dropwise, in a period of 2 minutes. The mixture is allowed to warm up to room temperature, stirring is continued for additional 2 hours, then cooled to 0°C and carefully reacted with a small amount of water.
The reaction mixture is extracted with water, then with dichloromethane (20-20 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using ethyl acetate as eluent. 0.08 g (27%) of the light drab coloured title compound was obtained, m.p.: 75 °C.
Example 140.
2-Dimethylamino-4-phenylpyrimidine carboxylic acid [2-(3-hydroxyphenyl)-2- oxoethyl] methylamide
Ar = Phenyl, X = Me2N, R = Me, Y = H, W and Z together C=O, R2 = H, R3 = OH, R4 = H (Table 11.)
The mixture of 2-dimethylamino-4-phenylpyrimidinecarboxylic acid [2-(3- hydroxyphenyl)-2-hydroxyethylJmethylamide (0.21 g, 0.54 mmol) and pyridinium dichromate (1.0 g, 2.66 mmol) in dichloromethane (5 ml) is stirred at room temperature for 4 hours. To the suspension ether (20 ml) is added, the mixture is filtered through celite, evaporated, chromatographed on silicagel using chloroform, then chloroform : ethyl acetate 4:1, 2:1, lmixtures as eluents. 0.08 g (38 % white crystalline amide was obtained; m.p.: 106 °C.
Example 144.
(2-Dimethylamino-4-phenylpyrimidin-5-yl)-[2-(3-hydroxyphenyl)morphoIin-4-ylJ- methanone
Ar = Phenyl, X = Me2N, R and Z together CH2CH2O, Y = H, W = H, R2 = H, R3 = OH, R4 = H
a) l-(3-Benzyloxyphenyl)-2-(2-hydroxyethylamino)ethanol
To the solution of l-(3-Benzyloxyphenyl)-2-bromomethanone (4.58 g 15 mmol) in methanol (80 ml) under ice-water cooling, sodium borohydride (2.80 g, 74 mmol) is added in small portions in a period of 30 minutes. The mixture is stirred at 0 °C for 30 minutes, then at room temperature for 1 hour. The reaction mixture is evaporated, chloroform (50 ml) is added to it, and washed with 2 % hydrochloric acid solution (50ml) then water (50 ml), dried over sodium sulphate and evaporated to obtain l-(3-benzyloxyphenyl)-2- bromomethanol (3.43 g) in the form of yellow oil, purity by HPLC-MS: 90%. To the crude product ethanolamine (20 ml) is added and the mixture is stirred at 90 °C for 3 hours. After cooling, ethyl acetate (80 ml) is added to the mixture and washed with water (3 x 100 ml). From the organic phase the product is extracted with diluted hydrochloric acid. Following alkalinisation with sodium carbonate, the aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulphate and evaporated. 1.55 g of l-(3- benzyloxyphenyl)-2-(2-hydroxyethylamino)ethanol is obtained in the form of yellow- coloured solid, m.p.: 114 °C, after recrystallisation from ethyl acetate (15 ml).
b) 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- hydroxyethyl]-(2-hydroxyethyl)amide
To activated 2-dimethylamino-4-phenylpyrimidine-5 -carboxylic acid (1.48 g, ~1 mmol/g, 1.48 mmol) bound to PS-TFP resin, NN-dimethylformamide (20 ml), then after 5 minutes of swelling l-(3-benzyloxyphenyl)-2-(2-hydroxyethylamino)ethanol (0.40 g, 1.39 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours, then filtered and washed consecutively with 50-50 ml of NN-dimethylformamide, tefrahydrofuran and dichloromethane. After evaporation the resulting oil (0.36 g) is chromatographed on silicagel using chloroform, and chloroform - ethyl acetate 9:1, 4:1 mixtures as eluents. 0.21 g of the title amide is obtained as white solid material, m.p.: 89 °C.
c) (2-Dimethylamino-4-phenylpyrimidin-5-yl)-[2-(3-hydroxyphenyl)morpholin-4-yl]- methanone
To 2-dimethylamino-4-phenylpyrimidin-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- hydroxyethyl]-(2-hydroxyethyl)amide (0.20 g, 0.39 mmol) 48% hydrogen bromide solution (4 ml) is added. The mixture is heated at 100 °C for 1 hour, cooled to room temperature, poured onto water and neutralized (pH = 7) with sodium carbonate solution. The precipitate is filtered off, washed with water and dried. The crude product is chromatographed on silicagel using chloroform and chloroform - ethyl acetate 9:1 mixture as eluent. 0.023 g light-yellow title compound is obtained, m.p.: 140 °C.
Example 145.
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- chloroethyl] methylamide Ar = Phenyl, X = Me2N, R = Me, Y = H, Z = Cl, W = H, R2 = H, R3 = OCH2C6H5, R4 = H
(Table 11.)
To the solution of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-hydroxyethyl]methylamide (1.0 g, 2.07 mmol) in toluene (20 ml), thionyl chloride (1.0 ml) is added. The reaction mixture is stirred at 40°C for 1 hour and evaporated in vacuum. 1.0 g (96%) pale-yellow crystalline amide is obtained, m.p.: 65 °C.
Example 146.
2-Dimethylamino-4-phenyIpyrimidine-5-carboxylic acid [2-amino-2-(3- benzyloxyphenyl)ethyl]methylamide
Ar = Phenyl, X = Me2N, R = Me, Y = H, Z = NH2, W = H, R2 = H, R3 = OCH2C6H5, R4 = H
(Table 11.)
To the solution of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-chloroethylJmethylamide (0.64 g, 1.28 mmol) in NN- dimethylformamide (13 ml), phthalimide potassium (0.36 g, 1.92 mmol) is added, the reaction mixture is stirred at room temperature for 16 hours, then water (70 ml) is added to it. The precipitated material is filtered off, washed thoroughly with water and dried (0.97 g). To this material ethanol (8 ml) and hydrazine hydrate (121 μl, 2.5 mmol) are added and the mixture is heated at 80°C for 2 hours. After cooling the resulting white precipitate is filtered off, the filtrate is evaporated; the residue is dissolved in ethyl acetate and washed with water (50 ml). From the organic phase the product is extracted with 5% cifric acid solution (3 x 50 ml) in the form of its salt, the aqueous phase is then alkalinized (pH=9), extracted with dichloromethane, dried over sodium sulphate and evaporated. 0.40 g (65%) of white crystalline material is obtained, m.p.: 147 °C.
Example 148.
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzyIoxyphenyl)-2- hydroxypropyl] methylamide
Ar = Phenyl, X = Me2Ν, R = Me, Y = H, Z = OH, W = Me, R2 = H, R3 = OCH2C6H5, R4 =
H
(Table 11.)
To the solution of 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3- benzyloxyphenyl)-2-oxoethylJmethylamide (0.60 g, 1.25 mmol) in tefrahydrofuran (15 ml, under nitrogen atmosphere and ice-water cooling methylmagnesium bromide 3 mol/1 solution in diethyl ether (3 ml, 9.0 mmol) is added. The reaction mixture is stirred at 0°C for 1 hour, then at room temperature for 24 hours. The mixture is poured onto ice, 5% cifric acid solution (50 ml) is added to it, the mixture is extracted with ethyl acetate (50 ml), the organic phase is dried over sodium sulphate, evaporated, the residue is chromatographed on silicagel using ethyl acetate as eluent. 0.10 g (16%) white crystalline title compound is obtained, m.p.: 68 °C. Purity by HPLC-MS: 99 %.
Table 11.
Figure imgf000052_0001
(I) Ar = Phenyl, X = Me2N, Y = H, Q = m-phenylene
Figure imgf000052_0002
Figure imgf000053_0001
Example 149. (±) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxyphenylmethyl) piperidin-1-yl] methanone (I) Ar =phenyl, X = Me(C6H5CH2)N, R and Y together -(CH2)4-, R2 = R3 = R4 = H (Table 12.) a) Ethyl (2-benzoyl-3-dimethylamino)acrylate (V) (Herrero, M. T. et al, Tetrahedron 2002, 58(42), 8581-8589 The mixture of ethyl benzoylacetate (25g, 117 mmol) and NN-dimethylformamide dimethyl acetal (18.2 ml, 128 mmol) is stirred at 110°C in microwave reactor (50W) for 40 minutes. After evaporation in vacuum 29 g (100 %) of the title compound is obtained, which is used without further purification. LC/MS: [MH+] 248.3 (C,4Hι7ΝO3 247.292) b) Ethyl 4-phenyl-2-methoxypyrimidine-5-carboxylate (XI)
Ar = phenyl, X = MeO
The mixture of ethyl 2-benzoyl-3-(dimethylamino)acrylate (57.9g, 234.12 mmol), O-methylisocarbamide sulphate (35g, 284.68 mol), sodium hydrogencarbonate (23.9g, 284.68 mmol) and N-methylpyrrolidinone (647 ml) is heated at 80 °C for 12 hours. To the reaction mixture ethyl acetate and water are added, the organic phase is washed with hydrochloric acid solution, dried over sodium sulphate, evaporated in vacuum, chromatographed on silicagel using dichloromethane - heptane solvent mixture as eluent. 28 g (46 %) of the title compound was obtained. LC/MS [MH+] 259.1 (Cι4H,4Ν2O3 258.276)
c) Ethyl 2-(benzylmethylamino)-4-phenylpyrimidine-5-carboxylate (IX)
Ar = phenyl, X = Me(C6H5CH2)N
The mixture of ethyl-4-phenyl-2-methoxypyrimidine-5-carboxylate (28 g, 108.41 mmol) and benzylmethylamine (70 ml, 542 mmol) is stirred in microwave reactor (200W) at 170
°C for 40 minutes. To the mixture dichloromethane is added, washed with hydrochloric acid solution, dried over sodium sulphate, evaporated in vacuum, chromatographed on silicagel using dichloromethane - heptane solvent mixture as eluent. 4.74 g (12 %) of the title compound is obtained.
Η-NMR δ: 1.05 (t, 3H), 3.15 (s, 3H), 4.1 (q, 2H), 4.95 (s, 2H), 7.1-7.55 (m, 10H), 8.8 (s,
1H).
d) 2-(BenzyImethylamino)-4-phenylpyrimidine-5-carboxylic acid (II)
Ar = phenyl, X = Me(C6H5CH2)N
The mixture of ethyl 2-(benzylmethylamino)-4-phenylpyrimidine-5-carboxylate (4.74 g,
13.64 mmol), potassium hydroxide (2.7 g, 40.93 mmol), ethanol (90 ml) and water (100 ml) is stirred at 80 °C for 2 hours. The reaction mixture is poured onto 3N hydrochloric acid solution. The precipitated material is filtered off, dried at 40 °C for 12 hours.
4.24 g, (97 %) of the title compound is obtained.
Η-NMR δ: 3.18 (s, 3H), 4.84 (s, 2H), 6.9-7.5 (m, 10H), 8.8 (s, 1H).
e) (±) Anti-terf-butyI-2-(hydroxyphenylmethyl)piperidine-l-carboxylate (XVII)
A = CH2, B = CH, R5 = H, n = 1, PG = Boc To the solution of bromobenzene (1.11 ml, 7.03 mmol) in dry tefrahydrofuran (35 ml) at
-78 °C, under nitrogen atmosphere, the solution of butyl lithium in hexane (2.5 N, 4.22 ml, 10.55 mmol) is added. The solution is stirred at -78°C for 10 minutes, then tert-butyl-
2-formylpiperidine-l-carboxylate (1.5 g, 7.03 mmol) dissolved in tefrahydrofuran (5 ml) is added to it. The reaction mixture is allowed to warm up to room temperature, stirred for 1 hour, poured onto water - ethyl acetate mixture. The aqueous phase is extracted with ethyl acetate (2 x 50 ml), the organic phase is washed with water, dried over sodium sulphate, evaporated in vacuum and chromatographed on silicagel using ethyl acetate / heptane solvent mixture as eluent. 0.305 g (15 %) of the title compound is obtained.
LC/MS [MH+] 292.4 (Cι7H25NO3 291.388)
Η-NMR δ: 1.15 (s, 9H), 1.3-1.8 (m, 4H), 1.95-2.15 (bd, 1H), 2.15-2.3 (bs, 1H), 2.78 (dt,
1H), 3.75-4 (bd, 1H), 4.15-4.3 (m, 1H), 4.9 (dd, 1H), 7.1-7.35 (m, 5H).
f) (±) Anti-phenylpiperidin-2-ylmethanol (Ilia)
A = CH2, B - CH, R5 - H, n = 1
(Journal of Organic Chemistry (1990), 55(9), 2578-80).
The mixture of (±) Anti tert-butyl-2-(hydroxyphenylmethyl)piperidin-l-carboxylate (0.485 g, 1.66 mmol) and trifluoroacetic acid (1.92 ml, 24.97 mmol) is stirred at room temperature for 1 hour. Water and IN aqueous sodium hydroxide solution is added to it and the mixture is extracted twice with dichloromethane. The organic phase is washed with water, dried, evaporated in vacuum. 0.243 g, (76 %) of the title compound is obtained.
1H-ΝMR δ: 1-1,8 (m, 6H), 2.4-2.7 (m, 2H), 2.8-3.1 (m, 1H), 4.53 (d, 1H), 7.1-7.4 (m, 5H).
g) (±) Anti- [2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxyphenyl methyl)piperidin-l -yl] methanone (I)
Ar = phenyl, X = Me(C6H5CH2)N, R and Y together -(CH2)4-, R2 = R3 = R4 = H The mixture of 2-(benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (0.149 g, 0.47 mmol), (±) anti-phenylpiperidin-2-ylmethanol (0.089 g, 0.47 mmol), l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (0.178 g, 0.93 mmol), 1- hydroxybenzotriazole (0.126 g, 0.93 mmol), triethylamine (0.13 ml, 0.93 mmol), acetonitrile (12 ml) and dichloromethane (6 ml) is stirred at room temperature for 12 hours, then poured onto water - ethyl acetate mixture. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuum. The residue is chromatographed on silicagel using ethyl acetate - heptane solvent mixture as eluent. 0.305g (15 %) of the title amide is obtained.
LC/MS [MH+] 493 (C31H32N4O2 492.62)
Example 150.
(Table 12.)
(±) Anti- [2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- methoxyphenyl)methylJpiperidin-l-yl}methanone (I)
Ar = phenyl, X = Me(C6H5CH2)N, R and Y together -(CH2)4-, R2 = H, R3 = OH, R4 - H
a) (±) Anti-tørt-butyl 2-[hydroxy-(3-methoxyphenyl)methyl]piperidin-l-carboxylate (XVII)
A = CH2, B = CH, R5 = 3-MeO, n = 1, PG - Boc
The title compound (0.243 g) was prepared starting from tert-butyl-2-formylpiperidin-l- carboxylate (1.5 g) and 3-methoxybromobenzene (1.34 ml) according to the method described in Example 149e).
LC/MS [MH+] 322.4 (C,8H27NO4 321.414)
Η-NMR δ: 1.12 (s, 9H), 1.3-1.75 (m, 3H), 1.95-2.15 (bd, 1H), 2.1-2.3 (bs, 1H), 2.78 (dt,
1H), 3.72 (s, 3H), 3.75-4 (bd, 1H), 4.15-4.3 (m, 1H), 4.85 (dd, 1H), 6.7-6.9 (m, 3H), 7.12
( , 1H).
b) (±) Anti-(3-methoxyphenyl)piperidin-2-ylmethanol (Ilia)
A = CH2, B = CH, R5 = 3-MeO, n = 1
(European Journal of Medicinal Chemistry (1980), 15(2), 111-17. WO 02/34718)
The title compound (0.160 g) was prepared starting from (±) anti-tert-butyl 2-[hydroxy-(3- methoxyphenyl)methyl]piperidine-l -carboxylate (0.243 g) according to the method described in Example 149f).
LC/MS [MH+] 222, (C,3H19NO2 221.298)
Η-NMR δ: 1.1-2.1 (m, 6H), 2.45-2.75 (m, 2H), 2.9-3.1 (m, 1H), 3.74 (s, 3H), 4.48 (d, 1H),
6.7-6.9 (m, 3H), 7.2 (d, 1H).
c) (±) Anti [2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3-methoxy- phenyl)methyl]piperidin-l-yl}methanone (I) The title compound (0.170 g) was prepared starting from 2-(benzylmethylamino)-4- phenylpyrimidine-5 -carboxylic acid (0.283 g) and (±) Anti-(3-methoxyphenyl)piperidin-2- ylmethanol (0.196 g) according to the method described in Example 149g). LC/MS) [MH+] 523; (C32H34N4O3 522.646)
Example 151.
(Table 12. )
(+) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- hydroxyphenyl)methyl]piperidin-l-yl}-methanone (I)
Ar = phenyl, X = Me(C6H5CH2)N, R and Y together -(CH2)4-, R2 = H, R3 = OH, R4 = H To the solution of (+) Anti [2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy- (3 -methoxy-phenyl)methyl]piperidin-l -yljmethanone (0.066 g, 0.13 mmol) in dichloromethane (3 ml) is added at -60 °C the dichloromethane solution of boron fribromide (IN, 0.95 ml, 0.95 mmol). The resulting solution is stirred at -15 °C for 2 hours, then poured onto the mixture of water and dichloromethane. The aqueous phase is extracted twice with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using ethyl acetate - heptane solvent mixture as eluent. 0.047 g (73 %) title compound is obtained. LC/MS [MH+] 509; (C3ιH32N4O3 508.619)
Example 152.
(Table 12.)
(±) Anti- [2-(Benzylmethylamino)-4-phenylpyrimidin-5-yl]- { 2-[(3-fluorophenyl)- hydroxymethyl]piperidin-l-yl}methanone (I)
Ar = phenyl, X = Me(C6H5CH2)N, R and Y together -(CH2)4-, R2 = H, R3 = F, R4 = H a) (±) Anti -tert-butyl 2-[(3-fluorophenyl)hydroxymethyl]piperidin-l-carboxylate
(XVII)
The title compound (0.207 g) was prepared starting from tert-butyl-2-formylpiperidine-l- carboxylate (1.79 g) and 3-fluorobromobenzene (1.41 ml) according to the method described in Example 149e).
LC/MS [MH+] 310.1; (C,7H24FNO3 309.379)
Η-NMR δ: 1-1.25 (s, 9H), 1.3-1.75 (m, 3H), 1.95-2.15 (bd, 1H), 2.2-2.5 (bs, 1H), 2.68 (dt,
1H), 3.75-3.95 (bd, 1H), 4-4.2 (m, 1H), 4.75 (dd, 1H), 6.7-7.15 (m, 4H). b) (±) Anti-(3-fluorophenyl)piperidin-2-ylmethanol (Ilia)
(US 4,260,623)
The title compound (0.122 g) was prepared starting from (±) anti- tert-butyl 2-[(3- fluorophenyl)hydroxymethyl]piperidin-l -carboxylate (0.27 g) according to the method described in Example 149f).
LC/MS [MH+] 210, (C,2H,6FNO2 209.262)
c) (±) Anti-[2-(Benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-fIuorophenyl)- hydroxymethyl]piperidin-l-yl}methanone (I)
The title compound (0.053 g) was prepared starting from 2-(benzylmethylamino)-4- phenylpyrimidine-5-carboxylic acid (0.122 g) and (±) anti-(3-fluorophenyl)piperidin-2- ylmethanol (0.186 g) according to the method described in Example 149g). LC/MS [MH+] 511; (C3ιH3ιFN4O2 510.61)
Example 153.
(Table 12.)
(±) Anti-[2-(Benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-3-yl- methyl)piperidin-l-yl]methanone
a) (±) Anti -tert-buty\ 2-(hydroxypyridin-3-ylmethyl)piperidin-l-carboxylate (XVII)
To the solution of 3-bromopyridine (0.54 ml, 5.58 mmol) in dry tefrahydrofuran (6 ml) is added at room temperature the tefrahydrofuran solution of t-propyl magnesium chloride (2N, 0.54 ml, 5.58 mmol). The reaction mixture is stirred at room temperature for 2 hours, then the solution of tert-butyl 2-formylpiperidine-l -carboxylate (1.19 g, 5.58 mmol) in tefrahydrofuran (6 ml) is added to it and stirring is continued for 12 hours. The reaction mixture is poured onto the mixture of water and dichloromethane. The aqueous phase is exfracted twice with dichloromethane (2 x 50 ml). The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using ethyl acetate - heptane solvent mixture as eluent. 0.478 g (40 %) title compound is obtained. Η-NMR δ: 1.38 (s, 9H), 1-1.95 (m, 4H), 2.2-2.32 (bd, 1H), 2.94 (dt, 1H), 3.05-3.3 (bs,
1H), 4-4.2 (bd, 1H), 4.4-4.55 (m, 1H), 5.15 (dd, 1H), 7.34-7.48 (m, 1H), 7.9 (d, 1H), 8.6-
8.75 (m, 2H).
b) (±) Anti-piperidin-2-yl-pyridin-3-ylmethanol (Ilia)
The title compound (0.17 g) was prepared starting from (±) anti-tert-butyl 2-(hydroxy- pyridin-3-ylmethyl)piperidine-l -carboxylate (0.478 g) according to the method described in Example 149f).
Η-NMR δ: 1-1.8 (m, 6H), 2.2-2.8 (m, 5H), 3 (d, 1H), 4.6 (d, 1H), 7.1-7.25 (m, 2H), 7.6 (d, 1H), 8.3-.5 (m, 2H).
c) (±) Anti-[2-(Benzylmethylamino)-4-phenyIpyrimidin-5-yl]-[2-(hydroxypyridin-3-yl- methyl)piperidin-l-yl]methanone (I)
The title compound (0.13 g) was prepared starting from 2-(benzylmethylamino)-4- phenylpyrimidine-5 -carboxylic acid (0.232 g) and (±) anti-piperidin-2-yl-pyridin-3- ylmethanol (0.139 g) according to the method described in Example 149g) LC/MS [MH+] 494; (C30H3jN5O2 493.6)
Example 154.
Table 12.)
(±) Anti-[2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidin-5-yl]-[2-
(hydroxyphenyImethyl)piperidin-l-yl]methanone (I)
a) Ethyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate (V)
(EP 0 638 557 Al)
The title compound (31 g) was prepared starting from ethyl 2-chlorobenzoylacetate (25 g) according to the method described in Example 149a).
LC/MS [MH+] 282.2 (C,4H16ClNO3 281.737)
b) Ethyl 4-(2-chIorophenyl)-2-methoxypyrimidine-5-carboxylate (XI)
The title compound (12.96 g) was prepared starting from ethyl 2-(2-chlorobenzoyl)-3- (dimethylamino)acrylate (31 g) according to the method described in Example 149b). LC/MS [MH+] 293.3 (Cι4H13ClN2O3 292.721) Η-NMR δ: 1 (t, 3H), 4.05 (s, 3H), 4.1 (q, 2H), 7.2-7.4 (m, 4H), 9.05 (s, 1H).
c) Ethyl 2-(benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylate (IX) The title compound (2.69 g) was prepared starting from ethyl 4-(2-chlorophenyl)-2- methoxypyrimidine-5-carboxylate (12.96 g) according to the method described in Example. 149c).
Η-NMR δ: 1.15 (t, 3H), 3.3 (s, 3H), 4.2 (q, 2H), 5.05 (bs, 2H), 7.1-7.6 (m, 9H), 9.08 (s, 1H).
d) 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxyIic acid (II)
The title compound (1.55 g) was prepared starting from ethyl 2-(Benzylmethylamino)-4- (2-chlorophenyl)pyrimidine-5-carboxylate (2.69 g) according to the method described in Example 149d). Η-NMR δ: 3.13 (bs, 3H), 4.88 (bs, 2H), 7-7.4 (m, 9H), 8.92 (s, 1H).
e) (±) Anti-[2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidin-5-yl]-[2- (hydroxyphenylmethyl)piperidin-l-yl]methanone (I)
The title compound (0.068 g) was prepared starting from 2-(benzylmefhylamino)-4-(2- chlorophenyl)pyrimidine-5-carboxylic acid (0.298 g) and (±) anti-phenyl-piperidin-2- ylmethanol (0.161 g) according to the method described in Example 149e). LC/MS [MH+] 527 (C3,H3,ClN4O2 526)
Example 155.
(Table 12.)
(±) Anti-[2-(benzyImethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-2- ylmethyl)piperidin-l-yl]methanone
a) (±) Anti -tert-butyl 2-(hydroxypyridin-2-ylmethyl)piperidine-l-carboxylate (XVII)
The title compound (0.11 g) was prepared starting from tert-butyl 2-formylpiperidine-l- carboxylate (1.5 g) and 2-bromopyridine (0.67 ml) according to the method described in Example 153a).
Η-NMR δ: 1.1 (s, 9H), 1-1.9 (m, 4H), 2-2.2 (m, 1H), 3 (t, 1H), 3.9-4.2 (m, 2H), 4.5 (d, 1H), 4.9 (t, 1H), 7-7.25 (m, 2H), 7.55 (t, 1H), 8.5 (d, 1H). LC/MS [MH+] 293.3; (C16H24N2O3 292.3) b) (±) Anti -piperidin-2-yl-pyiridin-2ylmethanol (Ilia) The title compound (0.057 g) was prepared starting from (±) anti -tert-butyl 2-(hydroxy- pyridin-2-ylmethyl)piperidine-l -carboxylate (0.11 g) according to the method described in Example 149f). Η-NMR δ: 1-2 (m, 6H), 2.45-2.75 (m, 1H), 2.8-2.95 (m, 1H), 3-3.2 (m, 1H), 4.63 (d, 1H), 7.1-7.4 (m, 3H), 7.55-7.7 (m, 1H), 8.45-8.55 (m, 1H). c) (±) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-2- ylmethyl)piperidin-l-yl]methanone (I) The title compound (0.03g) was prepared starting from 2-(benzylmethylamino)-4- phenylpyrimidine-5-carboxylic acid (0.095 g) and (±) anti-piperidin-2-yl-pyridin-2- ylmethanol (0.057 g) according to the method described in Example 149g). LC/MS [MH+] 494; (C3oH31N5O2 493)
Table 12.
Figure imgf000061_0001
Ar = Phenyl, X = Me(C6H5CH2)N
Figure imgf000061_0002
Example 150.
Figure imgf000062_0001
85-90
Example 151. OH 105-115
Example 152.
Figure imgf000062_0002
92-105
Example 153. 92-106
Example 154. 85-105
Example 155.
Figure imgf000062_0003
113-130
Compounds of Table 12A were prepared according to method B described in Example 17e) Table 12 A.
Figure imgf000062_0004
I R = Me, Y = H, Z = OH, W = H
Figure imgf000062_0005
Figure imgf000063_0001
Figure imgf000064_0001
Table 12B.
Figure imgf000064_0002
Figure imgf000064_0003
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Table 13.
Figure imgf000068_0001
IX
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0003
Table 14.
Figure imgf000071_0001
II
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Biological screening method
In vitro radioligand binding assays were used for determination of the affinities of the compounds for both the orexin- 1 and orexin-2 receptors.
In the frame of hr-125I-orexin-A radioligand competition (displacement) experiments a fixed concentration of hr-125I-orexin-A is incubated with increasing concentrations of unlabeled test compound in the presence of highly purified plasmamembranes bearing either the human recombinant orexin- 1 (hr-OX-1) or the human recombinant orexin-2 (hr- OX-2) receptors. Specific binding of hr-125I-orexin-A to plasmamembranes is measured at each concentrations of the unlabeled compound and thus a competition curve is generated. The concentration of unlabeled compound displacing 50% of specific binding (IC50) is calculated. In case of competitive interaction the binding affinity constant of the unlabeled compound (K ) is calculated according to the Cheng-Prusoff equation (Kj = IC5o/(l + L*/KD). Affinity of unlabeled compound for the receptor is equal to 1/Kι.
In vitro cell culturing and preparation of highly purified plasmamembrane fractions containing orexin receptors
Culturing the Chinese hamster ovarian cells expressing human recombinant orexin -1 or orexin-2 receptor proteins (CHO-hr-OX- 1 or CHO-hr-OX-2 cells) was carried out in cell culture medium (MEM medium, supplemented with 40 mg/1 prolin, 20 mg/1 gentamycin, 300 mg/1 geneticin, 10% dialysed fetal calf serum).
We have worked out a new method for the separation of plasmamembrane fractions enriched in orexin- 1 or orexin-2 receptor proteins.
Adherent cells were plated into Greiner flasks (175 cm2). 4-6 days later culture medium was removed and cells were scarped in calcium- and magnesium-free phosphate buffered saline (PBS, 20 ml/flask). The cell suspension was cenfrifuged at 1,000 g for 5 minutes (4°C). The resulting pellet was resuspended and homogenized with a teflon pestle (4°C), then layered onto a discontinous sucrose gradient and cenfrifuged at 105,000 g. Plasmamembrane fraction accumulated in the interface between 14 and 34% sucrose layers was separated and pelleted by a further centrifugation step at 105,000 g for 60 min (4°C). The final pellet was resuspended in binding assay buffer and stored at -80°C up to the day of radioligand binding experiment. In vitro 125I-orexin-A binding
For 125I-orexin-A competition binding studies, ahquots of cellmembrane fractions containing either hr-orexin-1 or hr-orexin-2 receptors were incubated with I25I-orexin-A in binding assay buffer at 25°C for 60 minutes. Nonspecific binding was defined by 1 μM hr- orexin-A in both cases.
Test compounds were dissolved at a concentration of 1 mM in dimethylsulfoxide (DMSO). Serial dilution series were prepared from stock solutions (100% DMSO) with binding assay buffer in such a way that each samples contained a final concentration of 1% of DMSO in the receptor binding reaction mixture. After the incubation, samples were filtered through Whatman GF/C glass fibre filters using a SKATRON cell harvester, and the filters were washed with 5 ml of ice-cold buffer. The radioactivity remained on the filter was counted in a gamma counter (Wallac Automatic Gamma Counter 1470 Wizard).
Abbreviations: EGTA ethylene glycol - bis(β-aminoethyl ether)-NNN',NPtetraacetic acid Tris tris-(hydroxymethyl)aminomethane HEPES N-2-hydroxyethylpiperazine-N-2-ethanesulphonic acid

Claims

Claims
1. The compounds of the general formula (I)
Figure imgf000078_0001
-wherein
X stands for Cι.4-alkyl group; amino group - optionally substituted with one or two C alkyl group; Cι_4-alkyl-S-group; saturated or partially saturated mono- or bicyclic moiety containing 1 or 2 or 3 heteroatoms (N, O or S) and connecting to the pyrimidine ring through the nitrogen atom; or benzylamino-, phenylethylamino-, N-CM alkylbenzylamino-, N-CM alkylphenylethylamino-, N-Cι.4-hydroxyalkylbenzylamino-, N-CM- hydroxyalkylphenylethylamino-, cyclohexylmethylamino-, N-(C ι_4-cyclohexyl- methyl)amino- group - where the aromatic ring is optionally substituted with one or two identical or different C alkyl- or C alkoxy- or hydroxyl- group or halogen atom; or X stands for a Het-Cj.4 alkyl-N(R')-group -where Het represents a saturated or unsaturated heterocyclic ring containing one or two identical or different heteroatoms (N, O or S) optionally substituted with one or more identical or different CM alkyl-, Cj. 4 alkoxy group or halogen atom-, and R1 represents CM alkyl group or CM- hydroxy alkyl group;
Ar stands for phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms or methylenedioxyphenyl group -these groups may optionally be substituted with one or more identical or different CM alkyl group, halogen atom, hydroxyl group, C alkoxy group, trihalogenomethyl group, -NHCM alkyl, -N(C alkyl)2 or-NHC(=O)-C,.4 alkyl group;
R represents hydrogen atom or Cι.4-alkyl group; Y represents hydrogen atom or Cj.4-alkyl group; W represents hydrogen atom or Cι_4-alkyl group; Z represents hydroxyl group, halogen atom, Cι_4-alkoxy group, amino-group, Cι.4-alkyl- amino-group, or -NHCOCι.4-alkyl group; or
R + Y may represent -together with the included nitrogen and carbon atoms - a
group
Figure imgf000079_0001
- wherein A stands for CH2 group, oxygen atom, NH group or NCj.4-alkyl group and n = 0, 1 , 2 R + Z together may represent a -(CH2)m-G-group, wherein m = 1, 2, 3, and G means oxygen atom, CH2, NH, NCι_4-alkyl group; Z + W together may represent an oxo group; Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms - optionally substituted with one or more identical or different Cι.4-alkyl-, CM-alkoxy- or hydroxyl group, or halogen atom; or it means a
group
Figure imgf000079_0002
wherein the R2 stands for hydrogen atom, halogen atom, hydroxyl-, cyano-, or CM- alkoxy- or Ci_4-alkyl- group; R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, cyano-, Cι_4-alkylamino-, di(C].4)alkylamino-, benzylamino-, benzyl-(Ci.4)alkylamino- group, nitro group, benzyl group, phenylethyl group or Cj.4- alkyl group, -OR5 group-, wherein R5 represents a Cj.4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group, or -NH-C(=O)-R6 group, wherein R6 stands for phenyl group or 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, optionally substituted with halogen atom, Cι.4- alkyl group, Cι.4-alkoxy group; or a -NH-C(=O)-NH-R7 group where R7 stands for Cι_ -alkyl group, benzyl group, or phenyl group, optionally mono- or polysubstituted with halogen atom, ^-alkoxy group, Cι.4-alkyl group or trihalogenomethyl group, R4 stands for hydrogen atom, halogen atom, hydroxyl group, cyano group, Cj.4 alkoxy group or CM alkyl group; or R3 and R4 together mean a -O-CH2-O-group; with the proviso that, if Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom - optionally substituted with one or more identical or different CM alkyl-, C1.4 alkoxy-, hydroxyl-group or halogen atom, W represents hydrogen atom, Z represents hydroxyl group, R + Y may form -together with the included nitrogen and carbon atoms- a
-group
Figure imgf000080_0001
where n = 1, A represents NH- or NCι-4-alkyl or -CH2- group, and the meaning of Ar is as defined above, then the meaning of X is different from CM alkyl-group or from an amino group optionally substituted with one or two CM alkyl group. - and their salts, isomers and solvates.
2. The compounds of the general formula (I)
Figure imgf000080_0002
-wherein
X stands for Cι.4-alkyl group; amino group - optionally substituted with one or two CM alkyl group; CM-alkyl-S-group; saturated or partially saturated mono- or bicyclic moiety containing 1 or 2 or 3 heteroatoms (N, O or S) and connecting to the pyrimidine ring through the nitrogen atom; or benzylamino-, phenylethylamino-, N-CM alkylbenzylamino-, N-CM alkylphenylethylamino-, N-Cι.4-hydroxyalkylbenzylamino-, N-Cι.4- hydroxyalkylphenylethylamino-, cyclohexylmethylamino-, N-(Cι_4-cyclohexyl- methyl)amino- group - where the aromatic ring is optionally substituted with one or two identical or different Cj.4 alkyl- or CM alkoxy- or hydroxyl- group or halogen atom; or X stands for a Het-Cj.4 alkyl-N(R')-group -where Het represents a saturated or unsaturated heterocyclic ring containing one or two identical or different heteroatoms (N, O or S) optionally substituted with one or more identical or different Cj.4 alkyl-, Ci. 4 alkoxy group or halogen atom-, and R1 represents CM alkyl group or Cj.4- hydroxy alkyl group;
Ar stands for phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms or methylenedioxyphenyl group -these groups may optionally be substituted with one or more identical or different CM alkyl group, halogen atom, hydroxyl group, C alkoxy group, trihalogenomethyl group, -NHCM alkyl, -N(C alkyl)2 or -NHC(=O)-C alkyl group;
R represents hydrogen atom or Cι.4-alkyl group;
Y represents hydrogen atom or Cι_4-alkyl group;
W represents hydrogen atom or Cι.4-alkyl group;
Z represents hydroxyl group, halogen atom, Cι.4-alkoxy group, amino-group, Cι_4-alkyl- amino-group, or -NHCOCι.4-alkyl group; or
R + Y may represent -together with the included nitrogen and carbon atoms - a
-group
Figure imgf000081_0001
- wherein A stands for CH2 group, oxygen atom, NH group or NCj.4-alkyl group and n = 0, 1 , 2 R + Z together may represent a -(CH2)m-G-group, wherein m = 1, 2, 3, and G means oxygen atom, CH2, NH, NCι.4-alkyl group; Z + W together may represent an oxo group; Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms - optionally substituted with one or more identical or different Cι_4-alkyl-, CM-alkoxy- or hydroxyl group, or halogen atom; or it means a
group
Figure imgf000082_0001
wherein the R2 stands for hydrogen atom, halogen atom, hydroxyl-, CM-alkoxy- or Ci. 4-alkyl- group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι_4-alkylamino-, di(Cj.4)alkylamino-, benzylamino-, benzyl-(Cu 4)alkylamino- group, nitro group, benzyl group, phenylethyl group or Cι.4-alkyl group, -OR5 group-, wherein R5 represents a Cι.4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group, or -NH-C(=O)-R6 group, wherein R6 stands for phenyl group or 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, optionally substituted with halogen atom, Cj.4- alkyl group, Cι_4-alkoxy group; or a -NH-C(=O)-NH-R7 group where R7 stands for Cι.4-alkyl group, benzyl group, or phenyl group, optionally mono- or polysubstituted with halogen atom, Cι.4-alkoxy group, Cι_4-alkyl group or trihalogenomethyl group,
R4 stands for hydrogen atom, halogen atom, hydroxyl group, CM alkoxy group or CM alkyl group; with the proviso that, if Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom - optionally substituted with one or more identical or different CM alkyl-, CM alkoxy-, hydroxyl -group or halogen atom, W represents hydrogen atom, Z represents hydroxyl group, R + Y may form -together with the included nitrogen and carbon atoms- a -group
Figure imgf000083_0001
where n = l, A represents NH- or
Figure imgf000083_0002
or -CH2- group, and the meaning of Ar is as defined above, then the meaning of X is different from Cι_4 alkyl-group or from an amino group optionally substituted with one or two CM alkyl group. - and their salts, isomers and solvates.
3. The compounds of the general formula (I) as defined in Claim 1 or 2,
Figure imgf000083_0003
-wherein the meaning of X and Ar is defined in claim 1, W means hydrogen atom or Cι_4-alkyl- group;
Z stands for hydroxyl group, halogen atom, CM-alkoxy group, amino group, Cj. ^alkylamino group, -NHCOCj.4 alkyl group; or Z + W form together an oxo-group; R + Y form -together with the included nifrogen and carbon atoms- a
-group
Figure imgf000083_0004
wherein A stands for oxygen atom, -CH2-, -NH-, -NCι_ -alkyl- group and the value of n is 0, 1 or 2; Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms -optionally substituted with one or more identical or different
Figure imgf000084_0001
alkyl-, Cj.4 alkoxy-, hydroxyl- group or halogen atom, with the proviso that, if W represents hydrogen atom, Z represents hydroxyl group, n is 1, A represents -NH-, or -NCι.4 alkyl- or -CH2- group, then the meaning of X is different from CM alkyl group and different from an amino group -optionally substituted with one or more CM alkyl- group;
- and their salts, isomers or solvates.
4. The compounds of the general formula (I) as defined in Claim 1 or 2
Figure imgf000084_0002
- wherein the meanings of X and Ar are as defined in Claim 1., W represents hydrogen atom or CM alkyl group;
Z stands for hydroxyl group, halogen atom, Cj.4-alkoxy group, amino group, Ci. ^alkylamino group, -NHCOCi.4-alkyl group; or Z + W form together an oxo-group; R + Y may form -together with the included nitrogen and carbon atoms- a
-group
Figure imgf000084_0003
-where A stands for oxygen atom, -CH -, -NH-, -NCι.4-alkyl- group and the value of n is 0, 1 or 2; Q represents an group
Figure imgf000085_0001
where R2 stands for hydrogen atom, halogen atom, hydroxyl group, CM alkoxy group or CM alkyl group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cj.4-alkylamino-, di(Cι_4)alkylamino-, benzylamino-, benzyl-(Cι_4)alkylamino- group, nitro group, benzyl group, phenylethyl group or Cι-4-alkyl group, -OR5 group - wherein R5 represents a Cι.4-alkyl group or benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group; or -NH-C(=O)-R6 group, wherein R6 stands for phenyl group, 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms -optionally substituted with halogen atom, CM alkyl group, C alkoxy group; or -NH-C(=O)-NH-R7 group where R7 stands for Cι_4-alkyl group or benzyl group; or a phenyl group, optionally mono- or polysubstituted with halogen atom, CM-alkoxy group, Cι.4-alkyl group or trihalogenomethyl group;
R4 represents hydrogen atom, halogen atom, hydroxyl group, Cι_ -alkoxy group or Cj.4 alkyl group;
- and their salts, isomers and solvates.
5. The compounds of the general formula (I) as defined in Claims 1 , 2, 3 or 4 - wherein X represents benzylamino group, -N-Ci^-alkyl-benzyl-amino group - where the aromatic ring of the benzyl group may optionally be substituted with one or more identical or different Cι-4-alkyl group, CM-alkoxy group, halogen atom or hydroxyl group; Ar represents phenyl group -optionally substituted with one or more identical or different Ci.4-alkyl group, Cι_4-alkoxy group, halogen atom trihalogenomethyl group or hydroxyl group; R+Y may form -together with the included nitrogen atom and carbon atoms- a ■group
Figure imgf000086_0001
wherein - A means oxygen atom, -CH2-, -NH- or -N-Cι-4.alkyl- group and the value of n is 0, 1 or 2; W represents hydrogen atom; Z represents hydroxyl group; Q represents a phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatom -where these groups may optionally be substituted with one or more identical or different halogen atom, CM alkyl-, CM alkoxy-, hydroxyl-group; - and their salts, isomers and solvates.
6. The compounds of the general formula (I) as defined in Claim 1 or 2,
Figure imgf000086_0002
-where
X and Ar have the meaning as defined in claim 1., Y represents hydrogen atom or CM alkyl group; W represents hydrogen atom or CM alkyl group;
R + Z form together a -(CH2)m-G-group, where the value of m is 1, 2 or 3 and G represents oxygen atom, -CH2-, -NH- or -NCι.4-alkyl- group;
Q represents a 5- or 6-membered heterocyclic ring containing 1-3 heteroatom -optionally substituted with one or more identical or different C alkyl-, CM alkoxy-, hydroxyl-group or halogen atom, or a group
Figure imgf000087_0001
wherein R2 represents hydrogen atom, halogen atom, hydroxyl group, CM alkoxy group or
Ci.4 alkyl group;
R3 stands for hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι.4-alkylamino-, di(Cι.4)alkylamino-, benzylamino-, benzyl-(CM)alkylamino- group, nifro group, benzyl group, phenylethyl group or Cι_4-alkyl group,
-OR5 group - wherein R5 represents a Cι_4-alkyl group; or a benzyl group -optionally substituted with one or more halogen atom, trihalogenomethyl group; or
-NH-C(=O)-R6 group, wherein R6 stands for phenyl group -optionally substituted with halogen atom, CM alkyl group, CM alkoxy group; or a 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, or -NH-C(=O)-NH-R7 group wherein R7 means CM alkyl group, benzyl group or a phenyl group -optionally substituted with halogen atom, CM alkoxy group, C alkyl group or trihalogenomethyl group,
R4 stands for hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or C alkyl group;
- as well as their salts, isomers and solvates.
7. The compounds of the general formula (I) as defined in Claim 1 or 2, - where
Figure imgf000087_0002
X and Ar have the meaning as defined in claim 1., R represents hydrogen atom or CM alkyl group; Y represents hydrogen atom or C alkyl group; W represents hydrogen atom or C alkyl group; Z stands for hydroxyl group, halogen atom, Cι.4-alkoxy group, amino group, Cι.4-alkyl- amino group, -NHCOCι- -alkyl group; or
Z + W form together an oxo-group;
Q represents
- group
Figure imgf000088_0001
wherein R2 represents hydrogen atom, halogen atom, hydroxyl group, CM alkoxy group or
CM alkyl group;
R3 represents hydrogen atom, halogen atom, hydroxyl group, trihalogenomethyl group, amino-, Cι_4-alkylamino-, di(Cι.4)alkylamino-, benzylamino-, benzyl-(Cι_4)alkylamino- group, nitro group, benzyl group, phenyl ethyl group or Cι.4-alkyl group,
-OR5 group - wherein R5 represents a Cι.4-alkyl group; or a benzyl group, optionally substituted with one or more halogen atom, trihalogenomethyl group; or
-NH-C(=O)-R6 group, wherein R6 stands for phenyl group -optionally substituted with halogen atom, Cι.4 alkyl group, C alkoxy group; or a 4-7-membered cycloalkyl group, methylenedioxyphenyl group, CM alkyl group, benzyl group or a heterocyclic ring containing 1 or 2 or 3 heteroatoms, or -NH-C(=O)-NH-R7 group wherein R7 means Cj.4 alkyl group, benzyl group or a phenyl group -optionally substituted with one or more halogen atom, C alkoxy group, C alkyl group or trihalogenomethyl group,
R4 stands for hydrogen atom, halogen atom, hydroxyl group, C alkoxy group or C alkyl group;
- as well as their salts, isomers and solvates.
8. The compounds of the general formula (I) as defined in Claim 1 or 2, - where
Figure imgf000088_0002
X and Ar have the meaning as defined in claim 1 ,
R represents hydrogen atom or Cι.4 alkyl group;
Y represents hydrogen atom or Cι_4 alkyl group;
W represents hydrogen atom or Cj.4 alkyl group;
Z stands for hydroxyl group, halogen atom, Cj. -alkoxy group, amino group, Cι_4-alkyl- amino group, -NHCOCj.4-alkyl group; or
Z + W form together an oxo-group;
Q represents a 5- or 6-membered heterocyclic ring containing 1-3 identical or different heteroatoms -optionally substituted with one or more identical or different CM alkyl-, Cι- alkoxy-, hydroxyl-group or halogen atom;
- as well as their salts, isomers and solvates.
9. The following compounds of the general formula (I) as defined in Claim 1 or 2: 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxyphenyl) ethyl] methyl amide;
2-Dimethylamino-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
4-Phenyl-2-[(thiophen-2-yl-methyl)amino]pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxy- phenyl)ethyl]methyl amide;
2-Benzylamino-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxyphenyl) ethyl] methyl amide;
2-[Benzyl-(2-hydroxyethyl)amino]-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-methylphenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-methoxyphenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2- (3-hydroxyphenyl)ethyl]methyl amide;
2-(2-Chlorobenzylamino)-4-phenylpyrimidine-5- carboxylic acid [2-hydroxy-2-(3-hydroxy phenyl)ethyl]methyl amide; 2-Dimethylamino-4-phenylpyrimidine-5- carboxylic acid [2-(3-benzyloxyphenyl)-2- fluoroethyl]methylamide;
4-Phenyl-2-[methyl-(pyridin-2-ylmethyl)amino]pyirimidine-5-carboxylic acid [2-hydroxy-
2-(3-hydroxyphenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-(2-iodophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-phenylpyrimidine-5-carbonyl) methy lamino] - 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-thiophen-3-yl-pyrimidine-5- carbonyl)methylamino]- 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-thiophen-2-yl-pyrimidine-5- carbonyl)methylamino]-l-hydroxyethyl}phenyl ester;
2,2-Dimethylpropionic acid 3- {2-[(2-dimethylamino-4-(2-chlorophenyl)pyrimidine-5- carbonyl)methy lamino] -1 -hydroxy ethyl} phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(3-chlorophenyl)pyrimidine-5- carbonyl)methylamino]- 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(3-fluorophenyl)pyrimidine-5- carbonyl)methylamino] - 1 -hydroxyethyl } phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino-4-(4-methoxyphenyl)pyrimidine-5- carbonyl)methylamino]-l-hydroxyethyl}phenyl ester;
2,2-Dimethylpropionic acid 3-{2-[(2-dimethylamino- 4-(3,4-methylenedioxyphenyl) pyrimidine-5-carbonyl)methylamino]- 1 -hydroxyethyl }phenyl ester;
2-Dimethylamino-4-phenylpirimidine-5-carboxylic acid [2-(3-benzyloxyphenyl)-2- hydroxy ethyl] methyl amide
2-Dimethylamino-4-(2-fluorophenyl)pyrimidine-5-carboxylic acid [2-(3-benzyloxy phenyl)-2-hydroxyethyl]methyl amide;
2-Dimethylamino-4-(2-chlorophenyl)pyrimidine-5- carboxylic acid [2-(3-benzyloxy phenyl)-2-hydroxyethyl]methyl amide;
4-Phenyl-2-[(pyridin-2-yl-methyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy- 1- methyl-2-phenylethyl)methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy- 1 -methyl-2- phenylethyl)methyl amide; 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid (2-hydroxy- 1 - methyl-2-phenylethyl)methyl amide;
2-Benzylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy- 1 -methyl-2- phenylethyl)methyl amide;
4-Phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy- 1 - methyl-2-phenylethyl)methyl amide;
4-Phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (2-hydroxy- 1 - methyl-2-phenylethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-2- carbonyl)amino]phenyl} ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3-benzoylaminophenyl)-2- hydroxyethyl]methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-hydroxy-2-[3-(2-methoxy benzoylamino)phenyl]ethyl}methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid { 2-hydroxy-2- [3 -(3 -methoxy benzoylamino)phenyl]ethyl}methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2-{3-[(thiophen-2- carbonyl)amino]phenyl}ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(thiophen-3- carbonyl)amino]phenyl } ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-{3-[(furan-3-carbonyl)amino] phenyl } -2 -hydroxy ethyl)methy 1 amide ;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-3- carbonyl)amino]phenyl}ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (2-hydroxy-2- {3-[(pyridin-4- carbonyl)amino]phenyl } ethyl)methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(2,2-dimethylpropionyl amino)phenyl]-2-hydroxyethyl}methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(cyclopentanecarbonyl amino)phenyl]-2-hydroxyethyl }methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-hydroxy-2-[3-(3-chloro benzoylamino)phenyl]ethyl}methyl amide; 2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid {2-[3-(3-tert-butylureido) phenyl]-2-hydroxyethyl } methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5 -carboxylic acid [2-hydroxy-2-(4-hydroxy- phenyl)ethyl]mefhyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-fluoro phenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5 -carboxylic acid [2-hydroxy-2-(4-fluoro phenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(3-mefhoxy- phenyl)ethyl] methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-hydroxy-2-(4-methoxy- phenyl)ethyl]methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-phenyl-2-hydroxyethyl)- methyl amide;
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-(3-aminophenyl)-2- hydroxyethyl]methyl amide;
2-Benzylamino-4-phenylpyrimidine-5-carboxylic acid [2-(3 ,4-dihydroxyphenyl)-2- hydroxyethyl]methyl amide;
2-Dimethylamino-4-phenylpyrimidine-5- carboxylic acid [2-(3-benzyloxyphenyl)-2- fluoroethyl]methyl amide;
(±) Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxyphenylmethyl)- piperidin- 1 -yl]methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- methoxyphenyl)methyl]piperidin-l-yl}methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(3- hydroxyphenyl)methyl]piperidin-l-yl}methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-fluorophenyl) hydroxymethyl]piperidin- 1 -yl } methanone;
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyiridin-3-yl- methyl)piperidin- 1 -yljmethanone;
(±) Anti- [2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidin-5 -yl] - [2-(hydroxyphenyl- methyl)piperidin- 1 -yl] methanone (±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-2- ylmethyl)piperidin- 1 -yl]methanone
2-(Benzylmethylamino)-4-(2-bromophenyl)pyrimidine-5-carboxylic acid [2-(3,4- dihydroxyphenyl)-2-hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-(2-bromophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3- hydroxyphenyl)ethyl]methyl amide
2-(Benzylmethylamino)-4-(2-fluorophenyl)pyrimidine-5-carboxylic acid [2-(4-chloro- phenyl)-2-hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5 -carboxylic acid [2-(4-chlorophenyl)-2- hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid (2-benzo[l,3]dioxol-5-yl-2- hydroxyethyl)methyl amide
2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid [2-(3,4- dihydroxyphenyl)-2-hydroxyethyl]methyl amide
2-(Benzylmethylamino)-4-phenylpyrimidine-5-carboxylic acid [2-(4-cyanophenyl)-2- hydroxyethyl]methyl amide
4-(2-Chlorophenyl)-2-dimethylaminopyrimidine-5-carboxylic acid (2-hydroxy-2- {3-
[(pyridine-4-carbonyl)amino]phenyl } ethyl)methyl amide
2-(Ethyl-pyridin-3-ylmethyl-amino)-4-(2-fluorophenyl)pyrimidine-5-carboxylic acid [2- hydroxy-2-(3-hydroxyphenyl)ethyl]methyl amide
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(4-fluorophenyl)- hydroxymefhyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy-/?-tolyl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(hydroxyphenylmethyl)piperidin-l-yl]-[2-(3-methoxybenzylamino)-4- phenylpyrimidin-5 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-chlorophenyl)- hydroxymethyljpiperidin- 1 -yl } methanone
(±)Anti-{2-[(4-chlorobenzyl)methylamino]-4-phenylpyrimidin-5-yl}-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-ylJ-[2-(hydroxy-w-tolyl- methyl)piperidin- 1 -yljmethanone (±)Anti-{2-[(4-fluorobenzyl)methylamino]-4-phenylpyrimidin-5-yl}-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy-o-tolyl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(2-fluorophenyl)- hydroxymethyljpiperidin- 1 -yl} methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[hydroxy-(4-methoxy- phenyl)methyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(4-fluorobenzylamino)-4-phenylpyrimidin-5-ylJ-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-{2-[(3-chloro-4- fluorophenyl)hydroxymethyl]piperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-ylJ-{2-[(3,4-difluorophenyl)- hydroxymethy ljpiperidin- 1 -yl } methanone
(±)Anti-[2-(3-chlorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(+)Anti-[2-(benzylmethylamino)-4-(2-chlorophenyl)-pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxypyridin-4-yl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-(2-fluorophenyl)pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-2-[(3-chlorobenzyl)methylaminoJ-4-phenylpyrimidin-5-yl}-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-ylJ-{2-[(2-chlorophenyl)- hydroxymethyl Jpiperidin- 1 -yl } methanone
(±)Anti-[2-(benzylmethylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy-thiophen-3-yl- methyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(3-chloro-4-fluorobenzylamino)-4-phenylpyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-{2-[(3-chloro-4-fluorobenzyl)methylaminoJ-4-phenylpyrimidin-5-yl}-[2- (hydroxyphenylmethyl)-piperidin- 1 -yljmethanone (+)Anti-[2-(benzylmethylamino)-4-(4-chlorophenyl)pyrimidin-5-yl]-[2-(hydroxy- phenylmethyl)piperidin- 1 -yljmethanone
(±)Anti-[2-(3-chloro-4-fluorobenzylamino)-4-phenylpyrimidin-5-ylJ-[2-(hydroxy- thiophen-3-yl-methyl)piperidin- 1 -yljmethanone.
10. Pharmaceutical composition, characterized in that, it contains a compound of the general formula (I)
Figure imgf000095_0001
- wherein the meanings of X, Ar, R, Z, W, Y and Q are as defined in Claim 1 or 2- or its salt, isomer or solvate.
11. Pharmaceutical composition, as defined in Claim 10, characterized in that it contains a compound of the general formula (I), as defined in Claims 2-8
Figure imgf000095_0002
- wherein the meanings of X, Ar, R, Z, W, Y and Q are as defined in Claims 2-6 or its salt, isomer or solvate.
12. Pharmaceutical composition, characterized in that it contains a compound of the general formula (I)
Figure imgf000095_0003
- wherein the meanings of X, Ar, R, Z, W, Y and Q are as defined in Claim 1 or 2- or its salt, isomer or solvate, and at least one excipient used in the pharmaceutical industry.
13. Use of the compounds of the general formula (I)
Figure imgf000096_0001
- wherein the meanings of X, Ar, R, Z, W, Y and Q are as defined in Claim 1 or 2- to prepare medicines, pharmaceutical compositions, suitable to antagonize the orexin- 1 receptors or the orexin- 1 and orexin-2 receptors, and thus suitable to treat or prevent diseases connected with the activity of the orexine receptors.
14. Process for the preparation of the compounds of the general formula (I)
Figure imgf000096_0002
- wherein the meanings of X, Ar, R, Z, W, Y and Q are as defined above - c h a r a c t e r i z e d b y that a compound of the general formula (II) or its ester or its activated derivative Ar
Figure imgf000096_0003
- wherein the meanings of X and Ar are as defined in Claim 1 or 2 - is reacted with a compound of the general formula (III)
Figure imgf000096_0004
- wherein the meanings of R, Y, W, Z and Q are as defined in Claim 1 or 2, and the resulting compound of the general formula (I) is liberated from its salt or the resulting compound is transformed into its salt.
15. Compounds of the general formula (II) - wherein Ar
Figure imgf000097_0001
the meanings of X and Ar are as defined in Claim 1 or 2 - and their activated derivatives and CM alkyl esters.
16. Compounds of the general formula (III) - wherein
Figure imgf000097_0002
the meanings of R, Y, W, Z and Q are as defined in Claim 1 or 2, and their salts.
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HUP0400405A2 (en) 2005-09-28
WO2005075458A8 (en) 2006-01-19
US20070043037A1 (en) 2007-02-22
EP1718632B1 (en) 2009-04-22
US7812031B2 (en) 2010-10-12
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HU0400405D0 (en) 2004-04-28
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