Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D401/04—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D249/12—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D401/12—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D401/14—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D409/02—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
  • C07D409/04—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
• • C—CHEMISTRY; METALLURGY
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the invention relates to triazole compounds and the use of these compounds. These have valuable therapeutic properties and can be used to treat diseases which respond to the influence of dopamine D 3 receptor ligands.
• Triazole compounds with anti-allergic or anti-psychotic activity are known from US 4,338,453; 4,408,049 and 4,577,020.
• WO 93/08799 and WO 94/25013 describe compounds of the type in question here which are endothelin receptor antagonists. In Pharmazie 46. (1991), 109-112,
• Neurons receive their information, among other things, via G protein-coupled receptors. There are numerous substances that act through these receptors. One of them is dopamine.
• Dx and D 2 receptors Two subtypes of dopamine receptors were clearly defined pharmacologically, namely the Dx and D 2 receptors.
• a third subtype has recently been found, namely the D 3 receptor, which appears to mediate some effects of the antipsychotics and anti-Parkinson agents (JC Schwartz et al., The Dopamine D 3 Receptor as a Target for Antipsychotics, in Novel Anti-psychotic drugs, HY Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).
• D receptors are mainly expressed in the limbic system, it is assumed that a selective D 3 ligand should have the properties of known antipsychotics, but not their dopamine D 2 receptor-mediated neurological side effects (P. Sokoloff et al., Localization and Function of the D 3 Dopamine Receptor, Pharmaceutical Research / Drug Res. 42 (1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a
• the present invention therefore relates to the compounds of the general formula I:
• R 1 is H, -C-C 6 alkyl, which is optionally substituted by OH, OCi-C ⁇ -alkyl, halogen or phenyl, C 3 -C 6 cycloalkyl or phenyl;
• R 2 for H, -C-C 6 alkyl, which is optionally substituted by OH, OC ⁇ -C 6 alkyl, halogen or phenyl, C " ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl thio, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, halogen, CN, COOR 3 , CONR 3 R 4 , NR 3 R 4 'S0 R 3 , S0 2 NR 3 R 4 or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are independently selected from 0,
• R 3 and R 4 independently of one another are H, -CC 6 alkyl, which is optionally substituted by OH, OCi-C ⁇ -alkyl, halogen or phenyl, or phenyl;
• X represents CH 2 or CH 2 CH 2 ;
• Halogen or phenyl is substituted, C 3 -C 6 cycloalkyl, optionally halogen-substituted (1 or 2 halogen atoms)
• R 6 , R 7 and R 8 are independently selected from H,
• C 1 -C 6 -Alkylthio, halogen or phenyl is substituted, OH, -C-C 6 -alkoxy, SH, -C-C 6 -alkylthio, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halogen , CN, N0 2 , S0 2 R 3 , S0 2 NR 3 R 4 , CONR 3 R 4 , NHS0 2 R 3 and
• the compounds according to the invention are selective dopamine D 3 receptor ligands which attack regioselectively in the limbic system and, because of their low affinity for the D 2 receptor, have fewer side effects than the classic neuroleptics, which are D 2 Receptor antagonists.
• the compounds are therefore useful for the treatment of diseases which respond to dopamine D 3 ligands, ie they are effective for the treatment of those diseases in which the dopamine D 3 receptors are influenced (modulated) to improve the disease. image or to cure the disease.
• Such diseases are, for example, diseases of the cardiovascular system and the kidney, diseases of the central nervous system, in particular Schizophrenia, mood disorders, neurotic stress and somatoform disorders, psychoses, Parkinson's, attention deficit disorders, hyperactivity in children, epilepsy, amnestic and cognitive disorders, such as learning and memory impairment (impaired cognitive function), anxiety, dementia, Delirium, personality disorders, sleep disorders (e.g. Restless Legs Syndrome), sexual life disorders (male impotence), eating disorders and addiction disorders. They can also be used to treat stroke.
• Addiction disorders include mental disorders and behavioral disorders caused by the misuse of psychotropic substances such as drugs or drugs, as well as other addiction disorders such as gambling addiction (impulse control disorders not elsewhere classified).
• Addictive substances are, for example: opioids (e.g. morphine, heroin, codeine); Cocaine; Nicotine; Alcohol; Substances that interact with the GABA chloride-channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; Cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetarnine (ecstasy); Amphetamine and amphetamine-like substances such as methylphenidate or other stimulants including caffeine.
• opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol come into consideration as addictive substances.
• the compounds according to the invention are preferably used for the treatment of mood disorders; neurotic, stress and somatoform disorders and psychoses, e.g. Schizophrenia, used.
• Alkyl (also in residues such as alkoxy, alkylthio, alkylo etc.) means a straight-chain or branched alkyl group having 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms.
• the alkyl group can have one or more substituents which are independently selected from OH, OC-C 6 alkyl, halogen or phenyl.
• the alkyl group can in particular comprise 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the ⁇ or ⁇ position.
• CF 3 , CHF 2 , CF 2 C1 or CH 2 F are particularly preferred.
• alkyl group examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.
• Cycloalkyl is especially C 3 -Cg-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Alkylene stands for straight-chain or branched radicals. If A has no group Z, A comprises 4 to 10 carbon atoms, preferably 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of the groups Z mentioned, A comprises 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms.
• alkylene groups comprise at least one of the groups Z, these can be arranged anywhere in the alkylene chain or in position 1 or 2 of group A (as viewed from the triazole radical).
• the CONR 2 and COO radicals are preferably arranged such that the carbonyl group faces the triazole ring.
• Z preferably represents CH 2 , 0 and in particular S.
• _CH 2 - ⁇ -cH 2 -, -CH 2 CH 2 C (CH 3 ) CHCH 2 - or -CH 2 CH 2 CH (CH 3 ) CH 2 -.
• Halogen means F, Cl, Br or I, preferably F or Cl.
• R 1 is preferably H, Cx-Ce-Al yl or C 3 -C 6 cycloalkyl.
• R 2 represents an aromatic radical, it is preferably one of the following radicals:
• R 9 to R 11 are H or the above-mentioned substituents of the aromatic radical
• R 12 is H, C ⁇ -C 6 alkyl or phenyl and T is N or CH.
• the substituents are preferably in the m or p position.
• the aromatic radical is particularly preferably a group of the formula:
• R 9 , R 10 and R 12 have the meanings given above.
• the specified phenyl, pyridyl, thiazolyl and pyrrole radicals are particularly preferred.
• the radicals R 9 to R 11 are preferably H, C ⁇ -C 6 alkyl, OR 3 , CN, phenyl, which is optionally substituted by C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy or halogen, CF 3 and Halogen and especially for H, C ⁇ -C 6 alkyl, OR 3 and halogen.
• R 3 has the meanings given above.
• R 2 particularly preferably represents H, C ⁇ -C 6 -alkyl, NR 3 R 4 (R 3 and R 4 independently of one another represent H or Ci-C ⁇ -alkyl), phenyl or a 5-membered aromatic heterocyclic radical, the 1st or has 2 heteroatoms which are independently selected from N, S and 0.
• the heterocyclic radical is preferably a pyrrole or pyridine radical.
• X is preferably CH 2 CH 2 .
• At least one of the radicals R 6 , R 7 and R 8 is preferably H.
• the radicals R 6 , R 7 and R 8 are preferably and independently selected from H, C ⁇ -C 6 alkyl, halogen-substituted C ⁇ -C 6 alkyl, OH, CC 6 alkoxy, C ⁇ -C 6 alkylthio-C - C 6 -alkyl, halogen, N0 2 , CN, S0 2 R 3 , S0 2 NR 3 R 4 and CONR 3 R 4 .
• the fused phenyl group particularly preferably has one or two substituents, ie one or two of the radicals R 6 , R 7 and R 8 represent CC 6 alkyl, halogen, CN, S0 2 NR 3 R 4 , N0 2 or CF 3 .
• R 1 represents H, CC 6 alkyl or phenyl
• R 2 represents H, C ⁇ -C 6 -alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl
• A represents -SC 3 -C ⁇ o-alkylene, which may have a double bond or C 3 -C 6 - May include cycloalkyl
• R 6 , R 7 and R 8 are selected from H, C -C 6 alkyl, C ⁇ -C 6 alkoxy
• Halogen S0 2 NR 3 R 4 , CN, N0 2 or CF 3 .
• the invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids.
• suitable physiologically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Further usable acids are described in advances in drug research, volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966.
• the compounds of formula I can have one or more centers of asymmetry.
• the invention therefore includes not only the racemates, but also the enantiomers and diastereomers in question.
• the respective tautomeric forms also belong to the invention.
• Y 1 represents a customary leaving group such as shark, alkylsulfonyloxy, arylsulfonyloxy etc., with a compound of the general formula (III)
• Y 1 has the meaning given above and A 2 is C 2 -C ⁇ o-alkylene, where A 1 and A 2 together have 3 to 10 C atoms and A 1 and / or A 2 optionally comprise at least one Z group ; or
• C 3 -C 9 alkylene which can contain a group Z, chain-extended, one after deprotection or reduction
• Z 2 is CO or a methylene group and Z 2 and A 2 together have 4 to 10 carbon atoms, or
• Compounds of general formula XX can also be obtained by reacting compounds of formula II with azides, e.g. Sodium azide, and subsequent reduction, e.g. described in H. Staudinger, Helv. Chim. Acta 1919, 2, 635 or R. Carrie, Bull. Chem. Soc. Fr 1985, 815.
• azides e.g. Sodium azide
• reduction e.g. described in H. Staudinger, Helv. Chim. Acta 1919, 2, 635 or R. Carrie, Bull. Chem. Soc. Fr 1985, 815.
• the compounds of the type of formula (IV) are either known or can be prepared by known methods, e.g. described in A.R. Katritzky, C.W. Rees (ed.) "Comprehensive Heterocyclic Chemistry", Pergamon Press, or "The Chemistry of Heterocyclic Compounds” J. Wiley & Sons Inc. NY and the literature cited therein or in S. Kubota et al. Chem. Pharm. Bull 1975, 23rd, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim 1975, 23, 955.
• R 1, R 2 , R 5 , R 5 , R 7 , R 8 , A, B and X have the meanings given in connection with formula I.
• the compounds according to the invention and the starting materials and the intermediates can also be prepared analogously to the methods described in the patent publications mentioned at the outset.
• the reactions described above are generally carried out in a solvent at temperatures between room temperature and the boiling point of the solvent used.
• Usable solvents are, for example, esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.
• Suitable acid-binding agents are inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium methylate, sodium ethylate, sodium hydride or organometallic compounds, such as butyllithium or alkylmagnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also serve as solvents.
• Processes (f) and (g) are carried out under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride, optionally in an acidic medium or in the presence of a Lewis acid, e.g. Zinc chloride or by means of catalytic hydrogenation.
• reducing conditions e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride, optionally in an acidic medium or in the presence of a Lewis acid, e.g. Zinc chloride or by means of catalytic hydrogenation.
• the crude product is isolated in the customary manner, for example by filtration, distilling off the solvent or extraction from the reaction mixture etc.
• the compounds obtained can be purified in the customary manner, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.
• the acid addition salts are in a conventional manner by mixing the free base with the corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl t-butyl ether, a ketone, such as Acetone or methyl ethyl ketone or an ester such as ethyl acetate.
• an organic solvent for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl t-butyl ether, a ketone, such as Acetone or methyl ethyl ketone or an ester such as ethyl acetate.
• the compounds according to the invention are administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally).
• the application can also be done with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active ingredient is about 10 to 1000 mg per patient per day oral administration and approximately 1 to 500 mg per patient and day with parenteral administration.
• the invention also relates to pharmaceutical compositions which contain the compounds according to the invention.
• These agents are in the usual galenical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions or sprays.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (cf. H. Sucker et al., Pharmaceutical technology, Thieme-Verlag, Stuttgart, 1978).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.
• Example 5 3- [3- (6-bromo-l, 2,3,4-tetrahydronaphth-2-ylamino) propylmercapto] -4-methyl1-5-phenyl-1,2,4 (4H) -triazole, obtained by analogous reaction of 6-bromotetralon-2 with 3- (3-aminopropylmercapto) 4-methyl-5-phenyl-l, 2, 4 (4H) -triazole.
• Salt precipitation was carried out with ethereal hydrochloric acid at 0 ° C.
• Example 13 3- [3- (6-Bromo-l, 2,3,4-tetrahydronaphth-2-yl-methylamino) propylmercapto] -4-methyl-5-phenyl-l, 2,4 (4H) - triazole hydrochloride
• Example 14 3- [3- (6-Methyl-l, 2,3, 4-tetrahydronaphth-2-yl-methylamino) propyl-mercapto] -4-methyl-5-phenyl-l, 2, 4 (4H) - triazole
• 3- 3- [3- (6-methyl-1,2,3,4-tetrahydronaphth-2-ylamino) propylmercapto] -4-methyl-5-phenyl-1, 2, 4 (4H ) -triazole (Example 4) with methyl iodide in a manner known per se, the above substance was obtained.
• the hydrochloride was obtained by treatment with ethereal hydrochloric acid.
• R 7 represents hydrogen
• R 7 represents hydrogen
• Aerosil® chemically pure silica in submicroscopic fine distribution
• potato starch as 6% paste
• the core consists of 9 parts corn starch, 3 parts milk sugar and 1 part vinyl pyrrolidone-vinyl acetate mixed polymer 60:40.
• the saccharification mass consists of
• cloned human D 3 receptor-expressing CCL 1.3 mouse fibroblasts available from Res. Biochemicals Internat. One Strathmore Rd., Natick, MA 01760-2418 USA.
• the D 3 expressing cells were in RPMI-1640 with 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U / ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, MD, USA) increased. After 48 h the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 g. The pelvis was briefly let washed with lysis buffer (5 mM Tris-HCl, pH 7, 4 with 10% glycerol) and then at a concentration of 10 7 cells / ml
• the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 2 mM MgCl 2 , 10 ⁇ M quinolinol, 0.1 % Ascorbic acid and 0.1% BSA) in a concentration of approx. 10 6 cells / 250 ⁇ l test batch and incubated at 30 ° C. with 0.1 nM! 25 iodosulpiride in the presence and absence of test substance.
• the non-specific binding was determined with 10 _6 M spiperone.
• the Ki values were determined using non-linear regression analysis with the LIGAND program.
• HEK-293 cells with stably expressed human dopamine D2A receptors were cultivated in RPMI 1640 with Glutamax I TM and 25 mM HE-PES with 10% fetal calf serum albumin. All media contained 100 units per ml penicillin and 100 ⁇ g / ml streptomycin. The cells were kept in a humid atmosphere with 5% CO 2 at 37 ° C.
• the cell preparation for binding studies was carried out by trypsinization (0.05% trypsin solution) for 3-5 minutes at room temperature. The cells were then centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4 ° C. for 30 minutes. After centrifugation at 250 g for 10 minutes, the residue was kept at -20 ° C until use. Receptor binding tests
• the batches (1 ml) were composed of 1 ⁇ 10 5 cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 M MgCl 2 and 2 mM CaCl 2 , pH 7, 4 with HC1) and 0, 1 nM i 25 I-spiperone (total binding) or additionally 1 ⁇ M haloperidol (non-specific binding) or test substance.
• incubation buffer 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 M MgCl 2 and 2 mM CaCl 2 , pH 7, 4 with HC1
• 1 nM i 25 I-spiperone total binding
• 1 ⁇ M haloperidol non-specific binding
• the Ki values were determined using non-linear regression analysis with the LIGAND program or by converting the ICso values using the formula by Cheng and Prusoff.
• the compounds according to the invention show very good affinities for the D 3 receptor ( ⁇ 1 ⁇ molar, in particular ⁇ 200 nmolar) and bind selectively to the D 3 receptor.
• Table 3 shows the pKi-D 3 values and the selectivity values (Kj_ (D 2 ) / Kj . (D 3 )) for the compounds of Examples 1, 14 and 26.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Addiction (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Heart & Thoracic Surgery (AREA)
• Psychology (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Hospice & Palliative Care (AREA)
• Diabetes (AREA)
• Child & Adolescent Psychology (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Anesthesiology (AREA)
• Vascular Medicine (AREA)
• Gynecology & Obstetrics (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (12)

Applications Claiming Priority (2)

Publications (1)

Family

ID=7894006

Family Applications (3)

Family Applications Before (2)

Country Status (28)

Cited By (6)

Families Citing this family (47)

Citations (10)

Family Cites Families (25)

• 2000
  • 2000-01-10 TW TW089100271A patent/TWI274750B/zh not_active IP Right Cessation
  • 2000-01-10 AR ARP000100079A patent/AR022229A1/es not_active Application Discontinuation
  • 2000-01-10 AR ARP000100080A patent/AR022230A1/es not_active Application Discontinuation
  • 2000-01-10 AR ARP000100078A patent/AR022228A1/es not_active Application Discontinuation
  • 2000-01-12 EP EP00902583A patent/EP1140908B1/de not_active Expired - Lifetime
  • 2000-01-12 ES ES00903574T patent/ES2334326T3/es not_active Expired - Lifetime
  • 2000-01-12 CN CNB008049432A patent/CN1267430C/zh not_active Expired - Fee Related
  • 2000-01-12 DE DE50015802T patent/DE50015802D1/de not_active Expired - Lifetime
  • 2000-01-12 JP JP2000593605A patent/JP4615125B2/ja not_active Expired - Fee Related
  • 2000-01-12 TR TR2001/02026T patent/TR200102026T2/xx unknown
  • 2000-01-12 AT AT00902583T patent/ATE424398T1/de not_active IP Right Cessation
  • 2000-01-12 DE DE50015576T patent/DE50015576D1/de not_active Expired - Lifetime
  • 2000-01-12 CN CN00804933A patent/CN1347414A/zh active Pending
  • 2000-01-12 US US09/889,161 patent/US6602867B1/en not_active Expired - Lifetime
  • 2000-01-12 CA CA002359952A patent/CA2359952A1/en not_active Abandoned
  • 2000-01-12 CA CA2359948A patent/CA2359948C/en not_active Expired - Fee Related
  • 2000-01-12 HU HU0200522A patent/HUP0200522A3/hu unknown
  • 2000-01-12 WO PCT/EP2000/000176 patent/WO2000042037A1/de not_active Ceased
  • 2000-01-12 KR KR1020077004587A patent/KR100775720B1/ko not_active Expired - Fee Related
  • 2000-01-12 AT AT00901535T patent/ATE366729T1/de not_active IP Right Cessation
  • 2000-01-12 JP JP2000593606A patent/JP2002534521A/ja not_active Ceased
  • 2000-01-12 EP EP00903574A patent/EP1144405B1/de not_active Expired - Lifetime
  • 2000-01-12 ES ES00901535T patent/ES2288839T3/es not_active Expired - Lifetime
  • 2000-01-12 CO CO00001265A patent/CO5150182A1/es unknown
  • 2000-01-12 AT AT00903574T patent/ATE449768T1/de not_active IP Right Cessation
  • 2000-01-12 HU HU0200709A patent/HUP0200709A3/hu unknown
  • 2000-01-12 CZ CZ20012551A patent/CZ303926B6/cs not_active IP Right Cessation
  • 2000-01-12 CN CNB008049424A patent/CN1149209C/zh not_active Expired - Fee Related
  • 2000-01-12 ID IDW00200101733A patent/ID29930A/id unknown
  • 2000-01-12 BR BR0007500-0A patent/BR0007500A/pt not_active Application Discontinuation
  • 2000-01-12 EP EP00901535A patent/EP1140907B1/de not_active Expired - Lifetime
  • 2000-01-12 HR HR20010590A patent/HRP20010590A2/hr not_active Application Discontinuation
  • 2000-01-12 CO CO00001268A patent/CO5150227A1/es unknown
  • 2000-01-12 WO PCT/EP2000/000177 patent/WO2000042036A1/de not_active Ceased
  • 2000-01-12 PL PL349841A patent/PL201889B1/pl unknown
  • 2000-01-12 NZ NZ512864A patent/NZ512864A/xx not_active IP Right Cessation
  • 2000-01-12 PL PL350246A patent/PL200238B1/pl unknown
  • 2000-01-12 SK SK985-2001A patent/SK9852001A3/sk unknown
  • 2000-01-12 KR KR1020017008780A patent/KR100730667B1/ko not_active Expired - Fee Related
  • 2000-01-12 BR BR0007504-3A patent/BR0007504A/pt not_active Application Discontinuation
  • 2000-01-12 KR KR1020017008777A patent/KR100687682B1/ko not_active Expired - Fee Related
  • 2000-01-12 JP JP2000593604A patent/JP4933694B2/ja not_active Expired - Fee Related
  • 2000-01-12 US US09/889,163 patent/US6583166B1/en not_active Expired - Lifetime
  • 2000-01-12 WO PCT/EP2000/000175 patent/WO2000042038A1/de not_active Ceased
  • 2000-01-12 AU AU24367/00A patent/AU773047B2/en not_active Ceased
  • 2000-01-12 AU AU25412/00A patent/AU772948B2/en not_active Ceased
  • 2000-01-12 CO CO00001269A patent/CO5150224A1/es unknown
  • 2000-01-12 CZ CZ20012550A patent/CZ20012550A3/cs unknown
  • 2000-01-12 DE DE50014472T patent/DE50014472D1/de not_active Expired - Lifetime
  • 2000-01-12 CA CA002359942A patent/CA2359942A1/en not_active Abandoned
  • 2000-01-12 IL IL14413600A patent/IL144136A0/xx active IP Right Grant
  • 2000-01-12 ID IDW00200101681A patent/ID29552A/id unknown
  • 2000-01-12 AU AU22897/00A patent/AU2289700A/en not_active Abandoned
  • 2000-01-12 US US09/889,156 patent/US6579892B1/en not_active Expired - Lifetime
  • 2000-01-12 IL IL14413700A patent/IL144137A0/xx unknown
  • 2000-01-12 HK HK02106847.0A patent/HK1045311B/zh not_active IP Right Cessation
  • 2000-01-12 NZ NZ512830A patent/NZ512830A/en not_active IP Right Cessation
  • 2000-01-12 TR TR2001/02025T patent/TR200102025T2/xx unknown
  • 2000-01-12 SK SK986-2001A patent/SK9862001A3/sk unknown
• 2001
  • 2001-07-03 IL IL144136A patent/IL144136A/en not_active IP Right Cessation
  • 2001-07-11 NO NO20013444A patent/NO20013444L/no not_active Application Discontinuation
  • 2001-07-11 NO NO20013443A patent/NO20013443L/no not_active Application Discontinuation
  • 2001-08-03 BG BG105784A patent/BG65086B1/bg unknown
  • 2001-08-03 BG BG105783A patent/BG65105B1/bg unknown
  • 2001-08-10 ZA ZA200106585A patent/ZA200106585B/en unknown
  • 2001-08-10 ZA ZA200106584A patent/ZA200106584B/en unknown

Patent Citations (11)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events