1,3,4-Substituted pyrazoles as 5-ht receptor antagonists for the treatment of psychoses and neurological disorders

• US 20070105871A1
• Filed: 03/08/2004
• Published: 05/10/2007
• Est. Priority Date: 04/05/2003
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Schiemann, Kai, Seyfried, Christoph, Schadt, Oliver, Bartoszyk, Gerd, Van Amsterdam, Christoph
• Granted Patent: US 7,566,709 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

Compounds of the formula (I) and salts and solvates thereof, in which X, R¹, R², R⁵ and Q have the meanings indicated in claim 1, are suitable as ligands of 5 HT receptors; as well as intermediate compounds of the formula (IA).

Claims

1. Compounds of the formula I

2. Compounds of the formula I according to claim 1, in which R¹ denotes phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro- , dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxy- or triethoxyphenyl, thiophen-2-yl or thiophen-3-yl.

3. Compounds of the formula I according to claim 1, in which R³ denotes H.

4. Compounds of the formula I according to claim 1, in which R⁴ denotes H.

5. Compounds of the formula I according to claim 1, in which R² denotes phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-difluoro- or dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl.

6. Compounds of the formula I according to claim 1, in which X has the meaning N.

7. Compounds of the formula IA:

8. Process for the preparation of compounds of the formula IA

9. Compounds of the formula I according to claim 1 and physiologically acceptable salts and solvates thereof as medicaments.

10. Use of the compounds of the formula I according to claim 1, and salts and solvates thereof, for the preparation of a medicament for the treatment and prophylaxis of diseases which can be influenced by the binding of the compounds of the formula I to 5-HT receptors.

11. Use of compounds of the formula I according to claim 1 and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament having a 5-HT receptor-antagonistic action.

12. Use of compounds of the formula I according to claim 1 and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament having a 5-HT2A receptor-antagonistic action.

13. Pharmaceutical composition characterised by a content of at least one compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates.

14. Process for the preparation of pharmaceutical compositions, characterised in that a compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates is converted into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or adjuvant.

15. Use of compounds of the formula according to claim 1 and/or physiologically acceptable salts or solvates thereof for the preparation of a medicament for the prophylaxis and/or treatment of psychoses, neurological disorders, amyotrophic lateral sclerosis, eating disorders, such as bulimia, anorexia nervosa, of premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

16. Compounds of the formula I in which Het denotes one of the following radicals: