Preventive and/or Therapeutic Agent For Disease In Which Mitochondrial Benzodiazephine Receptor Participates

• US 20080249154A1
• Filed: 12/24/2004
• Published: 10/09/2008
• Est. Priority Date: 12/26/2003
• Status: Abandoned Application

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Ohmoto, Kazuyuki, Manako, Junichiro, Kato, Masashi, Katsumata, Seishi
• Application Number:
  US10/584,280
• Publication Number:
  US 20080249154A1
• Time in Patent Office: Days
• US Class Current: 514/393
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

A compound represented by formula (I)

(wherein ring A is a nitrogen-containing ring which may have a substituent(s), E is a binding bond or a spacer of which main chain has an atom number of 1-8, Q is a hydrogen atom, a hydrocarbon group which may have a substituent(s) or a cyclic group which may have a substituent(s).), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. Since the compounds of the present invention represented by formula (I), a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof have the affinity to MBR, they are useful for the prevention and/or treatment for disease caused by stress.

Claims

1. A compound represented by formula (I):

2. The compound according to claim 1,

wherein ring A is

3. The compound according to claim 2, which is represented by formula (I-1):

4. The compound according to claim 3, wherein

5. The compound according to claim 3, which is a compound represented by formula (I-1-1):

6. The compound according to claim 3, which is a compound represented by formula (I-1-2):

7. The compound according to claim 5 or 6, wherein E¹ is

8. The compound according to claim 5 or 6, wherein L¹ is a nitrogen atom, a sulfur atom which may be oxidized, or C1-4 alkylene.

9. The compound according to claim 3, which is

(1) N-[2-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-(4-fluorophenyl)acetamide,

(2) N-[2-(4-chlorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-2-phenylacetamide,

(3) N-(2-tert-butyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-2-phenylacetamide,

(4) 2-phenyl-N-(2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)acetamide,

(5) 2-(4-fluorophenyl)-N-(2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)acetamide,

(6) N-[2-(4-chlorophenyl)-5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-2-(4-fluorophenyl)acetamide, or

(7) tert-butyl 2-(4-chlorophenyl)-3-{[(4-fluorophenyl)acetyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate.

10. A pharmaceutical composition comprising a compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or diluent.

11. The pharmaceutical composition according claim 10, which is a preventive and/or therapeutic agent for mitochondrial benzodiazepine receptor mediated disease.

12. The pharmaceutical composition according to claim 11, wherein a mitochondrial benzodiazepine receptor mediated disease is a disease caused by stress.

13. The pharmaceutical composition according to claim 12, wherein a disease caused by stress is a central nervous system disease caused by stress, a respiratory system disease caused by stress and/or digestive system disease caused by stress.

14. The pharmaceutical composition according to claim 13, wherein a central nervous system caused by stress is anxiety-related disease, sleep disorder, depression and/or epilepsy, a respiratory system disease caused by stress is asthma, a digestive system disease caused by stress is irritable bowel syndrome.

15. A pharmaceutical composition combining of the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof and one kind or more kind selected from antianxiety drugs, antidepressant drugs, antiparkinson drugs, therapeutic drugs for schizophrenia, antiepileptic drugs, therapeutic drugs for asthma, therapeutic drugs for peptic ulcer, adjustive drugs for gastrointestinal function, antidiarrheals, evacuants, antihypertensive drugs, antiarrhythmic drugs, inotropic drugs and therapeutic drugs for urination disorder.

16. A method for prevention and/or treatment for a mitochondrial benzodiazepine receptor mediated disease in a mammal, which comprises administering to a mammal an effective dose of the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide, a solvate or a prodrug thereof.

17. (canceled)