HETEROCYCLIC DERIVATIVE AND USE THEREOF

• US 20110028493A1
• Filed: 04/03/2009
• Published: 02/03/2011
• Est. Priority Date: 04/04/2008
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Nakagawa, Hideyuki, Matsunaga, Nobuyuki, Nakada, Yoshihisa, Ohba, Yusuke
• Granted Patent: US 8,461,348 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 25/08 : Antiepileptics; Anticonvulsants
• 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 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/04 : 1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
• CPC Class Codes: C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/20 : having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 277/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 285/12 : 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
• CPC Class Codes: C07D 307/54 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present invention aims to provide a compound having superior pharmacological action, physicochemical properties and the like and useful as an sGC activation drug, or an agent for the prophylaxis and/or treatment of diseases such as hypertension, ischemic cardiac disease, cardiac failure, kidney disease, arteriosclerotic disease, atrial fibrillation, pulmonary hypertension, diabetes, diabetic complications, metabolic syndrome, peripheral arterial obstruction, erectile dysfunction and the like.

An sGC activation drug containing a compound represented by the formula (II):

wherein each symbol is as defined in the specification, or a salt thereof, as an active ingredient.

Claims

1. An sGC activating agent comprising a compound represented by the formula (I):

2. The sGC activating agent according to claim 1, wherein, in the formula (I), when both X₁ and Y₁ are bonds, the substituent of the optionally substituted aromatic hydrocarbon ring or the substituent of the optionally substituted 5- or 6-membered aromatic heterocycle for ring D₁ is selected from the group consisting of a halogen atom, an alkyl group substituted by a halogen atom, and an alkoxy group substituted by a halogen atom.

3. A compound represented by the formula (II):

4. The compound according to claim 3, wherein the ring A₂ is a pyrazole ring optionally further substituted by a substituent selected from the group consisting of

a C_1-6 alkyl group optionally substituted by a halogen atom, and

a C_1-6 alkoxy group.

5. The compound according to claim 3, wherein the ring A₂ is pyrazole.

6. The compound according to claim 3, wherein the ring B₂ is an optionally substituted 5-membered aromatic heterocycle.

7. The compound according to claim 3, wherein the ring B₂ is an optionally substituted thiazole ring, an optionally substituted oxazole ring, an optionally substituted furan ring, an optionally substituted thiophene ring, an optionally substituted oxadiazole ring or an optionally substituted thiadiazole ring.

8. The compound according to claim 3, wherein the ring B₂ is an optionally substituted thiazole ring.

9. The compound according to claim 3, wherein the ring D₂ is an optionally substituted aromatic hydrocarbon ring.

10. The compound according to claim 3, wherein the ring D₂ is an optionally substituted benzene ring.

11. The compound according to claim 3, wherein the ring D₂ is an optionally further substituted benzene ring substituted by a C_1-6 alkyl group optionally substituted by a halogen atom.

12. The compound according to claim 3, wherein the ring D₂ is a benzene ring substituted by substituent selected from a halogen atom and a C_1-6 alkyl group optionally substituted by a halogen atom.

13. The compound according to claim 3, wherein R₂ is a carboxyl group.

14. The compound according to claim 3, wherein R₂ is present at the 4-position on the pyrazole ring.

15. The compound according to claim 3, wherein X₂ is a C_1-6 alkylene group.

16. The compound according to claim 3, wherein Y₂ is a bond or an optionally substituted C_1-6 alkylene group.

17. The compound according to claim 3, wherein Y₂ is a bond.

18. The compound according to claim 3, wherein the ring A₂ is a pyrazole ring optionally further substituted by a substituent selected from the group consisting of

a C_1-6 alkyl group optionally substituted by a halogen atom, and

a C_1-6 alkoxy group;

R₂ is a carboxyl group;

ring D₂ is a benzene ring substituted by a halogen atom, and a C_1-6 alkyl group optionally substituted by a halogen atom.

33. A prodrug of the compound of any according to any of claims 3 to 32.

34. A medicament comprising the compound of any according to any of claims 3 to 32 or a prodrug thereof as an active ingredient.

35. The medicament according to claim 34, which is an sGC activating agent.

36. The medicament according to claim 34, which is an agent for the prophylaxis or treatment of at least one kind selected from the group consisting of hypertension, ischemic cardiac diseases, cardiac failure, kidney disease, arteriosclerotic diseases, atrial fibrillation, pulmonary hypertension, diabetes, diabetic complications, metabolic syndrome, peripheral arterial obstruction and erectile dysfunction.

37. Use of the compound of any according to any of claims 3 to 33 or a prodrug thereof for the production of an agent for the prophylaxis or treatment of at least one kind selected from the group consisting of hypertension, ischemic cardiac diseases, cardiac failure, kidney disease, arteriosclerotic diseases, atrial fibrillation, pulmonary hypertension, diabetes, diabetic complications, metabolic syndrome, peripheral arterial obstruction and erectile dysfunction.

38. The compound of any according to any of claim 3 to 33 or a prodrug thereof, which is used as an agent for the prophylaxis or treatment of at least one kind selected from the group consisting of hypertension, ischemic cardiac diseases, cardiac failure, kidney disease, arteriosclerotic diseases, atrial fibrillation, pulmonary hypertension, diabetes, diabetic complications, metabolic syndrome, peripheral arterial obstruction and erectile dysfunction.

39. A method for the prophylaxis or treatment of at least one kind selected from the group consisting of hypertension, ischemic cardiac diseases, cardiac failure, kidney disease, arteriosclerotic diseases, atrial fibrillation, pulmonary hypertension, diabetes, diabetic complications, metabolic syndrome, peripheral arterial obstruction and erectile dysfunction in a mammal, comprising administering an effective amount of the compound of any according to any of claims 3 to 33 or a prodrug thereof to the mammal.

19. 1-({4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylic acid or a salt thereof.

20. 1-({4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylic acid or a salt thereof.

21. 1-({2-[2-Fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic acid or a salt thereof.

22. 1-({2-[3-Chloro-5-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic acid or a salt thereof.

23. A compound represented by the formula (III):

24. The compound according to claim 23, wherein the ring A₃ is a benzene ring optionally further substituted by a halogen atom.

25. The compound according to claim 23, wherein the ring A₃ is a benzene ring.

26. The compound according to claim 23, wherein the ring B₃ is an optionally substituted thiazole ring.

27. The compound according to claim 23, wherein the ring D₃ is an optionally further substituted benzene ring substituted by a trihalo(C_1-6)alkyl group.

28. The compound according to claim 23, wherein R₃₁ is a carboxyl group, R₃₂ is a hydrogen atom or a halogen atom.

29. The compound according to claim 23, wherein X₃ is methylene.

30. 4-({4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)benzoic acid or a salt thereof.

31. 4-{[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]methyl}benzoic acid or a salt thereof.

32. 4-({4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)benzoic acid or a salt thereof.