Benzofuran derivative

• US 20060189621A1
• Filed: 03/03/2004
• Published: 08/24/2006
• Est. Priority Date: 03/07/2003
• Status: Active Grant

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Mizoguchi, Toshimi, Tamura, Masahiro, Sato, Seiichi, Koshi, Tomoyuki, Ohkuchi, Masao, Yasuoka, Kyoko, Totsuka, Junko
• Granted Patent: US 7,314,877 B2
• Time in Patent Office: Days
• US Class Current: 514/252.10
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/00 Drugs for immunological or allergic disorders
• 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: C07D 405/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention is directed to a compound represented by formula (1):
(wherein R¹ represents an alkyl group which may have a substituent or an alkenyl group which may have a substituent; and

each of R² and R³ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a dihydroxyalkyl group, or an alkynyl group, or R² and R³ form, together with the nitrogen atom adjacent thereto, a nitrogen-containing saturated heterocyclic group which may have a substituent) and a drug composition containing the compound. The compound exhibits tumor necrosis factor (TNF-α) production inhibitory effect and improved absorption upon oral administration.

Claims

1. A benzofuran derivative represented by formula (1):

2. A compound according to claim 1, wherein R¹ is a C1-C12 alkyl group which may have a substituent or a C2-C12 alkenyl group which may have a substituent.

3. A compound according to claim 2, wherein the substituent which may be possessed by the alkyl or alkenyl group represented by R¹ is a C6-C14 aryl group or a heteroaryl group having a 5-membered or 6-membered ring containing one to three nitrogen atoms, and the aryl or heteroaryl group may be substituted by one to three members selected from among halogen atoms, alkyl groups, and alkoxy groups.

4. A compound according to claim 1, wherein each of R² and R³ represents a hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or alkynyl group, or R² and R³ form, together with the nitrogen atom adjacent thereto, a 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, and the heterocyclic group may be substituted by a halogen atom, alkyl group, alkoxycarbonyl group, or aralkyl group.

5. A compound according to claim 1, wherein R¹ represents a cyclopropylmethyl group, a cinnamyl group, a halogenocinnamyl group, a benzyl group, a halogenobenzyl group, a dihalogenobenzyl group, or a (halogenophenyl)propyl group;

each of R² and R³ is a hydrogen atom, a C1-C7 alkyl group, or a C1-C7 hydroxyalkyl group;

the heterocyclic group formed by R² and R³ is a piperazinyl group which may be substituted by a C1-C7 alkyl group.

6. A compound according to claim 1, which is 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 4-N,N,-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-dimethylaminomethyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-(4-fluorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 2-(4-chlorocinnamyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 6-(1-benzofuran-5-yl)-2-(4-fluorobenzyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-(2-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, or 4-aminomethyl-2-(2-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one.

7. A drug containing, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 to 6.

8. A drug according to claim 7, which is a drug for preventing or treating a pathological condition caused by excessive production of tumor necrosis factor (TNF-α

).

9. A drug according to claim 7, which is a drug for preventing or treating an immune disease, an inflammatory disease, or an allergic disease.

10. A drug according to claim 7, which is a drug for preventing or treating rheumatism, arthritis, or ulcerative colitis.

11. A tumor necrosis factor (TNF-α

) production inhibitor containing, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 to 7.

12. A drug composition containing a compound or a salt thereof as recited in any one of claims 1 to 6 and a pharmacologically acceptable carrier therefor.

13. A drug composition according to claim 12, which is a drug composition for preventing or treating a pathological condition caused by excessive production of tumor necrosis factor (TNF-α

).

14. A drug composition according to claim 12, which is a drug composition for preventing or treating an immune disease, an inflammatory disease, or an allergic disease.

15. A drug composition according to claim 12, which is a drug composition for preventing or treating rheumatism, arthritis, or ulcerative colitis.

16. Use of a compound or a salt thereof as recited in any one of claims 1 to 6 in manufacture of a drug.

17. Use according to claim 16, wherein the drug is a drug for preventing or treating a pathological condition caused by excessive production of tumor necrosis factor (TNF-α

).

18. Use according to claim 16, wherein the drug is a drug for preventing or treating an immune disease, an inflammatory disease, or an allergic disease.

19. Use according to claim 16, wherein the drug is a drug for preventing or treating rheumatism, arthritis, or ulcerative colitis.

20. A method for treating a pathological condition caused by excessive production of tumor necrosis factor (TNF-α

), characterized by administering a compound or a salt thereof as recited in any one of claims 1 to 6.

21. A method for treating an immune disease, an inflammatory disease, or an allergic disease, characterized by administering a compound or a salt thereof as recited in any one of claims 1 to 6.

22. A method according to claim 21, which is a method for the treatment of rheumatism, arthritis, or ulcerative colitis.