Benzofuran derivative

• US 7,314,877 B2
• Filed: 03/03/2004
• Issued: 01/01/2008
• Est. Priority Date: 03/07/2003
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Tamura, Masahiro, Sato, Seiichi, Mizoguchi, Toshimi, Yasuoka, Kyoko, Totsuka, Junko, Kumai, Natsuyo, Koshi, Tomoyuki, Ohkuchi, Masao
• Primary Examiner(s): Habte; Kahsay
• Application Number:
  US10/547,779
• Publication Number:
  US 20060189621A1
• Time in Patent Office: 1,399 Days
• Field of Search: 544/238, 514/252.01
• US Class Current: 514/252.01
• 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;

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 the group consisting of halogen atoms, alkyl groups, and alkoxy groups.

3. 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.

4. 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;

or R² and R³ form together with the nitrogen atom adjacent thereto, a piperazinyl group which may be substituted by a C1-C7 alkyl group.

5. 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.

6. A pharmaceutical composition containing a compound or a salt thereof as recited in claim 1, and a pharmacologically acceptable carrier therefor.

7. A method for treating a patient with a disease or condition in which excessive production of tumor necrosis factor (TNF-α

) is implicated, comprising administering a compound or a salt thereof as recited in claim 1 to said patient, wherein said disease or condition is rheumatism, arthritis, or ulcerative colitis.

8. A compound according to claim 2, 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.

9. A process for preparing the benzofuran derivative according to claim 1, comprising carrying out the following reaction scheme: