Substituted imidazoles useful in the treatment of inflammatory diseases

• US 6,521,655 B1
• Filed: 11/03/2000
• Issued: 02/18/2003
• Est. Priority Date: 04/24/1997
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Beers, Scott A., Wu, Wei, Wachter, Michael P., Malloy, Elizabeth A.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US09/705,508
• Time in Patent Office: 837 Days
• Field of Search: 546/280.4, 514/336, 514/397, 548/315.1
• US Class Current: 514/397
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 7/0812 comprising a heterocyclic ring

Abstract

This invention relates to a series of substituted imidazoles of Formula I

pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, and are useful in the treatment of diseases associated with overproduction of inflammatory cytokines.

Claims

1. A compound of Formula I

wherein:

R₁ is phenyl, substituted phenyl where the substituents are selected from the group consisting of C_1-5alkyl, halogen, nitro, trifluorormethyl, and nitrile, or thiophen-2-yl or thiophen-3-yl;

R₂ is phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C_1-5alkyl, halogen, nitro, trifluoromethyl, and nitrile, or thiophen-2-yl or thiophen-3-yl which are optionally C_1-4alkyl substituted, and at least one of R₁ and R₂ is thiophen-2-yl or thiophen-3-yl;

R₃ is hydrogen, SEM, C_1-5alkoxycarbonyl, aryloxycarbonyl, arylC_1-5alkyloxycarbonyl, arylC_1-5alkyl, substituted arylC_1-5alkyl where the aryl substituents are independently selected from one or more members of the group consisting of C_1-5alkyl, C_1-5alkoxy, halogen, amino, C_1-5alkylamino, and diC_1-5alkylamino, phthalimidoC_1-5alkyl, amninoC_1-5alkyl, diaminoC_1-5alkyl, succinimidoC_1-5alkyl, C_1-5alkylcarbonyl, arylcarbonyl, C_1-5alkylcarbonylC_1-5alkyl, and aryloxycarbonylC_1-5alkyl;

R₄ is (A)—

(CH₂)_q—

X where;

A is vinylene, ethynylene or

 

where

R₅ is selected from the group consisting of hydrogen, C_1-5alkyl, phenyl and phenylC_1-5alkyl,

q is 0-9;

X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine, ethynyl, substituted ethynyl where the substituents are selected from one or more of the group consisting of fluorine, bromine chlorine and iodine, C_1-5alkyl, substituted C_1-5alkyl where the alkyl substituents are selected from the group consisting of one or more C_1-5alkoxy trihaloalkyl, phthalimido and amino, C_3-7cycloalkyl, C_1-5alkoxy, substituted C_1-5alkoxy where the alkyl substituents are selected from the group consisting of phthalimido and amino, phthalimidooxy, phenoxy, substituted phenoxy where the phenyl substituents are selected from the group consisting of C_1-5alkyl, halogen and C_1-5alkoxy, phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C_1-5alkyl, halogen and C_1-5alkoxy, arylC_1-5alkyl, substituted arylC_1-5alkyl where the aryl substituents are selected from the group consisting of C_1-5alkyl, halogen and C_1-5alkoxy, aryloxyC_1-5alkylamino, C_1-5alkylamino, diC_1-5alkylamino, nitrile, oxime, benzyloxyiminio, C_1-5alkyloxyimino, phthalimido, succinimido, C_1-5alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy where the phenyl substitutents are selected from the group consisting of C_1-5alkyl, halogen and C_1-5alkoxy, phenylC_1-5alkylcarbonyloxy, where the phenyl substitutents are selected from the group consisting of C_1-5alkyl, halogen and C_1-5alkoxy, aminocarbonyloxy, C_1-5alkylaminocarbonyloxy, diC_1-5alkylaminocarbonyloxy, C_1-5alkoxycarbonyloxy, substituted C_1-5alkoxycarbonyloxy where the alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl and hexyl, phenoxycarbonyloxy, substituted phenoxycarbonyloxy where the phenyl substituents are selected from the group consisting of C_1-5alkyl, C_1-5alkoxy, and halogen, C_1-5alkylthio, substituted C_1-5alkylthio where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C_1-5alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are selected from the group consisting of bromine, fluorine, chloride, C_1-5alkoxy and trifluoromethyl;

with the proviso;

and if A is vinylene, q is 0 then X is not phenyl;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where R₁ is substituted phenyl and R₂ is thiophen-2-yl or thiophen-3-yl.

3. The compound of claim 1 where R₁ is phenyl and R₂ is selected from the group consisting of 2-thiophenyl and 3-thiophenyl.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.