2-substituted imidazoles useful in the treatment of inflammatory diseases

• US 6,040,320 A
• Filed: 06/29/1998
• Issued: 03/21/2000
• Est. Priority Date: 06/30/1997
• 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:
  US09/106,698
• Time in Patent Office: 631 Days
• Field of Search: 546/274.1, 514/341
• US Class Current: 514/341
• 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 233/84 Sulfur atoms
• 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 409/14 containing three or more hetero rings

Abstract

This invention relates to substituted imidazoles of Formula I ##STR1## pharmaceutical compositions containing them, methods of using them and intermediates useful in their manufacture. The compounds of the invention modulate the production of a number of inflammatory cytokines, and are useful in the treatment of diseases associated with the production of inflammatory cytokines.

Claims

1. A compound of Formula I ##STR32## wherein:

one of R1 and R2 is phenyl optionally substituted by one or more of the members of the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl and nitrile;

the other is pyridyl optionally substituted by one or more of the members of the group consiting of C1-5alkyl and halogen;

R₃ is hydrogen, SEM, C_1-5 alkoxycarbonyl, aryloxycarbonyl, aryiC_1-5 alkyloxycarbonyl, arylC_1-5 alkyl, phthalimidoC_1-5 alkyl, aminoC_1-5 alkyl, diaminoC_1-5 alkyl, succinmidoC_1-5 alkyl, C_1-5 alkylcarbonyl, arylcarbonyl, C_1-5 alylcarbonylC_1-5 alkyl, aryloxycarbonylC_1-5 alkyl, or

substituted arylC_1-5 alkyl

wherein the aryl substituents are independently selected from one or more members of the group consisting of C_1-5 alkyl, C_1-5 alkoxy, halogen, amino, C_1-5 alkylamino, and diC_1-5 alkylamino;

R₄ is (A)_n -(CH₂)_q -X wherein;

A is sulfur;

n is 1;

q is 0-9;

X is selected from the group consisting of amino, C_1-5 alkylamino, phthalimido, amido, phenylcarbonyl, C_1-5 alkylaminocarbonyl, phenylaminocarbonyl, arylC_1-5 alkylaminocarbonyl, C_1-5 alkylsulfonyl, phenylsulfonyl,

substituted amido

wherein the carbonyl substituent is selected from the group consisting of C_1-5 alkyl, phenyl, arylC_1-5 alkyl, thienyl, furanyl, and naphthyl,

substituted phenylcarbonyl

wherein the phenyl substituents are independently selected from one or members of the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy,

substituted C_1-5 alkylsulfonyl

wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido,

substituted phenylsulfonyl

wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, C_1-5 alkoxy and trifluoromethyl,

with the proviso;

if A is sulfur and X is other than, C_1-5 alkylaminocarbonyl, phenylarninocarbonyl, arylC_1-5 alkylaminocarbonyl, C_1-5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where R₁ is substituted phenyl and R₂ is pyridin-2-yl, pyridin-3-yl, pyridin4-yl.

3. The compound of claim 2 where R₁ is 4-fluorophenyl and R₂ is pyridin-4-yl.

4. The compound of claim 3 where R₃ is hydrogen, C_1-5 alkyl, arylC_1-5 alkyl, or substituted arylC_1-5 alkyl.

5. The compound of claim 4 where R₃ is hydrogen or phenylC_1-5 alkyl.

6. The compound of claim 5 where q is 0-6.

7. The compound of claim 6 where X is phthalimido, amido, substituted amido, C_1-5 alkylsulfonyl, hydroxyC_1-5 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, or substituted amido.

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

10. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier or diluent.

8. A compound and pharmaceutically acceptable salts thereof selected from 5(4)-(4-fluorophenyl)-2-(3-(naphth-1-ylamido)prop-1-yl)thio-4(5)-(4-pyridyl)-imidazole (Cp#28);

5(4)-(4-fluorophenyl)-2-(3-(phenylsulfonamido)prop-1-yl)thio-4(5)-(4-pyridyl)-imidazole (Cp#30).