Claims
- 1. A compound of Formula I ##STR37## wherein: R.sub.1 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C.sub.1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile, or pyridinyl;
- R.sub.2 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C.sub.1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile or pyridinyl where the pyridinyl is optionally C.sub.1-4 alkyl substituted;
- R.sub.3 is hydrogen, SEM, C.sub.1-5 alkoxycarbonyl, aryloxycarbonyl, arylC.sub.1-5 -alkyloxycarbonyl, arylC.sub.1-5 alkyl, substituted arylC.sub.1-5 alkyl where the aryl substituents are independently selected from one or more members of the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxy, halogen, amino, C.sub.1-5 alkylamino, and diC.sub.1-5 alkylamino, phthalimidoC.sub.1-5 -alkyl, aminoC.sub.1-5 alkyl, diaminoC.sub.1-5 alkyl, succinimidoC.sub.1-5 alkyl, C.sub.1-5 alkylcarbonyl, arylcarbonyl, C.sub.1-5 alkylcarbonylC.sub.1-5 alkyl, aryloxycarbonylC.sub.1-5 alkyl;
- R.sub.4 is (A)--(CH.sub.2).sub.q --X where:
- A is vinylene, ethynylene or ##STR38## where R.sub.5 is selected from the group consisting of hydrogen, C.sub.1-5 alkyl, phenyl and phenylC.sub.1-5 alkyl;
- 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.sub.1-5 alkyl, substituted C.sub.1-5 alkyl where the alkyl substituents are selected from the group consisting of one or more C.sub.1-5 alkoxy trihaloalkyl, phthalimido and amino, C.sub.3-7 cycloalkyl, C.sub.1-5 alkoxy, substituted C.sub.1-5 alkoxy 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.sub.1-5 alkyl, halogen and C.sub.1-5 alkoxy), phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C.sub.1-5 alkyl, halogen and C.sub.1-5 alkoxy, arylC.sub.1-5 alkyl, substituted arylC.sub.1-5 alkyl where the aryl substituents are selected from the group consisting of C.sub.1-5 alkyl, halogen and C.sub.1-5 alkoxy, arylhydroxyC.sub.1-5 alkyl amino, C.sub.1-5 alkylamino, diC.sub.1-5 alkylamino, nitrile, oxime, benxyloxyimino, C.sub.1-5 alkyloxyimino, phthalimido, succinimido, C.sub.1-5 alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy where the phenyl substitutents are selected from the group consisting of C.sub.1-5 alkyl, halogen and C.sub.1-5 alkoxy, phenylC.sub.1-5 alkylcarbonyloxy, where the phenyl substitutents are selected from the group consisting of C.sub.1-5 alkyl, halogen and C.sub.1-5 alkoxy, aminocarbonyloxy, C.sub.1-5 alkylaminocarbonyloxy, diC.sub.1-5 alkylaminocarbonyloxy, C.sub.1-5 alkoxycarbonyloxy, substituted C.sub.1-5 alkoxycarbonyloxy 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.sub.1-5 alkyl, C.sub.1-5 alkoxy, and halogen, C.sub.1-5 alkylthio, substituted C.sub.1-5 alkylthio where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C.sub.1-5 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are selected from the group consisting of bromine, fluorine, chloride, C.sub.1-5 alkoxy and trifluoromethyl; with the proviso:
- if A is ##STR39## q is 0 and X is H, R.sub.3 may not be SEM; and pharmaceutically acceptable salts thereof.
- 2. The compound of claim 1 where R.sub.1 is substituted phenyl and R.sub.2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
- 3. The compound of claim 2 where R.sub.1 is 4-fluorophenyl and R.sub.2 is pyridin-4-yl.
- 4. The compound of claim 3 where R.sub.3 is hydrogen, arylC.sub.1-5 alkyl, or substituted arylC.sub.1-5 alkyl.
- 5. The compound of claim 4 where R.sub.3 is hydrogen or phenylC.sub.1-5 alkyl.
- 6. The compound of claim 5 where A is ethynylene and q is 0-5.
- 7. The compound of claim 6 where X is succinimido, hydroxy, methyl, phenyl, C.sub.1-5 alkylsulfonyl, C.sub.3-6 -cycloalkyl, C.sub.1-5 alkylcarbonyloxy, C.sub.1-5 alkoxy, phenylcarbonyloxy, C.sub.1-5 alkylamino, diC.sub.1-5 alkylamino, or nitrile.
- 8. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-hydroxypropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(6-hydroxyhexyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
- 9. A compound 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole and pharmaceutically acceptable salts thereof.
- 10. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(5-cyanopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-dimethylaminobutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-(phenylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-methylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-cyclopentylpropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-(butylsulfonyl)pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
- 11. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(octyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-butylthiopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-phenylpentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(5-chloropentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phthalimidolpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-N-succinimidopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
- 12. The compound of claim 1 where R.sub.1 is phenyl and R.sub.2 is selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
- 13. The compound of claim 12 where R.sub.2 is pyridin-3-yl.
- 14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
- 15. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier or diluent.
- 16. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier or diluent.
- 17. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier or diluent.
Parent Case Info
This application claims the benefit of provisional application 60/044,252 filed Apr. 27, 1997 under 119 (e).
This invention relates to a series of substituted imidazoles, pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, particularly, TNF-.alpha., and IL-1.beta.. Compounds of this invention are useful in the treatment of diseases associated with overproduction of inflammatory cytokines, such as rheumatoid arthritis, inflammatory bowel disease, septic shock, osteoporosis, and osteoarthritis.
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