Claims for Patent: 4,055,652

Summary for Patent: 4,055,652

Title:	1-[.beta.(R-thio)phenethyl]imidazoles and derivatives thereof
Abstract:	Novel 1-[.beta.-(R-thio)phenethyl]-imidazoles and the corresponding 1-[.beta.-(R-sulfinyl)phenethyl]imidazoles and 1-[.beta.-(R-sulfonyl)phenethyl]imidazoles wherein R is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl, substituted aralkyl, aryl or substituted aryl; and the antimicrobial acid addition salts thereof, are useful as antifungal, anti-bacterial and anti-protozoal agents.
Inventor(s):	Walker; Keith A. M. (Palo Alto, CA)
Assignee:	Syntex (U.S.A.) Inc. (Palo Alto, CA)
Application Number:	05/664,453
Patent Claims:	1. A compound of the formula: ##STR10## and the antimicrobial acid addition salts thereof, wherein: R is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl, substituted aralkyl, aryl or substituted aryl, said substituted aralkenyl and substituted aralkyl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano and said substituted aryl containing at least one substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino alkanoylamino and cyano; R.sup.1 is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, thiocyano or the group ##STR11## in which R.sup.2 is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl or substituted aryl, and substituted aralkyl and said substituted aryl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano; and wherein with reference to the above, alkyl has 1 to 20 carbon atoms, cycloalkyl has 5 to 8 carbon atoms, cycloalkyl has 6 to 11 carbon atoms, alkenyl and alkynyl have 2 to 12 carbon atoms, aryl has 6 to 10 carbon atoms, aralkyl has 7 to 14 carbon atoms, aralkenyl has 8 to 14 carbon atoms, lower alkyl and lower alkoxy have 1 to 6 carbon atoms and alkanoylamino has 2 to 12 carbon atoms; m, n and p are independently selected from the integers zero, 1 and 2; provided that the value of m cannot be greater than the value of n except when R.sup.1 is the group ##STR12## and R.sup.2 is aryl or substituted aryl. 2. The compound of claim 1 which is 1-[2,4-dichloro-.beta.-(4'-chlorobenzylsulfinyl)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 3. The compound of claim 1 which is 1-[2,4-dichloro-.beta.-(n-heptylsulfinyl)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 4. The compound of claim 1 which is 1-[2,4-dichloro-.beta.-(2',4'-dichlorobenzylsulfinyl)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 5. The compound of claim 1 which is 1-[2,4-dichloro-.beta.-(3',4'-dichlorophenylsulfinyl)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 6. A compound of claim 1 wherein m is zero. 7. A compound of claim 6 wherein R.sup.1 is halo and R is alkyl, alkenyl, aralkenyl, halo substituted aralkenyl, aralkyl, halo or lower alkoxy substituted aralkyl, aryl or halo or lower alkoxy substituted aryl. 8. A compound of claim 7 wherein R is alkyl containing 1 to 12 carbon atoms, 2-alkenyl, 3-phenyl-2-alkenyl, halo substituted 3-phenyl-2alkenyl, benzyl, halo or lower alkoxy substituted benzyl, phenyl or halo or lower alkoxy substituted phenyl. 9. A compound of claim 8 wherein [R.sup.1 ].sub.p is 2,4-dihalo. 10. The compound of claim 9 which is 1-[2,4-dichloro-.beta.-(2-octenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 11. The compound of claim 9 which is 1-[2,4-dichloro-.beta.-(3-phenyl-2-propenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 12. The compound of claim 9 which is 1-{2,4-dichloro-.beta.-[3-(4'-chlorophenyl)-2- propenylthio]phenethyl}imidazole and the antimicrobial acid addition salts thereof. 13. The compound of claim 9 which is 1-{2,4-dichloro-.beta.-[3-(4'-fluorophenyl)-2-propenylthio]phenethyl}imida zole and the antimicrobial acid addition salts thereof. 14. A compound of claim 9 wherein R is alkyl containing 4 to 10 carbon atoms, halo or methoxy substituted benzyl, or halo or methoxy substituted phenyl. 15. The compound of claim 14 which 1-[2,4-dibromo-.beta.-(n-pentylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 16. The compound of claim 14 which is 1-[2,4-dibromo-.beta.-(n-hexylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 17. The compound of claim 14 which is 1-[2,4-dibromo-.beta.-(n-heptylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 18. The compound of claim 14 which is 1-[2,4-dibromo-.beta.-(4'-chlorobenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 19. The compound of claim 14 which is 1-[2,4-dibromo-.beta.-(3',4'-dichlorophenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 20. The compound of claim 14 which is 1-[2,4-dichloro-.beta.-(4'-fluorobenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 21. The compound of claim 14 which is 1-[2,4-dichloro-.beta.-(4'-methoxybenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 22. The compound of claim 14 which is 1-[2,4-dichloro-.beta.-(4'-methoxyphenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 23. The compound of claim 14 which is 1-[2,4-difluoro-.beta.-(n-heptylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 24. The compound of claim 14 which is 1-[2,4-difluoro-.beta.-(n-octylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 25. The compound of claim 14 which is 1-[2,4-difluoro-.beta.-(n-nonylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 26. A compound of claim 14 wherein [R.sup.1 ].sub.p is 2,4-dichloro and R is a straight chain alkyl containing 4 to 10 carbon atoms, chloro substituted benzyl or chloro substituted phenyl. 27. The compound of claim 26 which is 1-[2,4-dichloro-.beta.-(n-butylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 28. The compound of claim 26 which is 1-[2,4-dichloro-.beta.-(n-octylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 29. The compound of claim 26 which is 1-[2,4-dichloro-.beta.-(n-nonylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 30. The compound of claim 26 which is 1-[2,4-dichloro-.beta.-(3',4',5'-trichlorophenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 31. A compound of claim 26 wherein R is a straight chain alkyl containing 5 to 7 carbon atoms, 4-chloro-, 2,4-dichloro- or 3,4-dichlorobenzyl, or 4-chloro-, 2,4-dichloro- or 3,4-dichlorophenyl. 32. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(n-pentylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 33. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(n-hexylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 34. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(n-heptylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 35. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(4'-chlorobenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 36. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(2',40'-dichlorobenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 37. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(3',4'-dichlorobenzylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 38. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(4'-chlorophenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 39. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(2',4'-dichlorophenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 40. The compound of claim 31 which is 1-[2,4-dichloro-.beta.-(3',4'-dichlorophenylthio)phenethyl]imidazole and the antimicrobial acid addition salts thereof. 41. A composition useful for inhibiting the growth of fungi, bacteria or protozoa which comprises an effective amount of a compound of the formula: ##STR13## or an antimicrobial acid addition salt thereof, wherein: R is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl, substituted aralkyl, aryl and substituted aryl, said substituted aralkenyl and substituted aralkyl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano and said substituted aryl containing at least one substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino, alkanoylamino and cyano; R.sup.1 is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, thiocyano and the group ##STR14## in which R.sup.2 is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl and substituted aryl, said substituted aralkyl and said substituted aryl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano; and wherein with reference to the above, alkyl has 1 to 20 carbon atoms, cycloalkyl has 5 to 8 carbon atoms, cycloalkyl alkyl has 6 to 11 carbon atoms, alkenyl and alkynyl have 2 to 12 carbon atoms, aryl has 6 to 10 carbon atoms, aralkyl has 7 to 14 carbon atoms, aralkenyl has 8 to 14 carbon atoms, lower alkyl and lower alkoxy have 1 to 6 carbon atoms and alkanoylamino has 2 to 12 carbon atoms; m, n and p are independently selected from the integers zero, 1 and 2; provided that the value of m cannot be greater than the value of n except when R.sup.1 is the group ##STR15## and R.sup.2 is aryl or substituted aryl; in admixture with a suitable carrier. 42. A composition of claim 41 for pharmaceutical use wherein the carrier is a pharmaceutically acceptable, non-toxic carrier. 43. A composition of claim 42 for topical administration wherein the compound of Formula (I) is present in an amount ranging between 0.1 and 10.0 weight percent of the composition. 44. A method of inhibiting the growth of fungi, bacteria or protozoa which comprises applying to a host object containing, or subject to attack by fungi, bacteria or protozoa, an effective amount of a compound of the formula ##STR16## or an antimicrobial acid addition salt thereof or a composition containing same as an active ingredient, wherein: R is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl cycloalkyl, cycloalkyl alkyl, aralkyl, substituted aralkyl, aryl or substituted aryl, said substituted aralkenyl and substituted aralkyl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano and said substituted aryl containing at least one substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino alkanoylamino and cyano; R.sup.1 is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, thiocyano or the group ##STR17## in which R.sup.2 is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl or substituted aryl, said substituted aralkyl and said substituted aryl containing at least one substituent on the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano; and wherein with reference to the above, alkyl has 1 to 20 carbon atoms, cycloalkyl has 5 to 8 carbon atoms, cycloalkyl alkyl has 6 to 11 carbon atoms, alkenyl and alkynyl have 2 to 12 carbon atoms, aralkyl has 7 to 14 carbon atoms, aralkenyl has 8 to 14 carbon atoms, lower alkyl and alkoxy have 1 to 6 carbon atoms and alkanoylamino has 2 to 12 carbon atoms; m, n and p are independently selected from the integers zero, 1 and 2; provided that the value of m cannot be greater than the value of n except when R.sup.1 is the group ##STR18## and R.sup.2 is aryl or substituted aryl. 45. The method of claim 44 wherein the compound of Formula (I) is administered topically. 46. The method of claim 44 wherein the compound of Formula (I) is administered orally or parenterally.