Patent EA-002982-B1 (EA)
Title: Heterocyclic thioesters and ketones
Inventor: LI JIA-HE
IPC: C07D207/06
Filed: 1997-09-09
Abstract: 1. A compound of formula II:   or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; Z is selected from S, CH2 and CHR1; R1 is C1-C5 straight or branched chain alkyl, substituted on one or more Ar1 positions; R2 is selected from the group consisting of C3-C5 straight or branched chain alkyl, C5-C7 cycloalkyl, and Ar1, Ar1 is phenyl, pyridyl, fluorenyl, thioindolyl or naphthyl or biphenyl, wherein said Ar1 is unsubstituted or substituted on one or more positions with halo, trifluoromethyl, methoxy, or the mixture thereof. 2. The compound of Claim 1, wherein: n is 1; and X is O. 3. The compound of Claim 2, wherein Z is CH2. 4. The compound of Claim 3, which is selected from the group consisting of: (2S)-2-(1-oxo-5-phenyl)-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine; 3,3-dimethyl-1-[(2S)-1-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedion; (2S)-2-(1-oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; (2S)-2-(1-oxo-4-phenyl)-butyl-1-(2-cyclohexyl-1,2-dioxoethyl)pyrrolidine and 2-(1-oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine. 5. The compound of Claim 2, wherein Z is S. 6. The compound of Claim 5, which is selected from the group consisting of: 2-phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 1-{2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]pyrrolidinyl}-3,3-dimethylpentane-1,2-dione; 2-phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 2-phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3-phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 4-phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 4-phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 3-(para-methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-di(para-fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 4,4-di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(1-naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 2,2-diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-[4-(trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(3-chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-[3-(trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(3-fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; and 3-(3,4-dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 7. The compound of Claim 1, wherein: n is 2; and X is O. 8. The compound of Claim 7, wherein Z is CH2. 9. The compound of Claim 8, which is selected from the group consisting of: 2-(1-oxo-6-phenyl)hexyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine; 3,3-dimethyl-1-[2-(4-phenylbutanoyl)piperidino]-1,2-pentandion and  3,3-dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentandion. 10. The compound of Claim 7, wherein Z is S. 11. The compound of Claim 10, which is selected from the group consisting of: 2-phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate; 2-phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate; 3-phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate; 4-phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate; 1,5-diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate; 1,5-diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate; 3-(para-methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)-piperidine-2-carbothioate; 3-(para-methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)-piperidine-2-carbothioate; 3-(1-naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)-piperidine-2-carbothioate; 2,2-diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 3,3-diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 3-(1-naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 4-phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 3-(3-chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; 3-(2-fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate. 12. The compound of Claim 7, wherein Z is CHR1. 13. The compound of Claim 12, which is selected from the group consisting of: 2-{1-oxo-[2-(2'-phenyl)ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine. 14. A compound which is 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate. 15. A compound which is 3-(1-naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 16. A compound which is 2,2-diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 17. A compound which is 3,3-diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate. 18. A compound which is 3-[4-(trifluoromethyl)phenyl] propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 19. A compound which is 3-(2-naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 20. A compound which is 3,3-dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidyn]-1,2-pentandion. 21. A compound which is (2S)-2-(1-oxo-4-phenyl)butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidyn. 22. A pharmaceutical composition comprising: 1) an effective amount of the compound formula II:   or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; X is O or S; Z is selected from S, CH2 and CHR1; R1 is C1-C5 straight or branched chain alkyl, substituted on one or more Ar1 positions; R2 is selected from the group consisting of C3-C5 straight or branched chain alkyl, C5-C7 cycloalkyl, and Ar1, Ar1 is phenyl, pyridyl, fluorenyl, thioindolyl or naphthyl or biphenyl, wherein said Ar1 is unsubstituted or substituted on one or more positions with halo, trifluoromethyl, methoxy, or the mixture thereof; and 2) a pharmaceutically acceptable carrier. 23. The pharmaceutical composition of Claim 22, wherein said compound is selected from the group consisting of: (2S)-2-(1-oxo-5-phenyl)-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine; 3,3-dimethyl-1-[(2S)-1-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedion; (2S)-2-(1-oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; (2S)-2-(1-oxo-4-phenyl)-butyl-1-(2-cyclohexyl-1,2-dioxoethyl)pyrrolidine and 2-(1-oxo-4-phenyl)-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; 2-phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 1-{2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]pyrrolidinyl}-3,3-dimethylpentane-1,2-dione; 2-phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 2-phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3-phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 4-phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 4-phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate; 3-(para-methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 3,3-di(para-fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; 4,4-di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(1-naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 2,2-diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-[4-(trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(3-chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-[3-(trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(3-fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 3-(2-chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; and 3-(3,4-dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate. 2-(1-oxo-6-phenyl)hexyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine; 3,3-dimethyl-1-[2-(4-phenylbutanoyl)piperidino]-1,2-pentandion, 3,3-dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentandion, 2-phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecar