NOVEL PIPERIDINE DERIVATIVES
20170266175 · 2017-09-21
Assignee
Inventors
Cpc classification
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
C07D233/20
CHEMISTRY; METALLURGY
C07C317/02
CHEMISTRY; METALLURGY
International classification
C07D233/20
CHEMISTRY; METALLURGY
C07C317/02
CHEMISTRY; METALLURGY
Abstract
The invention relates to a compound of formula (I)
##STR00001##
wherein A.sup.1, A.sup.2 and R.sup.1 to R.sup.3 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
Claims
1. A compound of formula (I) ##STR00170## wherein R.sup.1 is haloalkylsulfonyl, haloalkyl, alkylsulfonyl, phenylalkylsulfonyl, halogen or alkyl; R.sup.2 is hydrogen or halogen; R.sup.3 is hydrogen or halogen; A.sup.1 is heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is 1H-imidazolyl, 1H-[1,2,4]triazolyl, thiazolyl, oxazolyl or 1H-pyrazolyl and wherein substituted heterocyclyl is heterocyclyl substituted with one or two substituents independently selected from alkyl, phenyl, phenylalkyl and alkoxyalkyl; A.sup.2 is heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxodihydroquinazolinyl, oxodihydrobenzoimidazolyl, 1H-pyrrolopyridine, oxodihydroindolyl, benzoimidazol-1-yl, 3-oxo-4H-benzo[1,4]oxazinyl, oxo-1H-imidazolyl, benzo[d]isoxazolyl, oxo-4H-[1,2,4]triazolyl, oxo-5H-imidazopyridinyl or oxopiperidinyl and wherein substituted heterocyclyl is heterocyclyl substituted with one or two substituents independently selected from alkyl, halogen, alkoxycarbonylalkyl, alkoxyalkyl, pyrrolidinyl, hydroxyalkyl, alkylcarbonyloxyalkyl, alkylsulfonylalkyl, morpholinyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, alkylpiperazinyl, halophenyl and carboxyalkyl; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein R.sup.1 is haloalkylsulfonyl, haloalkyl or alkylsulfonyl.
3. A compound according to claim 1 or 2, wherein R.sup.1 is trifluoromethylsulfonyl, trifluoromethyl or methylsulfonyl.
4. A compound according to any one of claims 1 to 3, wherein R.sup.2 is hydrogen or chloro.
5. A compound according to any one of claims 1 to 4, wherein R.sup.4 is hydrogen.
6. A compound according to any one of claims 1 to 5, wherein A.sup.1 is alkylthiazolyl, heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is 1H-imidazolyl, 1H-[1,2,4]triazolyl, oxazolyl or 1H-pyrazolyl and wherein substituted heterocyclyl is heterocyclyl substituted with one or two substituents independently selected from alkyl, phenyl, phenylalkyl and alkoxyalkyl.
7. A compound according to any one of claims 1 to 6, wherein A.sup.1 is alkyl-1H-imidazolyl or dialkyl-1H-imidazolyl.
8. A compound according to any one of claims 1 to 7, wherein A.sup.1 is methyl-1H-imidazolyl, propyl-1H-imidazolyl or dimethyl-1H-imidazolyl.
9. A compound according to any one of claims 1 to 8, wherein A.sup.2 is oxodihydroquinazolinyl, alkyloxodihydrobenzoimidazolyl, (alkylpyrrolidinyl)oxodihydrobenzoimidazolyl or 1H-pyrrolopyridine.
10. A compound according to any one of claims 1 to 9, wherein A.sup.2 is oxodihydroquinazolinyl, methyloxodihydrobenzoimidazolyl, (methylpyrrolidinyl)oxodihydrobenzoimidazolyl or 1H-pyrrolopyridine.
11. A compound according to any one of claims 1 to 10 selected from 3-{1-[5-Methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[1,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(4-Methanesulfonyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[5-Methyl-2-(4-phenylmethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-7-fluoro-3,4-dihydro-1H-quinazolin-2-one; (6-Chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester; 1-(2-Methoxy-ethyl)-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 5-Chloro-3-ethyl-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[5-Methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[3,2-c]pyridine; 1-Methyl-3-{1-[5-methyl-2-(4-phenylmethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-{1-[2-(4-Methanesulfonyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 7-Fluoro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-6-pyrrolidin-1-yl-1,3-dihydro-benzoimidazol-2-one; 3-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 5-Chloro-3-methyl-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 6-Bromo-3-[1-[[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-1,4-dihydroquinazolin-2-one; 5-Chloro-3-(2-methoxy-ethyl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[5-Benzyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 5-Chloro-3-(2-hydroxy-ethyl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-{1-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 5-Chloro-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-{1-[1,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 5-Chloro-3-(2-methanesulfonyl-ethyl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; Acetic acid 2-(6-chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-ethyl ester; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[2-(2-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-6-morpholin-4-yl-1,3-dihydro-benzoimidazol-2-one; 3-{1-[2-(3,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[5-Propyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[2,3-b]pyridine; 2-(6-Chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetamide; 3-{1-[1-(2-Methoxy-ethyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 2-(6-Chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-N-methyl-acetamide; 3-{1-[5-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-{1-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 1-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 5-Chloro-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one; 3-{1-[1-Methyl-5-(4-trifluoromethyl-phenyl)-1H-[1,2,4]triazol-3-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-benzoimidazole; 3-{1-[2-(3,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-7-fluoro-3,4-dihydro-1H-quinazolin-2-one; 6-(4-Methyl-piperazin-1-yl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 4-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-4H-benzo[1,4]oxazin-3-one; 3-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[2,3-b]pyridine; 1-Methyl-3-{1-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-[1,2,4]triazol-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 5-(4-Bromophenyl)-3-[1-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-1H-imidazol-2-one; 6-Fluoro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-benzo[d]isoxazole; 3-{1-[2-(4-Chloro-3-fluoro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[4-Methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[3,2-c]pyridine; 3-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-indole; 1-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one; 1-{1-[2-(3,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 1-{1-[2-(2-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 1-Methyl-3-{1-[5-propyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; Sodium; (6-chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetate; 1-Methyl-3-{1-[5-phenyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[2-(2,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 5-Chloro-1-{1-[2-(3-chloro-4-methyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 5-Chloro-1-{1-[2-(4-chloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-(1-{5-Methyl-2-[4-(2-methyl-propane-1-sulfonyl)-phenyl]-1H-imidazol-4-ylmethyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(3,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[2,3-b]pyridine; 3-{1-[3-Methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-Methyl-3-{1-[1-methyl-5-(4-trifluoromethyl-phenyl)-1H-[1,2,4]triazol-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 5-(4-Bromophenyl)-2-[1-[[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-4H-1,2,4-triazol-3-one; 1-Methyl-3-{1-[4-methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-{1-[2-(4-Chloro-3-fluoro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 3-{1-[5-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[3,2-c]pyridine; 5-Chloro-1-{1-[2-(3-fluoro-4-methyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 1-[1-[[4-Methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-5H-imidazo[4, 5-c]pyridin-4-one; 1-Methyl-3-(1-{5-methyl-2-[4-(2-methyl-propane-1-sulfonyl)-phenyl]-1H-imidazol-4-ylmethyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one; 1-[1-[[4-Methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]piperidin-2-one; 1-{1-[2-(2,4-Dichloro-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 5-Chloro-1-[1-(5-methyl-2-p-tolyl-1H-imidazol-4-ylmethyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one; 1-[1-[[2-[4-(Trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-5H-imidazo[4,5-c]pyridin-4-one; and 5-(4-Bromophenyl)-3-[1-[[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-1H-imidazol-2-one.
12. A compound according to any one of claims 1 to 11 selected from 3-{1-[5-Methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; 3-{1-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[1,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[2-(4-Methanesulfonyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 3-{1-[5-Methyl-2-(4-trifluoromethanesulfonyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[3,2-c]pyridine; 1-{1-[2-(4-Methanesulfonyl-phenyl)-5-methyl-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3-methyl-1,3-dihydro-benzoimidazol-2-one; 3-{1-[5-Propyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one; 6-(4-Methyl-piperazin-1-yl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; and 3-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1H-pyrrolo[3,2-c]pyridine.
13. A process for the manufacture of a compound according to any one of claims 1 to 12 comprising one of the following steps: (a) the reaction of a compound of formula (II) ##STR00171## in the presence of a compound of formula (III) ##STR00172## and a base; or (b) the reaction of a compound of formula (IV) ##STR00173## in the presence of a compound of formula (III) as defined above and a reducing agent; wherein X is Cl, Br, I or —OSO.sub.2R, R is methyl or p-toluyl and A.sup.1, A.sup.2, R.sup.1 to R.sup.3 are as defined in any one of claims 1 to 10.
14. A compound according to any one of claims 1 to 12, when manufactured according to a process of claim 13.
15. A compound according to any one of claims 1 to 12 for use as a therapeutically active substance.
16. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 12 and a therapeutically inert carrier.
17. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, diabetic nephropathy or lupus nephritis.
18. A compound according to any one of claims 1 to 12 for use in the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, diabetic nephropathy or lupus nephritis.
19. A method for the treatment or prophylaxis of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, diabetic nephropathy or lupus nephritis, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 12.
20. The invention as hereinbefore described.
Description
EXAMPLES
Example 1
1-Methyl-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one
[0220] ##STR00034##
[0221] 1-Methyl-3-(4-piperidyl)benzimidazol-2-one (CAS 53786-10-0) (100 mg; 0.432 mmol) was dissolved in DMF (1.5 ml) and Ca(OH).sub.2 (67 mg; 96%; 0.865 mmol) was added. The suspension was stirred at RT for 15 min, then a solution of 4-(chloromethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole; hydrochloride (intermediate 1) (135 mg; 0.432 mmol) in DMF (1.5 ml) was added dropwise. After the addition, the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with diluted NaOH and brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (20 g silica gel; DCM/MeOH 100:0-90:10) to obtain the title compound as light brown solid (141 mg). MS (ESI): 470.3 (M+H).sup.+.
[0222] The following examples were prepared in analogy to example 1:
TABLE-US-00001 Ex. Name Structure MS (ESI) Reagents 2 1-{1-[5-Methyl-2-(4- trifluoromethyl-phenyl)- 1H-imidazol-4- ylmethyl]-piperidin-4- yl}-1,3-dihydro-indol-2- one
Example 12
5-(4-Bromophenyl)-3-[1-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]methyl]-4-piperidyl]-1H-imidazol-2-one
[0223] ##STR00106##
[0224] 5-(4-Bromophenyl)-3-(4-piperidyl)-1H-imidazol-2-one; trifluoroacetic acid salt (intermediate 42) was dissolved in ethanol and diisopropylethyl amine (6 equivalents) was added at 0° C. Then [5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methyl methanesulfonate (intermediate 27) (1 equivalent) was added and the mixture was heated to reflux for 16 h. The solvent was removed in vacuo and the remaining residue was dissolved in EtOAc, washed with water and brine. After removal of the solvent, the remaining residue was purified by column chromatography over silica gel to obtain the title compound. MS (ESI): 559.9 (M+H).sup.+.
[0225] The following examples were prepared in analogy to example 12:
TABLE-US-00002 Ex. Name Structure MS (ESI) Reagents 13 1-[1-[[4-Methyl-2-[4- (trifluoromethyl)phenyl]- 1H-imidazol-5- yl]methyl]-4-piperidyl]- 5H-imidazo[4,5- c]pyridin-4-one
Example 30
5-Chloro-3-(2-hydroxy-ethyl)-1-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one
[0226] ##STR00112##
[0227] Acetic acid 2-(6-chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-ethyl ester (example 29) (85 mg; 0.1476 mmol) was dissolved in MeOH (1 ml) and a solution of NaOH (12 mg; 0.295 mmol) in water (300 μl) was added. The yellow solution was stirred at RT for 1.5 h, then the MeOH was removed and water was added. The mixture was extracted with EtOAc and the combined extracts were washed with diluted NaOH solution and brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining crude material was purified by column chromatography (10 g silica gel; DCM/MeOH 100:0-90:10) to obtain the title compound as white solid (60 mg). MS (ESI): 534.2 (M+H).sup.+.
Example 34
(6-Chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid
[0228] (6-Chloro-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylmethyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester (example 33) (85 mg; 0.1512 mmol) was dissolved in MeOH (1 ml) and a solution of NaOH (12 mg; 0.302 mmol) in water (300 ul) was added. The yellow solution was stirred at RT for 1.5 h and the MeOH was removed. To the remaining residue water and 0.1N HCl (1512 μl) were added. The pH was carefully adjusted to 7 by addition of 0.1N HCl. The precipitate that formed was filtered off, washed with a small amount of water and a small amount of diethyl ether and dried to obtain the title compound as light brown solid (58 mg). MS (ESI): 548.3 (M+H).sup.+.
Example 52
3-{1-[3-Methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-ylmethyl]-piperidin-4-yl}-3,4-dihydro-1H-quinazolin-2-one
[0229] ##STR00113##
[0230] 3-Methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-4-carbaldehyde (Intermediate 25) (75 mg) and 3-(4-piperidyl)-1,4-dihydroquinazolin-2-one (CAS 79098-75-2) (68 mg) were dissolved in DCM (4 ml). Then sodium triacetoxyborohydride (94 mg) and AcOH (51 μl) were added and the mixture was stirred for 20 h. Saturated NaHCO.sub.3 solution was added and the mixture was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining solid was triturated with EtOAc to obtain the title compound as white solid (103 mg). MS (ESI): 470.3 (M+H).sup.+.
Intermediates
Intermediate 1
4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole; hydrochloride
[0231] ##STR00114##
Step 1:
[0232] To a refluxing solution of 4-(trifluoromethyl)-benzamidine; hydrochloride dihydrate (CAS 175278-62-3) (5 g; 19.18 mmol) in isopropanol (70 ml) was added 2,3-butanedione (2.10 ml; 24.0 mmol) and the reaction mixture was heated to reflux for 23 h. The reaction mixture was concentrated to dryness, water (20 ml) and 4N HCl (40 ml) were added and the brown suspension was heated to reflux for 3 h. The mixture was again concentrated to dryness and residual water was removed by co-evaporation with toluene (six times). The remaining [5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol; hydrochloride (light brown solid, 5.93 g) was used in the next step without further purification.
Step 2:
[0233] [5-Methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol; hydrochloride obtained in step 1 (930 mg; 3.18 mmol) was suspended in toluene (10 ml). A solution of SOCl.sub.2 (2 ml; 28.6 mmol) in toluene (2 ml) was added dropwise at RT. After the addition was complete, the reaction mixture was heated to 65° C. for 5 min, then cooled to RT and stirred at RT for 2 h. Diethyl ether (˜50 ml) was added and the light brown precipitate was filtered off, washed with diethyl ether and dried. The title compound (891 mg, off-white solid) was used without further purification. MS (ESI): 239.1 (M+H—HCl).sup.+.
[0234] The following intermediates were prepared in analogy to intermediate 1:
TABLE-US-00003 Int. Name Structure MS (ESI) Starting reagent 2 4-(Chloromethyl)-2-(4- chlorophenyl)-5-methyl-1H- imidazole; hydrochloride
[0235] Intermediate 12: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 2.38 (s, 3H), 3.30 (s, 3H), 4.91 (s, 2H), 8.14 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H).
[0236] Intermediate 13: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 2.36 (s, 3H), 4.87 (s, 2H), 8.31 (d, J=8.7 Hz, 2H), 8.37 (d, J=8.7 Hz, 2H).
[0237] Intermediate 15: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 2.40 (s, 3H), 4.79 (s, 2H), 4.94 (s, 2H), 7.17 (m, 2H), 7.30 (m, 3H), 7.93 (d, J=8.4 Hz, 2H), 8.29 (d, J=8.4 Hz, 2H).
[0238] Intermediate 16: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 4.94 (s, 2H), 7.45 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.2 Hz, 2H), 7.76 (d, J=7.2 Hz, 2H), 7.92 (d, J=8.3 Hz, 2H), 8.30 (d, J=8.3 Hz, 2H).
Intermediate 6a
3-Chloro-4-(trifluoromethyl)benzamidine; hydrochloride
[0239] ##STR00130##
[0240] A solution of 3-chloro-4-(trifluoromethyl)-benzonitrile (2 g; 98%; 9.53 mmol) in CHCl.sub.3 (16 ml) and MeOH (4 ml) was cooled to 0° C. Then HCl-gas was bubbled through this solution for 45 min. The flask was closed and stored overnight in the fridge. Then argon was bubbled through to remove excess of HCl-gas and all solvents were evaporated. NH.sub.3 (2M solution in MeOH; 24 ml; 47.7 mmol) was added and the solution was stirred at RT for 2 h. The reaction mixture was concentrated to dryness. Then again NH.sub.3 (2M solution in MeOH; 24 ml; 47.7 mmol) was added and the reaction mixture was stirred at RT overnight. The solvents were removed and the remaining white foamy solid (2.56 g) was used without purification for the next step. MS (ESI): 223.1 (M+H).sup.+.
[0241] The following intermediates were prepared in analogy to intermediate 6a:
TABLE-US-00004 Int. Name Structure MS (ESI) Starting reagent 9a 4-Chloro-3-fluoro- benzamidine; hydrochloride
Intermediate 13a
4-(Trifluoromethylsulfonyl)benzamidine; hydrochloride
[0242] ##STR00133##
[0243] To a suspension of NH.sub.4Cl (910 mg, 17 mmol) in toluene (20 ml) was added trimethylaluminum (2M solution in heptane, 8.5 ml, 17 mmol) dropwise at 0° C. Then a solution of 4-(trifluoromethylsulfonyl)benzonitrile (CAS 312-21-0) (800 mg, 3.4 mmol) in toluene (10 ml) was added and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT and was added to a suspension of silica gel (40 g) in DCM (200 ml). This mixture was stirred at RT for 1 h, filtered and the filter cake was washed with DCM/MeOH 4:1 (350 ml). The tile compound was obtained by evaporation of the filtrate as white solid (1.08 g). MS (ESI): 253.3 (M+H).sup.+.
[0244] The following intermediates were prepared in analogy to intermediate 13a:
TABLE-US-00005 Int. Name Structure MS (ESI) Starting reagent 14a 4- Isobutylsulfonylbenzamidine; hydrochloride
Intermediate 14b
4-Isobutylsulfonylbenzonitrile
[0245] ##STR00136##
Step 1:
[0246] To a solution of 2-methylpropane-1-thiol (1.68 ml, 15.4 mmol) in DMF (20 ml) was added sodium hydride (55% dispersion in oil, 404 mg, 16.8 mmol) portionwise at 0° C. The reaction mixture was stirred at RT for 1 h. Then a solution of 4-fluorobenzonitrile (1.7 g, 14.0 mmol) in DMF (5 ml) was added dropwise. After 4 h 1N NaOH solution was added and the mixture was extracted with diethyl ether. The combined organic extracts were washed three times with brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (50 g silica gel; heptane/DCM 1:1) to obtain 4-isobutylsulfonylbenzonitrile as colorless oil (1.83 g). MS (ESI): 209.1 (M+NH.sub.4)+.
Step 2:
[0247] To a solution of 4-isobutylsulfonylbenzonitrile (1.83 g, 9.6 mmol) in MeOH (35 ml) was added a solution of Oxone (10 g) in water (35 ml) dropwise at 0° C. The reaction mixture was stirred at RT for 4 h and the MeOH was removed under vacuum. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to obtain the title compound as white solid (2.23 g). MS (ESI): 282.3 (M+OAc).sup.−.
Intermediate 15b
4-Benzylsulfonylbenzonitrile
[0248] ##STR00137##
[0249] The title compound was prepared in analogy to intermediate 14b using phenylmethanethiol instead of 2-methylpropane-1-thiol and was obtained as white solid. MS (ESI): 256.3 (M−H).sup.−.
Intermediate 17
4-(Chloromethyl)-5-(2-methoxyethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole; hydrochloride
[0250] ##STR00138##
Step 1:
[0251] To a solution of methyl 5-methoxy-3-oxo-pentanoate (CAS 62462-05-9) (2.0 g, 12 mmol) in AcOH (3.0 ml) was added a solution of NaNO.sub.2 (948 mg, 14 mmol) in water (3.5 ml) dropwise at 0° C. The reaction mixture was stirred at RT for 1 h before additional water (10 ml) was added. After another 2 h, the reaction mixture was extracted with EtOAc and the combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. Methyl 2-hydroxyimino-5-methoxy-3-oxo-pentanoate (2.23 g) remained as a light brown oil and was used for the next reaction step without purification. MS (ESI): 188.1 (M−H).sup.−.
Step 2:
[0252] A solution of [4-(trifluoromethyl)phenyl]methanamine (2.24 g, 12.8 mmol) and methyl 2-hydroxyimino-5-methoxy-3-oxo-pentanoate (2.2 g, 11.6 mmol) in acetonitrile (30 ml) was heated to reflux for 5 h. The reaction mixture was then concentrated and the remaining residue was purified by column chromatography (first with 100 g silica gel; heptane/EtOAc 4:1 to 2:1 and a second time with 50 g silica gel; DCM/EtOAc 2:1). Methyl 5-(2-methoxyethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylate was obtained as light yellow solid (935 mg). MS (ESI): 327.4 (M−H).sup.−.
Step 3:
[0253] To a solution of methyl 5-(2-methoxyethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylate (100 mg, 0.3 mmol) in THF (4 ml) was added lithium aluminum hydride (28 mg, 0.73 mmol) and the mixture was stirred at RT for 2 h. Saturated NH.sub.4Cl solution was added and the mixture was extracted with EtOAc. The combined organic layers were dried with Na.sub.2SO.sub.4 and concentrated. The remaining solid was triturated with DCM to obtain [5-(2-methoxyethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol (70 mg) as white solid. MS (ESI): 299.4 (M−H).sup.−.
Step 4:
[0254] To a suspension of [5-(2-methoxyethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol (70 mg, 0.23 mmol) in toluene (3.0 ml) was added thionyl chloride (85 μl) and the mixture was stirred at RT. After completion of the reaction, diethyl ether was added and the precipitate was filtered and washed with diethyl ether. The title compound was obtained as white solid (78 mg). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 2.98 (t, J=6.6 Hz, 2H), 3.27 (s, 3H), 3.60 (t, J=6.6 Hz, 2H), 4.88 (s, 2H), 7.95 (d, J=8.1 Hz, 2H), 8.18 (d, J=8.1 Hz, 2H).
[0255] The following intermediates were prepared in analogy to intermediate 17:
TABLE-US-00006 Int. Name Structure Starting reagent 18 4-(Chloromethyl)-5- propyl-2-[4- (trifluoromethyl)phenyl]- 1H-imidazole; hydrochloride
[0256] Intermediate 19: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 4.29 (s, 2H), 4.98 (s, 2H), 7.20-7.45 (m, 5H), 8.00 (d, J=9 Hz, 2H), 8.31 (d, J=9 Hz, 2H).
Intermediate 20
4-(Chloromethyl)-1,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazole; hydrochloride
[0257] ##STR00141##
Step 1:
[0258] A solution of ethyl 2-hydroxyimino-3-oxo-butanoate (CAS 66508-93-8) (3.0 g, 18.9 mmol) and [4-(trifluoromethyl)phenyl]methanamine (3.63 g, 20.7 mmol) in acetonitrile (40 ml) was heated to reflux overnight. The reaction mixture was then cooled to 0° C. and the precipitate that formed was filtered off, washed with acetonitrile and dried to obtain ethyl 5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylate as white solid (3.45 g). MS (ESI): 299.0 (M+H).sup.+.
Step 2:
[0259] To a suspension of ethyl 5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylate (1.0 g, 3.35 mmol) and potassium tert-butoxide (414 mg, 3.69 mmol) in acetonitrile (10 ml) was added methyl iodide (230 ml, 3.69 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated and DCM and saturated NaHCO.sub.3 solution were added. After phase separation, the aqueous was extracted with DCM and the combined organic layers were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; heptane/EtOAc 5:1 to 3:1) to obtain ethyl 3,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (181 mg, white solid) and the desired ethyl 1,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (424 mg) as white solid. MS (ESI): 313.0 (M+H).sup.+.
Step 3:
[0260] To a solution of ethyl 1,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (175 mg, 0.56 mmol) in THF (3 ml) was added lithium aluminum hydride (28 mg, 0.73 mmol) and the mixture was stirred at RT for 2 h. Saturated NH.sub.4Cl solution was added and the mixture was extracted with EtOAc. The combined organic layers were dried with Na.sub.2SO.sub.4 and concentrated. The remaining solid was triturated with DCM to obtain [1,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]methanol (96 mg) as white solid. MS (ESI): 271.3 (M+H).sup.+.
Step 4:
[0261] To a suspension of [1,5-dimethyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]methanol (80 mg, 0.3 mmol) in toluene (3.0 ml) was added thionyl chloride (108 μl) and the mixture was stirred at RT. After completion of the reaction, diethyl ether was added and the precipitate was filtered and washed with diethyl ether. The title compound was obtained as white solid (96 mg). NMR (CDCl.sub.3, 300 MHz): δ 2.46 (s, 3H), 3.81 (s, 3H), 4.92 (s, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H).
Intermediate 21
4-(Chloromethyl)-1-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazole; hydrochloride
[0262] ##STR00142##
Step 1:
[0263] To a suspension of sodium hydride (55% dispersion in oil, 64 mg, 1.3 mmol) in DMF (4 ml) was added a solution of ethyl 5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylate (331 mg, 1.1 mmol) in DMF (1 ml) and the reaction mixture was stirred at RT for 1.5 h. Then 2-bromoethyl methyl ether (110 μl) was added and the reaction mixture was heated to 100° C. overnight. The mixture was cooled to RT and again sodium hydride (55% dispersion in oil, 6 mg) and 2-bromoethyl methyl ether (10 μl) were added. The reaction mixture was again heated to 100° C. overnight. Then water was added and the mixture was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (50 g silica gel; heptane/EtOAc 4:1 to 2:1) to obtain ethyl 3-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (122 mg, light yellow oil) and the desired ethyl 1-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (123 mg) as light yellow oil. MS (ESI): 357.4 (M+H).sup.+.
Step 2:
[0264] To a suspension of lithium aluminum hydride (14 mg, 0.4 mmol) in THF (4 ml) was added a solution of ethyl 1-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (115 mg, 0.3 mmol) in THF (4 ml) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h. A mixture of Na.sub.2SO.sub.4 (1 g), silica gel (1 g) and 20 drops of water was added portionwise and stirring was continued for 10 min. The mixture was filtered and the filtrate was evaporated to obtain [1-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]methanol (89 mg) as light yellow solid. MS (ESI): 315.0 (M+H).sup.+.
Step 3:
[0265] To a solution of [1-(2-methoxyethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]methanol (85 mg, 0.3 mmol) in toluene (5.0 ml) was added thionyl chloride (100 μl) and the mixture was stirred at RT. After completion of the reaction all volatiles were removed under vacuum to obtain the title compound as orange solid (90 mg). NMR (CDCl.sub.3, 300 MHz): δ 2.61 (s, 3H), 3.31 (s, 3H), 3.67 (t, J=5.1 Hz, 2H), 4.43 (t, J=5.1 Hz, 2H), 4.78 (s, 2H), 7.87 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).
Intermediate 22
5-(Chloromethyl)-1-methyl-3-[4-(trifluoromethyl)phenyl]-1,2,4-triazole
[0266] ##STR00143##
Step 1:
[0267] To a solution of 2-benzyloxyacetohydrazide (CAS 39256-35-4) (2.84 g; 15.8 mmol) in MeOH (40 ml) were added 4-(trifluormethyl)-benzonitrile (CAS 455-18-5) (5.39 g; 31.5 mmol) and potassium tert-butoxide (1.06 g; 9.46 mmol) and the mixture was heated to reflux for 22 h. The yellow solution was cooled to RT and water was added. MeOH was removed under vacuum and the remaining aqueous layer was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (50 g silica gel; heptane/EtOAc 90:10-75:25) to obtain 5-(benzyloxymethyl)-3-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole as with solid (3.93 g). MS (ESI): 334.2 (M+H).sup.+.
Step 2:
[0268] To a solution of 5-(benzyloxymethyl)-3-[4-(trifluoromethyl)phenyl]-1H-1,2,4-triazole (1 g; 3 mmol) in THF (15 ml) were added powdered KOH (313 mg; 86%; 4.8 mmol), methyl iodide (280 μl; 4.5 mmol) and Bu.sub.4NBr (97 mg, 0.3 mmol) and the suspension was stirred overnight at RT. Then water was added and the mixture was extracted with EtOAc. The organic layers were combined, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (50 g silica gel; heptane/EtOAc 90:10-80:20) to obtain 5-(benzyloxymethyl)-1-methyl-3-[4-(trifluoromethyl)phenyl]-1,2,4-triazole (849 mg, light yellow solid, MS (ESI): 348.2 (M+H).sup.+) and 3-(benzyloxymethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazole (141 mg, light yellow oil, MS (ESI): 348.2 (M+H).sup.+).
Step 3:
[0269] A suspension of 5-(benzyloxymethyl)-1-methyl-3-[4-(trifluoromethyl)phenyl]-1,2,4-triazole (830 mg; 2.39 mmol), ammonium formate (1.55 g; 23.9 mmol) and palladium (10% on carbon, 80 mg) in EtOH (12 ml) was heated to reflux for 20 h. Ammonium formate (775 mg; 97%; 11.9 mmol) was added and the black suspension was heated to reflux for additional 4 h. Again ammonium formate (775 mg) was added and the mixture was heated to reflux overnight. The reaction mixture was cooled to RT, filtered through celite. The filter cake was washed with EtOH and the filtrate was evaporated. The remaining residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 70:30-30:70) to obtain [2-methyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]methanol (488 mg) as white solid. MS (ESI): 258.1 (M+H).sup.+.
Step 4:
[0270] A solution of thionyl chloride (0.62 ml; 8.54 mmol) in toluene (1 ml) was added to a suspension of [2-methyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]methanol (244 mg; 0.949 mmol) in toluene (4 ml) at RT. After the addition was complete, the mixture was heated to 65° C. for 5 min and then cooled to RT and stirred for 2.5 h at this temperature. Then diethyl ether was added and the precipitate was filtered off, washed with diethyl ether and dried to obtain the title compound (269 mg) as white solid. MS (ESI): 276.3 (M+H).sup.+. .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 3.99 (s, 3H), 5.06 (s, 2H), 7.84 (d, J=8.0 Hz, 2H), 8.18 (d, J=8.0 Hz, 2H).
Intermediate 23
3-(Chloromethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazole
[0271] ##STR00144##
[0272] The title compound was prepared in analogy to intermediate 22 from 3-(benzyloxymethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-triazole and was obtained as brown solid. .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): δ 4.00 (s, 3H), 4.77 (s, 2H), 7.94 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.1 Hz, 2H).
Intermediate 24
3-(Chloromethyl)-4-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole
[0273] ##STR00145##
Step 1:
[0274] Ethyl-2-chloroacetoacetate (CAS 609-15-4) (1.82 ml; 95%; 12.41 mmol) was added at RT to a solution of sodium acetate trihydrate (1.69 g; 12.41 mmol) in EtOH (70 ml) and water (3.5 ml). The mixture was stirred for 20 min at RT and then cooled to 0° C. In a second flask, a solution of NaNO.sub.2 (856 mg; 12.41 mmol) in water (12 ml) was added dropwise to a white suspension of 4-aminobenzotrifluoride (2.0 g; 12.41 mmol) in 6N HCl (19.5 ml) at 0° C. This reaction mixture was stirred at 0° C. until all solids dissolved. This solution was then transferred dropwise to the first solution. During the addition a solid precipitated. After the addition was completed, the yellow reaction mixture was stirred at 0° C. for 1 h, then concentrated to ˜½ volume and stored overnight at −24° C. The precipitated solid was filtered off, washed with cold water and dried. The residue was triturated with toluene to obtain ethyl 2-chloro-2-[[4-(trifluoromethyl)phenyl]hydrazono]acetate (3.294 g) as light brown solid. MS (ESI): 293.4 (M−H).sup.−.
Step 2:
[0275] Propionaldehyde (2.0 ml; 96%; 26.4 mmol) was added during 25 min to a suspension of K.sub.2CO.sub.3 (256 mg; 1.851 mmol) in morpholine (5 ml) at 25° C. The mixture was then stirred at 25-30° C. for 2.5 h. After concentration of the reaction mixture it was filtered and the filtrate was distilled under vacuum to obtain 4-[prop-1-enyl]morpholine (2.15 g, colorless oil) containing ˜20% morpholine. This material was used in the next reaction step without further purification.
Step 3:
[0276] To a stirred solution of 4-[prop-1-enyl]morpholine (product from step 2, 270 mg; 80%; 1.967 mmol) in dry chloroform (3 ml, ethanol free) was added triethylamine (235 μl; 1.967 mmol) followed by a suspension of ethyl 2-chloro-2-[[4-(trifluoromethyl)phenyl]hydrazono]acetate (product from step 1, 500 mg; 1.967 mmol) in dry chloroform (3 ml, ethanol free). After the addition was completed, the yellow solution was stirred at 40° C. for 1 h, then at RT overnight. Water was added and the pH adjusted to 5 by addition of 0.1N HCl. This mixture was extracted with chloroform and the combined organic layers were washed with saturated NaHCO.sub.3 solution and water, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was dissolved in dioxane (6 ml) and 2N HCl (1.5 ml) was added. The solution was heated to reflux for 1 h and then concentrated to dryness. The remaining residue was dissolved in chloroform and this solution was washed with water. The organic layer was dried with Na.sub.2SO.sub.4 and evaporated. The remaining material was purified by column chromatography (20 g silica gel; heptane/EtOAc 95:5-90:10) to obtain ethyl 4-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-3-carboxylate (106 mg) as light brown oil that solidified after standing.
Step 4:
[0277] A solution of ethyl 4-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-3-carboxylate (100 mg; 0.335 mmol) in THF (4 ml) was added dropwise to a cooled suspension of lithium aluminum hydride (15 mg; 0.396 mmol) in THF (2 ml). The resulting suspension was stirred at RT for 2 h. A mixture of Na.sub.2SO.sub.4 (0.5 g), silica gel (0.3 g) and 8 drops of water was added portionwise and stirring was continued for 10 min. The solids were filtered off and washed with THF and the filtrate was evaporated. The remaining residue was purified by column chromatography (10 g silica gel; heptane/EtOAc 90:10-70:30) to obtain [4-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]methanol (59 mg) as yellow oil that solidified after standing. MS (ESI): 257.4 (M+H).sup.+.
Step 5:
[0278] To a solution of [4-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]methanol (54 mg; 0.211 mmol) in toluene (1 ml) was added thionyl chloride (76.4 μl) and the solution was stirred at RT for 2.5 h. All volatiles were removed to obtain the title compound (56 mg) as brown oil that solidified in the freezer. NMR (DMSO-d.sub.6, 300 MHz): δ 2.15 (s, 3H), 4.82 (s, 2H), 7.85 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H) 8.45 (s, 1H).
Intermediate 25
3-Methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-4-carbaldehyde
[0279] ##STR00146##
Step 1:
[0280] To a mixture of [4-(trifluoromethyl)phenyl]boronic acid (5.0 g, 26 mmol), 3-methyl-1H-pyrazole (1.08 g, 13 mmol) and pyridine (2.11 ml) in DCM (160 ml) were added anhydrous cupric(II)acetate (9.563 g, 53 mmol) and 4 Å molecular sieves and the reaction mixture was stirred at RT overnight. The mixture was then filtered with Celite and concentrated. The remaining residue was purified by column chromatography (100 g silica gel; heptane/EtOAc 95:5-80:20) to obtain 3-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole (2.3 g) as white solid. MS (ESI): 227.4 (M+H).sup.+.
Step 2:
[0281] To a solution of 3-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole (1.0 g, 4 mmol) in DMF (10 ml) was added phosphorus oxychloride (607 μl) and the mixture was heated to 90° C. After 4 h again phosphorus oxychloride (405 μl) was added and heating to 90° C. was continued overnight. The reaction mixture was then poured on ice-water and this mixture was extracted with diethyl ether. The combined extracts were dried with Na.sub.2SO.sub.4 and concentrated. The remaining residue was purified by column chromatography (silica gel; heptane/EtOAc 4:1-2:1) to obtain the title compound (460 mg) as white solid. MS (ESI): 313.4 (M+OAc).sup.−.
Intermediate 26
[2-[4-(Trifluoromethyl)phenyl]-1H-imidazol-4-yl]methyl methanesulfonate
[0282] ##STR00147##
Step 1:
[0283] A solution of 4-(trifluoromethyl)benzamidine; hydrochloride (8 g, 35.62 mmol) and 1,3-dihydroxyacetone dimer (6.42 g, 36.62 mmol) in ammonia solution (30%, 90 ml) was heated to 80° C. for 1 h. The reaction mixture was cooled and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; EtOAc/hexane 4:1) to obtain [2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol as a pale brown solid. (3.2 g, 37%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 4.42 (d, J=5.6 Hz, 1H), 4.58 (d, J=5.76 Hz, 1H), 4.91 & 5.16 (a pair oft, J=5.6 Hz & 5.4 Hz, 1H), 6.94 & 7.16 (a pair of s, 1H), 4.91 & 5.16 (a pair of t, J=5.6 Hz & 5.4 Hz, 1H), 7.79 (d, J=8.12 Hz, 2H), 8.10 (d, J=8.16 Hz, 1H), 8.14 (d, J=8.20 Hz, 1H), 12.61 & 12.77 (a pair of s, 1H).
Step 2:
[0284] To a solution of [2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol (3 g, 12.38 mmol) in DCM (40 ml) was added triethylamine (3.4 ml, 24.39 mmol) followed by dropwise addition of mesyl chloride (1.43 ml, 18.5 mmol) at 0° C. The reaction mixture was stirred at RT for 2 h, washed with water and brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; DCM/MeOH 96:4) to obtain the title compound as a pale brown solid. (2.6 g, 65%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 2.26 (s, 3H), 4.38 (s, 2H), 7.69 (s, 1H), 7.87 (d, J=8.44 Hz, 2H), 8.16 (d, J=8.2 Hz, 2H), 13.3 (brs, 1H).
Intermediate 27
[5-Methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methyl methanesulfonate
[0285] ##STR00148##
Step 1:
[0286] To a solution of 4-(trifluoromethyl)benzamidine; hydrochloride (10 g, 44.52 mmol) and 2,3-butanedione (4.6 g, 53.42 mmol) in water (50 ml) was added 2N NaOH solution (23 ml) at 0° C. until the pH of the mixture was adjusted to 8. The reaction mixture was stirred at 0° C. for 2.5 h. The precipitate that formed was collected by filtration and washed with water. Then 4N HCl (76 ml) was added and the mixture was heated to reflux for 4 h. The reaction mixture was then cooled to 0° C. and the pH was adjusted to 9 by slow addition of 8N NaOH solution. The precipitate that formed was collected by filtration washed successively with cold water, and 50% aqueous ethanol and dried under vacuum. The remaining solid was purified by column chromatography (silica gel; EtOAc/hexane 4:1) to obtain [5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol as a pale yellow solid (5.8 g, 51%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 2.14 & 2.25 (a pair of s, 3H), 4.35 (brs, 1H), 4.44 (brs, 1H), 4.70 (brs, 1H), 5.02 (brs, 1H), 7.76 (d, J=7.68 Hz, 2H), 7.99 (d, J=8.8 Hz, 2H), 8.05 (d, J=7.44 Hz, 1H), 8.11 (d, J=6.88 Hz, 1H), 12.40 & 12.53 (a pair of brs, 1H).
Step 2:
[0287] To a solution of [5-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methanol (2.5 g, 9.76 mmol) in DCM (80 ml) was added triethylamine (2.72 ml, 19.51 mmol) followed by dropwise addition of mesyl chloride (1.13 ml, 14.60 mmol) at 0° C. The reaction mixture was stirred at RT for 2 h, washed with water and brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; DCM/MeOH 96:4) to obtain the title compound as a pale brown solid. (3.1 g, 95%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 2.23 (s, 3H), 2.37 (s, 3H), 4.36 (s, 2H), 7.83 (d, J=8.2 Hz, 2H), 8.15 (d, J=8 Hz, 2H), 9.96 (brs, 1H).
Intermediate 28
4-(Bromomethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]thiazole
[0288] ##STR00149##
Step 1:
[0289] A solution of 4-trifluoromethyl-thiobenzamide (CAS 72505-21-6) (4 g, 19.5 mmol) and 3-chloro-2-butanone (3.9 ml, 39 mmol) in isopropanol (20 ml) was heated to reflux for 30 h. The reaction mixture was concentrated to a volume of 10 ml, cooled to 50° C. and diisopropylether (20 ml) was added dropwise. The solution was cooled to RT, the resulting crystals were filtered off, washed with ice cold diisopropylether and dried in vacuo to give 2.6 g (8.9 mmol) of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-thiazole hydrochloride as off-white crystals. MS (ESI): 258.4 (M+H).sup.+.
Step 2:
[0290] 4,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-thiazole hydrochloride (2.6 g, 8.9 mmol) was suspended in ethyl acetate and ice water. Triethylamine (1.2 ml, 8.9 mmol) was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 dried with sodium sulfate and the solvent was removed under reduced pressure. The residue was dried in vacuo and dissolved in acetonitrile (30 ml) under an argon atmosphere. The solution was cooled to 0° C., N-bromosuccinimide (2.05 g, 11.5 mmol) and 2,2′-azobis(2-methylpropionitrile) (145 mg, 0.89 mmol) were added and the reaction mixture was stirred at RT for 14 h. Water was added and the formed precipitate was filtered off, washed with water and dried in vacuo to give yellow crystals. The crystals were purified by column chromatography (silica gel, n-heptane/dichloromethane) to give 385 mg (1.2 mmol) of the title compound as off-white crystals. MS (ESI): 336.2 (M+H).sup.+.
Intermediate 29
5-Chloro-3-methyl-1-(4-piperidyl)benzimidazol-2-one
[0291] ##STR00150##
Step 1:
[0292] 5-Chloro-1-(4-piperidyl)-2-benzimidazolone (3 g; 97%; 11.56 mmol) was added portionwise to a solution of di-tert-butyl-dicarbonate (2.575 g; 98%; 11.56 mmol) in THF (35 ml) at 0° C. After the addition was completed, the reaction mixture was stirred for 1.5 h at 0° C. The reaction mixture was allowed to warm to RT and diluted Na.sub.2CO.sub.3 solution (˜30 ml) was added. The mixture was extracted with diethyl ether and the organic layers were combined, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was triturated with diethyl ether to obtain tert-butyl 4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidine-1-carboxylate (3.936 g) as with solid. MS (ESI): 352.4 (M+H).sup.+.
Step 2:
[0293] To a suspension of sodium hydride (55% dispersion in oil, 27 mg; 0.625 mmol) in DMF was added a solution of tert-butyl 4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidine-1-carboxylate (200 mg; 0.568 mmol) in DMF (2 ml) dropwise at RT. After 1 h a solution of methyl iodide (38.9 μl; 0.625 mmol) in DMF (0.5 ml) was added dropwise and the reaction mixture was stirred at RT for 1.5 h. Again methyl iodide (38.9 μl; 0.625 mmol) in DMF (0.5 ml) was added and the reaction mixture was stirred for 3.5 h at RT. Then ice/water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na.sub.2SO.sub.4 and evaporated to obtain tert-butyl 4-(5-chloro-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-1-carboxylate (200 mg) as white foam. MS (ESI): 366.0 (M+H).sup.+.
Step 3:
[0294] To a solution of tert-butyl 4-(5-chloro-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-1-carboxylate (200 mg; 0.547 mmol) in DCM (2 ml) was added TFA (0.5 ml) at RT. The solution was stirred at RT for 1.5 h. All volatiles were removed and the residue was partitioned between IN NaOH solution and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried with Na.sub.2SO.sub.4 and evaporated to obtain the title compound (129 mg) as with solid. MS (ESI): 266.1 (M+H).sup.+.
[0295] The following intermediates were prepared in analogy to intermediate 29:
TABLE-US-00007 Int. Name Structure MS (ESI) Reagent used in step 2 30 5-Chloro-3-ethyl-1-(4- piperidyl)benzimidazol- 2-one
Intermediate 36
5-Chloro-3-(2-methylsulfonylethyl)-1-(4-piperidyl)benzimidazol-2-one
[0296] ##STR00157##
Step 1:
[0297] A solution of tert-butyl 4-[5-chloro-3-(2-methylsulfonylethyl)-2-oxo-benzimidazol-1-yl]piperidine-1-carboxylate (195 mg; 0.458 mmol, prepared in analogy to tert-butyl 4-(5-chloro-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-1-carboxylate (Intermediate 29, step 2) using 2-chloroethylmethylsulfide instead of methyl iodide) in MeOH (2.5 ml) was cooled to 0° C. and a solution of Oxone (422 mg; 0.687 mmol) in water (2 ml) was added slowly. The reaction mixture was stirred for 4 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried with Na.sub.2SO.sub.4 and evaporated to obtain tert-butyl 4-[5-chloro-3-(2-methylsulfonylethyl)-2-oxo-benzimidazol-1-yl]piperidine-1-carboxylate (203 mg) as white foam. MS (ESI): 458.1 (M+H).sup.+.
Step 2:
[0298] The title compound was prepared in analogy to intermediate 29 from tert-butyl 4-[5-chloro-3-(2-methyl sulfonylethyl)-2-oxo-benzimidazol-1-yl]piperidine-1-carboxylate and was obtained as white foam. MS (ESI): 358.1 (M+H).sup.+.
Intermediate 37
1-Methyl-3-(4-piperidyl)-4H-quinazolin-2-one
[0299] ##STR00158##
Step 1:
[0300] To a suspension of sodium hydride (55% dispersion in oil, 15 mg; 0.3 mmol) in DMF (0.5 ml) was added a solution of 3-(1-benzyl-4-piperidyl)-1,4-dihydroquinazolin-2-one (CAS 79098-88-7) (100 mg, 0.3 mmol) in DMF (2 ml). The mixture was stirred at RT for 1 h and then a solution of methyl iodide (21 μl) in DMF (2 ml) was added and the reaction mixture was stirred at RT overnight. More methyl iodide (4 μl) was added and the reaction mixture was heated to 40° C. for 1 h. Ice water was added and the mixture was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated to obtain 3-(1-benzyl-4-piperidyl)-1-methyl-4H-quinazolin-2-one (104 mg) as yellow oil. MS (ESI): 336.4 (M+H).sup.+.
Step 2:
[0301] A solution of 3-(1-benzyl-4-piperidyl)-1-methyl-4H-quinazolin-2-one (102 mg) in ethanol (12 ml) was kept under an atmosphere of hydrogen in the presence of palladium (10% on carbon, 10 mg) for 2 days. The solution was then filtered with Dicalit and the filtrate was evaporated to obtain the title compound (75 mg) as greenish oil which was used in the next reaction step without further purification. MS (ESI): 244.3 (M−H).sup.−.
Intermediate 38
1-(2-Methoxyethyl)-3-(4-piperidyl)-4H-quinazolin-2-one
[0302] ##STR00159##
[0303] The title compound was prepared in analogy to intermediate 37 from 3-(1-benzyl-4-piperidyl)-1,4-dihydroquinazolin-2-one using 2-bromoethyl methyl ether instead of methyl iodide in step 1 and was obtained as greenish oil which was used in the next reaction step without further purification. MS (ESI): 290.3 (M+H).sup.+.
Intermediate 39
7-Fluoro-3-(4-piperidyl)-1,4-dihydroquinazolin-2-one
[0304] ##STR00160##
Step 1:
[0305] To a mixture of 4-fluoro-2-nitrobenzoic acid (4.0 g, 22 mmol), 4-amino-1-benzylpiperidine (4.523 g, 24 mmol), 1-hydroxybenzotriazole (584 mg, 4 mmol) and triethylamine (6.024 ml, 43 mmol) in EtOAc (60 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.971 g, 26 mmol) and the mixture was stirred overnight. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was triturated with EtOAc to obtain N-(1-benzyl-4-piperidyl)-4-fluoro-2-nitro-benzamide (4.0 g) as weak yellow solid. MS (ESI): 356.5 (M−H).sup.−.
Step 2:
[0306] A suspension of lithium aluminum hydride (5.04 g, 132.8 mmol) in dioxane (30 ml) was heated to reflux. Then a solution of N-(1-benzyl-4-piperidyl)-4-fluoro-2-nitro-benzamide (5.9 g, 37.9 mmol) in dioxane (55 ml) was added dropwise over a period of 30 min and heating to reflux was continued for 6 h. The reaction mixture was cooled to 0° C. and water (10 ml) was added carefully. The mixture was then poured onto 50% aqueous NaOH solution (50 ml) and extracted with diethyl ether. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (200 g silica gel; DCM/MeOH 97:3-90:10) to obtain 2-amino-N-(1-benzyl-4-piperidyl)-4-fluoro-benzamide as yellow oil (1.75 g). MS (ESI): 314.1 (M+H).sup.+.
Step 3:
[0307] To a solution of 2-amino-N-(1-benzyl-4-piperidyl)-4-fluoro-benzamide (1.3 g, 4.1 mmol) in THF (20 ml) was added 1,1′-carbonyl-diimidazole at 0° C. The reaction mixture was stirred for 15 min at 0° C. and then at RT for 4 h. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was triturated with EtOAc to obtain 3-(1-benzyl-4-piperidyl)-7-fluoro-1,4-dihydroquinazolin-2-one as white solid (1 g). MS (ESI): 338.5 (M−H).sup.−.
Step 4:
[0308] A solution of 3-(1-benzyl-4-piperidyl)-7-fluoro-1,4-dihydroquinazolin-2-one (1.36 g) in ethanol (12 ml) was kept under an atmosphere of hydrogen in the presence of palladium (10% on carbon, 136 mg) overnight. The reaction mixture was filtered with Dicalite and the filtrate was evaporated to obtain the title compound as white solid (1.1 g). MS (ESI): 250.3 (M+H).sup.+.
Intermediate 40
3-(4-Piperidyl)-1H-pyrrolo[3,2-c]pyridine
[0309] ##STR00161##
Step 1:
[0310] To a mixture of 1H-pyrrolo[3,2-c]pyridine (CAS 271-34-1) (180 mg, 1.5 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (607 mg, 3 mmol) in MeOH (5 ml) was added potassium hydroxide (342 mg, 6.1 mmol) and the mixture was heated to reflux overnight. More tert-butyl 4-oxopiperidine-1-carboxylate (155 mg) was added and the reaction mixture was again heated to reflux overnight. The reaction mixture was poured on ice water and was extracted with DCM. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was triturated with MeOH and filtered. The filtrate was evaporated and the remaining oil was purified by column chromatography (50 g silica gel; DCM/MeOH 98:2-90:10) to obtain tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (350 mg) as light orange solid. MS (ESI): 298.5 (M−H).sup.−.
Step 2:
[0311] To a mixture of tert-butyl 4-(1H-pyrrolo[3,2-c]pyri din-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (350 mg) and PtO.sub.2 (40 mg, 80.5%) in ethanol (8 ml) hydrogen pressure (4.1 bar) was applied overnight. The reaction mixture was filtered with Dicalite and the filtrate was evaporated. 160 mg from the remaining residue were again dissolved in ethanol (5 ml), PtO.sub.2 (40 mg, 80.5%) was added and again hydrogen pressure (4.1 bar) was applied overnight. The reaction mixture was filtered with Dicalite and the filtrate was evaporated to obtain tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-3-yl)piperidine-1-carboxylate (138 mg) as light yellow solid. MS (ESI): 300.5 (M−H).sup.−.
Step 3:
[0312] To a solution of tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-3-yl)piperidine-1-carboxylate (138 mg) in DCM (3 ml) was added TFA (350 μl) and the mixture was stirred at RT for 3 h. Then 1N NaOH solution was added until the pH was adjusted to 12 and the mixture was extracted with DCM. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated to obtain the title compound (50 mg) as light yellow solid. MS (ESI): 202.3 (M+H).sup.+.
Intermediate 41
5-chloro-1-(4-piperidyl)indolin-2-one
[0313] ##STR00162##
Step 1:
[0314] To sodium hydride (55% dispersion in oil, 5.454 g, 125 mmol) was carefully added DMSO (80 ml) and the mixture was heated slowly to 100° C. Then a solution of diethyl malonate (7.915 ml, 52 mmol) in DMSO (10 ml) was added and 10 min after completion of the addition a solution of 2,4-dichloronitrobenzene (10 g, 52 mmol) in DMSO (10 ml) was added. The mixture was heated to 100° C. for 1.5 h, then stirred at RT overnight and finally poured on water and extracted with diethyl ether. The organic extracts were dried with Na.sub.2SO.sub.4 and evaporated to obtain a brown oil that was subjected to Kugelrohr distillation. Diethyl 2-(5-chloro-2-nitro-phenyl)propanedioate was obtained with ˜85% purity (15.3 g) and was used in the next reaction step without further purification. MS (ESI): 314.3 (M−H).sup.−.
Step 2:
[0315] To a solution of diethyl 2-(5-chloro-2-nitro-phenyl)propanedioate (15.3 g from step 1, ˜15.3 g) in DMSO (150 ml) were added lithium chloride (4.314 g) and water (960 μl) and the mixture was heated to 120° C. for 4 d. Then water was added and the mixture was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated and the remaining residue was purified by column chromatography (200 g silica gel; heptane/EtOAc 4:1) to obtain ethyl 2-(5-chloro-2-nitro-phenyl)acetate (6.98 g) as light brown oil. MS (ESI): 242.3 (M−H).sup.−.
Step 3:
[0316] To a mixture of ethyl 2-(5-chloro-2-nitro-phenyl)acetate (6.6 g) and PtO.sub.2 (1.32 g, 80.5%) in benzene (200 ml) hydrogen pressure (2.8 bar) was applied for 3 h. The reaction mixture was filtered with Dicalite and the filtrate was evaporated to obtain ethyl 2-(2-amino-5-chloro-phenyl)acetate (5.8 g) that was used in the next reaction step without further purification. MS (ESI): 214.1 (M+H).sup.+.
Step 4:
[0317] To a mixture of ethyl 2-(2-amino-5-chloro-phenyl)acetate (5.6 g) and tert-butyl 4-oxopiperidine-1-carboxylate (7.833 g) in DCM (50 ml) were added sodium triacetoxyborohydride (8.170 g) and AcOH (4.5 ml) and the mixture was stirred at RT for 4 d. Saturated NaHCO.sub.3 solution was added and the mixture was extracted with EtOAc. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated and the remaining residue was triturated with EtOAc to obtain tert-butyl 4-(5-chloro-2-oxo-indolin-1-yl)piperidine-1-carboxylate (4.48 g) as white solid. MS (ESI): 349.2 (M−H).sup.−.
Step 5:
[0318] To a solution of tert-butyl 4-(5-chloro-2-oxo-indolin-1-yl)piperidine-1-carboxylate (650 mg) in DCM (6.5 ml) was added TFA (1.42 ml) and the mixture was stirred at RT for 1 h. Then 1N NaOH solution was added until the pH was adjusted to 12 and the mixture was extracted with DCM. The combined extracts were dried with Na.sub.2SO.sub.4 and evaporated to obtain the title compound (430 mg) as light brown solid. MS (ESI): 251.1 (M+H).sup.+.
Intermediate 42
5-(4-Bromophenyl)-3-(4-piperidyl)-1H-imidazol-2-one; trifluoroacetic acid salt
[0319] ##STR00163##
Step 1:
[0320] A solution of 2-bromo-1-(4-bromophenyl)ethanone (30.53 g, 100 mmol) in DCM (50 ml) was added to a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (20 g, 90 mmol) and sodium acetate (8.18 g, 90 mmol) in DCM (150 ml) at 0° C. The reaction mixture was stirred at RT for 16 h. A solution of sodium cyanate (9.73 g, 140 mmol) in water (10 ml) was added to the reaction mixture followed by the addition of glacial acetic acid (20 ml). The reaction mixture was again stirred at RT for 16 h. The reaction mixture was poured into crushed ice and stirred for half an hour. The organic layer was separated and washed successively with water, saturated NaHCO.sub.3 solution and citric acid solution and finally again with water, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was stirred with diethyl ether (200 ml) and filtered; the solid thus obtained was again stirred with methanol (100 ml) for 0.5 h and filtered to get a light yellow solid, which was dried under high vacuum to get tert-butyl 4-[5-(4-bromophenyl)-2-oxo-1H-imidazol-3-yl]piperidine-1-carboxylate (10.75 g). MS (ESI): 422 (M+H).sup.+.
Step 2:
[0321] Tert-butyl 4-[5-(4-bromophenyl)-2-oxo-1H-imidazol-3-yl]piperidine-1-carboxylate was dissolved in a mixture of DCM and TFA 4:1 (3 ml/1 mmol) at 0° C. and the mixture was stirred for 2 h. DCM was completely evaporated, the remaining residue was dissolved in chloroform and again evaporated to remove residual of TFA. The title compound obtained by this procedure was used in the next reaction steps without further purification.
Intermediate 43
5-(4-Bromophenyl)-2-(4-piperidyl)-4H-1,2,4-triazol-3-one; trifluoroacetic acid salt
[0322] ##STR00164##
Step 1:
[0323] Ethoxycarbonylisothiocyanate (11 g, 83 mmol) was added to a solution of bromobenzene (15.8 g, 100 mmol) in DCM (85 ml). Anhydrous aluminium chloride (22.34 g, 167 mmol) was added portionwise to the reaction mixture at 0° C. The reaction mixture was then stirred at the same temperature for 4 h. Ice cold water was added carefully over a period of 1 h. The organic layer was separated, washed with water, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by silica gel column chromatography (silica gel; hexane/EtOAc 95:5) to obtain ethyl N-(4-bromobenzenecarbothioyl)carbamate (3.3 g). MS (ESI): 288 (M+H).sup.+.
Step 2:
[0324] Hydrazine hydrate (125 ml, 2.5 mol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (25 g, 0.125 mol) in ethanol (225 ml) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was cooled and sodium borohydride (17.7 g, 0.48 mmol) was added portionwise. The reaction mixture was stirred at the same temperature for 2 h. The solvent was evaporated and the residue was dissolved in DCM. The DCM solution was washed with water, dried with Na.sub.2SO.sub.4 and evaporated to obtain tert-butyl 4-hydrazinopiperidine-1-carboxylate (18 g).
Step 3:
[0325] Diisopropylethyl amine (20.7 g, 129 mmol) was added to a solution of tert-butyl 4-hydrazinopiperidine-1-carboxylate (16.43 g, 76 mmol, from step 2) and ethyl N-(4-bromobenzenecarbothioyl)carbamate (20 g, 70 mmol, from step 1) in THF (440 ml). The reaction mixture was heated to reflux for 2 h, then cooled and the precipitate that formed was filtered. The white solid thus obtained was dried to obtain tert-butyl 4-[3-(4-bromophenyl)-5-oxo-4H-1,2,4-triazol-1-yl]piperidine-1-carboxylate (14 g). MS (ESI): 423 (M+H).sup.+.
Step 4:
[0326] Tert-Butyl 4-[3-(4-bromophenyl)-5-oxo-4H-1,2,4-triazol-1-yl]piperidine-1-carboxylate was converted to the title compound in analogy to intermediate 42, step 2 and was used for the next reaction step without further purification.
Intermediate 44
6-Bromo-3-(4-piperidyl)-1,4-dihydroquinazolin-2-one; hydrochloride
[0327] ##STR00165##
Step 1:
[0328] Tert-butyl 4-aminopiperidine-1-carboxylate (34.76 g, 173.5 mmol) was added to a solution of 5-bromo-2-nitro-benzaldehyde (20357-20-4) (36.30 g, 157 mmol) in methanol (200 ml) and the reaction mixture was stirred at RT for 1 h. Sodium borohydride (8.95 g, 236.5 mmol) was added portionwise to the reaction mixture at 0° C. and stirring was continued for 1 h. Saturated ammonium chloride solution was added at 0° C. and the methanol was evaporated. The mixture was extracted with EtOAc and the combined organic layers were washed with water, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; hexane/EtOAc 95:5 to 90:10) to obtain tert-butyl 4-[(5-bromo-2-nitro-phenyl)methylamino]piperidine-1-carboxylate (40 g). MS (ESI): 414 (M+H).sup.+.
Step 2:
[0329] Ammonium chloride (11.61 g, 217.05 mmol) was added to a suspension of tert-butyl 4-[(5-bromo-2-nitro-phenyl)methylamino]piperidine-1-carboxylate (30 g, 72.4 mmol) and zinc dust (33.13 g, 506.65 mmol) in methanol (700 ml). The reaction mixture was heated under refluxed for 1 h. The reaction mixture filtered through Celite and the filtrate was evaporated. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with water, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by silica gel column chromatography to obtain tert-butyl 4-[(2-amino-5-bromo-phenyl)methylamino]piperidine-1-carboxylate (18 g). MS (ESI): 384 (M+H).sup.+.
Step 3:
[0330] Carbonyldiimidazole (2.63 g, 16.2 mmol) was added to a solution of tert-butyl 4-[(2-amino-5-bromo-phenyl)methylamino]piperidine-1-carboxylate (5.0 g, 13.0 mmol) and triethylamine (5.48 ml, 38.9 mmol) in acetonitrile (40 ml) and the reaction was stirred at RT for 2 h. Another portion of carbonyldiimidazole (1.68 g, 1.03 mmol) was added and stirring was continued for another 2 h. The Solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water, dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography (silica gel; hexane/EtOAc 70:30 to 60:40) to obtain tert-butyl 4-(6-bromo-2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate (2.5 g). MS (ESI): 410 (M+H).sup.+.
Step 4:
[0331] Tert-butyl 4-(6-bromo-2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate was dissolved in a saturated solution of HCl gas in EtOAc. After 2 h, all volatiles were removed to obtain the title compound that was used for the next reaction step without further purification.
Intermediate 45
1-(4-Piperidyl)-5H-imidazo[4,5-c]pyridin-4-one; hydrochloride
[0332] ##STR00166##
Step 1:
[0333] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (31.75 g, 158.5 mmol) in DMF (30 ml) was added to a solution of 4-chloro-3-nitro-pyridine (CAS 13091-23-1) (25 g, 157.6 mmol) and triethylamine (25.65 ml, 189 mmol) in DMF (100 ml) and the reaction mixture was stirred at RT for 15 h. The reaction mixture was poured into ice-cold water and this mixture was stirred for 2 h, then allowed to settle for another 2 h and filtered. The orange solid that was collected was washed with water, dried and re-crystallized from EtOAc to obtain tert-butyl 4-[(3-nitro-4-pyridyl)amino]piperidine-1-carboxylate (44 g).
Step 2:
[0334] Palladium (2.5 g, 10% on carbon) was added to a solution of tert-butyl 4-[(3-nitro-4-pyridyl)amino]piperidine-1-carboxylate (25 g, 77.5 mmol) in ethanol (375 ml) and hydrogen pressure (50 psi) was applied in a parr shaker for 16 h. The reaction mixture was filtered through Celite and the filtrate was evaporated. The remaining residue was triturated with diethyl ether to obtain tert-butyl 4-[(3-amino-4-pyridyl)amino]piperidine-1-carboxylate (18.45 g). MS (ESI): 293 (M+H).sup.+.
Step 3:
[0335] 4-Toluene sulfonic acid (0.65 g, 3.4 mmol) was added to a solution of tert-butyl 4-[(3-amino-4-pyridyl)amino]piperidine-1-carboxylate (10.0 g, 34.22 mmol) and triethylorthoformate (10.14 g, 68 mmol) in toluene (70 ml) and the mixture was heated to reflux for 16 h. The solvent was evaporated and the remaining residue was triturated with diethyl ether to obtain tert-butyl 4-imidazo[4,5-c]pyridin-1-ylpiperidine-1-carboxylate (7.5 g). MS (ESI): 303 (M+H).sup.+.
Step 4:
[0336] 3-Chloroperbenzoic acid (7.4 g, 33 mmol, 77%) was added to a solution of tert-butyl 4-imidazo[4,5-c]pyridin-1-ylpiperidine-1-carboxylate (10 g, 33 mmol) in DCM (100 ml) at 10° C. and the reaction mixture was stirred at RT for 18 h. The solvent was evaporated and the remaining residue was purified by column chromatography (neutral alumina; DCM/MeOH 95:5 to 70:30) to obtain tert-butyl 4-(5-oxidoimidazo[4,5-c]pyridin-5-ium-1-yl)piperidine-1-carboxylate (8.2 g). MS (ESI): 319 (M+H).sup.+.
Step 5:
[0337] A solution of tert-butyl 4-(5-oxidoimidazo[4,5-c]pyridin-5-ium-1-yl)piperidine-1-carboxylate (10 g, 31.4 mmol) in acetic anhydride (100 ml) was heated to reflux for 18 h. The acetic anhydride was evaporated under reduced pressure. The remaining residue was purified by column chromatography (neutral alumina; DCM/MeOH 97:3) to obtain 1-(1-acetyl-4-piperidyl)-5H-imidazo[4,5-c]pyridin-4-one (4.8 g). MS (ESI): 261 (M+H).sup.+.
Step 6:
[0338] Concentrated HCl (24 ml) was added to a solution of 1-(1-acetyl-4-piperidyl)-5H-imidazo[4,5-c]pyridin-4-one (6.0 g, 18.8 mmol) in ethanol (48 ml) and the reaction mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure and the remaining residue was precipitated with ethanol. The precipitate was filtered off and washed with diethyl ether to obtain the title compound as brown solid (4.5 g). MS (ESI): 219 (M+H).sup.+.
Intermediate 46
3-(4-Piperidyl)-5-pyrrolidin-1-yl-1H-benzimidazol-2-one; hydrochloride
[0339] ##STR00167##
Step 1:
[0340] To a solution of 2,4-dichloro-1-nitro-benzene (65 g, 0.34 mol) in DMF was added tert-butyl 4-aminopiperidine-1-carboxylate (114 g, 0.57 mol) and K.sub.2CO.sub.3 (94 g, 0.68 mol) and the mixture was heated to 85-90° C. for 48 h. DMF was removed under vacuum and water was added to the remaining residue. The mixture was extracted with EtOAc and the extracts were dried with Na.sub.2SO.sub.4 and evaporated. The remaining residue was purified by column chromatography to obtain tert-butyl 4-(5-chloro-2-nitro-anilino)piperidine-1-carboxylate (75 g) as a yellow powder. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 1.40 (s, 9H), 1.40-1.45 (m, 2H), 1.89-1.92 (m, 2H), 2.96 (brs, 2H), 3.87-3.90 (m, 3H), 6.70-6.73 (m, 1H), 7.27 (brs, 1H), 7.95-8.09 (m, 2H).
Step 2:
[0341] A mixture of tert-butyl 4-(5-chloro-2-nitro-anilino)piperidine-1-carboxylate (60 g, 0.17 mol), K.sub.2CO.sub.3 (47 g, 0.34 mol) and pyrrolidine (265 mL) was heated to reflux. After completion of the reaction, all volatiles were distilled off and water was added to the residual material. The solid formed was filtered and dried to give tert-butyl 4-(2-nitro-5-pyrrolidin-1-yl-anilino)piperidine-1-carboxylate (60 g) as a yellow solid. MS (ESI): 391 (M+H).sup.+.
Step 3:
[0342] A solution of tert-butyl 4-(2-nitro-5-pyrrolidin-1-yl-anilino)piperidine-1-carboxylate in ethanol was subjected to catalytic hydrogenation using palladium on carbon as a catalyst and applying a hydrogen pressure of 50 psi for 12 hours in presence of catalytic amount of triethylamine. The reaction mixture was filtered over Celite under argon. The filtrate is concentrated under reduced pressure in presence of argon to give tert-butyl 4-(2-amino-5-pyrrolidin-1-yl-anilino)piperidine-1-carboxylate as black viscous mass which was immediately used as such for the next step. MS (ESI): 361 (M+H).sup.+.
Step 4:
[0343] A mixture of tert-butyl 4-(2-amino-5-pyrrolidin-1-yl-anilino)piperidine-1-carboxylate (69 g, 0.19 mol), triethylamine (80 mL, 0.58 mol) and 1,1′-carbonyl-diimidazole (62 g, 0.38 mol) in acetonitrile (600 ml) was stirred at RT for 4 h and then heated to reflux for 30 min. The solvent was removed, water was added and the mixture was extracted with DCM. The organic extracts were concentrated and the remaining residue was purified by column chromatography with neutral alumina to obtain tert-butyl 4-(2-oxo-6-pyrrolidin-1-yl-3H-benzimidazol-1-yl)piperidine-1-carboxylate (45 g) as a white solid. MS (ESI): 387 (M+H).sup.+.
Step 5:
[0344] Tert-butyl 4-(2-oxo-6-pyrrolidin-1-yl-3H-benzimidazol-1-yl)piperidine-1-carboxylate (1 g) was dissolved in a HCl solution in dioxane (20 ml) and the mixture was stirred at RT. After 10 min all volatiles were removed to obtain the title compound (897 mg) as purple solid that was used in the next reaction step without further purification. MS (ESI): 287.1 (M+H).sup.+.
[0345] The following intermediates were prepared in analogy to intermediate 46:
TABLE-US-00008 Int. Name Structure MS (ESI) Reagent used in step 2 47 Morpholino-3-(4- piperidyl)-1H- benzimidazol-2- one; hydrochloride
Example 82
Cathepsin Enzyme Inhibition Assay
[0346] Enzyme activity is measured by observing the increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore whose emission is quenched in the intact peptide.
[0347] Assay buffer: 100 mM potassium phosphate pH 6.5, EDTA-Na 5 mM, Triton X-100 0.001%, DTT 5 mM.
[0348] Enzymes (all at 1 nM): human and mouse Cathepsin S, Cat K, Cat B, Cat L.
[0349] Substrate (20 μM): Z-Val-Val-Arg-AMC, except for Cat K which uses Z-Leu-Arg-AMC (both from Bachem).
[0350] Z=Benzyloxycarbonyl.
[0351] AMC=7-Amino-4-Methyl-Coumarin.
[0352] DTT=dithiothreitol.
[0353] Final volume: 100 μL.
[0354] Excitation 360 nm, Emission 465 nm.
[0355] Enzyme is added to the substance dilutions in 96-well microtitre plates and the reaction is started with substrate. Fluorescence emission is measured over 20 minutes, during which time a linear increase is observed in the absence of inhibitor. IC.sub.50 are calculated by standard methods.
[0356] Inhibition of human Cat S, mouse Cat S, human Cat K, mouse Cat K, human Cat B, mouse Cat B, human Cat L and mouse Cat L have been measured separately. The results obtained for human Cat S are expressed in the following table.
[0357] The compounds of the invention have a CatS IC.sub.50 below 5 uM. Particular compounds of the invention have a CatS IC.sub.50 below 1 uM, in particular below 0.1 uM.
[0358] The compound of formula (I) is a preferential human Cat S inhibitor with a selectivity over human Cat K, Cat B and Cat L of at least 10 fold.
TABLE-US-00009 CatS IC.sub.50 Example uM 1 0.28 2 0.78 3 0.45 4 2.545 5 2.045 6 0.42 7 0.245 8 3.275 9 0.19 10 0.28 11 0.46 12 0.59 13 2.75 14 4.321 15 4.56 16 1.5 17 0.195 18 0.195 19 0.47 20 1.035 21 4.07 22 1.96 23 1.02 24 0.985 25 0.18 26 0.15 27 0.22 28 0.19 29 0.28 30 0.23 31 0.31 32 0.33 33 0.13 34 0.93 35 0.257 36 0.77 37 0.595 38 0.47 39 0.242 40 0.077 41 0.875 42 0.287 43 0.445 44 0.385 45 0.11 46 0.305 47 0.145 48 0.45 49 1.195 50 0.605 51 1.845 52 1.375 53 0.145 54 0.135 55 0.35 56 0.225 57 0.995 58 3.35 59 0.285 60 0.915 61 1.935 62 0.3 63 0.667 64 0.928 65 0.585 66 0.45 67 1.383 68 0.65 69 1.67 70 0.245 71 0.084 72 0.024 73 0.175 74 0.094 75 0.06 76 0.317 77 0.155 78 1.07 79 2.87 80 0.099 81 0.17
Example A
[0359] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
TABLE-US-00010 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg
[0360] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.
Example B
[0361] Capsules containing the following ingredients can be manufactured in a conventional manner:
TABLE-US-00011 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
[0362] The components are sieved and mixed and filled into capsules of size 2.
Example C
[0363] Injection solutions can have the following composition:
TABLE-US-00012 Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml
[0364] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.