Claims
- 1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR12## wherein: n is 0-4;
- Y is ##STR13## and when R.sub.3 is OH, then Y can also be ##STR14## R.sub.2 is H or deuterium; R.sub.3 is OH, OR.sub.7, NR.sub.7 OR.sub.8 or NR.sub.7 R.sub.8 ;
- where R.sub.7 and R.sub.8 are independently H, alkyl, cycloalkyl, benzyl, or phenyl;
- R.sub.4 is H or lower alkyl;
- R.sub.5 and R.sub.6 are optionally and independently selected from H, OH, alkyl, alkoxy, and phenyloxy;
- AA is independently selected from the group consisting of (a) and (b) where (a) is defined as an amino acid of formula II ##STR15## wherein R.sub.7 and R.sub.8 are defined as above and R.sub.9 is (CR.sub.6 R.sub.7).sub.0-6 --R.sub.10 ;
- where R.sub.10 is a radical optionally selected from R.sub.11, where R.sub.11 is described below; and
- where group (b) is selected from the group consisting of: ##STR16## where W and X are optionally CH.sub.2, or O; R.sub.1 is R.sub.10 --CO--, where R.sub.10 is defined previously;
- R.sub.11 is H, alkyl, alkenyl, hydroxy, benzyl, alkoxy, 2-(alkyoxy)ethoxy, 2-(alkyoxy)aminoethyl and 2-(alkyoxy)-N-alkylaminoethyl, alkylacyloxy, alkylacyl, halo, haloalkyl, guanidino, mono- and di-alkylguanidino, alkylacylguanidino, alkylacylguanidino, amidino, mono- and di-alkylamidino, amino, mono- and dialkylamino, carboxy, alkylcarboxy, carbalkoxy, carbalalkoxy, carbalkoxyalkenyl, carboxamido, mono- and dialkylcarboxamido, mono- and diarcarboxamido, thio, alkylthio, sulfonamido, mono- and di-alkylsulfonamido, morpholinosulfonamido, alkylsulfonyl, nitro, cyano, N-morpholinoalkyl, N-morpholinoalkoxy, N-mono and N,N-dialkylaminoalkyl and N-mono- and N,N-dialkylaminoethoxy.
- 2. The compound according to claim 1 selected from the group consisting of: N-�4-(N,N-Dimethylaminomethyl)!benzoyl-L-valyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid (p-chlorophenyl)-phenyl-phosphinyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid (p-methoxyphenyl)-phenyl-phosphinyl-oxymethyl ketone.
- 3. The compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-valyl-L-alanyl-L-aspartic acid diphenyl-phosphinyloxymethylketone, N-�4-(N,N-Dimethylaminomethyl)!benzoyl-L-valyl-L-alanyl-L-aspartic acid diphenylphosphinyloxymethylketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid (p-methoxyphenyl)-phenyl-phosphinylmethyl ketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid (p-chlorophenyl)-phenyl-phosphinyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid di-(p-methoxyphenyl)phosphinyloxymethyl ketone.
- 4. The compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid (m-methoxyphenyl)-phenyl-phosphinyloxymethyl ketone, N-4-(Pyridyl)carbomethoxy-L-valyl-L-alanyl-L-aspartic acid diphenylphosphinyl-oxymethyl ketone, N-Benzyloxycarbonyl-L-valyl-D-aspartic acid diphenylphosphinyloxymethyl ketone and N-3-(Quinuclidinyl)carbonyl-L-valyl-L-alanyl-L-aspartic acid diphenyl-phosphinyloxymethyl ketone.
- 5. A pharmaceutical composition for inhibiting interleukin-1.beta. protease comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR17## wherein: n is 0-4;
- Y is ##STR18## and when R.sub.3 is OH, then Y can also be ##STR19## R.sub.2 is H or deuterium; R.sub.3 is OH, OR.sub.7, NR.sub.7 OR.sub.8 or NR.sub.7 R.sub.8 ;
- where R.sub.7 and R.sub.8 are independently H, alkyl, cycloalkyl, benzyl, or phenyl;
- R.sub.4 is H or lower alkyl;
- R.sub.5 and R.sub.6 are optionally and independently selected from H, OH, alkyl, alkoxy, and phenyloxy;
- AA is independently selected from the group consisting of (a) and (b) where (a) is defined as an amino acid of formula II ##STR20## wherein R.sub.7 and R.sub.8 are defined as above and R.sub.9 is (CR.sub.6 R.sub.7).sub.0-6 -R.sub.10 ;
- where R.sub.10 is a radical optionally selected from R.sub.11, where R.sub.11 is described below; and
- where group (b) is selected from the group consisting of: ##STR21## where W and X are optionally CH.sub.2, or O; R.sub.11 is R.sub.10 --C--, where R.sub.10 is defined previously;
- R.sub.11 is H, alkyl, alkenyl, hydroxy, benzyl, alkoxy, 2-(alkyoxy)ethoxy, 2-(alkyoxy)aminoethyl and 2-(alkyoxy)-N-alkylaminoethyl, alkylacyloxy, alkylacyl, halo, haloalkyl, guanidino, mono- and di-alkylguanidino, alkylacylguanidino, amidino, mono- and di-alkylamidino, amino, mono- and dialkylamino, carboxy, alkylcarboxy, carbalkoxy, carbalalkoxy, carbalkoxyalkenyl, carboxamido, mono- and dialkylcarboxamido, mono- and diarcarboxamido, thio, alkylthio, sulfonamido, mono- and di-alkylsulfonamido, morpholinosulfonamido, alkylsulfonyl, nitro, cyano, N-morpholinoalkyl, N-morpholinoalkoxy, N-mono and N,N-dialkylaminoalkyl and N-mono- and N,N-dialkylaminoethoxy, in combination with a pharmaceutically acceptable carrier.
- 6. The pharmaceutical composition of claim 5 wherein said compound is selected from the group consisting of: N-�4-(N,N-Dimethylaminomethyl)! benzoyl-L-valyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid diphenylphosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid (p-chlorophenyl)-phenyl-phosphinyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid (p-methoxyphenyl)-phenyl-phosphinyl-oxymethyl ketone.
- 7. The pharmaceutical composition of claim 5 wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-valyl-L-alanyl-L-aspartic acid diphenyl-phosphinyloxymethylketone, N-�4-(N,N-Dimethylaminomethyl)!benzoyl-L-valyl-L-alanyl-L-aspartic acid diphenylphosphinyloxymethylketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid (p-methoxyphenyl)-phenyl-phosphinyloxymethyl ketone, N-Benzyloxycarbonyl-L-valyl-L-aspartic acid (p-chlorophenyl)-phenyl-phosphinyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid di-(p-methoxyphenyl)phosphinyloxymethyl ketone.
- 8. The pharmaceutical composition of claim 5 wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid (m-methoxyphenyl)-phenyl-phosphinyloxymethyl ketone, N-4-(Pyridyl)carbomethoxy-L-valyl-L-alanyl-L-aspartic acid diphenylphosphinyl-oxymethyl ketone, N-Benzyloxycarbonyl-L-valyl-D-aspartic acid diphenylphosphinyloxymethyl ketone and N-3-(Quinuclidinyl)carbonyl-L-valyl-L-alanyl-L-aspartic acid diphenyl-phosphinyloxymethyl ketone.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No. 08/248,791, filed May 25, 1994, now abandoned, which is a continuation-in-part of Ser. No. 08/73,219, filed Jun. 4, 1993 now abandoned.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
5055451 |
Krantz et al. |
Oct 1991 |
|
5462939 |
Dolle et al. |
Oct 1995 |
|
5585486 |
Dolle et al. |
Dec 1996 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
0 519748 A2 |
Jun 1992 |
EPX |
WO 9115577 |
Oct 1991 |
WOX |
WO 9305071 |
Mar 1993 |
WOX |
Continuations (1)
|
Number |
Date |
Country |
Parent |
248791 |
May 1994 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
73219 |
Jun 1993 |
|