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US 5,686,469 AGranted
Aminomethylene derivaties as immunosuppressants
AssigneeMiles Inc.
InventorsRichard D. Connell, David G. Osterman, Michael E. Katz, Robert D. Dally
Life of this patent
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Abstract
Compounds which suppress human T-lymphocyte proliferation are disclosed. The active compounds essentially contain at least the following structure: ##STR1##
Claims35
A compound having the following generalized structure:
- ##STR49## wherein A is ##STR50## wherein R.sup.4 is (C.sub.1 -C.sub.8) alkyl optionally substituted with C.sub.6 cycloalkyl, --CO.sub.2 R wherein R is (C.sub.1 -C.sub.6) alkyl optionally substituted with phenyl, carboxamido, phenyl optionally substituted with hydroxyl or methoxy, (C.sub.1 -C.sub.6) alkoxy, or benzyloxy;
- R.sup.5 is acyl, an amino acid residue, hydrogen, or --CO.sub.2 R' wherein R' is (C.sub.1 -C.sub.8) alkyl optionally substituted with phenyl or a (C.sub.2 -C.sub.6) alkenyl group;
- X.sup.2 is oxygen;
- m is 0 or 1;
- R.sup.6 is (C.sub.1 -C.sub.12) alkyl, (C.sub.3 -C.sub.10) cycloalkyl, (C.sub.6 -C.sub.12) bicycloalkyl, (C.sub.7 -C.sub.14) tricycloalkyl, or (C.sub.9 -C.sub.16) tetracycloalkyl, any of said cycloalkyl moieties being optionally substituted with (C.sub.1 -C.sub.8) alkoxycarbonyl, (C.sub.3 -C.sub.7) cycloalkyl, or a bicyclic heterocycle containing up to four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur;
- an aryl moiety selected from the group consisting of phenyl, naphthyl, and fluorenone, said aryl moieties being optionally substituted up to three-fold with (C.sub.1 --C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkoxy, (C.sub.1 -C.sub.6) acyloxy, or phenyl;
- or a heteroaryl group selected from 6-membered heteroaryl tings containing up to two nitrogen atoms, and 5-membered heteroaryl rings containing one oxygen or sulfur atom, said heteroaryl groups being optionally subsitiuted with (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.5) alkoxy, or halogen;
- R.sup.1 is hydrogen or (C.sub.1 -C.sub.6) alkyl;
- one of R.sup.2 and R.sup.3 is hydrogen, and the other is (C.sub.1 -C.sub.12) alkyl optionally substituted with (C.sub.3 -C.sub.10) cycloalkyl, phenyl optionally substituted with hydroxyl or (C.sub.1 -C.sub.6) alkoxy, (C.sub.1 -C.sub.6) alkoxy, or benzyloxy, with the proviso that when n is 2, R.sup.2 or R.sup.3 is not unsubstituted benzyl;
- n is an integer of 2 or 3;
- X.sup.1 is oxygen or NR.sup.7, where R.sup.7 is hydrogen or (C.sub.1 -C.sub.6) alkyl;
- J is the divalent moiety ##STR51## wherein R.sup.8 is hydrogen or (C.sub.1 -C.sub.10) alkyl optionally substituted with (C.sub.5 -C.sub.7) cycloalkyl, phenyl, (C.sub.1 -C.sub.8) alkoxy, or (C.sub.7 -C.sub.11) arylalkoxy;
- K is ##STR52## wherein p is an integer 2, 3, or 4;
- and L is hydrogen, (C.sub.1 -C.sub.10) alkyl, or phenyl, said alkyl and phenyl groups being optionally substituted up to three times with (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.8) alkoxy, hydroxyl, or amino optionally substituted with acyl, benzoyl, or --CO.sub.2 R' in which R' is (C.sub.1 -C.sub.8) alkyl optionally substituted with phenyl or a (C.sub.2 -C.sub.6) alkenyl group;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A compound having the following generalized structure:
- ##STR53## wherein A is ##STR54## wherein R.sup.4 is (C.sub.1 -C.sub.6) alkyl optionally substituted with C.sub.6 cycloalkyl, --CO.sub.2 R wherein R is (C.sub.1 -C.sub.4) alkyl optionally substituted with phenyl, carboxamido, phenyl optionally substituted with hydroxyl or methoxy, (C.sub.1 -C.sub.4) alkoxy, or benzyloxy;
- R.sup.5 is acetyl, an amino acid residue, hydrogen, or --CO.sub.2 R' wherein R' is (C.sub.1 -C.sub.6) alkyl optionally substituted with phenyl or a (C.sub.2 -C.sub.4) alkenyl group;
- X.sup.2 is oxygen;
- m is 0 or 1;
- R.sup.6 is (C.sub.1 -C.sub.10) alkyl, (C.sub.3 -C.sub.8) cycloalkyl, (C.sub.5 -C.sub.12) bicycloalkyl, (C.sub.7 -C.sub.14) tricycloalkyl, or (C.sub.9 -C.sub.14) tetracycloalkyl, any of said cycloalkyl moieties being optionally substituted with (C.sub.1 -C.sub.6) alkoxycarbonyl, (C.sub.3 -C.sub.7) cycloalkyl, or a bicyclic heterocycle containing up to four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur;
- an aryl moiety selected from the group consisting of phenyl, naphthyl, and fluorenonyl, said aryl moieties being optionally substituted up to three-fold with (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkoxy, (C.sub.1 -C.sub.6) acyloxy, or phenyl;
- or a heteroaryl group selected from 6-membered heteroaryl rings containing up to two nitrogen atoms, and 5-membered heteroaryl rings containing one oxygen or sulfur atom, said heteroaryl groups being optionally subsitiuted with (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.5) alkoxy, or halogen;
- R.sup.1 is hydrogen or (C.sub.1 -C.sub.4) alkyl;
- one of R.sup.2 and R.sup.3 is hydrogen, and the other is (C.sub.1 -C.sub.9) alkyl optionally substituted with (C.sub.5 -C.sub.8) cycloalkyl, phenyl optionally substituted with hydroxyl or (C.sub.1 -C.sub.4) alkoxy, (C.sub.1 -C.sub.6)alkoxy, or benzyloxy, with the proviso that when n is 2, R.sup.2 or R.sup.3 i not unsubstituted benzyl;
- n is an integer of 2 or 3;
- X.sup.1 is oxygen or NR.sup.7, where R.sup.7 is hydrogen or (C.sub.1 -C.sub.4) alkyl;
- J is the divalent moiety ##STR55## wherein R.sup.8 is hydrogen or (C.sub.1 -C.sub.8) alkyl optionally substituted with (C.sub.5 -C.sub.7) cycloalkyl, phenyl, (C.sub.1 -C.sub.6) alkoxy, or (C.sub.7 -C.sub.9) arylalkoxy;
- K is ##STR56## wherein p is an integer 2 or 3;
- and L is hydrogen, (C.sub.1 -C.sub.8) alkyl, or phenyl, said alkyl and phenyl groups being optionally substituted up to three times with (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.6) alkoxy, hydroxyl, or amino optionally substituted with acyl, benzoyl, or --CO.sub.2 R' in which R' is (C.sub.1 -C.sub.6) alkyl optionally substituted with phenyl or a (C.sub.2 -C.sub.4) alkenyl group;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A compound having the following generalized structure:
- ##STR57## wherein A is ##STR58## wherein R.sup.4 is (C.sub.1 -C.sub.4) alkyl optionally substituted with C.sub.6 cycloalkyl;
- R.sup.5 is hydrogen or --CO.sub.2 R' wherein R' is (C.sub.1 -C.sub.5) alkyl optionally substituted with phenyl or a (C.sub.2 -C.sub.3) alkenyl group;
- X.sup.2 is oxygen;
- m is 0 or 1;
- R.sup.6 is (C.sub.1 -C.sub.8) alkyl, (C.sub.4 -C.sub.8) cycloalkyl, (C.sub.5 -C.sub.12) bicycloalkyl, (C.sub.7 -C.sub.14) tricycloalkyl, or (C.sub.9 -C.sub.14) tetracycloalkyl, any of said cycloalkyl moieties being optionally substituted with (C.sub.1 -C.sub.4) alkoxycarbonyl, (C.sub.4 -C.sub.6) cycloalkyl, or a 2-oxo-hexahydro-thieno(3,4-d)imidazol-4-yl group;
- an aryl moiety selected from the group consisting of phenyl, naphthyl, and 4-fluorenonyl, said aryl moieties being optionally substituted up to three-fold with methoxy, acetoxy, or phenyl;
- or a heteroaryl group selected from 6-membered heteroaryl rings containing one nitrogen atom, and 5-membered heteroaryl rings containing one oxygen or sulfur atom;
- R.sup.1 is hydrogen;
- one of R.sup.2 and R.sup.3 is hydrogen, and the other is (C.sub.1 -C.sub.6) alkyl optionally substituted with (C.sub.5 -C.sub.6) cycloalkyl, phenyl, (C.sub.1 -C.sub.6) alkoxy, or benzyloxy, with the proviso that when n is 2, R.sup.2 or R.sup.3 is not unsubtituted benzyl;
- n is an integer of 2 or 3;
- X.sup.1 is oxygen or NR.sup.7, where R.sup.7 is hydrogen;
- J is the divalent moiety ##STR59## wherein R.sup.8 is hydrogen or (C.sub.1 -C.sub.6) alkyl;
- K is ##STR60## wherein p is 2;
- and L is hydrogen or (C.sub.1 -C.sub.6) alkyl or phenyl, said alkyl and phenyl groups being optionally substituted up to three times with (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy, hydroxyl, or amino optionally substituted with acyl, benzoyl, or --CO.sub.2 R' in which R' is (C.sub.1 -C.sub.4) alkyl optionally substituted with phenyl or a (C.sub.3 -C.sub.4) alkenyl group;
- or a pharmaceutically acceptable salt thereof.
12 more elements
Dependencies are inferred from the claim text.