Diaminopropionic acid derivatives
A compound of formula 1a which is useful for treating reperfusion injury, and salts, prodrugs, and related compounds.
1. A compound of formula:
wherein R 1 is a group of the formula
where A is hydrogen, hydroxy, amino, or halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; R 2 is a group of the formula
where R 3 is hydrogen, carboxy, or lower alkyl;
n is 0 or 1;
U, V, and W are independently hydrogen, halogen, or lower alkyl provided U and V are not both hydrogen;
X is carbonyl, phenyl-substituted loweralkylene, or sulfonyl;
Y is lower alkylene which may be substituted with one or more of amino, substituted amino, lower alkyl, or cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio; and k is 0 or 1;
when k is 1:
Z is hydrogen, lower alkylthio, —COOH, —CONH 2 , or amino, or when k is 0 or 1, Z is: 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, hydroxy, phenylmethoxy, 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]phenyl, [(2,6-dichlorophenyl)methoxy]phenyl, or Z is one of the following:
cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of:
halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy or amino loweralkyl;
or a pharmaceutically acceptable salts and esters thereof.
2. A compound of claim 1 wherein Z is thiophene, furan, thiazole, cyclopentyl, cyclohexyl, piperidine, pyridine, naphthalene, benzothiophene, benzothiazole, 1,4-dioxa-8-thiaspiro[4,5]decyl, phenyl, or phenyl substituted by one or more of lower alkoxy, lower alkyl, chlorine, bromine, fluorine, hydroxy, nitro, cyano, amino, substituted amino, aminosulfonyl, alkoxycarbonyl, trifluoromethyl, or carboxy.
3. A compound of claim 1 wherein A, when present, is hydroxy, hydrogen, or amino and B is hydrogen or hydroxy; W is hydrogen and at least one of U and V are methyl or halogen, k is 0 or Y is lower alkylene; and Z is hydrogen, phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, thiazole, or isoxazole or a six-membered aromatic ring with one to three nitrogens any of which may be unsubstituted or substituted with at least one of:
halogen, hydroxy, lower alkoxy, nitro, amino, substituted amino, cyano, carboxy, trifluoromethyl, lower alkyl, aminosulfonyl, or lower alkoxycarbonyl.
4. A compound of claim 1 having formula
wherein R 1 is a group of the formula
at least one of U and V are chlorine, bromine, or methyl; k is 0 or Y is butylene; X is carbonyl, phenyl-substituted lower alkylene, or sulfonyl; and Z is hydrogen, phenyl, thiazole, or thiophene, or Z is phenyl, thiazole, or thiophene substituted with at least one of methyl or acetylamino.
5. A compound of claim 4 wherein R 3 is hydrogen.
6. Compounds of claim 5 which are:
3-(benzoylamino)-N-[2-chloro-4-[[(2,3-dihydro-2-oxo-1H-indol-4-ylmethyl)aminocarbonyl]benzoyl]-L-alanine;
3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)aminocarbonyl]benzoyl]-L-alanine;
N-[2-chloro-4-[[(1H-benzimidazol-4-ylmethyl)aminocarbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine;
N-[2-chloro-4-[[(1H-indol-4-ylmethyl)aminocarbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine;
N-[2-chloro-4-[[(2,3-dihydro-1H-indol-4-ylmethyl)aminocarbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine;
N-[2-bromo-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine;
N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-3-carbonyl)amino-L-alanine;
N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(5-methylthiophene-2-carbonyl)amino-L-alanine; and
N-[2-chloro-4-[[[(1H-indazol-4-yl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine.
7. A compound of claim 4 wherein R 3 is methyl.
8. A compound of formula:
wherein R 1 is a group of the formula
where A is hydrogen, hydroxy, amino, or halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; R 2 is a group of the formula
where R 3 is hydrogen, carboxy, or lower alkyl;
n is 0 or 1;
U, V, and W are independently hydrogen, halogen, or lower alkyl provided U and V are not both hydrogen;
X is carbonyl, phenyl-substituted loweralkylene, or sulfonyl;
Y is lower alkylene which may be substituted by one or more of amino, substituted amino, loweralkyl, or cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio; k is 0 or 1;
when k is 1, Z is:
hydrogen, lower alkylthio, —COOH, —CONH 2 , or amino, or when k is 0 or 1, Z is: 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, hydroxy, phenylmethoxy, 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]phenyl, [(2,6-dichlorophenyl)methoxy]phenyl, or Z is one of the following:
cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of:
halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, lower alkoxycarbonyl, acetoxy, or amino loweralkyl;
R 6 is lower alkyl or —CH 2 CH 2 —R 7 where R 7 is —N(CH 3 ) 2 ,
where R 8 is hydrogen or methyl and R 9 is lower alkyl or lower cycloalkyl; and pharmaceutically acceptable salts and esters thereof.
9. A compound of claim 8 wherein R 6 is ethyl.
10. A compound of claim 8 wherein R 6 is CH 2 CH 2 —R 7 .
11. A compound of claim 10 wherein R 7 is —N(CH 3 ) 2 ,
12. A compound of claim 8 wherein R 6 is
13. A compound of claim 12 wherein R 8 is hydrogen or methyl.
14. A compound of claim 12 wherein R 9 is ethyl or cyclohexyl.