Beta amino acid derivatives as integrin antagonists
Disclosed herein are novel pharmaceutical agents which are useful as integrin receptor antagonists that mediate the pathologic processes of angiogenesis and fibrosis and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by these integrins by inhibiting or antagonizing these integrins. The novel pharmaceutical agents include those of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods and intermediates useful for making the pharmaceutical agents and methods of using the pharmaceutical agents are also provided.
1. A compound of the formula:
wherein:
W is
wherein:
R A is —H or —F;
R B is —H, —OH, —NH 2 , —F, —CN, or alkoxy (C≦8) , wherein if R A is —F, then R B is —H or —F; and
m is 0-3;
A is C—R″ or N, wherein:
R″ is —H, —OH, —CO 2 R 1 , —C(═O)R 2 , or —N(R 1 )(C═O)R 3 , or alkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or a substituted version of any of the groups, wherein:
R 1 is —H, alkyl (C≦8) or substituted alkyl (C≦8) ;
R 2 is alkylamino (C≦8) , dialkylamino (C≦8) , heterocycloalkyl (C≦8) , heteroaryl (C≦8) , or a substituted version of any of the groups;
R 3 is alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , or a substituted version of any of the groups;
R′ is —H, alkyl (C≦8) or substituted alkyl (C≦8) ;
X is:
hydrogen, halo, or cyano;
alkyl (C≦12) , alkoxy (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , aryloxy (C≦12) , acyloxy (C≦12) , or a substituted version of any of the groups;
—(CH 2 ) n′ —CO 2 -alkyl (C≦6) , wherein, n′ is 0-3;
wherein
R 4 and R 5 are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or —CH 2 O-alkyl (C≦8) ;
R 6 is —OH, —CN, —NH 2 , —CF 3 , —CF 2 H, —CH 2 F, —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CH 2 OH, —CH 2 O-alkyl (C≦8) , or alkoxy (C≦8) , provided that where R 4 and R 5 are each —CF 3 , then R 6 is —OH, alkoxy (C≦8) or —NH 2 ;
wherein n is 1 or 2 and X 1 is —H or alkyl (C≦8) ; or
wherein:
A′ is a covalent bond, thereby forming a cyclopropane ring, —CF 2 —, —O—, alkanediyl (C≦6) or alkoxydiyl (C≦8) ; and
R 7 is —OH, —CN, —NH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CF 3 , —CF 2 H, —CH 2 F, —CH 2 OH, —CH 2 O-alkyl (C≦8) , alkyl (C≦8) or alkoxy (C≦8) ;
Y is:
t-butyl, neopentyl, norbornyl, or adamantyl;
wherein
R 8 and R 9 are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or —CH 2 O-alkyl (C≦8) ;
R 10 is —OH, —CN, —NH 2 , —CF 3 , —CF 2 H, —CFH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CH 2 OH, —CH 2 O-alkyl (C≦8) , or alkoxy (C≦8) , provided that where R 8 and R 9 are each —CF 3 , then R 10 is —OH, alkoxy (C≦8) or —NH 2 ;
wherein n″ is 1 or 2 and Y 1 is —H or alkyl (C≦8) ; or
wherein:
A″ is a covalent bond, thereby forming a cyclopropane ring, —O—, —CF 2 —, alkanediyl (C≦6) or alkoxydiyl (C≦8) ; and
R 11 is —OH, —CN, —NH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CF 3 , —CF 2 H, —CH 2 F, —CH 2 OH, —CH 2 O-alkyl (C≦8) , alkyl (C≦8) or alkoxy (C≦8) ;
L is hydrogen, hydroxy or alkoxy (C≦8) ; and
Z is hydrogen, fluorine, or hydroxy and is attached to either carbon atom 2 or 6;
provided that if W is
then X and Y are not both each t-butyl; and further provided that if W is
A is C—OH, Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl;
or a pharmaceutically acceptable salt or tautomer thereof.
2. The compound of claim 1 , further defined as:
wherein:
W is
wherein:
R A is —H or —F;
R B is —H, —OH, —NH 2 , —F, —CN, or alkoxy (C≦8) , wherein if R A is —F, then R B is —H or —F; and
m is 0-3;
A is C—R″ or N, wherein:
R″ is —H, —OH, —CO 2 R 1 , —C(═O)R 2 , or —N(R 1 )(C═O)R 3 , or alkoxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , or a substituted version of any of the groups, wherein:
R 1 is —H, alkyl (C≦8) or substituted alkyl (C≦8) ;
R 2 is alkylamino (C≦8) , dialkylamino (C≦8) , heterocycloalkyl (C≦8) , heteroaryl (C≦8) , or a substituted version of any of the groups;
R 3 is alkyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , heteroaryl (C≦8) , heterocycloalkyl (C≦8) , or a substituted version of any of the groups;
R′ is —H, alkyl (C≦8) or substituted alkyl (C≦8) ;
X is:
hydrogen, halo, or cyano;
alkyl (C≦12) , alkoxy (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , aryloxy (C≦12) , acyloxy (C≦12) , or a substituted version of any of the groups;
—(CH 2 ) 2′ —CO 2 -alkyl (C≦6) , wherein, n′ is 0-3;
wherein
R 4 and R 5 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;
R 6 is —OH, —CN, —NH 2 , —CF 3 , —CF 2 H, —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CH 2 OH, or alkoxy (C≦8) , provided that where R 4 and R 5 are each CF 3 , then R 6 is OH;
wherein n is 1 or 2; or
wherein:
A′ is a covalent bond, thereby forming a cyclopropane ring, alkanediyl (C≦6) or alkoxydiyl (C≦8) ; and
R 7 is —OH, —CN, —NH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CF 3 , —CF 2 H, or alkoxy (C≦8) ;
Y is:
t-butyl, neopentyl, norbornyl, or adamantyl;
wherein
R 8 and R 9 are each independently alkyl (C≦8) or substituted alkyl (C≦8) ;
R 10 is —OH, —CN, —NH 2 , —CF 3 , —CF 2 H, —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CH 2 OH, or alkoxy (C≦8) , provided that where R 8 and R 9 are each CF 3 , then R 10 is OH;
wherein n″ is 1 or 2; or
wherein:
A″ is a covalent bond, thereby forming a cyclopropane ring, alkanediyl (C≦6) or alkoxydiyl (C≦8) ; and
R 11 is —OH, —CN, —NH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CF 3 , —CF 2 H, or alkoxy (C≦8) ;
L is hydrogen, hydroxy or alkoxy (C≦8) ; and
Z is hydrogen or hydroxy and is attached to either carbon atom 2 or 6;
provided that if W is
then X and Y are not both each t-butyl; and
further provided that if W is
A is C—OH, Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl;
or a pharmaceutically acceptable salt or tautomer thereof.
3. The compound of claim 1 , wherein W is
4. The compound of claim 1 , wherein A is C—OH.
5. The compound of claim 1 , wherein X is halo.
6. The compound of claim 1 , wherein X is alkyl (C≦8) or substituted alkyl (C≦8) .
7. The compound of claim 1 , wherein X is cyano.
8. The compound of claim 1 , wherein X is heteroaryl.
9. The compound of claim 1 , wherein L is hydrogen.
10. The compound of claim 1 , wherein Y is t-butyl.
11. The compound claim 1 , wherein Y is 2-hydroxy-isopropyl.
12. The compound of claim 1 , wherein Y is
wherein R 8 and R 9 are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or —CH 2 O-alkyl (C≦8) ; R 10 is —OH, —CN, —NH 2 , —CF 3 , —CF 2 H, —CFH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CH 2 OH, —CH 2 O-alkyl (C≦8) , or alkoxy (C≦8) , provided that where R 8 and R 9 are each —CF 3 , then R 10 is —OH, alkoxy (C≦8) or —NH 2 .
13. The compound of claim 1 , wherein Y is
wherein: A″ is a covalent bond, thereby form a cyclopropane ring, —O—, —CF 2 —, alkanediyl (C≦6) or alkoxydiyl (C≦8) ; and R 11 is —OH, —CN, —NH 2 , —CO 2 H, —CO 2 -alkyl (C≦8) , —C(═O)NH 2 , —CF 3 , —CF 2 H, —CH 2 F, —CH 2 OH, —CH 2 O-alkyl (C≦8) , alkyl (C≦8) or alkoxy (C≦8) .
14. The compound of claim 1 , wherein Z is hydrogen.
15. The compound of claim 1 , wherein R′ is hydrogen.
16. The compound of claim 1 , further defined as:
or a pharmaceutically acceptable salt or tautomer thereof.
17. The compound of claim 1 , further defined as:
or a pharmaceutically acceptable salt or tautomer thereof.
18. A pharmaceutical composition comprising:
a) the compound of claim 1 ; and
b) an excipient.