Claims for Patent: 8,450,344

Summary for Patent: 8,450,344

Title:	Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
Abstract:	Disclosed are beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds. In particular, the invention provides compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. The compounds of the invention are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, and diseases characterized by abnormal growth, such as cancers. The invention further provides compositions containing the beta or gamma-amino isoquinoline amide compounds or substituted benzamide compounds.
Inventor(s):	Mitchell A. deLong, Jill Marie Sturdivant, Susan M. Royalty
Assignee:	Alcon Inc
Application Number:	US12/180,259
Patent Claims:	1. A compound of formula (I): or any optical isomer, diastereomer, enantiomer, tautomer, or physiologically acceptable salt thereof; wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; wherein one of R3 and R4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and the other of R3 and R4 is hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. 2. The compound according to claim 1, wherein one of R3 and R4 is C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. 3. The compound according to claim 2, wherein R1 and R2 are, independently, hydrogen or methyl. 4. The compound according to claim 1, wherein X1 and X2 are, independently, hydrogen, hydroxy, chloro or fluoro. 5. The compound according to claim 1, wherein one of R3 and R4 is C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein R1 and R2 are, independently, hydrogen or methyl; and wherein X1 and X2 are, independently, hydrogen, hydroxyl, chloro or fluoro. 6. The compound according to claim 5, wherein the other of R3 and R4 is hydrogen. 7. The compound according to claim 1, wherein one of R3 and R4 is aryl or heteroaryl. 8. The compound according to claim 7, wherein one of R3 and R4 is thienyl. 9. The compound according to claim 7, wherein one of R3 and R4 is monosubstituted phenyl or monosubstituted thienyl. 10. The compound according to claim 9, wherein the substituent is fluoro, chloro or cyano. 11. The compound according to claim 7, wherein one of R3 and R4 is unsubstituted phenyl or unsubstituted thienyl. 12. The compound according to claim 1, wherein X1 is hydroxy and X2 is hydrogen. 13. The compound according to claim 1, wherein a hydroxy is at the 1-position. 14. The compound according to claim 1, wherein a hydrogen is at the 1-position. 15. The compound according to claim 1 having a formula of: X R3 R2 R1 H (S)—C6H5 H H H (R)—C6H5 H H OH (S)—C6H5 H H OH (R)—C6H5 H H OH (S)—C6H5 Me Me H (±)-o-chloro-C6H4 H H OH (±)-o-chloro-C6H4 H H H (±)-p-fluoro-C6H4 H H OH (±)-p-fluoro-C6H4 H H H (S)-3-thienyl H H OH (S)-3-thienyl H H H (S)-3-thienyl Me Me OH (S)-3-thienyl Me Me H (S)-2-thienyl Me Me or the formula: X R4 R2 R1 OH (±)-3-thienyl Me Me H C6H5 H H H C6H5 Me Me OH C6H5 H H or the formula: X R1 R2 R3 H (S)—C6H5 Me Me H (R)-3-thienyl H H OH (R)-3-thienyl H H H (S)-2-thienyl H H OH (S)-2-thienyl H H OH (S)-2-thienyl Me Me H (R)—CH2-3-thienyl H H H (S)—CH2-2-thienyl H H H (S)-2-furyl H H H (S)-3-pyridyl H H H (S)-2-methoxy-5- H H pyridyl or the formula: X R1 R2 R3 H (±)-3-thienyl H H H (±)-3-thienyl Me Me H C6H5 Me H H 4-fluoro-C6H4 H H 16. The compound according to claim 1, wherein R1 and R2 are, independently, hydrogen or methyl; R3 is hydrogen, R4 is phenyl; X1 and X2 are hydrogen. 17. A compound of formula (II): or any optical isomer, diastereomer, enantiomer, tautomer, or physiologically acceptable salt thereof; wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; wherein one of R3, R4 and R5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and the other two of R3, R4 and R5 are, independently, hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and wherein, X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. 18. The compound according to claim 17, wherein one of R3, R4 and R5 is Cr C5 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. 19. The compound according to claim 18, wherein R1 and R2 are, independently, hydrogen or methyl. 20. The compound according to claim 17, wherein X1 and X2 are, independently, hydrogen, hydroxy, chloro or fluoro. 21. The compound according to claim 17, wherein one of R3, R4 and R5 is C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein R1 and R2 are, independently, hydrogen or methyl; and wherein X1 and X2 are, independently, hydrogen, hydroxyl, chloro or fluoro. 22. The compound according to claim 21, wherein the other of R3, R4 and R5 are hydrogen. 23. The compound according to claim 17, wherein one of R3, R4 and R5 is aryl or heteroaryl. 24. The compound according to claim 23, wherein one of R3, R4 and R5 is thienyl. 25. The compound according to claim 23, wherein one of R3, R4 and R5 is monosubstituted phenyl or monosubstituted thienyl. 26. The compound according to claim 25, wherein the substituent is fluoro, chloro or cyano. 27. The compound according to claim 23, wherein one of R3, R4 and R5 is unsubstituted phenyl or unsubstituted thienyl. 28. The compound according to claim 17, wherein X1 is hydroxy and X2 is hydrogen. 29. The compound according to claim 17, wherein a hydroxy is at the 1-position. 30. The compound according to claim 17, wherein a hydrogen is at the 1-position. 31. The compound according to claim 17, wherein R1 and R2 are, independently, hydrogen or methyl; R3 and R4 are hydrogen, R5 is phenyl; X1 and X2 are hydrogen. 32. A composition comprising a compound according to claim 1 and a carrier. 33. The composition of claim 32, wherein the carrier is saline buffered to a pH of about 5.5 to about 6.5. 34. A composition comprising a compound according to claim 17 and a carrier. 35. The composition of claim 34, wherein the carrier is saline buffered to a pH of about 5.5 to about 6.5. 36. A method of treating a disease in a subject comprising: administering to a subject an effective amount of a compound according to claim 1; wherein the disease comprises eye disease. 37. The method of claim 36, wherein the eye disease comprises glaucoma or a neurodegenerative eye disease.