Claims for Patent: 8,394,826

Summary for Patent: 8,394,826

Title:	Dual mechanism inhibitors for the treatment of disease
Abstract:	Provided are compounds that are inhibitors of both rho kinase and of a monoamine transporter (MAT) act to improve the disease state or condition. Further provided are compositions comprising the compounds. Further provided are methods for treating diseases or conditions, the methods comprising administering compounds according to the invention. One such disease may be glaucoma for which, among other beneficial effects, a marked reduction in intraocular pressure (IOP) may be achieved.
Inventor(s):	Mitchell A. deLong, Jill Marie Sturdivant, Susan M. Royalty
Assignee:	Alcon Inc
Application Number:	US12/694,965
Patent Claims:	1. A compound according to Formula I: and salts thereof, wherein R1, R2, and R3 are independently hydrogen, C1-C4 alkyl, aryl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, C1-C4 carboxyl, or form a ring with each other or with A; wherein A is C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, or forms a ring structure with R1, R2 or R3; wherein B is hydrogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C22 alkyl, C1-C22 alkyl aryl, C1-C22 alkyl heteroaryl, C2-C22 alkenyl, C2-C22 alkynyl, C1-C22 carbonyl, C1-C22 carbonylamino, C1-C22 alkoxy, C1-C22 sulfonyl, C1-C22 sulfonylamino, C1-C22 thioalkyl, or C1-C22 carboxyl; wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl; wherein the double circle indicates an aromatic or heteroaromatic ring; and wherein each Z is independently a bond, is C1-C4 alkyl, heteroalkyl, or an O atom. 2. A compound according to claim 1, wherein R1 and R2 are methyl or hydrogen, and wherein X1, X2, and X3 are hydrogen. 3. A compound according to claim 1, wherein B is an aliphatic carbonyl group. 4. A compound according to claim 1, wherein B is a benzoic, pyridyl, naphthyl, benzothiophene, or thiazole carbonyl group. 5. A compound according to claim 1, wherein Z is a bond or —CH2—. 6. A compound according to claim 1, wherein X1, X2 and X3 are each hydrogen. 7. A compound according to claim 1, wherein A is —CH2CH2—. 8. A compound according to claim 1, wherein R1 and R2 are independently hydrogen or methyl. 9. A compound according to claim 1, wherein R3 is hydrogen or C1-C4 alkyl. 10. A compound according to Formula III: and salts and solvates thereof, wherein R1 and R2 are independently hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, or R1 and R2 together form a ring, either cycloalkyl or heterocycloalkyl; wherein R3 is hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, 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 R3 may from a ring with itself or R1 or R2; wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl; wherein B is hydrogen, C1-C18 alkyl, C1-C18 alkyl aryl, C1-C18 alkyl heteroaryl, C1-C18 carbonyl, C1-C18 carbonylamino, C1-C18 sulfonyl, C1-C18 sulfonylamino, or C1-C18 carboxyl; and wherein each Z is independently a bond, is C1-C4 alkyl, heteroalkyl, or an O atom. 11. A compound according to Formula IV: and salts thereof, wherein R1 and R2 are independently hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, or R1 and R2 together form a ring, either cycloalkyl or heterocyclyl; wherein R3 is a hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, 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; wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl; wherein B is hydrogen, C1-C18 alkyl, C1-C18 alkyl aryl, C1-C18 alkyl heteroaryl, C1-C18 carbonyl, C1-C18 carbonylamino, C1-C18 sulfonyl, C1-C18 sulfonylamino, or C1-C18 carboxyl; and wherein Z is a bond, C1-C4 alkyl, heteroalkyl, or an O atom. 12. A compound according to claim 11, wherein B is C1-C2 alkyl aryl, C2-carbonyl, C2-carbonyl amino, C2-carboxyl, or C2-hydroxyl aryl. 13. A compound according to Formula V: wherein Z is a bond or —CH2—; and B is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C22 alkyl, C1-C22 alkyl aryl, C1-C22 alkyl heteroaryl, C2-C22 alkenyl, C2-C22 alkynyl, C1-C22 carbonyl, C1-C22 carbonylamino, C1-C22 alkoxy, C1-C22 sulfonyl, C1-C22 sulfonylamino, C1-C22 thioalkyl, or C1-C22 carboxyl. 14. A compound selected from the group consisting of: 15. A compound according to Formula (VI): wherein R4 is methyl and n is 2. 16. 4-(3-Amino-1-(isoquinolino-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate. 17. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 18. A method for 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. 19. The method of claim 18, wherein the eye disease comprises glaucoma or a neurodegenerative eye disease. 20. A method of modulating kinase activity comprising: contacting a cell with a compound according to claim 1 in an amount effective to modulate kinase activity. 21. The method of claim 20, wherein the cell is in a subject. 22. A method of reducing intraocular pressure comprising: contacting a cell with a compound according to claim 1 in an amount effective to reduce intraocular pressure. 23. The method of claim 22, wherein the cell is in a subject. 24. The compound according to claim 1, wherein R1, R2, and R3 are each hydrogen; A is CH2; Z is bond; X1, X2, and X3 are each hydrogen; and is phenyl. 25. The compound of claim 24, wherein B is methyl. 26. The compound of claim 24, wherein B is C1-C4 carbonyl. 27. The compound of claim 26, wherein B is —C(O)-phenyl, —C(O)-dimethylphenyl, —C(O)—CH2-phenyl, —C(O)-cyclohexyl, or —C(O)-methylphenyl. 28. The compound according to claim 10, wherein R1, R2, and R3 are each hydrogen; Z is bond; and X1, X2, and X3 are each hydrogen. 29. The compound of claim 28, wherein B is C1-C4 carbonyl. 30. The compound of claim 29, wherein B is —C(O)-cyclopenyl, —C(O)-cyclohexyl, —C(O)-dimethylphenyl, —C(O)-buytl, —C(O)-phenyl, —C(O)-methoxyphenyl, —C(O)-adamantyl, —C(O)-propyl, or —C(O)—CH2-phenyl. 31. The compound according to claim 10, wherein R1 is CH3; R2 and R3 are each hydrogen; Z is bond; X1, X2, and X3 are each hydrogen; and B is C1-C4 carbonyl. 32. The compound according to claim 1, wherein the compound is selected from the following: 33. The compound according to claim 10, wherein the compound is selected from the following: