5-Substituted isoquinoline derivatives

• US 20050020623A1
• Filed: 07/22/2003
• Published: 01/27/2005
• Est. Priority Date: 07/22/2002
• Status: Active Grant

• Current Assignee: Asahi Kasei Pharma Corporation (Asahi Kasei Corporation)
• Original Assignee: Asahi Kasei Pharma Corporation (Asahi Kasei Corporation)
• Inventors: Seto, Minoru, Yamada, Rintaro
• Granted Patent: US 7,094,789 B2
• Time in Patent Office: Days
• US Class Current: 514/310
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Abstract

A compound represented by the following formula (1) or a salt thereof:
wherein R¹ represents hydrogen atom, a halogen atom and the like; R² represents hydrogen atom, a halogen atom, a C_1-6 alkyl group and the like; and R³ represents —O—X—C(A¹)(A¹¹)—C(A²)(A^2l)—N(A^3l)(A³)(X represents propylene group etc., A¹¹ and A²¹ represent hydrogen atom, or a C_1-6 alkyl group, A³¹ represents a C_1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A¹, A², and A³ represent hydrogen atom, a C_1-6 alkyl group and the like) and the like, which has an inhibitory activity on the phosphorylation of myosin regulatory light chain, and is useful for treatment of diseases relating to contraction of various cells and the like.

Claims

1. A compound represented by the following formula (1) or a salt thereof:

2. The compound or salt thereof according to claim 1, wherein R³ is a group represented by the formula (1-1).

3. The compound or salt thereof according to claim 1, wherein R³ is a group represented by a formula (1-2).

4. The compound or salt thereof according to claim 1 or 3, wherein R³ is a group represented by a formula (1-2);

X represents propylene group, butylene group, —

C(A⁵)(A⁵¹)—

, —

C(A⁵)(A⁵¹)—

C(A⁶)(A⁶l)—

, or a single bond;

A¹¹, A²¹, A⁵¹, and A⁶¹ independently represent hydrogen atom, or a C_1-6 alkyl group;

A³¹ is a C_1-6 alkyl group substituted with hydroxyl group, or hydrogen atom;

R⁴ is hydrogen atom, or a C_1-6 alkyl group; and

groups in each of one or more combinations selected from the group consisting of combinations of A³ and A², A³ and A¹, A³ and A^5, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ and A⁶, and A⁵ and A⁶ bind to each other to form a 5- or 6-membered ring (provided that among A¹, A², A³, A⁵, and A⁶, the group or groups not involved in the ring formation independently represent hydrogen atom, or a C_1-6 alkyl group).

5. The compound or salt thereof according to any one of claims 1 to 4, wherein the ring formed by groups in each of one or more combinations selected from the group consisting of combinations of A³ and A², A³ and A¹, A³ and A⁵, A³ and A⁶, A² and A¹, A² and A⁵, A² and A⁶, A¹ and A⁵, A¹ and A⁶, and A5 and A⁶ binding to each other is (i) a 6-membered ring, (ii) a ring consisting of carbon atoms, or when the ring contains a nitrogen atom to which A³ binds, a ring consisting of carbon atoms except for the nitrogen atom, or (iii) a saturated ring.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein X is —

C(A⁵)(A⁵¹)—

, or —

C(A⁵)(A⁵¹)—

C(A⁶)(A⁶¹)—

.

7. The compound or salt thereof according to any one of claims 1, 2, 5 and 6, wherein R³ is a group represented by the following formula (1-1-4) or formula (1-1-7).

8. The compound or salt thereof according to any one of claims 1 and 3 to 6, wherein R³ is a group represented by the following formula (1-2-4) or formula (1-2-7);

9. The compound or salt thereof according to any one of claims 1 to 8, wherein A³¹ is hydrogen atom.

10. The compound or salt thereof according to any one of claims 1 to 8, wherein A³¹ is a C_1-6 alkyl group substituted with hydroxyl group.

11. The compound or salt thereof according to any one of claims 1, 3 to 6, and 8 to 10, wherein R⁴ is hydrogen atom.

12. The compound or salt thereof according to claim 1, wherein R³ is a group represented by a formula (1-3).

13. The compound or salt thereof according to claim 1 or 12, wherein Y is a C_2-4 alkylene.

14. The compound or salt thereof according to any one of claims 1, 12 and 13, wherein R⁵ is —

(C_2-4 alkylene)(aryl), —

(C_2-4 alkylene)(thienyl), —

(C_2-4 alkylene)SO₂(aryl) or —

(C_2-4 alkylene)SO₂(thienyl), where the aryl is a phenyl group which may be substituted with one or more substituents selected from the group consisting a halogen atom, a C_1-6 alkyl group, CF₃ group, a C_1-6 alkoxyl group, cyano group, —

N(G⁷)(G⁸), —

CO₂(G⁹), —

S(O)_r(G⁹), and —

N(G⁹)SO₂(C_1-6 alkyl), where G⁹ is hydrogen atom, or a C_1-6 alkyl group, G⁷ and G⁸ independently represent hydrogen atom, or a C_1-6 alkyl group, and r is an integer of 0 to 2.

15. The compound or salt thereof according to any one of claims 1 to 14, wherein R¹ is hydrogen atom, hydroxyl group, or amino group.

16. The compound or salt thereof according to any one of claims 1 to 15, wherein R² is hydrogen atom, a C_1-6 alkyl group, a C_2-3 alkenyl group, a halogen atom, a —

(C_2-3 alkylene)O(G¹)13 , —

S(O)_p(C_1-6 alkyl), or cyano group.

17. The compound or salt thereof according to any one of claims 1 to 16, wherein R² is a C_1-6 alkyl group, or cyano group.

18. The compound or salt thereof according to any one of claims 1 to 16, wherein R¹ is hydrogen atom, hydroxyl group, or amino group, and R² is a C_1-6 alkyl group, —

(C_2-3 alkylene)O(G¹), a C_2-3 alkenyl group, —

S(O)_p(C_1-6 alkyl), or cyano group.

19. The compound or salt thereof according to any one of claims 1, 2, 5 to 7, 9, 10, 15, 16, and 18, wherein R¹ is hydrogen atom, hydroxyl group, or amino group, R² is a C_1-6 alkyl group, a C_2-3 alkenyl group, or cyano group, and R³ is a group represented by the formula (1-1-4) or formula (1-1-7).

20. The compound or salt thereof according to any one of claims 1, 3 to 6, 8 to 11, 15, 16, and 18, wherein R¹ is hydrogen atom, hydroxyl group, or amino group, R² is a C_1-6 alkyl group, —

(C_2-3 alkylene)O(G¹), a C_2-3 alkenyl group, or —

S(O)_p(C_1-6 alkyl), R³ is a group represented by the formula (1-2-4) or formula (1-2-7), and R⁴ is hydrogen atom.

21. The compound or salt thereof according to any one of claims 1, 3 to 6, 8 to 11, 15, 16, 18, and 20, wherein R¹ is hydrogen atom, hydroxyl group, or amino group, R² is a C_1-6 alkyl group, or a C_2-3 alkenyl group, R³ is a group represented by the formula (1-2-4) or formula (1-2-7), and R⁴ is hydrogen atom.

22. The compound or salt thereof according to any one of claims 1, 12 to 16, and 18, wherein R³ is a group represented by the formula (1-3), R¹ is hydrogen atom, hydroxyl group, or amino group, R² is hydrogen atom, or a C_1-6 alkyl group, and R⁵ is 3-phenylpropyl, 2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl, or 2-(phenylsulfonyl).

23. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

4-[(4-methyl-5-isoquinolyl)oxy]piperidine;

4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;

4-[(4-cyano-5-isoquinolyl)oxy]piperidine;

trans-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine;

trans-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine;

trans-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine;

cis-4-[(4-methyl-5-isoquinolyl)oxy]cyclohexylamine;

cis-4-[(4-ethyl-5-isoquinolyl)oxy]cyclohexylamine; and

cis-4-[(4-cyano-5-isoquinolyl)oxy]cyclohexylamine.

24. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

1-(2-hydroxyethyl)-4-[(4-methyl-5-isoquinolyl)oxy]piperidine;

1-(2-hydroxyethyl)-4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;

1-(2-hydroxyethyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine;

trans-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;

trans-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;

trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;

cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane;

cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane; and

cis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohexane.

25. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

1-(3-hydroxypropyl)-4-[(4-methyl-5-isoquinolyl)oxy]piperidine;

1-(3-hydroxypropyl)-4-[(4-ethyl-5-isoquinolyl)oxy]piperidine;

1-(3-hydroxypropyl)-4-[(4-cyano-5-isoquinolyl)oxy]piperidine;

trans-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;

trans-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;

trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane;

cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxyp ropyl)amino]cyclohexane;

cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane; and

cis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexane.

26. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]piperidine;

4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]piperidine;

trans-4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]cyclohexylamine;

trans-4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]cyclohexylamine;

cis-4-[(1-hydroxy-4-methyl-5-isoquinolyl)oxy]cyclohexylamine; and

cis-4-[(1-hydroxy-4-ethyl-5-isoquinolyl)oxy]cyclohexylamine.

27. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

4-[(4-methyl-5-isoquinolyl)amino]piperidine;

4-[(4-ethyl-5-isoquinolyl)amino]piperidine;

4-[(4-vinyl-5-isoquinolyl)amino]piperidine;

trans-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;

trans-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine;

trans-N-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediamine;

cis-N-(4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;

cis-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine; and

cis-N-(4-vinyl-5-isoquinolyl)-1,4-cyclohexanediamine.

28. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

1-(2-hydroxyethyl)-4-(4-methyl-5-isoquinolyl)aminopiperidine;

1-(2-hydroxyethyl)-4-(4-ethyl-5-isoquinolyl)aminopiperidine;

1-(2-hydroxyethyl)-4-(4-vinyl-5-isoquinolyl)aminopiperidine;

1-(3-hydroxypropyl)-4-(4-methyl-5-isoquinolyl)aminopiperidine;

1-(3-hydroxypropyl)-4-(4-ethyl-5-isoquinolyl)aminopiperidine;

1-(3-hydroxypropyl)-4-(4-vinyl-5-isoquinolyl)aminopiperidine;

trans-N-(4-methyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

trans-N-(4-ethyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

trans-N-(4-vinyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

trans-N-(4-methyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine;

trans-N-(4-ethyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine;

trans-N-(4-vinyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine;

cis-N-(4-methyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

cis-N-(4-ethyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

cis-N-(4-vinyl-5-isoquinolyl)-N′

-(2-hydroxyethyl)-1,4-cyclohexanediamine;

cis-N-(4-methyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine;

cis-N-(4-ethyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine; and

cis-N-(4-vinyl-5-isoquinolyl)-N′

-(3-hydroxypropyl)-1,4-cyclohexanediamine.

29. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

4-(1-hydroxy-4-methyl-5-isoquinolyl)aminopiperidine;

4-(1-hydroxy-4-ethyl-5-isoquinolyl)aminopiperidine;

trans-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine;

trans-N-(1-hydroxy-4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine;

cis-N-(1-hydroxy-4-methyl-5-isoquinolyl)-1,4-cyclohexanediamine; and

cis-N-(1-hydroxy-4-ethyl-5-isoquinolyl)-1,4-cyclohexanediamine.

30. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;

N-[(5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine; and

N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine.

31. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;

N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylenediamine;

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine; and

N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenediamine.

32. The compound or salt thereof according to claim 1, wherein the compound of the formula (1) is selected from the group consisting of

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-ethylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine;

N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-ethylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3-propylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-ethylenediamine;

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethylenediamine; and

N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethyl-enediamine.

36. An inhibitor of the phosphorylation of myosin regulatory light chain, which comprises a compound represented by the formula (1) or a salt thereof according to claim 1.

37. An inhibitor of the Rho/Rho kinase pathway, which comprises a compound represented by the formula (1) or a salt thereof according to claim 1.

33. A medicament comprising a compound represented by the formula (1) or a physiologically acceptable salt thereof.

34. The medicament according to claim 33, which is used for prophylactic and/or therapeutic treatment of glaucoma.

35. The medicament according to claim 33, which is used for prophylactic and/or therapeutic treatment of bronchial asthma and/or chronic obstructive pulmonary disease.