5-substituted isoquinoline derivatives Number:7,094,789 from the United States Patent and Trademark Office (PTO) owispatent A compound represented by the following formula (1) or a salt thereof: ##STR00001## wherein R.sup.1 represents hydrogen atom, a halogen atom and the like; R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group and the like; and R.sup.3 represents --O--X--C(A.sup.1)(A.sup.11)-C(A.sup.2)(A.sup.21)-N(A.sup.31)(A.sup.3) (X represents propylene group etc., A.sup.11 and A.sup.21 represent hydrogen atom, or a C.sub.1-6 alkyl group, A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A.sup.1, A.sup.2, and A.sup.3 represent hydrogen atom, a C.sub.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.<H isoquinoline, derivatives, 5, substituted, i, 7094789.html, Patent, pto, 7094789

Title: 5-substituted isoquinoline derivatives

Abstract: A compound represented by the following formula (1) or a salt thereof: ##STR00001## wherein R.sup.1 represents hydrogen atom, a halogen atom and the like; R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group and the like; and R.sup.3 represents --O--X--C(A.sup.1)(A.sup.11)-C(A.sup.2)(A.sup.21)-N(A.sup.31)(A.sup.3) (X represents propylene group etc., A.sup.11 and A.sup.21 represent hydrogen atom, or a C.sub.1-6 alkyl group, A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A.sup.1, A.sup.2, and A.sup.3 represent hydrogen atom, a C.sub.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.

Patent Number: 7,094,789 Issued on 08/22/2006 to Yamada, et al.

Inventors: Yamada; Rintaro (Fuji, JP), Seto; Minoru (Fuji, JP)
Assignee: Asahi Kasei Pharma Corporation (Tokyo, JP)

Appl. No.: 10/623,751

Filed: July 22, 2003

Foreign Application Priority Data


Jul 22, 2002 [JP]			2002-212053
Nov 12, 2002 [JP]			2002-327751

Current U.S. Class: 514/307 ; 514/310; 546/139; 546/143

Current International Class: C07D 217/02 (20060101); A61K 31/44 (20060101)

Field of Search: 546/139,143 514/307,310

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Primary Examiner: Davis; Zinna N.
Attorney, Agent or Firm: Birch, Stewart, Kolasch & Birch, LLP

Parent Case Text

This application claims priority on provisional Application No. 60/397,142 and 60/425,742 filed on Jul. 22, 2002 and Nov. 13, 2002, and claims priority under 35 U.S.C. .sctn. 119(a) based on Patent Application No(s). 2002-212053 and 2002-327751 filed in JAPAN on Jul. 22, 2002 and Nov. 12, 2002. The entire contents of all of these applications are hereby incorporated by reference.

Claims

What is claimed is:

1. A compound represented by the following formula (1) or a salt thereof: ##STR00052## wherein R.sup.1 represents hydrogen atom, a halogen atom, hydroxyl group, amino group, or a C.sub.1-6 alkoxyl group; R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), or cyano group; G.sup.1, G.sup.2, and G.sup.3 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; p represents an integer of from 0 to 2; R.sup.3 represents a group represented by the following formula (1-1), formula (1-2), or formula (1-3); ##STR00053## wherein (i) when R.sup.3 represents a group represented by the formula (1-1): R.sup.1 is hydrogen atom, hydroxyl group, or amino group; R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-8 alkylene )O(G.sup.1), a C.sub.2-8 alkenyl group, --S(O).sub.p(C.sub.1-6 alkyl), or cyano group; X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond; A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; and groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a 5- or 6-membered ring, provided that a group or groups among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group; (ii) when R.sup.3 represents a group represented by the formula (1-2): X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond; A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; R.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group; and A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; or groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 may bind to each other to form a 5- or 6-membered ring; and (iii) when R.sup.3 represents a group represented by the formula (1-3): Y represents a C.sub.2-6 alkylene group, a C.sub.2-6 alkylene group substituted with a C.sub.1-6 alkyl group, a C.sub.2-6 alkylene group substituted with phenyl group, a C.sub.2-6 alkylene group substituted with benzyl group, --(C.sub.1-6 alkylene)phenylene(C.sub.1-6 alkylene)-, 1,2-cyclohexylene group, or 1,3-cyclohexylene group; A.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group, or may binds to any one of carbon atoms of the alkylene moiety of Y to form a 4- to 7-membered ring; R.sup.5 represents --(C.sub.2-6 alkylene)(cycloalkyl), --(C.sub.2-6 alkylene)(aryl), --(C.sub.2-6 alkylene)(heteroaryl), --(C.sub.2-6 alkylene)S(O).sub.q(cycloalkyl), --(C.sub.2-6 alkylene)S(O).sub.q(aryl), --(C.sub.2-6 alkylene)S(O).sub.q(heteroaryl), --(C.sub.2-6 alkylene)N(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)N(G.sup.6)(aryl), --(C.sub.2-6 alkylene)N(G.sup.6)(heteroaryl), --(C.sub.2-6alkylene)CON(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)CON(G.sup.6)(aryl), or --(C.sub.2-6 alkylene)CON(G.sup.6)(heteroaryl); G.sup.6 represents hydrogen atom, or a C.sub.1-6 alkyl group; q represents an integer of from 0 to 2; wherein aryl is a phenyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C.sub.1-6 alkyl group, CF.sub.3 group, a C.sub.1-6 alkoxyl group, cyano group, --N(G.sup.7)(G.sup.8), --CO.sub.2(G.sup.9), --S(O).sub.r(G.sup.9), and --N(G.sup.9)SO.sub.2(C.sub.1-6 alkyl); G.sup.9 represents hydrogen atom, or a C.sub.1-6 alkyl group; G.sup.7 and G.sup.8 independently represents hydrogen atom, or a C.sub.1-6 alkyl group, or --N(G.sup.7)(G.sup.8) in said "aryl" as a whole may form a 4- to 7-membered ring which may contain oxygen atom, sulfur atom, or an N(G.sup.10) group, besides said nitrogen atom; G.sup.10 represents hydrogen atom, or a C.sub.1-6 alkyl group; wherein heteroaryl is selected from pyranyl, pyrazinyl, dioxolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl, and these groups may optionally be substituted with one or more substituents selected from the group consisting of a C.sub.1-6 alkyl group which may be substituted with a halogen atom, and a halogen atom; and r represents an integer of from 0 to 2.

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

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

4. The compound or salt thereof according to claim 3, wherein R.sup.3 is a group represented by a formula (1-2); X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond; A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; A.sup.31 is a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; R.sup.4 is hydrogen atom, or a C.sub.1-6 alkyl group; and groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a 5- or 6-membered ring provided that among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6, the group or groups not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group.

5. The compound or salt thereof according to claim 1, wherein the ring formed by groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 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 A.sup.3 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 claim 1, wherein X is --C(A.sup.5)(A.sup.51)-, or --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-.

7. The compound or salt thereof according to claim 2, wherein R.sup.3 is a group represented by the following formula (1-1-4) or formula (1-1-7) ##STR00054##

8. The compound or salt thereof according to claim 3, wherein R.sup.3 is a group represented by the following formula (1-2-4) or formula (1-2-7) ##STR00055##

9. The compound or salt thereof according to claim 1, wherein A.sup.31 is hydrogen atom.

10. The compound or salt thereof according to claim 1, wherein A.sup.31 is a C.sub.1-6 alkyl group substituted with hydroxyl group.

11. The compound or salt thereof according to claim 3, wherein R.sup.4 hydrogen atom.

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

13. The compound or salt thereof according to claim 12, wherein Y is a C.sub.2-4 alkylene.

14. The compound or salt thereof according to claim 12, wherein R.sup.5 is --(C.sub.2-4 alkylene)(aryl), --(C.sub.2-4 alkylene)(thienyl), --(C.sub.2-4 alkylene)SO.sub.2(aryl), or --(C.sub.2-4 alkylene)SO.sub.2(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.sub.1-6 alkyl group, CF.sub.3 group, a C.sub.1-6 alkoxyl group, cyano group, --N(G.sup.7)(G.sup.8), --CO.sub.2(G.sup.9), --S(O).sub.r(G.sup.9), and --N(G.sup.9)SO.sub.2(C.sub.1-6 alkyl), where G.sup.9 is hydrogen atom, or a C.sub.1-6 alkyl group, G.sup.7 and G.sup.8 independently represent hydrogen atom, or a C.sub.1-6 alkyl group, and r is an integer of 0 to 2.

15. The compound or salt thereof according to claim 1, wherein R.sup.1 is hydrogen atom, hydroxyl group, or amino group.

16. The compound or salt thereof according to claim 1, wherein R.sup.2 is hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-3 alkenyl group, a halogen atom, a --(C.sub.2-3 alkylene)O(G.sup.1)-, --S(O).sub.p(C.sub.1-6 alkyl), or cyano group.

17. The compound or salt thereof according to claim 1, wherein R.sup.2 is a C.sub.1-6 alkyl group, or cyano group.

18. The compound or salt thereof according to claim 1, wherein R.sup.1 is hydrogen atom, hydroxyl group, or amino group, and R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), a C.sub.2-3 alkenyl group, --S(O).sub.p(C.sub.1-6 alkyl), or cyano group.

19. The compound or salt thereof according to claim 7, wherein R.sup.1 is hydrogen atom, hydroxyl group, or amino group, R.sup.2 is a C.sub.1-6 alkyl group, a C.sub.2-3 alkenyl group, or cyano group, and R.sup.3 is a group represented by the formula (1-1-4) or formula (1-1-7).

20. The compound or salt thereof according to claim 8, wherein R.sup.1 is hydrogen atom, hydroxyl group, or amino group, R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), a C.sub.2-3 alkenyl group, or --S(O).sub.p(C.sub.1-6 alkyl), R.sup.3 is a group represented by the formula (1-2-4) or formula (1-2-7), and R.sup.4 is hydrogen atom.

21. The compound or salt thereof according to claim 8, wherein R.sup.1 is hydrogen atom, hydroxyl group, or amino group, R.sup.2 is a C.sub.1-6 alkyl group, or a C.sub.2-3 alkenyl group, R.sup.3 is a group represented by the formula (1-2-4) or formula (1-2-7), and R.sup.4 is hydrogen atom.

22. The compound or salt thereof according to claim 12, wherein R.sup.3 is a group represented by the formula (1-3), R.sup.1 is hydrogen atom, hydroxyl group, or amino group, R.sup.2 is hydrogen atom, or a C.sub.1-6 alkyl group, and R.sup.5 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]cyclohexyl-amine; 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-isoquin-olyl)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-hydroxy-ethyl)amino]cyclohexa- ne; trans-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohex- ane; trans-1-[(4-cyano-5-isoquin-olyl)oxy]-4-[(2-hydroxyethyl)amino]cycloh- exane; cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cycloh- exane; cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cyclohe- xane; and cis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(2-hydroxyethyl)amino]cycl- o-hexane.

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-isoquin-olyl)oxy]piperidine; 1-(3-hydroxypropyl)-4-[(4-ethyl-5-isoquinol-yl)oxy]piperidine; 1-(3-hydroxypropyl)-4-[(4-cyano-5-isoquinolyl)-oxy]piperidine; trans-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyclohexa- ne; trans-1-[(4-ethyl-5-isoquinolyl)-oxy]-4-[(3-hydroxypropyl)amino]cycloh- exane; trans-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cycl- ohexane; cis-1-[(4-methyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyc- lohexane; cis-1-[(4-ethyl-5-isoquinolyl)oxy]-4-[(3-hydroxypropyl)amino]cyc- lo-hexane; and cis-1-[(4-cyano-5-isoquinolyl)oxy]-4-[(3-hydroxy-propyl)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-isoquin-olyl)amino]piperidine; trans-N-(4-methyl-5-isoquinolyl)-1,4-cyclo-hexanediamine; trans-N-(4-ethyl-5-isoquinolyl)-1,4-cyclohexane-diamine; 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-isoquin-olyl)aminopiperidine; 1-(2-hydroxyethyl)-4-(4-ethyl-5-isoquinolyl)-aminopiperidine; 1-(2-hydroxyethyl)-4-(4-vinyl-5-isoquinolyl)amino-piperidine; 1-(3-hydroxypropyl)-4-(4-methyl-5-isoquinolyl)amino-piperidine; 1-(3-hydroxypropyl)-4-(4-ethyl-5-isoquinolyl)amino-piperidine; 1-(3-hydroxypropyl)-4-(4-vinyl-5-isoquinolyl)amino-piperidine; trans-N-(4-methyl-5-isoquinolyl)-N'-(2-hydroxyethyl)-1,4-cyclohexanediami- ne; trans-N-(4-ethyl-5-isoquinolyl)-N'-(2-hydroxyethyl)-1,4-cyclohexanedia- mine; trans-N-(4-vinyl-5-isoquin-olyl)-N'-(2-hydroxyethyl)-1,4-cyclohexane- diamine; trans-N-(4-methyl-5-isoquinolyl)-N'-(3-hydroxypropyl)-1,4-cyclohe- xanediamine; trans-N-(4-ethyl-5-isoquinolyl)-N'-(3-hydroxypropyl)-1,4-cyclo-hexanediam- ine; trans-N-(4-vinyl-5-isoquinolyl)-N'-(3-hydroxy-propyl)-1,4-cyclohexane- diamine; cis-N-(4-methyl-5-isoquinolyl)-N'-(2-hydroxyethyl)-1,4-cyclohexan- ediamine; cis-N-(4-ethyl-5-isoquin-olyl)-N'-(2-hydroxyethyl)-1,4-cyclohexa- nediamine; cis-N-(4-vinyl-5-isoquinolyl)-N'-(2-hydroxyethyl)-1,4-cyclohexa- nediamine; cis-N-(4-methyl-5-isoquinolyl)-N'-(3-hydroxypropyl)-1,4-cyclohe- xanediamine; cis-N-(4-ethyl-5-isoquinolyl)-N'-(3-hydroxypropyl)-1,4-cyclohexane-diamin- e; and cis-N-(4-vinyl-5-isoquinolyl)-N'-(3-hydroxypropyl)-1,4-cyclohexaned- iamine.

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)amino-piperidine; 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-carboxy-phenyl)propyl]-1,3-propylened- iamine; N-[(5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylenedi- amine; N-[(5-isoquinolyl)-sulfonyl]-N-[2-(phenylsulfonyl)ethyl]-1,3-propyl- enediamine; 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]ethylene-diamine; N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediam- ine; N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,- 3-propylenediamine; N-[(4-methyl-5-isoquin-olyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3-propylen- ediamine; N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]- -1,3-propylenediamine; N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenyl-propyl)ethylenediamine; N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethylen- ediamine; N-[(4-methyl-5-isoquin-olyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethy- lenediamine; and N-[(4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylene-- diamine.

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-propylenedia- mine; 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-propylen- ediamine; N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl- ]-1,3-propylenediamine; N-[(1-hydroxy-5-iso-quinolyl)sulfonyl]-N-(3-phenylpropyl)ethylenediamine; N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]ethyl-- enediamine; N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)-ethyl]ethylenediam- ine; N-[(1-hydroxy-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethy- lenediamine; N-[(1-amino-5-isoquinolyl)-sulfonyl]-N-(3-phenylpropyl)-1,3-propylenediam- ine; N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)propyl]-1,3- -propyl-enediamine; N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)-ethyl]-1,3-propylene- diamine; 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]ethyl-en- ediamine; N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)-ethyl]ethyl- enediamine; and N-[(1-amino-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]ethylenedi- amine.

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-pro- pylenediamine; N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)prop- yl]-1,3-propyl-enediamine; N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]-1,3- -propylenediamine; N-[(1-hydroxy-4-methyl-5-iso-quinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethy- l]-1,3-propylenedi-amine; N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-(3-phenyl-propyl)ethylen- ediamine; N-[(1-hydroxy-4-methyl-5-isoquinolyl)sul-fonyl]-N-[3-(3-carboxyp- henyl)propyl]ethylenediamine; N-[(1-hydroxy-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethy- lene-diamine; 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-propy- lenediamine; N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[3-(3-carboxyphenyl)-propy- l]-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)ethylenedi- amine; N-[(1-amino-4-methyl-5-isoquin-olyl)sulfonyl]-N-[3-(3-carboxyphenyl- )propyl]ethylenediamine; N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(2-thienyl)ethyl]ethyl-- enediamine; and N-[(1-amino-4-methyl-5-isoquinolyl)sulfonyl]-N-[2-(phenylsulfonyl)ethyl]e- thylenediamine.

33. The compound or salt thereof according to claim 1 wherein R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), or cyano group; and R.sup.3 represents a group represented by the formula (1-1) wherein X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond; and A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; and groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a saturated 6-membered ring, provided that a group or groups among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group.

34. The compound or salt thereof according to claim 1 wherein the groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 are groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, and A.sup.2 and A.sup.5.

35. The compound or salt thereof according to claim 1 wherein the groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 are groups in each of one or more combinations selected from the group consisting of combinations of, A.sup.3 and A.sup.5, and A.sup.2 and A.sup.5.

36. The compound or salt thereof according to claim 33 wherein R.sup.2 is a C.sub.1-6 alkyl group, a C.sub.2-3 alkenyl group, or cyano group.

37. The compound or salt thereof according to claim 34 wherein R.sup.2 is a C.sub.1-6 alkyl group, a C.sub.2-3 alkenyl group, or cyano group.

38. The compound or salt thereof according to claim 35 wherein R.sup.2 is a C.sub.1-6 alkyl group, a C.sub.2-3 alkenyl group, or cyano group.

39. The compound or salt thereof according to claim 1 wherein R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), or cyano group; and R.sup.3 represents a group represented by the formula (1-2), wherein X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond; A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; R.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group; and A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; or groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 may bind to each other to form a 5- or 6-membered ring.

40. The compound or salt thereof according to claim 1 wherein groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a 5- or 6-membered ring, provided that a group or groups among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group.

41. The compound or salt thereof according to claim 1 wherein the 5- or 6-membered ring is a saturated 6-membered ring.

42. The compound or salt thereof according to claim 1 wherein the groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 are groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, and A.sup.2 and A.sup.5.

43. The compound or salt thereof according to claim 1 wherein the groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 are groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.5, and A.sup.2 and A.sup.5.

44. The compound or salt thereof according to claim 1 wherein R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), a C.sub.2-3 alkenyl group, or --S(O).sub.p(C.sub.1-6 alkyl).

45. The compound or salt thereof according to claim 1 wherein R.sup.2 is a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), a C.sub.2-3 alkenyl group, or --S(O).sub.p(C.sub.1-6 alkyl).

46. The compound or salt thereof according to claim 1 wherein R.sup.2 is a halogen atom.

47. The compound or salt thereof according to claim 1 wherein R.sup.2 is a halogen atom.

48. The compound or salt thereof according to claim 1 wherein R.sup.2 is a halogen atom.

49. The compound or salt thereof according to claim 1 wherein R.sup.8 is a group represented by the formula (1-2) or the formula (1-3).

50. A pharmaceutical composition comprising a compound represented by the formula (1) according to claim 1 or a physiologically acceptable salt thereof.

Description

TECHNICAL FIELD

The present invention relates to a novel 5-substituted isoquinoline derivative or a salt thereof, and a medicament comprising said 5-substituted isoquinoline derivative or a salt thereof as an active ingredient.

BACKGROUND ART

Movements of cells includes contraction, migration, release, aggregation and the like, and phosphorylation of the myosin regulatory light chain is important for these cell movements. The myosin regulatory light chain is a subunit having a molecular weight of 20 kDa and constituting myosin, which exists in smooth muscle cells and various non-muscle cells such as neutrophils, leukocytes, platelets and nerve cells of warm-blooded animals (Barany, K., et al., Biochemistry of Smooth Muscle Contraction, pp. 21 35, 1996). Myosin existing in smooth muscle cells and various non-muscle cells such as neutrophils, leukocytes, platelets and nerve cells of warm-blooded animals is constituted by a myosin heavy chain subunit having a molecular weight of about 200 kDa, the myosin regulatory light chain subunit having a molecular weight of about 20 kDa, and a myosin constitutive light chain subunit having a molecular weight of about 17 kDa. The myosin regulatory light chain is mainly phosphorylated by the myosin light chain kinase to increase the activity of myosin ATPase existing in the myosin heavy chain subunit (Barany, M., et al., Biochemistry of Smooth Muscle Contraction, pp. 321 339, 1996). It is known that the activated myosin having the increased ATPase activity becomes possible to interact with actin and activates movement apparatuses of cytoskeleton to activate cell movements.

That is, it is known that activation of myosin relates to cell contraction (Kamm, K., et al., Annu. Rev. Physiol., 51, pp. 299 313, 1989). It is also known that activation of myosin relates to change of cell morphology (Schmidt, J. T. et al., J, Neurobiol., 52 (3), pp. 175 188, 2002). It is known that activation of myosin relates to cell migration (Niggli, V., FEBS Lett., 445, pp. 69 72, 1999), and it is also known that activation of myosin relates to cell release (Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp. 48 54, 1992). It is further known that activation of myosin relates to cell aggregation (Itoh, K., et al., Biochim. Biophys. Acta., 1136, pp. 52 56, 1992), and it is also known that activation of myosin relates to cell apoptosis (Mills, J. C. et al., J. Cell Biol., Vol. 140, No. 3, pp. 627 636, 1998).

Based on these findings, it is considered that an agent which inhibits the phosphorylation of the myosin regulatory light chain suppresses cell contraction, regulates change of cell morphology, suppresses cell migration, suppresses cell release, suppresses cell aggregation and suppresses cell apoptosis.

Cell contraction is deeply involved in diseases relating to contraction of various smooth muscle layers. Examples of such diseases include, for example, hypertension (A. P. Samlyo et al., Rev. Physiol. Biochem. Pharmacol., Vol. 134, pp. 209 34, 1999), angina pectoris (Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp. 1029 39, 1999; Satoh, H., et al., Jpn. J. Pharmacol., 79 (suppl.), p. 211, 1999), cerebral vascular spasm (M. Satoh et al., the 57th General Meeting of Japan Neurosurgical Society, Collection of Abstracts, 153, 1998; N. Ono et al., Pharmacol. Ther., Vol. 82, No. 2 3, pp. 123 31, 1991; Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp. 1029 39, 1999), erectile dysfunction (Andersson, K E. et al., World J. Vrol., 15, pp. 14 20, 1997), bronchial asthma (K. Iidzuka, Allergy, 47, 943, 1998; K. Iidzuka et al., Jpn. J. Respirology Society, 37, 196, 1999) and the like.

Change of cell morphology is deeply involved in diseases relating to morphological change of various cells. Examples of the diseases relating to change of cell morphology include, for example, various nerve dysfunctions as those relating to nerve cells. As the nerve dysfunctions, for example, neural damages caused by trauma, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and diabetic retinopathy and the like can be exemplified (Arakawa, Y., et al., BIO Clinica, 17 (13), pp. 26 28, 2002).

Cell migration is deeply involved in diseases relating to migration of various cells. Examples of such diseases include, for example, cancer invasion and metastasis (Itoh, K. et al., Nat. Med., Vol. 5, No. 2, pp. 221 5, 1999; Keely, P. et al., Trends Cell Biol., Vol. 8, No. 3, pp. 101 6, 1998), nephritis (Fujimoto, O. et al., Journal of Japanese Society of Internal Medicine, 88 (1), pp. 148 58, 1998) and the like.

Furthermore, it is considered that cell release is deeply involved in various allergies and the like (Keane-Myers A. et al., Curr. Allergy Asthma Rep., 1(6):550 557, 2001), and cell aggregation is considered to be deeply involved in thrombosis and the like (Nakai, K. et al., Blood, Vol. 90, No. 10, pp. 3736 42, 1997). Further, it is known that cell apoptosis is involved in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, viral diseases, hepatic diseases and the like (Thompson, C. B., Science, Vol. 267, pp. 1456 1462, 1995).

Based on these findings, it is considered that the inhibitor of the phosphorylation of myosin regulatory light chain of the present invention, which is an agent inhibiting the phosphorylation of the myosin regulatory light chain, is useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis.

It has been reported that 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), which is an isoquinoline derivative, inhibits phosphorylation of the myosin regulatory light chain of mesenteric artery (Suzuki, A. et al., Br. J. Pharmacol., 109, pp. 703 712, 1993), iris smooth muscle cell (Howe, P. H. et al., Biochem J., 255, pp. 423 429, 1988), and astrocyte (Mobley P. L., et al., Exp. Cell Res., 214, pp. 55 66, 1994).

DISCLOSURE OF THE INVENTION

Conventionally, it has been desired to provide a novel compound having an action of strongly inhibiting the phosphorylation of myosin regulatory light chain.

The inventors of the present invention direct their attentions to the physiological functions of isoquinoline derivatives, and synthesized various isoquinoline derivatives and studied pharmacological actions thereof. As a result, it was found that the compounds represented by the following formula (1) and salts thereof had the desired pharmacological action, and were useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of diseases relating to cell contraction, those relating to change of cell morphology, those relating to cell migration, those relating to cell release, those relating to cell aggregation, and those relating to cell apoptosis. The present invention was achieved on the basis of these findings.

The present invention thus provides a compound represented by the following formula (1) or a salt thereof:

##STR00002## wherein R.sup.1 represents hydrogen atom, a halogen atom, hydroxyl group, amino group, or a C.sub.1-6 alkoxyl group;

R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), or cyano group;

G.sup.1, G.sup.2, and G.sup.3 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

p represents an integer of from 0 to 2;

R.sup.3 represents a group represented by the following formula (1-1), formula (1-2), or formula (1-3);

##STR00003## wherein (i) when R.sup.3 represents a group represented by the formula (1-1):

X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond;

A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom; and

groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a 5- or 6-membered ring, provided that a group or groups among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group; (ii) when R.sup.3 represents a group represented by the formula (1-2):

X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond;

A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.31 represents a C.sub.1-6 alkyl group substituted with hydroxyl group, or hydrogen atom;

R.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group; and

A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; or

groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 may bind to each other to form a 5- or 6-membered ring; or (iii) when R.sup.3 represents a group represented by the formula (1-3):

Y represents a C.sub.2-6 alkylene group, a C.sub.2-6 alkylene group substituted with a C.sub.1-6 alkyl group, a C.sub.2-6 alkylene group substituted with phenyl group, a C.sub.2-6 alkylene group substituted with benzyl group, --(C.sub.1-6 alkylene)phenylene(C.sub.1-6 alkylene)-, 1,2-cyclohexylene group, or 1,3-cyclohexylene group;

A.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group, or may binds to any one of carbon atoms of the alkylene moiety of Y to form a 4- to 7-membered ring;

R.sup.5 represents --(C.sub.2-6 alkylene)(cycloalkyl), --(C.sub.2-6 alkylene)(aryl), --(C.sub.2-6 alkylene)(heteroaryl), --(C.sub.2-6 alkylene)S(O).sub.q(cycloalkyl), --(C.sub.2-6 alkylene)S(O).sub.q(aryl), --(C.sub.2-6 alkylene)S(O).sub.q(heteroaryl), --(C.sub.2-6 alkylene)N(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)N(G.sup.6)(aryl), --(C.sub.2-6 alkylene)N(G.sup.6)(heteroaryl), --(C.sub.2-6 alkylene)CON(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)CON(G.sup.6)(aryl), or --(C.sub.2-6 alkylene)CON(G.sup.6)(heteroaryl);

G.sup.6 represents hydrogen atom, or a C.sub.1-6 alkyl group;

q represents an integer of from 0 to 2;

said "aryl" is a phenyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C.sub.1-6 alkyl group, CF.sub.3 group, a C.sub.1-6 alkoxyl group, cyano group, --N(G.sup.7)(G.sup.8), --CO.sub.2(G.sup.9), --S(O).sub.r(G.sup.9), and --N(G.sup.9)SO.sub.2(C.sub.1-6 alkyl);

G.sup.9 represents hydrogen atom, or a C.sub.1-6 alkyl group;

G.sup.7 and G.sup.8 independently represents hydrogen atom, or a C.sub.1-6 alkyl group, or --N(G.sup.7)(G.sup.8) in the (aryl) as a whole may form a 4- to 7-membered ring which may contain oxygen atom, sulfur atom, or an N(G.sup.10) group, besides said nitrogen atom;

G.sup.10 represents hydrogen atom, or a C.sub.1-6 alkyl group;

said "heteroaryl" is selected from pyranyl, pyrazinyl, dioxolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl, and these groups may be substituted with one or more substituents selected from the group consisting of a C.sub.1-6 alkyl group which may optionally be substituted with a halogen atom, and a halogen atom; and

r represents an integer of from 0 to 2.

The present invention also provides a compound represented by the aforementioned formula (1) or a salt thereof, wherein

R.sup.1 represents hydrogen atom, a halogen atom, hydroxyl group, amino group, or a C.sub.1-6 alkoxyl group;

R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), or --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl);

G.sup.1, G.sup.2, and G.sup.3 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

p represents an integer of from 0 to 2;

R.sup.3 represents a group represented by the formula (1-1), formula (1-2), or formula (1-3);

wherein

(i) when R.sup.3 represents a group represented by the formula (1-1):

X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond;

A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.31 represents hydrogen atom; and

groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 bind to each other to form a 5- or 6-membered ring, provided that a group or groups among A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 not involved in the ring formation independently represent hydrogen atom, or a C.sub.1-6 alkyl group; (ii) when R.sup.3 represents a group represented by the formula (1-2):

X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond;

A.sup.11, A.sup.21, A.sup.51, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.31 represents hydrogen atom;

R.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group; and

A.sup.1, A.sup.2, A.sup.3, A.sup.5, and A.sup.6 independently represent hydrogen atom, or a C.sub.1-6 alkyl group; or

groups in each of one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 may bind to each other to form a 5- or 6-membered ring; or (iii) when R.sup.3 represents a group represented by the formula (1-3):

Y represents a C.sub.2-6 alkylene group, a C.sub.2-6 alkylene group substituted with a C.sub.1-6 alkyl group, a C.sub.2-6 alkylene group substituted with phenyl group, a C.sub.2-6 alkylene group substituted with benzyl group, --(C.sub.1-6 alkylene)phenylene(C.sub.1-6 alkylene)-, 1,2-cyclohexylene group, or 1,3-cyclohexylene group;

A.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group, or may binds to any one of carbon atoms of the alkylene moiety of Y to form a 4- to 7-membered ring;

R.sup.5 represents --(C.sub.2-6 alkylene)(cycloalkyl), --(C.sub.2-6 alkylene)(aryl), --(C.sub.2-6 alkylene)(heteroaryl), --(C.sub.2-6 alkylene)S(O).sub.q(cycloalkyl), --(C.sub.2-6 alkylene)S(O).sub.q(aryl), --(C.sub.2-6 alkylene)S(O).sub.q(heteroaryl), --(C.sub.2-6 alkylene)N(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)N(G.sup.6)(aryl), --(C.sub.2-6 alkylene)N(G.sup.6)(heteroaryl), --(C.sub.2-6 alkylene)CON(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)CON(G.sup.6)(aryl), or --(C.sub.2-6 alkylene)CON(G.sup.6)(heteroaryl);

G.sup.6 represents hydrogen atom, or a C.sub.1-6 alkyl group;

q represents an integer of from 0 to 2;

said "aryl" is a phenyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C.sub.1-6 alkyl group, CF.sub.3 group, a C.sub.1-6 alkoxyl group, cyano group, --N(G.sup.7)(G.sup.8), --CO.sub.2(G.sup.9), --S(O).sub.r(G.sup.9), and --N(G.sup.9)SO.sub.2(C.sub.1-6 alkyl);

G.sup.9 represents hydrogen atom, or a C.sub.1-6 alkyl group;

G.sup.7 and G.sup.8 independently represents hydrogen atom, or a C.sub.1-6 alkyl group, or --N(G.sup.7)(G.sup.8) in the (aryl) as a whole may form a 4- to 7-membered ring which may contain oxygen atom, sulfur atom, or an N(G.sup.10) group, besides said nitrogen atom;

G.sup.10 represents hydrogen atom, or a C.sub.1-6 alkyl group;

said "heteroaryl" is selected from pyranyl, pyrazinyl, dioxolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl, and these groups may be substituted with one or more substituents selected from the group consisting of a C.sub.1-6 alkyl group which may optionally be substituted with a halogen atom, and a halogen atom; and

r represents an integer of from 0 to 2.

The present invention further provides a compound represented by the aforementioned formula (1) or a salt thereof, wherein

R.sup.1 represents hydrogen atom, a halogen atom, hydroxyl group, amino group, or a C.sub.1-6 alkoxyl group;

R.sup.2 represents hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, --(C.sub.2-3 alkylene)O(G.sup.1), --(C.sub.2-3 alkylene)CO.sub.2(G.sup.1), --N(G.sup.2)(G.sup.3), --O(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)O(G.sup.1), --NH(C.sub.2-3 alkylene)N(G.sup.2)(G.sup.3), a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, a C.sub.1-6 alkoxyl group, --(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl), --S(O).sub.p(C.sub.1-6 alkyl), or --O(C.sub.2-3 alkylene)SO.sub.2(C.sub.1-6 alkyl);

G.sup.1, G.sup.2, and G.sup.3 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

p represents an integer of from 0 to 2;

R.sup.3 represents a group represented by the formula (1-1), formula (1-2), or formula (1-3);

wherein

A.sup.1, A.sup.11, A.sup.2, and A.sup.21 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.3 represents hydrogen atom, or a C.sub.1-6 alkyl group;

A.sup.31 represents hydrogen atom;

X represents propylene group, butylene group, --C(A.sup.5)(A.sup.51)-, --C(A.sup.5)(A.sup.51)-C(A.sup.6)(A.sup.61)-, or a single bond;

A.sup.5, A.sup.51, A.sup.6, and A.sup.61 independently represent hydrogen atom, or a C.sub.1-6 alkyl group;

alkyl groups represented by two of groups included in one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, A.sup.3 and A.sup.6, A.sup.2 and A.sup.1, A.sup.2 and A.sup.5, A.sup.2 and A.sup.6, A.sup.1 and A.sup.5, A.sup.1 and A.sup.6, and A.sup.5 and A.sup.6 may bind to each other to form a 5- or 6-membered ring;

R.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group;

Y represents a C.sub.2-6 alkylene group, a C.sub.2-6 alkylene group substituted with a C.sub.1-6 alkyl group, a C.sub.2-6 alkylene group substituted with phenyl group, a C.sub.2-6 alkylene group substituted with benzyl group, --(C.sub.1-6 alkylene)phenylene(C.sub.1-6 alkylene)-, 1,2-cyclohexylene group, or 1,3-cyclohexylene group;

A.sup.4 represents hydrogen atom, or a C.sub.1-6 alkyl group, or may binds to any one of carbon atoms of the alkylene moiety of Y to form a 4- to 7-membered ring;

R.sup.5 represents --(C.sub.2-6 alkylene)(cycloalkyl), --(C.sub.2-6 alkylene)(aryl), --(C.sub.2-6 alkylene)(heteroaryl), --(C.sub.2-6 alkylene)S(O).sub.q(cycloalkyl), --(C.sub.2-6 alkylene)S(O).sub.q(aryl), --(C.sub.2-6 alkylene)S(O).sub.q(heteroaryl), --(C.sub.2-6 alkylene)N(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)N(G.sup.6)(aryl), --(C.sub.2-6 alkylene)N(G.sup.6)(heteroaryl), --(C.sub.2-6 alkylene)CON(G.sup.6)(cycloalkyl), --(C.sub.2-6 alkylene)CON(G.sup.6)(aryl), or --(C.sub.2-6 alkylene)CON(G.sup.6)(heteroaryl);

G.sup.6 represents hydrogen atom, or a C.sub.1-6 alkyl group;

q represents an integer of from 0 to 2;

said "aryl" is a phenyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C.sub.1-6 alkyl group, CF.sub.3 group, a C.sub.1-6 alkoxyl group, cyano group, --N(G.sup.7)(G.sup.8), --CO.sub.2(G.sup.9), --S(O).sub.r(G.sup.9), and --N(G.sup.9)SO.sub.2(C.sub.1-6 alkyl);

G.sup.9 represents hydrogen atom, or a C.sub.1-6 alkyl group;

G.sup.7 and G.sup.8 independently represents hydrogen atom, or a C.sub.1-6 alkyl group, or --N(G.sup.7)(G.sup.8) in said "aryl" as a whole may form a 4- to 7-membered ring which may contain oxygen atom, sulfur atom, or an N(G.sup.10) group, besides said nitrogen atom;

G.sup.10 represents hydrogen atom, or a C.sub.1-6 alkyl group;

said "heteroaryl" is selected from pyranyl, pyrazinyl, dioxolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl, and these groups may optionally be substituted with one or more substituents selected from the group consisting of a C.sub.1-6 alkyl group which may be substituted with a halogen atom, and a halogen atom; and

r represents an integer of from 0 to 2, provided that, when R.sup.1 and R.sup.2 are hydrogen atoms, and R.sup.3 is a group represented by the formula (1-1), A.sup.3 is not hydrogen atom or a C.sub.1-6 alkyl group, and the alkyl groups represented by two of groups included in one or more combinations selected from the group consisting of combinations of A.sup.3 and A.sup.2, A.sup.3 and A.sup.1, A.sup.3 and A.sup.5, and A.sup.3 and A.sup.6 bind to each other to form a 5- or 6-membered ring.

From another aspect, the present invention provides a medicament containing a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient. The aforementioned medicament has an inhibitory action on phosphorylation of myosin regulatory light chain, and is useful as a medicament for prophylactic and/or therapeutic treatment of, for example, a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis, and the like.

More specifically, there are provided a medicament for decreasing phosphorylation amount of myosin regulatory light chain in a cell, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell contraction inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having an action to regulate change of cell morphology, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell migration inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell release inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell aggregation inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell apoptosis inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, and a medicament for inhibiting the Rho/Rho kinase pathway, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient.

The present invention also provides an inhibitor of the phosphorylation of myosin regulatory light chain containing a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof, and an inhibitor of the Rho/Rho kinase pathway comprising a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof.

From another aspect, the present invention provides use of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof for manufacture of the aforementioned medicaments. The present invention also provides a method for prophylactic and/or therapeutic treatment of a disease relating to