Cytoskeletal active rho kinase inhibitor compounds, composition and use
View Patent ↗The present invention is directed to synthetic cytoskeletal active compounds that are inhibitors of rho-associated protein kinase. The present invention is also directed to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The invention is additionally directed to a method of preventing or treating diseases or conditions associated with cytoskeletal reorganization. In one embodiment of the invention, the method treats increased intraocular pressure, such as primary open-angle glaucoma. The method comprises administering to a subject a therapeutically effective amount of a cytoskeletal active compound of Formula I or Formula II, wherein said amount is effective to influence the actomyosin interactions, for example by leading to cellular relaxation and alterations in cell-substratum adhesions.
1. A compound of Formula II:
wherein:
Q is (CR 4 R 5 ) n3 ;
n 1 is 2;
n 2 is 1;
n 3 is 1, 2, or 3;
R 2 is 5-indazolyl;
Ar is a bicyclic heteroaryl selected from indole, benzofuran or benzothiophene;
X is from 1 to 3 substituents on Ar, and each is independently selected from the group consisting of OR 8 , NR 8 R 9 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , CONR 8 R 9 , NR 8 C(═O)R 9 , NR 8 C(═O)OR 9 , OC(═O)NR 8 R 9 , and NR 8 C(═O)NR 9 R 10 ,
R 3 is H;
R 4 is H;
R 5 is H or alkyl;
R 8 -R 10 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents selected from the group consisting of OR 11 , NR 11 R 12 ,NO 2 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , OCF 3 , CONR 11 R 12 , NR 11 C(═O)R 12 , NR 11 C(═O)OR 12 , OC(═O)NR 11 R 12 , and NR 11 C(═O)NR 12 R 13 ;
wherein any two of the groups R 8 , R 9 and R 10 are optionally joined with a link selected from the group consisting of bond, —O—, —S—, —SO—, —SO 2 —, and —NR 17 — to form a ring;
R 11 -R 13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle.
2. The compound according to claim 1 , wherein Q is CH 2 , and R 3 is H.
3. The compound according to claim 1 , wherein R 5 is H.
4. The compound of claim 1 , wherein R 8 is H, alkyl, arylalkyl, cycloalkylalkyl, optionally substituted with OR 11 , NR 11 SO 2 R 12 , or CONR 11 R 12 .
5. The compound of claim 1 , wherein Ar is indole.
6. The compound of claim 1 , wherein Ar is benzofuran.
7. The compound of claim 5 , wherein X is from 1 to 3 substituents on Ar, and one of X is OR 8 , or NR 8 SO 2 R 9 .
8. A method for reducing intraocular pressure in a subject in need thereof, comprising the steps of:
identifying a subject in need thereof, and
administering to the subject the compound according to claim 1 , in an amount effective to inhibit actomyosin interactions.
9. A compound of Formula II:
wherein:
Q is (CR 4 R 5 ) n3 ;
n 1 is 2;
n 2 is 1;
n 3 is 1, 2, or 3;
R 2 is 5-indazolyl;
Ar is a bicyclic heteroaryl selected from indole, benzofuran or benzothiophene;
X is from 1 to 3 substituents on Ar, each independently in the form Y—Z, in which Z is attached to Ar;
Y is one or more substituents on Z, and each is independently selected from the group consisting of H, halogen, OR 8 , NR 8 R 9 , NO 2 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , OCF 3 , CONR 8 R 9 , NR 8 C(═O)R 9 , NR 8 C(═O)OR 9 , OC(═O)NR 8 R 9 , and NR 8 C(═O)NR 9 R 10 ;
Z is alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, and (heterocycle)alkynyl;
R 3 is H;
R 4 is H;
R 5 is H or alkyl;
R 8 -R 10 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents selected from the group consisting of OR 11 , NR 11 R 12 , NO 2 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , OCF 3 , CONR 11 R 12 , NR 11 C(═O)R 12 , NR 11 C(═O)OR 12 , OC(═O)NR 11 R 12 , and NR 11 C(═O)NR 12 R 13 ;
wherein any two of the groups R 8 , R 9 and R 10 are optionally joined with a link selected from the group consisting of bond, —O—, —S—, —SO—, —SO 2 —, and —NR 17 — to form a ring; and
R 11 -R 13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle.
10. The compound of claim 9 , wherein Ar is indole or benzofuran.
11. The compound of claim 9 , wherein one of Y is halogen, OR 8 , or NR 8 SO 2 R 9 .
12. The compound of claim 9 , wherein R 8 is H, alkyl, arylalkyl, cycloalkylalkyl, optionally substituted with OR 11 , NR 11 SO 2 R 12 , or CONR 11 R 12 .
13. A method for reducing intraocular pressure in a subject in need thereof, comprising the steps of:
identifying a subject in need thereof, and
administering to the subject the compound according to claim 9 , in an amount effective to inhibit actomyosin interactions.
14. A compound of Formula II:
wherein:
Q is (CR 4 R 5 ) n3 ;
n 1 is 2;
n 2 is 1;
n 3 is 1, 2, or 3;
R 2 is 5-indazolyl;
Ar is a bicyclic heteroaryl selected from indole, benzofuran or benzothiophene;
X is from 1 to 3 substituents on Ar, each independently in the form Y—Z, in which Z is attached to Ar;
Y is one or more substituents on Z, and each is independently OR 8 , NR 8 R 9 , NO 2 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , OCF 3 , CONR 8 R 9 , NR 8 C(═O)R 9 , NR 8 C(═O)OR 9 , OC(═O)NR 8 R 9 , or NR 8 C(═O)NR 9 R 10 ,
Z is alkyl;
R 3 is H;
R 4 is H;
R 5 is H or alkyl;
R 8 -R 10 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents selected from the group consisting of OR 11 , NR 11 R 12 , NO 2 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , OCF 3 , CONR 11 R 12 , NR 11 C(═O)R 12 , NR 11 C(═O)OR 12 , OC(═O)NR 11 R 12 , and NR 11 C(═O)NR 12 R 13 ;
wherein any two of the groups R 8 , R 9 and R 10 are optionally joined with a link selected from the group consisting of bond, —O—, —S—, —SO—, —SO 2 —, and —NR 17 — to form a ring; and
R 11 -R 13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle.
15. The compound of claim 14 , wherein Ar is indole or benzofuran.
16. The compound of claim 14 , wherein one of Y is OR 8 , or NR 8 SO 2 R 9 .
17. The compound of claim 16 , wherein R 8 is H, alkyl, arylalkyl, cycloalkylalkyl, optionally substituted with OR 11 , NR 11 SO 2 R 12 , or CONR 11 R 12 .
18. The compound according to claim 14 , wherein said compound is Compound 1.099, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide; Compound 1.101, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl) -1H-indol-1-yl)ethanol; Compound 1.103, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetic acid; Compound 1.105, which is 2-(5-((3-(1H -indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide; Compound 1.106, which is (R)-2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide; Compound 1.107, which is (S)-2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide; Compound 1.108, which is (R)-2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethanol; Compound 1.109, which is (S)-2-(6-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethanol; Compound 1.112, which is tert-butyl 2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetate; Compound 1.114, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)ethanol; or Compound 1.119, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetic acid.
19. A method for reducing intraocular pressure in a subject in need thereof, comprising the steps of:
identifying a subject in need thereof, and
administering to the subject the compound according to claim 14 , in an amount effective to inhibit actomyosin interactions.
20. A compound selected from the group consisting of: Compound 1.100, which is N -(1-((1H-indol-5-yl)methyl)piperidin-3-yl)-1H-indazol-5-amine; Compound 1.131, which is (R)-N -(1-(benzofuran-5-ylmethyl)piperidin-3-yl)-1H-indazol-5-amine; or Compound 1.138, which is (R)-N-(1-(benzo[b]thiophen-5-ylmethyl)piperidin-3-yl)-1H-indazol-5-amine.