Inhibitors of Rho associated protein kinases (ROCK) and methods of use

Patent metadata

Field	Value
Publication number	US-9808447-B2
Application number	US-201615231124-A
Country	US
Kind code	B2
Filing date	Aug 8, 2016
Priority date	Jan 24, 2012
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

Compounds and compositions having activity as inhibitors of Rho-associated proteinkinases (ROCKs), and methods of making and using the subject compounds are disclosed.

First claim

What is claimed is:

1. A method of reducing or inhibiting tumor growth in a subject with breast cancer, comprising: administering to the subject an effective amount of a composition comprising a compound having the chemical structure shown in Formula IV

wherein
R is H, alkyl, acetyl, or heteroalkyl;
R 1 is H, alkyl, acetyl, or heteroalkyl;
R 8 and R 9 are, independently of one another, H, —OH, acetyl, —C(O)NH 2 , alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl, wherein any one of the alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkoxy, alkyl, —OCX 3 , —OCHX 2 , —OCH 2 X, or halogen, or both R 8 together form a carbonyl; and
R 10 is cycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more of —OH, —C(O)NH 2 , —C(O)CH 3 , —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxyl, cycloalkyl, heterocycloalkyl, heteroarylcarbonyl, aryl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , or -tosyl;
R 6 and R 7 are, independently, H, alkyl, —SO 2 CH 3 , —C(O)CH 3 , or —C(O)NH 2 ;
X is independently H or halogen; and
n is 2 or 3,
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein n is 2.

3. The method of claim 1 , wherein R 8 and R 9 are, independently, H, alkyl, or alkyl substituted with —OH, —NH 2 , alkoxy, or halogen.

4. The method of claim 1 , wherein R 10 is an aryl or heteroaryl, any of which is optionally substituted in the ortho-, meta-, or para-position with —OH, —CO 2 CH 3 , —C(O)NH 2 , —NO 2 , —NH 2 , —NR 6 R 7 , alkoxy, alkylalkoxy, alkyl, —OSO 2 CH 3 , or tosyl.

5. The method of claim 1 , wherein the compound has the formula

6. The method of claim 1 , wherein the cancer is breast cancer.

7. The method of claim 1 , further comprising administering a second anticancer agent or an anti-inflammatory agent to the subject.

8. The method of claim 1 , further comprising administering Y27632, Wf536, Fasudil, H-1152P, and/or CID5056270 to the subject.

9. The method of claim 1 , further comprising administering an effective amount of ionizing radiation to the subject.

10. A method of reducing or inhibiting tumor growth in a subject with breast cancer, comprising: administering to the subject an effective amount of a composition comprising a compound having the chemical structure shown in Formula I

wherein
Z is CR or N;
R is H, alkyl, acetyl, or heteroalkyl;
R 1 is H, alkyl, acetyl, or heteroalkyl;
R 2 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or alkylaryl, any of which can be optionally substituted with one or more of —OH, —CH 2 OH, —C(O)NH 2 , acetyl, carbonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxy, heteroarylcarbonyl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , tosyl, or halogen; or
R 1 and R 2 can together form a cycloalkyl or heterocycloalkyl
R 6 and R 7 are, independently, H, alkyl, —SO 2 CH 3 , —C(O)CH 3 , or —C(O)NH 2 ;
X is independently H or halogen;
with the proviso that R and R 1 are not both H when R 2 is CH(CH 2 OH)Ph;
or a pharmaceutically acceptable salt or hydrate thereof.

11. The method of claim 10 , wherein the compound has the chemical structure shown in Formula III

wherein
R 8 and R 9 are, independently of one another, H, —OH, acetyl, —C(O)NH 2 , alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl, wherein any one of the alkyl, cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more of —OH, —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkoxy, alkyl, —OCX 3 , —OCHX 2 , —OCH 2 X, or halogen, or both R 8 together form a carbonyl; and
R 10 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more of —OH, —C(O)NH 2 , —C(O)CH 3 , —NO 2 , —NH 2 , —NR 6 R 7 , carbonyl, alkyl, alkoxy, alkylalkoxy, alkoxylalkoxy, halogenated alkoxyl, cycloalkyl, heterocycloalkyl, heteroarylcarbonyl, aryl, heteroaryl, —OCX 3 , —OCHX 2 , —OCH 2 X, —OSO 2 CH 3 , -tosyl, or halogen; and
n is 1, 2, or 3.

12. The method of claim 10 , wherein n is 1 or 2.

13. The method of claim 10 , wherein R 8 and R 9 are, independently, H, alkyl, or alkyl substituted with —OH, —NH 2 , alkoxy, or halogen.

14. The method of claim 10 , wherein n is 1, and CR 8 R 9 is the R isomer of CHalkyl, wherein the alkyl group is substituted with —OH, NH 2 , alkoxy, or halogen.

15. The method of claim 10 , wherein n is 1, and CR 8 R 9 is the S isomer of CHalkyl, wherein the alkyl group is substituted with —OH, NH 2 , alkoxy, or halogen.

16. The method of claim 10 , wherein R 10 is an aryl or heteroaryl, any of which is optionally substituted in the ortho-, meta-, or para-position with —OH, —CO 2 CH 3 , —C(O)NH 2 , —NO 2 , —NH 2 , —NR 6 R 7 , alkoxy, alkylalkoxy, alkyl, —OSO 2 CH 3 , tosyl, or halogen.

17. The method of claim 10 , wherein (CR 8 R 9 ) n R 10 have the combined structure:

18. The method of claim 10 , where the compound is

19. The method of claim 10 , further comprising administering a second anticancer agent or an anti-inflammatory agent to the subject.

20. The method of claim 10 , further comprising administering Y27632, Wf536, Fasudil, H-1152P, and/or CID5056270 to the subject.

21. The method of claim 10 , further comprising administering an effective amount of ionizing radiation to the subject.

Assignees

• H Lee Moffitt Cancer Ct & Res

Inventors

• Schonbrunn Ernst
• Li Rongshi
• Sebti Said M

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D213/40

  Acylated substituent nitrogen atom · CPC title

• C07D213/36

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title