SMALL MOLECULE RAC OR RHO INHIBITORS

• US 20170112896A1
• Filed: 05/19/2015
• Published: 04/27/2017
• Est. Priority Date: 05/20/2014
• Status: Abandoned Application

• Current Assignee: Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: Ohio State Innovation Foundation (Ohio State University)
• Inventors: BRIESEWITZ, Roger
• Application Number:
  US15/312,590
• Publication Number:
  US 20170112896A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2039/627 characterised by the linker
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/01 Hydrocarbons
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/012 from animals
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Disclosed herein are methods of inhibiting Rac or Rho in a cell or tissue or for treating a disease mediated at least in part by Rac or Rho, using a compound of the formula:

Claims

1. A method of inhibiting Rac or Rho in a cell or tissue and/or for treating a disease mediated at least in part by Rac or Rho, comprising administering to a cell, a tissue or a patient in need of Rac or Rho inhibition, a therapeutically effective amount of a compound of formula A

4. The method of claim 1, wherein R¹, R² and R⁴ are independently selected from the group consisting of C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁰, wherein R²⁰ is —

NH₂, —

NHC(═

NH)NH₂, —

NHR³⁰ or —

NHC(═

NH)NHR³⁰, and wherein R³⁰ is a fluorescent label, provided that only one of R¹, R² and R⁴ is C₁-C₆ alkyl.

5. The method of claim 4, wherein R¹, R² and R⁴ are independently selected from

—

CH₃, —

(CH₂)₃NHC(NH)NH₂, —

(CH₂)₃NHC(NH)NHR³⁰, —

(CH₂)₄NH₂ and —

(CH₂)₄NHR³⁰.

6. The method of claim 4, wherein R³⁰ is

7. The method of claim 1, wherein R³ is —

(CH₂)_p-L³-R²³, wherein p is 0, 1, 2 or 3, L³ is a covalent bond, C(O)NH or NHC(O), and R²³ is phenyl or naphthyl.

8. The method of claim 1, wherein R⁵ is —

(CH₂)_p-L⁵-R²⁵, wherein p is 0, 1, 2 or 3, L⁵ is a covalent bond, C(O)NH or NHC(O), and R²⁵ is phenyl or pyridyl, wherein the phenyl and pyridyl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH.

9. The method of claim 1, wherein R⁶ is selected from the group consisting of H, phenyl, C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁶, wherein R²⁶ is selected from the group consisting of NH₂, C(O)NH₂, NHC(═

NH)NH₂, and NH-L⁶-R³⁶, wherein L⁶ is a covalent bond, C(O), C(O)CH═

CH, C(O)NH or C(S)NH, and R³⁶ is selected from the group consisting of pheny, pyridyl, or a fluorescent label, wherein the phenyl or pyridyl are optionally substituted with 1 to 3 halo.

10. The method of claim 1, wherein R⁷ is —

(CH₂)_q-L⁷-R²⁷, wherein q is 0, 1, 2 or 3, L⁷ is a covalent bond, C(O)NH or NHC(O), and R²⁷ is H, OH, C(O)NH₂, heteroaryl, phenyl or naphthyl, wherein the heteroaryl, phenyl or naphthyl is optionally substituted with 1 to 3 substituents independently selected from halo and OH; and

wherein R⁷ is optionally selected from the group consisting of —

CH₃, —

CH₂Ph, —

CH₂Ph(4-fluoro), —

CH₂Ph(4-OH), —

CH₂-indolyl, —

CH₂OH, —

CH₂CH₂C(O)NH₂, —

CH₂-naphthyl, —

CH₂CH₂C(O)NH₂ and —

CH₂C(O)NH₂.

12. The method of claim 1, wherein R⁸ is selected from the group consisting of H, phenyl, C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁸, wherein R²⁸ is selected from the group consisting of OH, phenyl, naphthyl, heteroaryl, NH₂, NHC(═

NH)NH₂, and NH-L⁸-R³⁸, wherein the phenyl, naphthyl, and heteroaryl are optionally substituted with 1 to 3 halo or aralkyl;

L⁸ is a covalent bond, C(O), C(O)CH═

CH, C(O)NH, NHC(O)CH═

CH, or C(S)NH, and R³⁸ is selected from the group consisting of H, alkyl, phenyl, pyridyl, or a fluorescent label, wherein the phenyl or pyridyl are optionally substituted with 1 to 3 halo; and

wherein R⁸ is optionally selected from the group consisting of H, phenyl, n-butyl, isobutyl, —

CH₂-indolyl, —

(CH₂)₃NHC(═

NH)NH₂, —

CH₂C(O)NH₂,

—

(CH₂)₂COOH,

14. The method of claim 1, wherein R⁹ is —

(CH₂)_p-L⁹-R²⁹, wherein p is 0, 1, 2 or 3, L⁹ is a covalent bond, C(O)NH or NHC(O), and R²⁹ is H, OH, aryl or heteroaryl, wherein the aryl or heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH; and

wherein R⁹ is optionally selected from the group consisting of C₁-C₃ alkyl, —

C(CH)₃, —

CH₂OH, and —

CH(CH₂)OH.

15. The method of claim 1, wherein R²⁹ is selected from the group consisting of OH, phenyl, imidazole and pyridyl, and wherein the phenyl, imidazole and pyridyl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH.

17. The method of claim 1, wherein R¹⁰ is H or C₁-C₆ alkyl.

18. The method of claim 1, wherein R¹¹ is —

(CH₂)_p—

R⁴¹, wherein p is 0, 1, 2 or 3, and R⁴¹ is C(O)NH₂, NHC(═

NH)NH₂, C(O)NHR⁴², NHC(═

NH)NHR⁴², and wherein R⁴² is an amino acid residue; and

wherein R¹¹ is optionally —

CH₂CH₂C(O)NH₂, —

(CH₂)₃—

NHC(NH)NH₂, —

CH₂CH₂C(O)NHR⁴², or —

(CH₂)₃—

NHC(═

NH)NH—

R⁴², wherein R⁴² is optionally a norleucine residue, a lysine residue or an arginine residue.

20. The method of claim 1, wherein the compound of formula A is a compound selected from Table 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 1, wherein the compound of formula A is conjugated to an antibody.

22. The method of claim 21 wherein the antibody is a monoclonal antibody or a biologically active fragment or derivative of each thereof, that specifically binds EGFR.

23. The method of claim 1, wherein the compound of formula A is administered as a composition, and optionally, in combination with a pharmaceutically acceptable carrier.

24. A kit comprising the compound of formula A as defined in claim 1 and instructions for use in the method of claim 1.

2. A method of inhibiting Rac or Rho in a cell or tissue and/or for treating a disease mediated at least in part by Rac or Rho, comprising administering to a cell, a tissue or a patient in need of Rac or Rho inhibition, a therapeutically effective amount of a compound of formula I, II or III:

3. A method of inhibiting Rac or Rho in a cell or tissue and/or for treating a disease mediated at least in part by Rac or Rho, comprising administering to a cell, a tissue or a patient in need of Rac or Rho inhibition, a therapeutically effective amount of a compound of formula IB, BB, IIIB, IVB, VB or VIB:

11. (canceled)

13. (canceled)

16. (canceled)

19. (canceled)