COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS

• US 20090209573A1
• Filed: 10/28/2005
• Published: 08/20/2009
• Est. Priority Date: 10/28/2004
• Status: Abandoned Application

• Current Assignee: IRM LLC, The Scripps Research Institute
• Original Assignee: IRM LLC, The Scripps Research Institute
• Inventors: Schultz, Peter G., Wu, Xu, Ding, Sheng
• Application Number:
  US11/718,226
• Publication Number:
  US 20090209573A1
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.

Claims

1. A method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with a compound of Formula I:

in which

n is selected from 0, 1, 2 and 3;

Y is selected from NR₄ and S(O)_0-2;

wherein R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

L is selected from -Z-NR₅—

, -Z-NR₅C(O)— and

—

C(O)NR₅N═

CH—

;

wherein R₅ is selected from hydrogen and C_1-4alkyl;

wherein Z is C_5-10heteroaryl;

R₁ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl, halo-substituted-C_1-4alkoxy and —

NHC(O)R₅;

wherein R₅ is selected from hydrogen and C_1-4alkyl;

or R₁ and R₄ together with the atoms to which R₁ and R₄ are attached form imidazo[1,2-a]pyridine optionally substituted with 1 to 3 independently selected R₆ radicals;

wherein R₆ is selected from C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

R₂ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

R₃ is selected from hydrogen, hydroxy, halo, cyano, nitro, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl, halo-substituted-C_1-4alkoxy, —

NR₅C(O)R₅ and —

NR₅R₅—

;

wherein R₅ is independently selected from hydrogen and C_1-4alkyl; and

the pharmaceutically acceptable salts, hydrates, solvates and isomers thereof.

2. The method of claim 1 in which the compound is selected from formulae Ia, Ib, Ic and Id:

in which m is selected from 0, 1 and 2.

3. The method of claim 2 in which the compound is selected from:

N-[2-(4-ethoxy-phenylamino)-4′

-methyl-[4,5′

]bithiazolyl-2′

-yl]-propionamide;

N-[2-(4-methoxy-phenylamino)-4′

-methyl-[4,5′

]bithiazolyl-2′

-yl]-propionamide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (4-methoxy-benzylidene)-hydrazide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (4-methyl-benzylidene)-hydrazide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (3-hydroxy-4-methoxy-benzylidene)-hydrazide;

[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-(4-ethoxy-phenyl)-amine;

4-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenol;

[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-(2,4-dimethyl-phenyl)-amine;

(4-chloro-phenyl)-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

(2,4-dibromo-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

(2,4-dimethyl-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

N-{4-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenyl}-acetamide;

4-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenol;

N-{4-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenyl}-acetamide;

(4-chloro-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine; and

N-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-benzamide.

4. The method of claim 1 wherein the cell has a phenotype of Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function.

5. The method of claim 1 wherein the cell is contacted with the hedgehog antagonist in vivo or in vitro.

6. The method of claim 1 wherein the compound is administered to an animal as part of a therapeutic application.

7. The method of claim 7 wherein the therapeutic application is selected from pancreatic cancer, prostrate cancer, medulloblastoma, basal cell carcinoma and small-cell lung cancer.

8. A method for inhibiting unwanted proliferation of a cell, comprising contacting the cell with a compound of Formula I:

in which

n is selected from 0, 1, 2 and 3;

Y is selected from NR₄ and S(O)_0-2;

wherein R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

L is selected from -Z-NR₅—

, -Z-NR₅C(O)— and

—

C(O)NR₅N═

CH—

;

wherein R₅ is selected from hydrogen and C_1-4alkyl;

wherein Z is C_5-10heteroaryl;

R₁ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl, halo-substituted-C_1-4alkoxy and —

NHC(O)R₅;

wherein R₅ is selected from hydrogen and C_1-4alkyl;

or R₁ and R₄ together with the atoms to which R₁ and R₄ are attached form imidazo[1,2-a]pyridine optionally substituted with 1 to 3 independently selected R₆ radicals;

wherein R₆ is selected from C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

R₂ is selected from hydrogen, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-4alkoxy;

R₃ is selected from hydrogen, hydroxy, halo, cyano, nitro, C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkyl, halo-substituted-C_1-4alkoxy, —

NR₅C(O)R₅ and —

NR₅R₅—

;

wherein R₅ is independently selected from hydrogen and C_1-4alkyl; and

the pharmaceutically acceptable salts, hydrates, solvates and isomers thereof.

9. The method of claim 8 in which the compound is selected from formulae Ia, Ib, Ic and Id:

in which m is selected from 0, 1 and 2.

10. The method of claim 9 in which the compound is selected from:

N-[2-(4-ethoxy-phenylamino)-4′

-methyl-[4,5′

]bithiazolyl-2′

-yl]-propionamide;

N-[2-(4-methoxy-phenylamino)-4′

-methyl-[4,5′

]bithiazolyl-2′

-yl]-propionamide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (4-methoxy-benzylidene)-hydrazide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (4-methyl-benzylidene)-hydrazide;

2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (3-hydroxy-4-methoxy-benzylidene)-hydrazide;

[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-(4-ethoxy-phenyl)-amine;

4-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenol;

[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-(2,4-dimethyl-phenyl)-amine;

(4-chloro-phenyl)-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

(2,4-dibromo-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

(2,4-dimethyl-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine;

N-{⁴-[4-(2,7-dimethyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenyl}-acetamide;

4-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenol;

N-{4-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-ylamino]-phenyl}-acetamide;

(4-chloro-phenyl)-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-amine; and

N-[4-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-thiazol-2-yl]-benzamide.

11. The method of claim 8 wherein the cell is selected from pancreatic cancer, prostrate cancer, medulloblastoma, basal cell carcinoma and small-cell lung cancer.