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  Pharmaceutical Patents  

 

Title:  Compounds and compositions as hedgehog signaling pathway modulators
United States Patent: 
7,928,133
Issued: 
April 19, 2011

Inventors:
 Cheng; Dai (San Diego, CA), Han; Dong (San Diego, CA), Gao; Wenqi (San Diego, CA), Jiang; Jiqing (San Diego, CA), Pan; Shifeng (San Diego, CA), Wan; Yongqin (Irvine, CA), Jin; Qihui (San Diego, CA)
Assignee: 
IRM LLC (Hamilton, BM)
Appl. No.: 
12/374,739
Filed:  July 24, 2007
PCT Filed: 
July 24, 2007
PCT No.:
 PCT/US2007/074268
371(c)(1),(2),(4) Date:  August 17, 2009
PCT Pub. No.: 
WO2008/014291
PCT Pub. Date: 
January 31, 2008


 

Pharm Bus Intell & Healthcare Studies


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 -- see Original Patent.

Description of the Invention

BACKGROUND OF THE INVENTION

1. Field of the Invention

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.

2. Background of the Invention

During embryonic development, the hedgehog signaling pathway is essential for numerous processes such as the control of cell proliferation, differentiation and tissue patterning. The aberrant activity of the hedgehog signaling pathway, for example, as a result of enhanced activation, however may have pathological consequences. In this regard, activation of the hedgehog pathway in adult tissues can result in diseases such as psoriasis and specific types of cancer that include, but are not limited to, malignant lymphoma (LM), multiple myeloma (MM), cancers of the brain, muscle and skin, prostrate, medulloblastoma, pancreatic adenocarcinomas and small-cell lung carcinomas. Enhanced activation of the hedgehog signaling pathway contributes to the pathology and/or symptomology of a number of diseases. Accordingly, molecules that modulate the activity of the hedgehog signaling pathway are useful as therapeutic agents in the treatment of such diseases.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula I -- see Original Patent.

In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

In a third aspect, the present invention provides a method of treating a disease in an animal in which modulation of the hedgehog pathway activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for treating a disease in an animal in which hedgehog pathway activity, contributes to the pathology and/or symptomology of the disease.

In a fifth aspect, the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.

DESCRIPTION OF PREFERRED EMBODIMENTS

The therapeutic methods of the invention employ an antagonist of the hedgehog signaling pathway to inhibit growth and proliferation of non-melanoma skin cancer, myeloma, lymphoma, psoriasis, pancreatic cancer, prostrate cancer, medulloblastoma, basal cell carcinoma and small-cell lung cancer. These methods involve contacting such a tumor cell (in vitro or in vivo) with an inhibitor of the Hh signaling pathway, a compound of Formula I. In one embodiment, with respect to compounds of Formula I -- see Original Patent.

Preferred compounds of Formula I are selected from [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[6-(2-methyl-morpholin-4-- yl)-isoquinolin-1-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-quinolin-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-[1,6]naphthyridin-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[6-(2,6-dimethyl-morpholi- n-4-yl)-isoquinolin-1-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(6-morpholin-4-yl-isoquin- olin-1-yl)-amine, N-[4-Chloro-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-4-morpholin-4-yl-benzam- ide, N-[4-Chloro-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-4-cyclohexyl-benzam- ide, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(2-morpholin-4-yl-qui- nolin-5-yl)-amine, [4-Methyl-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(6-piperidin-1-yl-isoquin- olin-1-yl)-amine, (6-Azepan-1-yl-isoquinolin-1-yl)-[4-methyl-3-(5-phenyl-1H-imidazol-2-yl)-- phenyl]-amine, N-[4-Methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-4-morpholin-4-yl-benzam- ide, 4-Cyclohexyl-N-[4-methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-benzam- ide, N-{3-[5-(4-Chloro-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-4-morpho- lin-4-yl-benzamide, [4-Methyl-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(2-morpholin-4-yl-[1,6]na- phthyridin-5-yl)-amine, (6-Azepan-1-yl-isoquinolin-1-yl)-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-- phenyl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(7-morpholin-4-yl-isoquin- olin-1-yl)-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(6-piperidin-1-yl-isoquin- olin-1-yl)-amine, 3,5-Dimethoxy-N-[4-methyl-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-benzamide- , N-{3-[4-(4-Diethylamino-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-4-mor- pholin-4-yl-benzamide, N-{4-Chloro-3-[4-(4-chloro-phenyl)-1H-imidazol-2-yl]-phenyl}-4-morpholin-- 4-yl-benzamide, (6-Morpholin-4-yl-isoquinolin-1-yl)-[3-(5-phenyl-1H-imidazol-2-yl)-phenyl- ]-amine, N-{3-[5-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-4-mo- rpholin-4-yl-benzamide, (6-Morpholin-4-yl-isoquinolin-1-yl)-[3-(5-phenyl-1H-imidazol-2-yl)-phenyl- ]-amine, (2-Morpholin-4-yl-quinolin-5-yl)-[3-(5-phenyl-1H-imidazol-2-yl)-p- henyl]-amine, 6-Morpholin-4-yl-N-[3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-nicotinamide, N-{3-[5-(3-Chloro-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-4-morpholin-- 4-yl-benzamide, 4-Cyclohexyl-N-[3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-benzamide, 4-Morpholin-4-yl-N-[3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-benzamide, N-{3-[5-(2-Chloro-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-4-morpholin-- 4-yl-benzamide, 4-Cyclohexyl-N-{3-[4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-phenyl}-benzamid- e, N-{3-[5-(4-Cyano-phenyl)-1H-imidazol-2-yl]-4-methyl-phenyl}-3,5-dimetho- xy-benzamide, 6-Azepan-1-yl-N-[3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-nicotinamide, 4-Morpholin-4-yl-N-[3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-benzamide, N-{4-Methyl-3-[5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenyl}-4-m- orpholin-4-yl-benzamide, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-isoquinolin-1-yl-amine, 4-Cyclohexyl-N-{3-[4-(4-methoxy-phenyl)-1H-imidazol-2-yl]-phenyl}-benzami- de, 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-5'-carboxylic acid [3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-amide, 6-Azepan-1-yl-N-[2-methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-nicotinam- ide, N-{3-[4-(4-Cyano-phenyl)-1H-imidazol-2-yl]-phenyl}-4-cyclohexyl-benza- mide, 4-Morpholin-4-yl-N-[3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-benzenesul- fonamide, [2-Methyl-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-(6-morpholin-4-y- l-isoquinolin-1-yl)-amine, N-[4-Chloro-3-(5-methyl-4-phenyl-1H-imidazol-2-yl)-phenyl]-4-morpholin-4-- yl-benzamide, N-[4-Methyl-3-(5-methyl-4-phenyl-1H-imidazol-2-yl)-phenyl]-4-morpholin-4-- yl-benzamide, N-(6-Morpholin-4-yl-pyridin-3-yl)-3-(4-phenyl-1H-imidazol-2-yl)-benzamide- , N-[2-Methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-6-morpholin-4-yl-nicot- inamide, 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-5'-carboxylic acid [2-methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-amide, 4-Cyclohexyl-N-[2-methyl-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-benzamide, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2,6-dimethyl-morpholi- n-4-yl)-quinolin-5-yl]-amine, [4-Chloro-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2,6-dimethyl-morpholi- n-4-yl)-[1,6]naphthyridin-5-yl]-amine, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-2-methoxy-isonicotinami- de, 2-Chloro-N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-6-methyl-is- onicotinamide, 2,6-Dichloro-N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-isonicotin- amide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-2-methoxy-isonico- tinamide, 6-Chloro-N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-nicot- inamide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-6-trifluorometh- yl-nicotinamide, 2-Chloro-N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-6-methoxy-ison- icotinamide, Quinoline-3-carboxylic acid [4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-amide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-nicotinamide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-5-methoxy-2-(2,2,2-trif- luoro-ethoxy)-benzamide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-3,4-diethoxy-benzamide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-3-methoxy-4-methyl-benz- amide, 4-Chloro-N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-3-methox- y-benzamide, 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylic acid [4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-amide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-3-methoxy-2-methyl-benz- amide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-2,5-dimethoxy-ben- zamide, N-[4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-3,5-dimethoxy-4-- methyl-benzamide, 6-Methyl-benzo[1,3]dioxole-5-carboxylic acid [4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-amide, [4-Chloro-3-(4-phenyl-1H-imidazol-2-yl)-phenyl]-[7-(2,6-dimethyl-morpholi- n-4-yl)-quinolin-4-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[8-methyl-2-(2-methyl-mor- pholin-4-yl)-quinolin-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-quinazolin-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2,6-dimethyl-morpholi- n-4-yl)-quinazolin-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-quinoxalin-5-yl]-amine, [2-(2,6-Dimethyl-morpholin-4-yl)-quinoxalin-5-yl]-[4-methyl-3-(5-phenyl-1- H-imidazol-2-yl)-phenyl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[3-(2-methyl-morpholin-4-- yl)-benzo[d]isoxazol-7-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[6-(2-methyl-morpholin-4-- yl)-benzo[d]isoxazol-3-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-benzooxazol-4-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-1H-benzoimidazol-4-yl]-amine, [2-(2,6-Dimethyl-morpholin-4-yl)-benzothiazol-4-yl]-[4-methyl-3-(5-phenyl- -1H-imidazol-2-yl)-phenyl]-amine, [2-(2,6-Dimethyl-morpholin-4-yl)-benzothiazol-7-yl]-[4-methyl-3-(5-phenyl- -1H-imidazol-2-yl)-phenyl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[3-(2-methyl-morpholin-4-- yl)-benzo[d]isoxazol-5-yl]-amine, [4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenyl]-[2-(2-methyl-morpholin-4-- yl)-benzooxazol-5-yl]-amine, [2-(2,6-Dimethyl-morpholin-4-yl)-1H-benzoimidazol-4-yl]-[4-methyl-3-(5-ph- enyl-1H-imidazol-2-yl)-phenyl]-amine, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-methoxybenzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methylbenzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-(trifluoromethyl)benza- mide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2,3-dimethoxybenzam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)benzo[d]thiazole-6-ca- rboxamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-(trifluoromethoxy)benz- amide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-methoxy-2-methyl- benzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-hydroxynicot- inamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-hydroxy-6-meth- ylnicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methoxyisonicotinamide- , N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-methylpicolinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-ethoxy-2-methylbenzami- de, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-(2,2,2-trifluoroeth- oxy)nicotinamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-(trifluoromet- hyl)nicotinamide, 6-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-cyanonicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methylnicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-hydroxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methoxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-5-methylnicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-5-fluoronicotinamide, 5-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-ethoxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-ethyl-3-methoxybenzami- de, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methoxynicotinamide- , N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-fluoronicotinamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicotinamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methylnicotin- amide, 5,6-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicoti- namide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methylnicotinam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-ethoxyisonicotinam- ide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinamide, methyl 6-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenylcarbamoyl)nicotinat- e, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-(2-cyanopropan-2-yl)- isonicotinamide, 2-tert-butyl-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinam- ide, 4'-cyano-2-methyl-N-(6-thiomorpholinopyridin-3-yl)biphenyl-3-carboxam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl) phenyl)-3-fluoroisonicotinamide, 2-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinamide, 3-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-fluorobenzamid- e, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3,4-dimethoxy- benzamide, 3-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonic- otinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methylisonic- otinamide, 4-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicoti- namide, 2,5-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isoni- cotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-(1H-tetrazol-1-yl)ison- icotinamide, 4-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamide, 2,6-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-methylnicotinamide- , N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-hydroxy-6-(trifluorom- ethyl)nicotinamide, 2-acetamido-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinami- de, 3-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methylbenza- mide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methylbe- nzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-(trifluorometh- yl)benzamide, N-(4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl)-3-(morpholinomethyl)pyri- din-2-amine, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-hydroxypicolinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-hydroxypicolinamide, 6-bromo-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methylpicolinamide, 5-butyl-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamide, 4-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2,6-dimethoxynicotinamid- e, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-phenoxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2,6-dimethoxyisonicotina- mide, 6-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)picolinamid- e, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-fluoroisonicotinamid- e, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-ethoxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy- )isonicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-isopropoxynicotinamide- , N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-propoxynicotinamide, 2,3-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinam- ide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-hydroxy-6-methylis- onicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-propoxyisonicotinamide- , N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methyl-6-(trifluorome- thyl)nicotinamide, 5-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-methoxyisonic- otinamide, 3-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-met- hoxyisonicotinamide, 3,5-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)isonicotinam- ide, 2,6-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)nicotina- mide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(methyls- ulfonyl)benzamide, 2,3-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)benzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-isopropoxy-2-methylben- zamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-3-isopropoxy-2-me- thylbenzamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-2-isopropoxyisonicotinam- ide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methoxyni- cotinamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-ethoxybenzami- de, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-isopropoxy- benzamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-iso- propoxynicotinamide, N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-6-methoxy-2-methylnicoti- namide, 2,3-dichloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(e- thylsulfonyl)benzamide, 2-((2S,6R)-2,6-dimethylmorpholino)-N-(4-methyl-3-(4-phenyl-1H-imidazol-2-- yl)phenyl)thiazole-5-carboxamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(ethylsulfony- l)benzamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(isopropylsul- fonyl)benzamide, 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(propylsulfon- yl)benzamide, and 2-chloro-N-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl)-4-(methylsulfon- amido)-benzamide.

It is, therefore, specifically contemplated that compounds of Formula I which interfere with aspects of hedgehog, Ptc, or smoothened signal transduction activity will likewise be capable of inhibiting proliferation (or other biological consequences) in normal cells and/or cells having a patched loss-of-function phenotype, a hedgehog gain-of-function phenotype, a smoothened gain-of-function phenotype or a Gli gain-of-function phenotype. Thus, it is contemplated that in certain embodiments, these compounds may be useful for inhibiting hedgehog activity in normal cells, e.g., which do not have a genetic mutation that activates the hedgehog pathway. In preferred embodiments, the compounds are capable of inhibiting at least some of the biological activities of hedgehog proteins, preferably specifically in target cells.

Thus, the methods of the present invention include the use of compounds of Formula I which agonize Ptc inhibition of hedgehog signaling, such as by inhibiting activation of smoothened or downstream components of the signal pathway, in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, including normal cells, tissues, and organs, as well as those having the phenotype of Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function. For instance, the subject method has therapeutic and cosmetic applications ranging from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. Moreover, the subject methods can be performed on cells which are provided in culture (in vitro), or on cells in a whole animal (in vivo).

In another embodiment, the subject method can be to treat epithelial cells having a phenotype of Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function, Gli gain-of-function, or an over expression of hedgehog ligands phenotype. For instance, the subject method can be used in treating or preventing basal cell carcinoma or other hedgehog pathway-related disorders.

In certain embodiments, a compound of Formula I can inhibit activation of a hedgehog pathway by binding to smoothened or its downstream proteins. In certain embodiments, a subject antagonist may inhibit activation of a hedgehog pathway by binding to patched.

In another preferred embodiment, the subject method can be used as part of a treatment regimen for malignant medulloblastomas and other primary CNS malignant neuroectodermal tumors.

In another aspect, the present invention provides pharmaceutical preparations comprising, as an active ingredient, a hedgehog signaling modulator such as a compound of Formula I, a Ptc agonist, a smoothened antagonist, or downstream hedgehog pathway protein antagonist such as described herein, formulated in an amount sufficient to inhibit, in vivo, proliferation or other biological consequences of Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function.

The subject treatments using a compound of Formula I, patched agonists, smoothened antagonists, or downstream hedgehog pathway protein antagonists can be effective for both human and animal subjects. Animal subjects to which the invention is applicable extend to both domestic animals and livestock, raised either as pets or for commercial purposes. Examples are dogs, cats, cattle, horses, sheep, hogs, and goats.

Pharmacology and Utility

The present invention makes available methods and compounds for inhibiting activation of the hedgehog signaling pathway, e.g., to inhibit 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 the cell with a compound of Formula I, in a sufficient amount to agonize a normal Ptc activity, antagonize a normal hedgehog activity, antagonize smoothened activity, or antagonize Gli activity e.g., to reverse or control the aberrant growth state.

Members of the Hedgehog family of signaling molecules mediate many important short- and long-range patterning processes during vertebrate development. Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation. The effects of developmental cell interactions are varied: responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions). Sometimes cells induce their neighbors to differentiate like themselves (homeogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself. Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity. Moreover, inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation.

The vertebrate family of hedgehog genes includes three members that exist in mammals, known as Desert (Dhh), Sonic (Shh) and Indian (Ihh) hedgehogs, all of which encode secreted proteins. These various Hedgehog proteins consist of a signal peptide, a highly conserved N-terminal region, and a more divergent C-terminal domain. Biochemical studies have shown that autoproteolytic cleavage of the Hh precursor protein proceeds through an internal thioester intermediate which subsequently is cleaved in a nucleophilic substitution. It is likely that the nucleophile is a small lipophilic molecule which becomes covalently bound to the C-terminal end of the N-peptide, tethering it to the cell surface. The biological implications are profound. As a result of the tethering, a high local concentration of N-terminal Hedgehog peptide is generated on the surface of the Hedgehog producing cells. It is this N-terminal peptide which is both necessary and sufficient for short- and long-range Hedgehog signaling activities.

An inactive Hedgehog signaling pathway is where the transmembrane protein receptor Patched (Ptc) inhibits the activity of Smoothened (Smo), a seven transmembrane protein. The transcription factor Gli, a downstream component of Hh signaling, is prevented from entering the nucleus through interactions with cytoplasmic proteins, including Fused and Suppressor of fused (Sufu). As a consequence, transcriptional activation of Hedgehog target genes is repressed. Activation of the pathway is initiated through binding of any of the three mammalian ligands (Dhh, Shh or Ihh) to Ptc. Ligand binding results in a reversal of the repression of Smo, thereby activating a cascade that leads to the translocation of the active form of the transcription factor Gli to the nucleus. Nuclear Gli activates target gene expression, including Ptc and Gli itself.

Increased levels of Hedgehog signaling are sufficient to initiate cancer formation and are required for tumor survival. These cancers include, but are not limited to, prostate cancer ("Hedgehog signaling in prostate regeneration, neoplasia and metastasis", Karhadkar S S, Bova G S, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs J T, Berman D M, Beachy P A., Nature. Oct. 7, 2004; 431(7009):707-12; "Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling", Sanchez P, Hernandez A M, Stecca B, Kahler A J, DeGueme A M, Barrett A, Beyna M, Datta M W, Datta S, Ruiz i Altaba A., Proc Natl Acad Sci USA. Aug. 24, 2004;101(34):12561-6), breast cancer ("Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer", Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M., Cancer Res. Sep. 1, 2004;64(17):6071-4), medulloblastoma ("Medulloblastoma growth inhibition by hedgehog pathway blockade", Berman D M, Karhadkar S S, Hallahan A R, Pritchard J I, Eberhart C G, Watkins D N, Chen J K, Cooper M K, Taipale J, Olson J M, Beachy P A., Science. Aug. 30, 2002;297(5586):1559-61), basal cell carcinoma ("Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions", Williams J A, Guicherit O M, Zaharian B I, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter J A, Rubin L L, Wang F Y., Proc Natl Acad Sci USA. Apr. 15, 2003;100(8):4616-21; "Activating Smoothened mutations in sporadic basal-cell carcinoma", Xie J, Murone M, Luoh S M, Ryan A, Gu Q, Zhang C, Bonifas J M, Lam C W, Hynes M, Goddard A, Rosenthal A, Epstein E H Jr, de Sauvage F J., Nature. Jan. 1, 1998;391(6662):90-2), pancreatic cancer ("Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", Thayer S P, di Magliano M P, Heiser P W, Nielsen C M, Roberts D J, Lauwers G Y, Qi Y P, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw A L, Hebrok M., Nature. Oct. 23, 2003; 425(6960):851-6; "Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours", Berman D M, Karhadkar S S, Maitra A, Montes De Oca R, Gerstenblith M R, Briggs K, Parker A R, Shimada Y, Eshleman J R, Watkins D N, Beachy P A., Nature. Oct. 23, 2003; 425 (6960):846-51), and small-cell lung cancer ("Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer", Watkins D N, Berman D M, Burkholder S G, Wang B, Beachy P A, Baylin S B., Nature. Mar. 20, 2003; 422(6929):313-7).

Hedgehog pathway inhibitors (e.g. cyclopamine) have been shown to be useful in the treatment of psoriasis ("Cyclopamine: inhibiting hedgehog in the treatment of psoriasis" Cutis, 2006, 78(3):185-8; Br. J. Dermatology, April 2006; 154(4):619-23, "Psoriatic skin expresses the transcription factor Gli1: possible contribution of decreased neurofibromin expression", Endo H, Momota Y, Oikawa A, Shinkai H.).

Malignant lymphoma (ML) involves the cells of the lymphatic system, and is the fifth most common cancer in the U.S. ML includes Hodgkin's disease, and non-Hodgkin's diseases which are a heterogeneous group of lymphoid proliferative diseases. Hodgkin's disease accounts for approximately 14% of all malignant lymphomas. The non-Hodgkin's lymphomas are a diverse group of malignancies that are predominately of B-cell origin. In the Working Formulation classification scheme, these lymphomas been divided into low-, intermediate-, and high-grade categories by virtue of their natural histories (see "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49:2112-2135, 1982). The low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg, N. Engl. J. Med. 311:1471-1475, 1984). Although chemotherapy can induce remissions in the majority of indolent lymphomas, cures are rare and most patients eventually relapse, requiring further therapy. The intermediate- and high-grade lymphomas are more aggressive tumors, but they have a greater chance for cure with chemotherapy. However, a significant proportion of these patients will relapse and require further treatment.

Multiple myeloma (MM) is malignant tumor composed of plasma cells of the type normally found in the bone marrow. These malignant plasma cells accumulate in bone marrow and typically produce monoclonal IgG or IgA molecules. The malignant plasma cells home to and expand in the bone marrow causing anemia and immunosuppression due to loss of normal hematopoiesis. Individuals suffering from multiple myeloma often experience anemia, osteolytic lesions, renal failure, hypercalcemia, and recurrent bacterial infections. MM represents the second most common hematopoietic malignancy.

The present invention is predicated in part on the discoveries by the present inventors that lymphoma and multiple myeloma diseases are dependent on the hedgehog (Hh) signaling pathway using lymphoma and plasmacytoma cells isolated from transgenic E.mu.-Myc mice and Cdkn2a knockout mice, and discovering that hedgehog ligands mediate the interaction between stroma and lymphoma cells. The same was found for lymphoma and multiple myeloma samples isolated from patient samples from the bone (multiple myeloma) or from lymph nodes, bone marrow or spleens from non-Hodgkin's lymphoma (NHL) patients and also for chronic lymphocytic leukemia (CLL) samples. In addition, it was found that inhibition of the Hh signaling pathway induces apoptosis of stroma dependent lymphoma cells, and that overexpression of hedgehog pathway members inhibit cyclopamine induced apoptosis of lymphoma cells in vitro. Further, the inventors found that treating mice with hedgehog pathway inhibitors abrogates lymphoma expansion in vivo. Finally, the inventors discovered that there is no expression of Gli3 in spleen B-cells and in the majority of cyclopamine responsive lymphomas, but a predominant expression in all cyclopamine resistant lymphomas.

These data indicate that Hh signaling provides an important anti-apoptotic signal for the initial steps of transformation by c-Myc and plays an important role for lymphoma maintenance. Thus, disruption of the Hh signaling pathway provides novel means for treating lymphomas (e.g., NHL), multiple myelomas, CLL and other hematopoietic malignancies. In addition, expression of Gli3 in lymphomas provides a negative predictive factor for responsiveness to Hh inhibition and an important means for patient stratification.

In accordance with these discoveries, the invention provides methods for inhibiting growth of tumor cells, e.g., lymphoma and myeloma cells. The invention provides methods and compositions to treat lymphoma or myeloma in a subject by inhibiting growth of tumor cells. The methods are also useful to prevent tumorigenesis in a subject. Some of the methods are directed to treating lymphomas which do not have significant expression of Gli3 relative to spleen B cells. The methods involve administering to the subject in need of treatment a pharmaceutical composition that contains an antagonizing agent of Hh signaling (e.g., a compound of Formula I). Compound of the invention down-regulate cellular level or inhibit a biological activity of an Hh signaling pathway member.

This invention provides methods of prophylactic or therapeutic treatment of cancers of the blood and lymphatic systems, including lymphomas, leukemia, and myelomas. The methods employ an antagonist of hedgehog signaling pathway to inhibit growth and proliferation of lymphoma cells, leukemia cells, or myeloma cells. Lymphoma is malignant tumor of lymphoblasts derived from B lymphocytes. Myeloma is a malignant tumor composed of plasma cells of the type normally found in the bone marrow. Leukemia is an acute or chronic disease that involves the blood forming organs. NHLs are characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood and are classified according to the type of leucocyte most prominently involved.

By way of example, subjects suffering from or at risk of development of lymphoma (e.g., e.g., B-cell lymphoma, plasmoblastoma, plasmacytoma or CLL) can be treated with methods of the invention. Preferably, the subject is a human being. The methods entail administering to the subject a pharmaceutical composition containing an effective amount of a compound of Formula I to inhibit the hedgehog signaling pathway. The subject can be one who is diagnosed with lymphoma, with or without metastasis, at any stage of the disease (e.g., stage I to IV, Ann Arbor Staging System). Lymphomas suitable for treatment with methods of the invention include but are not limited to Hodgkin's disease and non-Hodgkin's disease. Hodgkin's disease is a human malignant disorder of lymph tissue (lymphoma) that appears to originate in a particular lymph node and later spreads to the spleen, liver and bone marrow. It occurs mostly in individuals between the ages of 15 and 35. It is characterized by progressive, painless enlargement of the lymph nodes, spleen and general lymph tissue. Classic Hodgkin's disease is divided into four subtypes: (1) nodular sclerosis Hodgkin's disease (NSHD); (2) mixed cellularity Hodgkin's disease (MCHD); (3) lymphocyte depletion Hodgkin's disease (LDHD); and (4) lymphocyte-rich classic Hodgkin's disease (cLRHD).

In some preferred embodiments, the present methods are used to treat non-Hodgkin's Lymphoma (NHL). Non-Hodgkin's disease is also called lymphosarcoma and refers to a group of lymphomas which differ in important ways from Hodgkin's disease and are classified according to the microscopic appearance of the cancer cells. Non-Hodgkin's lymphoma includes but is not limited to (1) slow-growing lymphomas and lymphoid leukemia (e.g., chronic lymphocytic leukemia, small lymphocytic leukemia, lymphoplasmacytoid lymphoma, follicle center lymphoma, follicular small cleaved cell, follicular mixed cell, marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, myeloma, large granular lymphocyte leukemia, mycosis fungoides, szary syndrome); (2) moderately aggressive lymphomas and lymphoid leukemia (e.g., prolymphocytic leukemia, mantle cell lymphoma, follicle center lymphoma, follicular small cleaved cell, follicle center lymphoma, chronic lymphocytic leukemia/prolymphocytic leukemia, angiocentric lymphoma, angioimmunoblastic lymphoma); (3) aggressive lymphomas (e.g., large B-cell lymphoma, peripheral T-cell lymphomas, intestinal T-cell lymphoma, anaplastic large cell lymphoma); and (4) highly aggressive lymphomas and lymphoid leukemia (e.g., B-cell precursor B-lymphoblastic leukemia/lymphoma, Burkitt's lymphoma, high-grade B-cell lymphoma, Burkitt's-like T-cell precursor T-lymphoblastic leukemia/lymphoma). The methods of the present invention can be used for adult or childhood forms of lymphoma, as well as lymphomas at any stage, e.g., stage I, II, III, or IV. The methods described herein can also be employed to treat other forms of leukemia, e.g., acute lymphocytic leukemia (ALL).

Some of the therapeutic methods of the invention are particularly directed to treating lymphomas or myelomas which do not express Gli3. As disclosed in the Examples below, it was observed that, while Gli1 and Gli2 were expressed in all lymphomas, detectable Gli3 expression was present mainly in lymphomas which were resistant to Hh pathway inhibition by cyclopamine. There is no expression of Gli3 in normal spleen B-cells and in the majority of cyclopamine responsive lymphomas. Thus, prior to treatment with Hh antagonists, subjects with lymphomas can be first examined for expression of Gli3 in a lymphoma cell sample obtained from the subject. Gli3 expression level in the sample can be compared to Gli3 expression level in normal spleen B cells obtained from the subject. Gli3 expression levels in the lymphoma or myeloma samples and the control cells can be determined using methods well known in the art, e.g., as described in the Examples below. A likely responsiveness to treatment with Hh antagonists described herein is indicated by the lack of detectable Gli3 expression in the lymphoma or myeloma samples or an expression level that is not significantly higher (e.g., not more than 25%, 50%, or 100% higher) than Gli3 expression level in the normal B cell. Other than being an additional step of the therapeutic methods of the invention, the pre-screening for lack of Gli3 expression can be used independently as a method for patient stratification.

In addition to lymphomas, the methods and compositions described above are also suitable for the treatment of myelomas. Multiple myeloma is a fatal neoplasm characterized by an accumulation of a clone of plasma cells, frequently accompanied by the secretion of Ig chains. Bone marrow invasion by the tumor is associated with anemia, hypogammaglobinemia, and granulocytopenia with concomitant bacterial infections. An abnormal cytokine environment, principally raised IL-6 and IL-1.beta. levels, often results in increased osteoclasis leading to bone pain, fractures, and hypercalcemia. Despite aggressive chemotherapy and transplantation, multiple myeloma is a universally fatal plasma proliferative disorder.

In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

Administration and Pharmaceutical Compositions:

In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.

Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Compounds of the invention can be administered in therapeutically effective amounts in combination with other therapies, such as radiation therapy, bone marrow transplantation or hormone therapy.

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, synergistic effects can occur with immunomodulatory, anti-inflammatory substances, other anti-tumor therapeutic agents, chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents and/or monoclonal antibodies useful against lymphomas or myelomas. Some of the well known anti-cancer drugs are described in the art, e.g., Cancer Therapeutics: Experimental and Clinical Agents, Teicher (Ed.), Humana Press (1.sup.st ed., 1997); and Goodman and Gilman's The Pharmacological Basis of Therapeutics, Hardman et al. (Eds.), McGraw-Hill Professional (10.sup.th ed., 2001). Examples of suitable anti-cancer drugs include 5-fluorouracil, vinblastine sulfate, estramustine phosphate, suramin and strontium-89. Examples of suitable chemotherapeutic agents include Asparaginase, Bleomycin Sulfate, Cisplatin, Cytarabine, Fludarabine Phosphate, Mitomycin and Streptozocin.

Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the following Reaction Schemes -- see Original Patent.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80.degree. C.

Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3.sup.rd edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, which involves:

(a) those of reaction scheme I and II; and

(b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention to a non-salt form;

(d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;

(f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.
 

Claim 1 of 6 Claims

1. A compound of Formula I -- see Original Patent.
 

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