Compositions and methods for the treatment of disease associated with trp-p8 expression

Abstract

Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Tip-p8 antagonists, and compositions comprising small-molecule Trp-p8 agonists as well as methods for identifying and characterizing novel small-molecule Trp-p8 modulators and methods for decreasing viability and/or inhibiting growth of Trp-p8 expressing cells, methods for activating Trp-p8-mediated cation influx, methods for stimulating apoptosis and/or necrosis, and related methods for the treatment of diseases, including cancers such as lung, breast, colon, and/or prostate cancers as well as other diseases, such as benign prostatic hyperplasia, that are associated with Trp-p8 expression.

1 . A compound of Formula VIII 
       
         
           
           
               
               
           
         
       
       wherein
 R 22  is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine; 
 R 23  is selected from the group consisting of H, an aliphatic group of up to 25 carbons, and an aryl group of up to 10 carbons selected from the group consisting of substituted phenyl, phenalkyl, substituted phenalkyl, naphthyl, substituted naphthyl, and pyridyl; and 
 R 24  is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms; and 
 R 25  is selected from the group consisting of H. 
 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient or diluent. 
     
     
         6 .- 7 . (canceled) 
     
     
         8 . A method for decreasing the viability of a Trp-p8 expressing cell, said method comprising the step of contacting said cell with a small-molecule Trp-p8 modulator in a concentration and for a time required to decrease the viability of said cell. 
     
     
         9 . The method of  claim 8  wherein said small-molecule Trp-p8 modulator is selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula VII, and a compound of Formula VIII. 
     
     
         10 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of H, OH, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); 
 R 2  is selected from the group consisting of H; 
 R 3  is selected from the group consisting of O, OH, acetate, lactate, carboxamide, butanamide, sulphanamide, and propanetriol; and 
 R 4  is selected from the group consisting of CH 3 —CH—CH 3  (isopropyl), isopropane-2-ol, and CH 3 —C═CH 2  (isopropenyl). 
 
     
     
         11 . The method of  claim 9  wherein said small-molecule Trp-p8 agonist is a compound of Formula II 
       
         
           
           
               
               
           
         
       
       wherein
 R 5  is selected from the group consisting of H, OH, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); 
 R 6  is selected from the group consisting of N; 
 R 7  is selected from the group consisting of O and N; 
 R 8  is selected from the group consisting of NH, O, and S; and 
 R 9  is selected from the group consisting of NO 2 . 
 
     
     
         12 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula III 
       
         
           
           
               
               
           
         
       
       wherein
 R 10  is selected from the group consisting of H and a C 1 -C 5  alkyl including, but not limited to, CH 3 , C 2 H 5 , CH 3 —CH—CH 3  (isopropyl) and CH 3 —C═CH 2  (isopropenyl); 
 R 11  is selected from the group consisting of OH, carboxamide, butanamide, propanetriol, and CONR′R″, wherein R′ is selected from the group consisting of H, CH 3 , C 2 H 5 , C 4 H 8  (cyclobutyl), and C 4 H 8 O, and wherein R″ is selected from the group consisting of C 2 H 5 O00H 2 , C 21 -1 5 , CH 3 —CH—CH 3  (isopropyl), HOCH 2 C(CH 3 ) 2 , HOCH 2 CH 2 , C 4 H 9  (tertbutyl), and C 4 1-1 9  (secbutyl); 
 R 12  is selected from the group consisting of H and a C1-C5 alkyl including, but not limited to, CH 3 , CH 3 —CH—CH 3  (isopropyl), CH 3 —C═CH 2  (isopropenyl), C 4 H 9  (secbutyl), C 4 H 9  (isobutyl), C 4 H 9  (n-butyl), and C 5 H 11  (isohexyl); and 
 R 13  is selected from the group consisting of H and a C 1 -C 5  alkyl including, but not limited to, CH 3 , C 2 H 5 , CH 3 —CH—CH 3  (isopropyl), CH 3 —C═CH 2  (isopropenyl), C 4 H 9  (secbutyl), and C 4 H 9  (isobutyl). 
 
     
     
         13 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula IV 
       
         
           
           
               
               
           
         
       
       wherein
 R 14  is selected from the group consisting of H, an aliphatic group of up to 25 carbons, and an aryl group of up to 10 carbons and 
 R 15  is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms. 
 
     
     
         14 - 17 . (canceled) 
     
     
         18 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula V 
       
         
           
           
               
               
           
         
       
       wherein
 R 16  is selected from the group consisting of a C 2 -C 6  alkylene group having at least one, but not more than three, hydroxyl groups; and 
 R 17  and R 18 , independently of one another, are selected from the group consisting of C 1 -C 10 -alkyl groups, C 5 -C 7 -cycloalkyl, C 6 -C 12 -aryl, wherein the total of the C atoms of R 17  and R 18  is not less than 3, or R 17  and R 18  together represent an alkylene group that, together with the carbon atom that carries the groups R 17  and R 18 , forms a 5-7-membered ring. 
 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula VII 
       
         
           
           
               
               
           
         
       
       wherein
 R 17  is selected from the group consisting of 2-pyridyl, 2-nitro-4-trifluoromethylphenyl, 2-nitro-4-chlorophenyl, 2-methoxyphenyl, 2-chlorophenyl, phenyl, 2-methyl-quinolin-3-yl, 4-methoxyphenyl, 4-fluorophenyl, 3-azepan1-yl-5-(4-trifluoromethoxy)phenylamino[1,3,5]triazyl, cyclohexyl, diphenylmethyl, 2-phenylethyl, 4-hydroxy-cyclohexyl, cycloheptyl, cyclopentyl, C-benzo[1,3]dioxol-5-yl-methyl, 2-pyridyl, and 4-chlorobenzyl; 
 R 18  is selected from the group consisting of 1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 3-benzylamino-2-nitrophenyl, 5-nitro-quinolin-8-yl, 1-yl-3-(2-isopropyl-5-methylcyclohexyloxy)-propan-2-ol, 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, benzyl-2-methylquinazolin-4-yl, 3-methyl-5-morpholin-4-yl-2-nitro-phenyl, 2-nitro-5-piperazin-1-yl-ethanol, 1-yl-3-(2-isopropyl-5-methyl-cyclohexyloxy)-propan-2-ol, 4-(2,5-dimethyl-pyrrol-1-yl)-2-nitro-phenyl, 2-nitro-3-trifluoromethanesulfonyl-phenyl, 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-(2-Fluoro-phenoxymethyl)-2-cyano oxazolyl, adamantly, 5-(benzo[1,3]dioxol-5-ylamino)-10b,10c-dihydro-anthra[1,9-cd]isoxazol-6-one-yl, 2-methylthiazolo[3,2-b][1,2,4]triazol-6-01 4-methylphenyl methyl, 3-benzyl-3H-quinazolin-4-one-2-yl, cyclopentyl, tetrahydronapthyl, cyclooctyl, cyclohexyl, C-[3-(4-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-methyl, C-(2-benzyl-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl, and 1-yl-3-(2-isopropyl-5-methyl cyclohexyloxy)-propan-2-ol; 
 R 19  and R 20  are each independently selected from the group consisting of H and O; and 
 R 21  is selected from the group consisting of 4-methylphenyl, 2-chloro-4-fluorophenyl, and 4-chlorophenyl. 
 
     
     
         21 . The method of  claim 9  wherein said small-molecule Trp-p8 modulator is a compound of Formula VIII 
       
         
           
           
               
               
           
         
       
       wherein
 R 22  is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine, amide; 
 R 23  is selected from the group consisting of H, tetrahydro isoquinolinyl, tetrahydro quinolinyl, 3-methyl indolinyl, indolinyl, 2-(N-methyl, N-phenylethyl)amino ethyl, 3-methyl indolinyl, 1-phenyl ethyl, 2-chloro benzyl, 2-methoxybenzyl, 2-methoxyphenyl, 2-cyclohex-1-enyl ethyl, (1-phenyl-cyclophenyl)-methyl, 2-(tetrahydroquinolinyl)-ethyl, 1-propyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, cycloheptyl, 3-cyclohexylsulfanylpropyl, 2-cyclohex-1-enyl ethyl, 2-(N-isopropyl, N-phenylethyl)amino ethyl, 1-methyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, 2-cyclopentylethyl, 2-phenylcyclopropyl, 1-phenoxyethyl, 4-butyloxyphenyl, (2-nitrophenoxy)methyl, 4,7,7-trimethyl-2-oxa-bicyclo[2.2.1]heptan-3-one, C-(1-phenyl-5-propyl-4H-pyrazol-4-yl)-methyl, benzyl, 2-chlorobenzyl, 1-[3-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-methoxy-phenyl]-2,3,4,9-tetrahydro-1H-b-carboline, C-[3-(4-butoxy-phenyl)-1H-pyrazol-4-yl]-methyl, 4-(azepane-1-sulfonyl)-phenyl, and 5-(7-chloro-quinolin-4-ylsulfanyl)-[1,3,4]thiadiazol-2-yl; 
 R 24  is selected from the group consisting of H, tetrahydro isoquinolinyl, tetrahydro quinolinyl, 3-methyl indolinyl, indolinyl, 3-methyl indolinyl, 1-propyl-1,2,3,4-pyrrolo[1,2-a]pyrazine, 1-methyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, and 1-[3-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-methoxy-phenyl]-2,3,4,9 tetrahydro-1H-b-carboline; and 
 R 25  is selected from the group consisting of H. 
 
     
     
         22 . A method for inducing apoptosis and/or necrosis in a cell expressing Trp-p8 or for treating a disease associate with Trp-p8 expression, said method comprising the step of administering to said cell a small-molecule Trp-p8 modulator selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula VII, and a compound of Formula VIII. 
     
     
         23 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the steps of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 1  is selected from the group consisting of H, OH, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); 
 R 2  is selected from the group consisting of OH, carboxamide, butanamide, and propanetriol; and 
 R 3  is selected from the group consisting of CH 3 —CH—CH 3  (isopropyl), isopropane-2-ol, and CH 3 —C═CH 2  (isopropenyl). 
 
     
     
         24 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 5  is selected from the group consisting of H, OH, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); 
 R 6  is selected from the group consisting of N; 
 R 7  is selected from the group consisting of O, CH 2 , and CH 3 —C—CH 3  (isopropyl); 
 R 8  is selected from the group consisting of NH; and 
 R 9  is selected from the group consisting of N02. 
 
     
     
         25 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 10  is selected from the group consisting of H, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); 
 R 11  is selected from the group consisting of OH, carboxamide, butanamide, and propanetriol; 
 R 12  is selected from the group consisting of H, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); and 
 R 13  is selected from the group consisting of H, CH 3 , CH 3 —CH—CH 3  (isopropyl), and CH 3 —C═CH 2  (isopropenyl); and a pharmaceutically acceptable carrier or diluent. 
 
     
     
         26 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 14  is selected from the group consisting of H, an aliphatic group of up to 25 carbons, and an aryl group of up to 10 carbons and 
 R 15  is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms. 
 
     
     
         27 .- 30 . (canceled) 
     
     
         31 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 16  is selected from the group consisting of a C 2 -C 6  alkylene group having at least one, but not more than three, hydroxyl groups; and 
 R 17  and R 18 , independently of one another, are selected from the group consisting of C 1 -C 10 -alkyl groups, C 5 -C 7 -cycloalkyl, C 6 -C 12 -aryl, wherein the total of the C atoms of R 17  and R 18  is not less than 3, or R 17  and R 18  together represent an alkylene group that, together with the carbon atom that carries the groups R 17  and R 18 , forms a 5-7-membered ring. 
 
     
     
         32 . (canceled) 
     
     
         33 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         34 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 17  is selected from the group consisting of 2-pyridyl, 2-nitro-4-trifluoromethylphenyl, 2-nitro-4-chlorophenyl, 2-methoxyphenyl, 2-chlorophenyl, phenyl, 2-methyl-quinolin-3-yl, 4-methoxyphenyl, 4-fluorophenyl, 3-azepan1-yl-5-(4-trifluoromethoxy)phenylamino[1,3,5]triazyl, cyclohexyl, diphenylmethyl, 2-phenylethyl, 4-hydroxy-cyclohexyl, cycloheptyl, cyclopentyl, C-benzo[1,3]dioxol-5-yl-methyl, 2-pyridyl, and 4-chlorobenzyl; 
 R 18  is selected from the group consisting of 1-benzyl-1-pyrazolo[3,4-d]pyrimidin-4-yl, 3-benzylamino-2-nitrophenyl, 5-nitro-quinolin-8-yl, 1-yl-3-(2-isopropyl-5-methylcyclohexyloxy)-propan-2-ol, 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, benzyl-2-methylquinazolin-4-yl, 3-methyl-5-morpholin-4-yl-2-nitro-phenyl, 2-nitro-5-piperazin-1-yl-ethanol, 1-yl-3-(2-isopropyl-5-methyl-cyclohexyloxy)-propan-2-ol, 4-(2,5-dimethyl-pyrrol-1-yl)-2-nitro-phenyl, 2-nitro-3-trifluoromethanesulfonyl-phenyl, 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-(2-Fluoro-phenoxymethyl)-2-cyano oxazolyl, adamantly, 5-(benzo[1,3]dioxol-5-ylamino)-10b,10c-dihydro-anthra[1,9-cd]isoxazol-6-one-yl, 2-methylthiazolo[3,2-b][1,2,4]triazol-6-01 4-methyl-phenyl methyl, 3-benzyl-3H-quinazolin-4-one-2-yl, cyclopentyl, tetrahydronapthyl, cyclooctyl, cyclohexyl, C-[3-(4-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-methyl, C-(2-benzyl-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl, and 1-yl-3-(2-isopropyl-5-methyl cyclohexyloxy)-propan-2-ol; 
 R 19  and R 20  are each independently selected from the group consisting of H and O; and 
 R 21  is selected from the group consisting of 4-methylphenyl, 2-chloro-4-fluorophenyl, and 4-chlorophenyl. 
 
     
     
         35 . A method for treating a disease associated with Trp-p8 expression of  claim 22 , said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
       
       in combination with a pharmaceutically acceptable carrier or diluent, wherein
 R 22  is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine, amide; 
 R 23  is selected from the group consisting of H, tetrahydro isoquinolinyl, tetrahydro quinolinyl, 3-methyl indolinyl, indolinyl, 2-(N-methyl, N-phenylethyl)amino ethyl, 3-methyl indolinyl, 1-phenyl ethyl, 2-chloro benzyl, 2-methoxybenzyl, 2-methoxyphenyl, 2-cyclohex-1-enyl ethyl, (1-phenyl-cyclophenyl)-methyl, 2-(tetrahydroquinolinyl)-ethyl, 1-propyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, cycloheptyl, 3-cyclohexylsulfanylpropyl, 2-cyclohex-1-enyl ethyl, 2-(N-isopropyl, N-phenylethyl)amino ethyl, 1-methyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, 2-cyclopentylethyl, 2-phenylcyclopropyl, 1-phenoxyethyl, 4-butyloxyphenyl, (2-nitrophenoxy)methyl, 4,7,7-trimethyl-2-oxa-bicyclo[2.2.1]heptan-3-one, C-(1-phenyl-5-propyl-1H-pyrazol-4-yl)-methyl, benzyl, 2-chlorobenzyl, 1-[3-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-methoxy-phenyl]-2,3,4,9 tetrahydro-1H-b-carboline, C-[3-(4-butoxy-phenyl)-1H-pyrazol-4-yl]-methyl, 4-(azepane-1-sulfonyl)-phenyl, and 5-(7-chloro-quinolin-4-ylsulfanyl)-[1,3,4]thiadiazol-2-yl; 
 R 24  is selected from the group consisting of H, tetrahydro isoquinolinyl, tetrahydro quinolinyl, 3-methyl indolinyl, indolinyl, 3-methyl indolinyl, 1-propyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, 1-methyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine, and 1-[3-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-methoxy-phenyl]-2,3,4,9 tetrahydro-1H-b-carboline; and 
 R 25  is selected from the group consisting of H. 
 
     
     
         36 . A method for identifying a Trp-p8 agonist, said method comprising the step of contacting a Trp-p8 expressing cell and a non-Trp-p8 expressing cell with a candidate Trp-p8 agonist for a time and in an amount sufficient to decrease the viability of said Trp-p8 expressing cell but not said non-Trp-p8 expressing cell. 
     
     
         37 . A method for identifying a Trp-p8 antagonist, said method comprising the step of contacting a Trp-p8 expressing cell with a Trp-p8 agonist and with a candidate Trp-p8 antagonist for a time and in an amount sufficient for said agonist to decrease the viability of said T rp-p8 expressing cell, wherein a Trp-p8 antagonist is detected by an increase in the viability of said Trp-p8 expressing cell.