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

• US 20050054651A1
• Filed: 08/20/2004
• Published: 03/10/2005
• Est. Priority Date: 08/22/2003
• Status: Active Grant

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Inventors: Chen, Feng, Moreno, Ofir, Graddis, Thomas J., Natarajan, Sateesh K., Laus, Reiner, Duncan, David F.
• Granted Patent: US 8,362,264 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• 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 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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
• CPC Class Codes: C07C 233/58 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 233/60 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 243/36 with acylating carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 243/38 with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 311/20 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/37 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/40 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 323/44 : X or Y being nitrogen atoms
• CPC Class Codes: C07C 333/06 : having nitrogen atoms of thiocarbamic groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07D 207/06 : with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/325 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/14 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/16 : Tryptamines
• CPC Class Codes: C07D 209/20 : substituted additionally by nitrogen atoms, e.g. tryptophane
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/06 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/04 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
• CPC Class Codes: C07D 215/08 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 215/46 : with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 217/06 : with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 223/04 : with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 235/26 : Oxygen atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/18 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/54 : Nitrogen atoms
• CPC Class Codes: C07D 251/54 : Three nitrogen atoms
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals
• CPC Class Codes: C07D 279/12 : not condensed with other rings
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/16 : substituted in position 7
• CPC Class Codes: C07D 317/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 493/08 : Bridged systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/6872 : Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Trp-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.

Claims

1. A compound of Formula VIII

2. The compound of claim 1 wherein R²³ 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-cyclophentyl)-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-tetrhydro-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.

3. The compound of claim 1 wherein R²⁴ 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-tetrahydro-pyrrolo[1,2-a]pyrazine, 1-methyl-1,2,3,4-tetrhydro-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.

4. The compound of claim 2 wherein R²⁴ 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-tetrahydro-pyrrolo[1,2-a]pyrazine, 1-methyl-1,2,3,4-tetrhydro-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.

5. A composition comprising a compound of claim 1, claim 2, claim 3, or claim 4 and a pharmaceutically acceptable excipient or diluent.

6. The composition of claim 5 further comprising a cancer therapeutic agent.

7. The composition of claim 6 wherein said cancer therapeutic agent is selected from the group consisting of an antimitotic agent, an alkylating agent, an antimetabolites, a cytotoxic antibiotic, an hormonal agent, an anti-estrogen, an anti-androgens, and a farnesyl transferase inhibitor.

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

11. The method of claim 9 wherein said small-molecule Trp-p8 agonist is a compound of Formula II

12. The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula III

13. The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula IV

14. The method of claim 13 wherein R¹⁴ and R¹⁵ together form a cyclic or heterocyclic group of up to 25 carbons and including the nitrogen atom.

15. The method of claim 14 wherein said cyclic or heterocyclic group is selected from the group consisting of 3-phenyl-piperidin-1-yl, 3-phenyl-pyrrolidin-1-yl, 6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl, and 4-pyrimidin-2-yl-piperazin-1-yl.

16. The method of claim 13 wherein R¹⁴ and R¹⁵ are aliphatic groups selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, n-decyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptylmethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 6-hydroxy-n-hexyl, 2-aminoethyl, 2-acetoxyethyl, 2-ethylcarboxyethyl, 4-hydroxybut-2-ynyl, and carboxymethyl.

17. The method of claim 13 wherein R¹⁴ is an aryl group selected from the group consisting of benzyl, naphthyl, 4-methoxyphenyl, 2-methoxy-4-methoxyphenyl, 3-methoxy-5-methoxyphenyl, 4-methyl-5-chlorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 3-methyl-4-methylphenyl, 3-hydroxy-4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-ethylphenyl, 2-fluoro-4-fluorophenyl, 4-nitrophenyl, 2-hydroxynaphthyl, pyridyl, [1-carbamoyl-2-(1H-indol-3-yl)-ethyl, 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl, 1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl, 1-carbamoyl-2-(4-hydroxyphenyl)ethyl, 1-carbamoyl-2-phenylethyl, 1-hydroxymethyl-2-(1H-indol-3-yl)ethyl, 1-hydroxymethyl-2-(4-chlorophenyl)ethyl, 1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl, 1-hydroxymethyl-2-hydroxy-2-phenylethyl, 1-hydroxymethyl-2-phenyl ethyl, 1-methoxymethyl-2-phenylethyl, 1-methyl-2-(4-chlorophenyl)-ethyl, 1-methyl-2-(5-fluoro-1H-indol-3-yl)-ethyl, 1-methyl-2-hydroxy-2-phenylethyl, 1-oxo-2-phenylethyl, 1-phenyl-cyclopentylmethyl, 2-(1-cyclopentyl-pyrrolidin-3-yl)-ethyl, 2-(1H-indol-3-yl)ethyl, 2-(2,3-dimethoxyphenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(2,4-dimethylphenyl)ethyl, 2-(2,5-dimethoxyphenyl)ethyl, 2-(2,5-dimethylphenyl)-ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(2-chloro-6-flourophenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(2-flourophenyl)ethyl, 2-(2-furyl)ethyl, 2-(2-methoxy-5-bromophenyl)ethyl, 2-(2-methoxyphenyl)-ethyl, 2-(2-methylphenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 2-(3-bromo-4-methoxyphenyl)ethyl, 2-(3-chlorophenyl)ethyl, 2-(3-ethoxyphenyl)ethyl, 2-(3-flourophenyl)ethyl, 2-(3-hydroxy-4-methoxyphenyl)-ethyl, 2-(3-hydroxyphenyl)ethyl, 2-(3-methoxy-4-ethoxyphenyl)ethyl, 2-(3-methoxy-4-hydroxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(3-triflouromethylphenyl)ethyl, 2-(4-bromophenyl)-ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-ethylphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-hydroxyphenyl)ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-methylsulfanylphenyl)ethyl, 2-(4-nitrophenyl)ethyl, 2-(4-sulfamoyl-phenyl)-ethyl, 2-(5-methoxy-1H-indol-3-yl)-ethyl, 2-(6-fluoro-1H-indol-3-yl)-ethyl, 2-(6-methoxy-1H-indol-3-yl)-ethyl, 2-(7-methyl-1H-indol-3-yl)-ethyl, 2-(N,N-dipropylamino)ethyl, 2-(pyridin-2-yl)-ethyl, 2-(pyridin-3-yl)-ethyl, 2-(pyridin-4-yl)-ethyl, 2,2-diphenylethyl, 2,3-diflourobenzyl, 2,3-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-diflourophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2-bromo-4-methylphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-flourophenyl, 2-chloro-4-iodophenyl, 2-chloro-4-nitrophenyl, 2-chloro-5-nitrophenyl, 2-chlorophenyl, 2-cyclohex-1-enyl-ethyl, 2-flouro-4-chlorophenyl, 2-flouro-5-nitrophenyl, 2-hydroxy-2-(3-hydroxyphenyl)ethyl, 2-hydroxy-2-(4-hydroxyphenyl)ethyl, 2-hydroxy-2-phenylethyl, 2-iodophenyl, 2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl, 2-methyl-2-phenylethyl, 2-methyl-4-broophenyl, 2-methyl-5-nitrophenyl, 2-methylphenyl, 2-nitro-4-flourophenyl, 2-nitrophenyl, 2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl, 2-oxo-2-phenylethyl, 2-phenyl-1H-benzoimidazol-5-yl, 2-phenyl-2-(4-chlorophenyl)ethyl, 2-phenyl-2-(4-flourophenyl)-ethyl, 2-phenyl-2-(4-methoxyphenyl)ethyl, 2-phenylethenyl, 2-phenylethyl, 2-pyridin-2-yl-benzooxazol-5-yl, 2-pyridin-3-yl-1H-benzoimidazol-5-yl, 2-thiophen-2-yl-ethyl), 2-trilfouromethyl-1H-benzoimidazol-5-yl, 3,4,5-triflourophenyl, 3,4,5-trimethoxyphenyl, 3,4-cyclopentanephenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-acetamidophenyl, 3-bromo-4-methylphenyl, 3-carboxamidophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-morpholin-4-yl-phenyl, 3-hydroxymethylphenyl, 3-nitrophenyl, 3-oxo-indan-5-yl, 3-phenylpropyl, 3-yl-acetophenone, 4-(1,1-dioxo-116-thiomorpholin-4-ylmethyl)-phenyl, 4-(1-hydroxyethyl)phenyl, 4-(2-hydroxyethyl)phenyl, 4-(4-ethyl-piperazin-1-yl)-phenyl, 4-(4-methyl-1H-benzoimidazol-2-yl)-phenyl, 4-(4-methyl-piperazin-1-ylmethyl)-phenyl, 4-(morpholine-4-sulfonyl)-phenyl, 4-[1,3-dioxo-2-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-isoindol-5-yloxy]-phenyl, 4-[2-(2-methoxy-phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy]-phenyl, 4-{2-[2-(3,4-dimethoxy-phenyl)-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy}-phenyl, 4-acetylphenyl, 4-azepan-1-ylmethyl-phenyl, 4-benzooxazol-2-yl-phenyl, 4-Biphenyl, 4-bromophenyl, 4-carboxamidophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-fluorophenyl, 4-hydroxymethylphenyl, 4-methoxyphenyl, 4-methyl-2-oxo-2H-chromen-7-yl, 4-methylcyclohexyl, 4-methylphenyl, 4-methylsulfanylphenyl, 4-nitrobenzyl, 4-pyrrolidin-1-ylmethyl-phenyl, 4-triflouromethylphenyl, benzo[1,3]dioxol-5-yl, benzoylamino, benzyloxy, bicyclo[2.2.1]hept-2-yl, C-1H-indazol-5-yl, cycloheptyl, indan-2-yl, N-(2-diethylamino-ethyl)-benzamide-4-yl, N′

-quinoxalin-2-yl-amino, and phenylcyclopropyl.

18. The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula V

19. The method of claim 18 wherein one or both of the alkyl groups of said R¹⁷ and R¹⁸ are substituted by 1 to 3 groups selected from the group consisting of hydroxyl, amino, thio, and halogen.

20. The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula VII

21. The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula VIII

22. A method for inducing apoptosis and/or necrosis in a cell expressing Trp-p8, 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, said method comprising the steps of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

24. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

25. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

26. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

27. The method of claim 26 wherein R¹⁴ and R¹⁵ together form a cyclic or heterocyclic group of up to 25 carbons and including the nitrogen atom.

28. The method of claim 27 wherein said cyclic or heterocyclic group is selected from the group consisting of 3-phenyl-piperidin-1-yl, 3-phenyl-pyrrolidin-1-yl, 6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl, and 4-pyrimidin-2-yl-piperazin-1-yl.

29. The method of claim 26 wherein R¹⁴ and R¹⁵ are each aliphatic groups independently selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, n-decyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptylmethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 6-hydroxy-n-hexyl, 2-aminoethyl, 2-acetoxyethyl, 2-ethylcarboxyethyl, 4-hydroxybut-2-ynyl, and carboxymethyl.

30. The method of claim 26 wherein R¹⁴ is an aryl group selected from the group consisting of benzyl, naphthyl, 4-methoxyphenyl, 2-methoxy-4-methoxyphenyl, 3-methoxy-5-methoxyphenyl, 4-methyl-5-chlorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 3-methyl-4-methylphenyl, 3-hydroxy-4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-ethylphenyl, 2-fluoro-4-fluorophenyl, 4-nitrophenyl, 2-hydroxynaphthyl, pyridyl, [1-carbamoyl-2-(1H-indol-3-yl)-ethyl, 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl, 1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl, 1-carbamoyl-2-(4-hydroxyphenyl)ethyl, 1-carbamoyl-2-phenylethyl, 1-hydroxymethyl-2-(1H-indol-3-yl)ethyl, 1-hydroxymethyl-2-(4-chlorophenyl)ethyl, 1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl, 1-hydroxymethyl-2-hydroxy-2-phenylethyl, 1-hydroxymethyl-2-phenyl ethyl, 1-methoxymethyl-2-phenylethyl, 1-methyl-2-(4-chlorophenyl)-ethyl, 1-methyl-2-(5-fluoro-1H-indol-3-yl)-ethyl, 1-methyl-2-hydroxy-2-phenylethyl, 1-oxo-2-phenylethyl, 1-phenyl-cyclopentylmethyl, 2-(1-cyclopentyl-pyrrolidin-3-yl)-ethyl, 2-(1H-indol-3-yl)ethyl, 2-(2,3-dimethoxyphenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(2,4-dimethylphenyl)ethyl, 2-(2,5-dimethoxyphenyl)ethyl, 2-(2,5-dimethylphenyl)-ethyl, 2-(2,6-dimethylphenyl)ethyl, 2-(2-chloro-6-flourophenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(2-flourophenyl)ethyl, 2-(2-furyl)ethyl, 2-(2-methoxy-5-bromophenyl)ethyl, 2-(2-methoxyphenyl)-ethyl, 2-(2-methylphenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 2-(3-bromo-4-methoxyphenyl)ethyl, 2-(3-chlorophenyl)ethyl, 2-(3-ethoxyphenyl)ethyl, 2-(3-flourophenyl)ethyl, 2-(3-hydroxy-4-methoxyphenyl)-ethyl, 2-(3-hydroxyphenyl)ethyl, 2-(3-methoxy-4-ethoxyphenyl)ethyl, 2-(3-methoxy-4-hydroxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(3-triflouromethylphenyl)ethyl, 2-(4-bromophenyl)-ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-ethylphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-hydroxyphenyl)ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-methylsulfanylphenyl)ethyl, 2-(4-nitrophenyl)ethyl, 2-(4-sulfamoyl-phenyl)-ethyl, 2-(5-methoxy-1H-indol-3-yl)-ethyl, 2-(6-fluoro-1H-indol-3-yl)-ethyl, 2-(6-methoxy-1H-indol-3-yl)-ethyl, 2-(7-methyl-1H-indol-3-yl)-ethyl, 2-(N,N-dipropylamino)ethyl, 2-(pyridin-2-yl)-ethyl, 2-(pyridin-3-yl)-ethyl, 2-(pyridin-4-yl)-ethyl, 2,2-diphenylethyl, 2,3-diflourobenzyl, 2,3-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-diflourophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2-bromo-4-methylphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-flourophenyl, 2-chloro-4-iodophenyl, 2-chloro-4-nitrophenyl, 2-chloro-5-nitrophenyl, 2-chlorophenyl, 2-cyclohex-1-enyl-ethyl, 2-flouro-4-chlorophenyl, 2-flouro-5-nitrophenyl, 2-hydroxy-2-(3-hydroxyphenyl)ethyl, 2-hydroxy-2-(4-hydroxyphenyl)ethyl, 2-hydroxy-2-phenylethyl, 2-iodophenyl, 2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl, 2-methyl-2-phenylethyl, 2-methyl-4-broophenyl, 2-methyl-5-nitrophenyl, 2-methylphenyl, 2-nitro-4-flourophenyl, 2-nitrophenyl, 2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl, 2-oxo-2-phenylethyl, 2-phenyl-1H-benzoimidazol-5-yl, 2-phenyl-2-(4-chlorophenyl)ethyl, 2-phenyl-2-(4-flourophenyl)-ethyl, 2-phenyl-2-(4-methoxyphenyl)ethyl, 2-phenylethenyl, 2-phenylethyl, 2-pyridin-2-yl-benzooxazol-5-yl, 2-pyridin-3-yl-1H-benzoimidazol-5-yl, 2-thiophen-2-yl-ethyl), 2-trilfouromethyl-1H-benzoimidazol-5-yl, 3,4,5-triflourophenyl, 3,4,5-trimethoxyphenyl, 3,4-cyclopentanephenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-acetamidophenyl, 3-bromo-4-methylphenyl, 3-carboxamidophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-morpholin-4-yl-phenyl, 3-hydroxymethylphenyl, 3-nitrophenyl, 3-oxo-indan-5-yl, 3-phenylpropyl, 3-yl-acetophenone, 4-(1,1-dioxo-116-thiomorpholin-4-ylmethyl)-phenyl, 4-(1-hydroxyethyl)phenyl, 4-(2-hydroxyethyl)phenyl, 4-(4-ethyl-piperazin-1-yl)-phenyl, 4-(4-methyl-1H-benzoimidazol-2-yl)-phenyl, 4-(4-methyl-piperazin-1-ylmethyl)-phenyl, 4-(morpholine-4-sulfonyl)-phenyl, 4-[1,3-dioxo-2-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-isoindol-5-yloxy]-phenyl, 4-[2-(2-methoxy-phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy]-phenyl, 4-{2-[2-(3,4-dimethoxy-phenyl)-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy}-phenyl, 4-acetylphenyl, 4-azepan-1-ylmethyl-phenyl, 4-benzooxazol-2-yl-phenyl, 4-Biphenyl, 4-bromophenyl, 4-carboxamidophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-fluorophenyl, 4-hydroxymethylphenyl, 4-methoxyphenyl, 4-methyl-2-oxo-2H-chromen-7-yl, 4-methylcyclohexyl, 4-methylphenyl, 4-methylsulfanylphenyl, 4-nitrobenzyl, 4-pyrrolidin-1-ylmethyl-phenyl, 4-triflouromethylphenyl, benzo[1,3]dioxol-5-yl, benzoylamino, benzyloxy, bicyclo[2.2.1]hept-2-yl, C-1H-indazol-5-yl, cycloheptyl, indan-2-yl, N-(2-diethylamino-ethyl)-benzamide-4-yl, N′

-quinoxalin-2-yl-amino, and phenylcyclopropyl.

31. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

32. The method of claim 31 wherein one or both of the alkyl groups of said R¹⁷ and R¹⁸ are substituted by 1 to 3 groups selected from the group consisting of hydroxyl, amino, thio, and halogen.

33. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

34. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

35. A method for treating a disease associated with Trp-p8 expression, said method comprising the step of administering to a mammal an efficacious amount of a composition comprising a compound having the formula:

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 Trp-p8 expressing cell, wherein a Trp-p8 antagonist is detected by an increase in the viability of said Trp-p8 expressing cell.