# US 2013/0190296 A1 · Compositions and methods for the treatment of disease associated with trp-p8 expression

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- Number: US 2013/0190296 A1
- Document ID: US20130190296A1
- Status: Published application
- Kind: A1
- Application number: 13/682,151
- Filed: 2012-11-20
- Published: 2013-07-25
- Earliest claimed: 2003-08-22
- Assignees: Dendreon Corporation
- Inventors: Sateesh K. Natarajan; Ofir Moreno; Thomas J. Graddis; David F. Duncan; Reiner Laus; Feng Chen
- Web page: https://patentgrep.com/patent/US20130190296A1

## CPC

- 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
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 233/58: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 243/36: with acylating carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 243/38: with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
- 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
- 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
- C07C 323/40: Y being a hydrogen or a carbon atom
- C07C 323/44: X or Y being nitrogen atoms
- C07C 333/06: having nitrogen atoms of thiocarbamic groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/16: Tryptamines
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 211/06: having no double bonds between ring members or between ring members and non-ring members
- C07D 213/40: Acylated substituent nitrogen atom
- C07D 215/04: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D 215/08: with acylated ring nitrogen atom
- C07D 215/46: with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 223/04: with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- 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
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 235/26: Oxygen atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/18: Oxygen or sulfur atoms
- 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
- C07D 241/54: Nitrogen atoms
- C07D 251/54: Three nitrogen atoms
- 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
- C07D 263/57: Aryl or substituted aryl radicals
- C07D 279/12: not condensed with other rings
- 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
- 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
- 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
- C07D 295/26: Sulfur atoms
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 311/16: substituted in position 7
- C07D 317/66: Nitrogen atoms not forming part of a nitro radical
- C07D 333/34: Sulfur atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 493/08: Bridged systems
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- G01N 2500/10: involving cells
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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.

## Claims

### Claim 1

A compound of Formula VIII
wherein
R22 is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine;
R23 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
R24 is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms; and
R25 is selected from the group consisting of H.

### Claim at position 2

-4. (canceled)

### Claim 5 (depends on 1)

A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or diluent.

### Claim at position 4

-7. (canceled)

### Claim 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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula I
wherein
R1 is selected from the group consisting of H, OH, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl);
R2 is selected from the group consisting of H;
R3 is selected from the group consisting of O, OH, acetate, lactate, carboxamide, butanamide, sulphanamide, and propanetriol; and
R4 is selected from the group consisting of CH3—CH—CH3 (isopropyl), isopropane-2-ol, and CH3—C═CH2 (isopropenyl).

### Claim 11 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 agonist is a compound of Formula II
wherein
R5 is selected from the group consisting of H, OH, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl);
R6 is selected from the group consisting of N;
R7 is selected from the group consisting of O and N;
R8 is selected from the group consisting of NH, O, and S; and
R9 is selected from the group consisting of NO2.

### Claim 12 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula III
wherein
R10 is selected from the group consisting of H and a C1-C5 alkyl including, but not limited to, CH3, C2H5, CH3—CH—CH3 (isopropyl) and CH3—C═CH2 (isopropenyl);
R11 is selected from the group consisting of OH, carboxamide, butanamide, propanetriol, and CONR′R″, wherein R′ is selected from the group consisting of H, CH3, C2H5, C4H8 (cyclobutyl), and C4H8O, and wherein R″ is selected from the group consisting of C2H5O00H2, C21-15, CH3—CH—CH3 (isopropyl), HOCH2C(CH3)2, HOCH2CH2, C4H9 (tertbutyl), and C41-19 (secbutyl);
R12 is selected from the group consisting of H and a C1-C5 alkyl including, but not limited to, CH3, CH3—CH—CH3 (isopropyl), CH3—C═CH2 (isopropenyl), C4H9 (secbutyl), C4H9 (isobutyl), C4H9 (n-butyl), and C5H11 (isohexyl); and
R13 is selected from the group consisting of H and a C1-C5 alkyl including, but not limited to, CH3, C2H5, CH3—CH—CH3 (isopropyl), CH3—C═CH2 (isopropenyl), C4H9 (secbutyl), and C4H9 (isobutyl).

### Claim 13 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula IV
wherein
R14 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
R15 is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms.

### Claim at position 11

14-17. (canceled)

### Claim 18 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula V
wherein
R16 is selected from the group consisting of a C2-C6 alkylene group having at least one, but not more than three, hydroxyl groups; and
R17 and R18, independently of one another, are selected from the group consisting of C1-C10-alkyl groups, C5-C7-cycloalkyl, C6-C12-aryl, wherein the total of the C atoms of R17 and R18 is not less than 3, or R17 and R18 together represent an alkylene group that, together with the carbon atom that carries the groups R17 and R18, forms a 5-7-membered ring.

### Claim 19

(canceled)

### Claim 20 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula VII
wherein
R17 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;
R18 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;
R19 and R20 are each independently selected from the group consisting of H and O; and
R21 is selected from the group consisting of 4-methylphenyl, 2-chloro-4-fluorophenyl, and 4-chlorophenyl.

### Claim 21 (depends on 9)

The method of claim 9 wherein said small-molecule Trp-p8 modulator is a compound of Formula VIII
wherein
R22 is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine, amide;
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-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;
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-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
R25 is selected from the group consisting of H.

### Claim 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.

### Claim 23 (depends on 22)

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
R1 is selected from the group consisting of H, OH, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl);
R2 is selected from the group consisting of OH, carboxamide, butanamide, and propanetriol; and
R3 is selected from the group consisting of CH3—CH—CH3 (isopropyl), isopropane-2-ol, and CH3—C═CH2 (isopropenyl).

### Claim 24 (depends on 22)

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
R5 is selected from the group consisting of H, OH, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl);
R6 is selected from the group consisting of N;
R7 is selected from the group consisting of O, CH2, and CH3—C—CH3 (isopropyl);
R8 is selected from the group consisting of NH; and
R9 is selected from the group consisting of N02.

### Claim 25 (depends on 22)

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
R10 is selected from the group consisting of H, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl);
R11 is selected from the group consisting of OH, carboxamide, butanamide, and propanetriol;
R12 is selected from the group consisting of H, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl); and
R13 is selected from the group consisting of H, CH3, CH3—CH—CH3 (isopropyl), and CH3—C═CH2 (isopropenyl); and a pharmaceutically acceptable carrier or diluent.

### Claim 26 (depends on 22)

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
R14 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
R15 is selected from the group consisting of H, OH, and an aliphatic group containing up to 25 carbon atoms.

### Claim at position 21

-30. (canceled)

### Claim 31 (depends on 22)

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
R16 is selected from the group consisting of a C2-C6 alkylene group having at least one, but not more than three, hydroxyl groups; and
R17 and R18, independently of one another, are selected from the group consisting of C1-C10-alkyl groups, C5-C7-cycloalkyl, C6-C12-aryl, wherein the total of the C atoms of R17 and R18 is not less than 3, or R17 and R18 together represent an alkylene group that, together with the carbon atom that carries the groups R17 and R18, forms a 5-7-membered ring.

### Claim 32

(canceled)

### Claim 33 (depends on 22)

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.

### Claim 34 (depends on 22)

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
R17 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;
R18 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;
R19 and R20 are each independently selected from the group consisting of H and O; and
R21 is selected from the group consisting of 4-methylphenyl, 2-chloro-4-fluorophenyl, and 4-chlorophenyl.

### Claim 35 (depends on 22)

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
R22 is a linker moiety, which may be selected from the group consisting of oxyacetamide, urea, carbamate, thiourea, sulfonamide, amine, amide;
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-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;
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-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
R25 is selected from the group consisting of H.

### Claim 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.

### Claim 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.