AU2004263156B2

AU2004263156B2 - Method for treating cachexia with retinoid ligands

Info

Publication number: AU2004263156B2
Application number: AU2004263156A
Authority: AU
Inventors: Roshantha A. Chandraratna; Guang Liang Jiang; Yang-Dar Yuan
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 2003-08-07
Filing date: 2004-08-06
Publication date: 2009-02-26
Anticipated expiration: 2024-08-06
Also published as: WO2005013949A2; AU2004263156A1; JP2007501800A; EP1653939A2; CA2535260A1; WO2005013949A3

Description

WO 2005/013949 PCT/US2004/025564 -1- METHOD FOR TREATING CACHEXIA WITH RETINOID LIGANDS RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.

60/493,138, filed on August 7, 2003 and U.S. Provisional Application No.

60/533,734, filed on December 31, 2003. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION Cachexia, which literally means 'bad condition', refers to involuntary weight loss, anorexia (loss of appetite), loss of protein and fat mass, gain in the proportion of body-water, and a variety of metabolic changes, which are associated with a primary disease, condition or disorder. Diseases, conditions or disorders which are typically associated with cachexia include, but are not limited to, cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, dementia, anorexia nervosa, major depression, an aged condition and sarcopenia. Cachexia is a strong independent risk factor for morbidity and mortality. Cancer cachexia occurs in about half of all cancer patients.

The fact that a large proportion of cancer patients have cachexia, coupled with the demonstrated relationship between cachexia and mortality has provided WO 2005/013949 PCT/US2004/025564 impetus for the search into underlying mechanisms and therapies that might prevent or reverse cachexia. However, this need has gone largely unmet.

SUMMARY OF THE INVENTION The present invention relates to a method of treating of cachexia in a subject in need of treatment. More specifically, the present invention relates to the use of retinoid compounds that act on retinoid X receptors (RXRs) for the treating of cachexia in a subject in need of treatment. The cachexia is associated with, in other words a complication of, a primary disease, condition or disorder. Primary diseases, conditions and disorders include, but are not limited to, cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, dementia, major depression, anorexia nervosa, an aged condition and sarcopenia. In one embodiment, the cachexia is associated with one or more of AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In another embodiment, the cachexia is associated with one or more of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic Sfibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In yet another embodiment, the cachexia is associated with one or more of AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In a specific embodiment, the cachexia is associated with cancer. In another specific embodiment, the cachexia is associated with AIDS.

In one embodiment, the method of treating cachexia in a subject in need thereof comprises administering to the subject a therapeutically effect amount of a compound represented by Structural Formula P XPERASUM9112728 19S Wa unend nM=lSoc)1/2009 -3- R, R1 Z Y B R1 R1 where: Z is represented by Structural Formula (II) R2 R2 n(H 2 C) I

R

2 R3 R2

(II);

Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two R4 groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRI=CRI-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl;

R

3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; R4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8

-CONR

9 Rio, -CH 2 0H, -CH 2 0RII, -CH 2 OCORII, -CHO, -CH(OR 2 2

-CHOR

1 3 0, -COR 7

-CR

7

(ORI

2 2

-CR

7 0Ri 3 0, or tri(lower alkyl)silyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;

R

8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl;

R

9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; PPERASUO)lM2728880 19 s poa Od-510 I/200 -4- SRi is lower alkyl, phenyl or lower alkylphenyl;

RI

2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

IN In a particular embodiment, Z is represented by Structural Formula (II); 5 Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, 04 oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 4 0 groups, and wherein Y is substituted by the Z and -CRi=CRI-CRI=CRI- groups on CI adjacent carbons; n is 1 or 2; R, and R 2 independently are lower alkyl or fluoroalkyl;

R

3 is hydrogen, lower alkyl, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio,

-CH

2 0RII, -CH 2 0COR l, -CHO, -CH(ORI 2 2 -CHORi 3 0, -COR7, -CR 7

(ORI

2 2

-CR

7 0Ri 3 0, or tri(lower alkyl)silyl; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; Ri is lower alkyl, phenyl or lower alkylphenyl; Ri2 is lower alkyl; and Ri 3 is a divalent alkyl radical of 2 to 5 carbons.

P:OPER\AS\2009\1272880 iv sp amalmK do-501/20l 0 In a further particular embodiment of compounds represented by Structural Formula Z is represented by Structural Formula Y is selected from thienyl or furyl, said groups being optionally substituted with one or two R 4 groups, and -6- 0 wherein Y is substituted by the Z and -CRi=CRi-CRi=CR 1 groups on adj acent carbons; n is 1 or 2; Ri and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is n^ hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, Cl or Br; R4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH 2 0H, -CH 2 0RIt, -CH 2 OCORII, -CHO, I\ -CH(ORI 2 2

-CHOR

13 0, -COR 7

-CR

7 (ORi 2 2

-CR

7 0R 13 0, or tri(lower alkyl)silyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl Sgroup of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl; R 12 is lower alkyl; and R 13 is divalent alkyl radical of 2 to 5 carbons.

Another group of compounds encompassed by Structural Formula include those where Z is represented by Structural Formula Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two R 4 groups, or Y is phenyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRI=CRi-CRi=CRi- groups on adjacent carbons; X is NRs; R 1 and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino; cyano, Cl or Br;

R

4 is lower alkyl, fluoroalkyl or halogen; Rs is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio,

-CH

2 0H, -CH 2 0RI1, -CHzOCOR 1, -CHO, -CH(OR 2 2 -CHORO30, -COR 7

-CR

7

(ORI

2 2

-CR

7 ORi 3 0, or tri(lower alkyl)silyl; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to carbons, or phenyl or lower alkylphenyl; R 11 is lower alkyl, phenyl or lower alkylphenyl; R 12 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons.

PlOPERkASUWI 27280 Ii s a,,iciws -7- In another embodiment, the invention includes a method of treating cachexia in a subject in need of treatment comprising administering a therapeutically effective amount of a compound represented by Structural Formula (IV):

H

(IV),

where R 20 is alkyl of 1 to 6 carbons, and B is -COOH, or -COOR 21 where R 21 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.

Another aspect of the invention is where a therapeutically effective amount of a compound represented by Structural Formula is used in a method of treating cachexia in a subject in need of treatment therefor: WO 2005/013949 PCT/US2004/025564 -8- I B R2 R R 3 where:

R

2 is hydrogen or lower alkyl;

R

3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2

OR

1 I, -CH 2 0COR 1 1 -CHO, -CH(OR 12 2

-CHOR

1 30, -COR 7

-CR

7

(OR

1 2 2

-CR

7 0R 3 0, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;

R

8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl;

R

9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

The invention further includes a method of treating a subject in need thereof for cachexia, comprising administering a therapeutically effective amount of a compound represented by Structural Formula (VI): R2 R 4 R2 R, R, n(H2C) B R2 R1 R, (VI), (Vwhere: where: n is 1 or 2; WO 2005/013949 PCT/US2004/025564 -9-

R

1 and R 2 independently are lower alkyl or fluoroalkyl;

R

3 is hydrogen, lower alkyl, -Cl or -Br; R4 is H, lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRgRio, -CH20H, -CH 2 0R 1

-CH

2 0COR 1 -CHO, -CH(OR 1 2 2

-CHOR

1 3 O, -COR 7

-CR

7

(ORI

2 2

-CR

7 0R 13 0, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl;

RI

1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

In another embodiment, the method of treating cachexia in a subject in need thereof includes administering a therapeutically effective amount of a compound represented by Structural Formula (VII): B

(VII),

where: R4 is lower alkyl of 1 to 6 carbons; B is -COOH or -COORs; and Rg is lower alkyl of 1 to 6 carbons; and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of said double bonds, or a pharmaceutically acceptable salt thereof.

WO 2005/013949 PCT/US2004/025564 In yet another embodiment, the compounds administered for treating cachexia in a subject in need thereof are represented by Structural Formula (VIII): R2 R2 X (V III), wherein: X is S or 0; alternatively, X is NR 5

R

2 is hydrogen or lower alkyl;

R

3 is hydrogen or lower alkyl;

R

5 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRR 1 o, -CH20H, -CH 2 ORII, -CH 2 0CORIi, -CHO, -CH(OR 1 2 2

-CHOR

1 30, -COR, -CR 7

(OR

12 2

-CR

7 0R 1 3 0, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, such as an alkyl of 1 to 5 carbons, a cycloalkyl of 3 to 5 carbons or an alkenyl group containing 2 to 5 carbons;

R

8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl;

R

9 and Ro 0 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl;

R

1 I is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

In a preferred embodiment, compounds of Structural Formula for treating cachexia are represented by Structural Formulas and (XI): WO 2005/013949 PCT/US2004/025564 -11

B

(IX)

B

R

3

(X)

B

(XI),

where: B is -COOH or -COORg; R3 is hydrogen, lower alkyl, -Cl or -Br; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; and Xis S orO.

Another aspect of the invention involves treating cachexia in a subject in need thereof comprising administering an effective amount of a compound represented by any one of Structural Formulas (XIII), (XIV) or (XV): WO 2005/013949 PCT/LS2004/025564 12

R

1 4 R2 y R, x

R

R2 R 3 R, A (XIII) I

A

R, R, R2

(XIV)

R2*' y R R2

R,

R, A (XV), where: X is 0, S, or (CRIR 1 n isO0, 1 or 2; Y is a bi-valent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4: (CRI Rj)p RC- -CR 1

X-(XVI)

WO 2005/013949 PCT/US2004/025564 -13-

X,

R

1

C-CR,

(XVII)

or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1- 6 alkyl or with 1 to 3 C 1 -6 fluoroalkyl groups; X is O, S or NH; RI is independently lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;

R

2 is independently lower alkyl of 1 to 6 carbons, -ORi, 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups jointly represent an oxo group; R3 is hydrogen, lower alkyl of 1 to 6 carbons, -OR 1 fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2

-NH

2 -NHCO(Ci-C 6 )alkyl, or -NHCO(Ci-

C

6 )alkenyl; A is hydrogen, COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0R 1 -CH20CORI -CHO, -CH(OR 1 2 2

-CH(OR

13

-COR

7

-CR

7

(OR

1 2 2

-CR

7 (ORi30), or Si(Ci.

6 alkyl) 3 R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; Ri 3 is divalent alkyl radical of 2-5 carbons; and R1 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 -Clo-alkylphenyl, naphthyl, C 1 -Clo-alkylnaphthyl, phenyl-C 1 -Clo alkyl, WO 2005/013949 PCT/US2004/025564 -14naphthyl-Ci-C 1 o alkyl, C 1 -Clo-alkenylphenyl having 1 to 3 double bonds, CI-C 0 oalkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Clo alkenyl having 1 to 3 double bonds, phenyl-Ci-Clo alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by CORs, or R 1 4 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C 1 to Clo alkyl group, with a Ci to Clo fluoroalkyl group, or with halogen, and the dashed line in Structural Formula (XVI) represents a bond or absence of a bond.

A further aspect of the invention is a method of treating cachexia in a subject in need thereof comprising administering a therapeutically effective amount of a compound represented by Structural Formula (XVIII):

SR

1 X R (XVIII), wherein: X is O, NR' or S; R' is alkyl of 1 to 6 carbons; Y is a bivalent cyclopropyl radical optionally substituted with one or two R 4 groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups optionally substituted with 1 to 4 RA groups;

R

1 is independently alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons;

R

2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;

R'

2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons; WO 2005/013949 PCT/US2004/025564

R

3 is hydrogen, alkyl of 1 to 6 carbons, fluoro substituted alkyl of 1 to 6 carbons, halogen, alkoxy of 1 to 8 carbons, or alkylthio of 1 to 6 carbons, -NO 2

-NH

2 -NHCO(Ci-C 6 )alkyl, -NHCO(Ci-C 6 )alkenyl, -NRiH or -N(Ri)z, benzyloxy or C -C 6 alkyl-substituted benzyloxy;

R

4 is -H or alkyl of 1 to 6 carbons, or fluoro substituted alkyl of 1 to 6 carbons; m is an integer having the values of 0 to 3, and B is -COOH or a pharmaceutically acceptable salt thereof, -COORs,

-COOCH

2

COR

7

-CONR

9 RIo, -CH 2 0H, -CH 2 0Rt -CH 2 0CORu1, -CHO,

-CH(OR

1 2 2

-CH(OR

13

-COR

7

-CR

7

(OR

12 2

-CR

7

(OR

13 0),

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;

R

8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a group of 5 to 10 phenyl or lower alkylphenyl;

R

9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl;

R

11 is lower alkyl, phenyl or lower alkylphenyl;

R

12 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2-5 carbons.

Yet another aspect of the invention is a method of treating cachexia in a subject in need thereof with a therapeutically effective amount of a compound represented by Structural Formula (XIX): R2 R2 R2

X,

X2 W X2 R 1 4 (XIX), wherein: Y is a bivalent radical having Formula or Formula WO 2005/013949 PCT/US2004/025564 -16-

(CR

1

R

1 )p 0

R

1 C CR 1 RC- CR 1 or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1- 6 alkyl or with 1 to 3 C1- 6 fluoroalkyl groups; p is an integer from 1 to 4; the two Xi groups jointly represent an oxo or thione function, or X 1 is independently selected from -H or alkyl of 1 to 6 carbons; the two X 2 groups jointly represent an oxo or a thione function, or X 2 is independently selected from -H or alkyl of 1 to 6 carbons, with the proviso that one of the joint X 1 grouping or of the joint X 2 grouping represents an oxo or a thione function; W is -C(Ri) 2 phenyl, naphthyl, or 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with a C 1 to Clo alkyl group, with a Ci to C 1 0 fluoroalkyl group, or with halogen;

R

1 is independently lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;

R

2 is independently lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;

R

3 is hydrogen, lower alkyl of 1 to 6 carbons, -ORI, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2

-NH

2 -NHCO(Ci-C 6 alkyl, or -NHCO(Ci-

C

6 )alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,

-COOR

8 -CONRgRio, -CH20H, -CH 2 0Rn, -CH20COR 11 -CHO, -CH(OR 1 2 2

-CH(OR

13

-COR

7

-CR

7

(OR

1 2 2

-CR

7

(OR

13 or -Si(C-6 alkyl) 3

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, WO 2005/013949 PCT/US2004/025564 -17- Rg is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R is phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl;

R

1 3 is divalent alkyl radical of 2-5 carbons;

R

1 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 -Clo-alkylphenyl, naphthyl, C 1 -Clo-alkylnaphthyl, phenyl- C1-Clo alkyl, naphthyl-C 1 -Clo-alkyl, C 1 -Clo-alkenylphenyl having 1 to 3 double bonds, C 1 -Co 1 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C 1 -Clo alkenyl having 1 to 3 double bonds, phenyl-Ci-Clo alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by CORg, or R 14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said carbocyclic aryl and heteroaryl groups being unsubstituted or substituted with a CI to C 1 o alkyl group, with a C 1 to Clo fluoroalkyl group, or with halogen; and the dashed line in Formula represents a bond or absence of a bond, provided that when the dashed line represents a bond then there are no R1 substituents on the carbons connected by said bond.

In another embodiment, the invention is a method of treating cachexia in a subject in need thereof comprising administering a therapeutically effective amount of a compound represented by Structural Formula (XX): WO 2005/013949 PCT/US20041025564 18- (R4)p (R 3 )m Jv\ N- Y(R 2

)-A-B

X R1

(XX),

wherein: X is O, S, or C(R)2 R is -H or alkyl of 1 to 6 carbons;

R

1 is alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-Ci-C 6 alkyl, or Cr-C 6 -alkylphenyl;

R

2 is H, alkyl of 1 to 6 carbons, -C1, -Br, -CF 3 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, -Cl, -Br, -CF 3 fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, benxyloxy, C 1

-C

6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, CI-C 6 alkyl substituted phenyloxy, or halogen substituted phenyloxy;

R

4 is independently alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; m is an integer having the values 0 to 3; p is an integer having the values 0 to 4; A is (CH2)q- where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, -COOH, -COOR 8 -CONRRjo, -CH 2 0H, -CH 2 0RII,

-CH

2 0CORI 1 -CHO, -CH(OR 1 2 2

-CHOR

13 0, -COR 7

-CR

7

(OR

12 2

-CR

7 0R 13 0, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, WO 2005/013949 PCT/US2004/025564 -19-

R

8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl;

R

9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof.

In a further embodiment, the invention is a method of treating cachexia in a subject in need thereof comprising administering a therapeutically effective amount of a compound represented by any one of Structural Formula (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXXVI), (XXXVII), (XXVIIa) or (XXVIIb):

R

3 xR 4 RI R2 R' R" z x R 6 15R3 R4

(XXI)

R3 R4i (xxIn)

(XXIII)

WO 2005/013949 WO 2005013949PCIIUS200I/02556I 20

(XXIV)

(XXV)

(XXVI)

(XxrVII) WO 2005/013949 PCT/US2004/025564 -21- R1 Rlo R R

I

R2 d ZZ R12 R18 R13 (XXVIIa) R 1 Rio R' R"' 11Z R12 (XXVIIb), wherein:

R

1 and R 2 each independently is hydrogen or lower alkyl or acyl having 1-4 carbon atoms; Y is C, O, S, N, CHOH, CO, SO, SO2, or a pharmaceutically acceptable salt;

R

3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N; R4 is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, R 4 does not exist if Y is N, or neither R 3 or R 4 exist if Y is S, O, CHOH, CO, SO, or SO 2 R' and R" are hydrogen, lower alkyl or acyl having 1-4 carbon atoms, -OH, alkoxy having 1-4 carbon atoms, thiol or thioether, or amino, or R' or R" taken together form an oxo(keto), methano, thioketo, HO-N=, NC-N=, (R 7 Rs)N-N=, R 1 7 0-

R

17 epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or halogen; and are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or and taken together form a cycloalkyl group having 3carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;

R

5 is hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR 7 -SRy,

-NR

7 Rs, or -(CF)nCF 3 but Rs is not hydrogen if R 6 Rio, R 1

R

12 and Rs 3 are all WO 2005/013949 PCT/US2004/025564 -22hydrogen, Z, and are all carbon, and R' and R" represent -OH,

C

1

-C

4 alkoxy or C1-C 4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group;

R

6 Rio, RI, R 1 2 and R 1 3 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR 7

-SR

7

-NR

7 Rs or (CF)nCF 3 and exist only if the Z, or from which R 6 Rio, R 1 1

R

1 2 or R 1 3 originates is C, or R 6 Rio, RI 1

R

1 2 and R 1 3 each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, Z or from which R 6

R

1 0

R

1

R

1 2 or

R

1 3 originates is N, and where one of R 6

R

10

R

11 Ri2 or R13 is X;

R

7 represents hydrogen or a lower alkyl having 1-6 carbons;

R

8 represents hydrogen or a lower alkyl having 1-6 carbons;

R

9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or qhydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4;

R

1 4 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;

R

1 7 is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyl, -OR 7 or -SR 7

-R

9 alkyl carboxylic acid optionally substituted with halogen, acyl, -OR 7 or -SR 7 alkenyl carboxylic acid optionally substituted with halogen, acyl, -OR 7 or -SR 7 alkyl amine optionally substituted with halogen, acyl, -OR 7 or -SR 7 or alkenyl amine optionally substituted with halogen, acryl, -OR 7 or -SR7;

R

1 8 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro,

-OR

7

-SR

7

-NR

7 Rs, or -(CF)nCF 3 X is -COOH, tetrazole, -PO3H, -SO 3 H, -CHO, -CH20H, -CONH 2

-COSH,

-COOR

9 -COSR9, -CONHR 9 or -COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or N on the ring; Z, and each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, and are not O or S if Z, or is attached by a double bond to one of Z, or or if one or more of Z, or is attached to one of Z, or that is O or S, and provided that one or more of Z, and are not N if one of Z, WO 2005/013949 PCT/US2004/025564 -23and is attached by a single bond to one of Z, and that is

N;

n is 0 to 3; and the dashed lines are optional double bonds.

The invention also includes the use of the compounds disclosed RXR agonists) herein for the manufacture of a medicament for treating cachexia associated with one or more of the diseases, disorders or conditions named above.

The invention further includes pharmaceutical compositions for treating cachexia comprising a compound an RXR agonist) disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the actual body weight (in grams) of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 2 is a graph showing the percentage of survival of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 3 is a graph showing the actual body weight of severe combined immunodeficiency (SCID) mice bearing metastatic H446 tumors versus days post transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 4 is a graph showing the weight of the right gastrocnemius muscle of mice bearing H292 tumor xenograft 62 days after transplantation, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 5 is a graph showing the average food intake of nude mice with and without H292 xenografts, and with and without treatment by an RXR agonist compound (Compound 1) in accordance with the invention.

FIG. 6 is a graph showing the actual body weight (in grams) of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by a RXR agonist compound (Compound 2) in accordance with the invention.

WO 2005/013949 PCT/US2004/025564 -24- FIG. 7 is a graph showing the average food intake of nude mice bearing H292 xenografts with and without treatment by an RXR agonist compound (Compound 2) in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

CACHEXIA

Cachexia, which literally means 'bad condition', refers to involuntary weight loss, anorexia (loss of appetite), loss of protein and fat mass, gain in the proportion of body-water, and a variety of metabolic changes, which are associated with a primary disease, condition or disorder. The metabolic changes that can occur with cachexia include, for example, an elevation of resting energy expenditures (REEs) (Ann. Surg., 197: 152 (1983)), glucose intolerance and insulin resistance (Cancer Res., 44:1718 (1984)), an increase in fat oxidation rates (Metabolism, 35: 304 (1986)) and whole body protein turnover (Cancer Res., 82: 42 (1998)). The pattern of weight loss in cachexia is different from normal starvation. For example, the normal adaptive response to nutrient deprivation is to draw on energy-dense lipid while sparing protein, resulting in loss of fat and relative preservation of lean body mass. In contrast, cachectic patients experience severe and incapacitating muscle wasting with relative sparing of adipose tissue.

Disease, conditions or disorders that are typically associated with cachexia include, but are not limited to, cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, dementia, major depression, anorexia nervosa, an aged condition and sarcopenia. More typically, the disease, conditions or disorders that are associated with cachexia include, but are not limited to, cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders irritable bowel syndrome and WO 2005/013949 PCT/US2004/025564 inflammatory bowel disease), Parkinson's disease, dementia, major depression, anorexia nervosa, an aged condition and sarcopenia. Cachexia is a strong independent risk factor for morbidity and mortality. For example, cancer cachexia occurs in about half of all cancer patients and is more common in patients with lung and upper gastronintestinal cancers (for a more detailed description see the publications: Nature Reviews Cancer, 2: 862 (2002); Proc. Natl. Acad. Sci. USA, 100: 5384 (2003); CA Cancer J. Clin., 52: 72 (2002)). Cancer patients with an involuntary 5% weight loss have a shorter median survival rate than patients with stable weight. Cancer patients with weight loss can respond poorly to chemotherapy and also can require increased chemotherapy treatments (Am. J. Med., 69: 491 (1980)). The fact that a large proportion of cancer patients have cachexia, coupled with the demonstrated relationship between cachexia and mortality, has provided impetus for the search into underlying mechanisms and therapies that might prevent or reverse cachexia and provide a model for identifying additional therapies.

Studies indicate that deregulation of neuroendocrine hormones, particularly catecholamines, glucagon, corticosterone, leptin and growth hormone are involved in the induction of cachexia (for reviews see Int. J. Cardiol., 85: 111 (2002); J Nutrition, 129: 290S (1999)). More importantly, inappropriate production and release of cytokines such as TNF-a, interleukin-1, interleukin-6, interferon-y, leukemia inhibitory factor, and ciliary neurotrophic factor, either alone or in combination, are able to cause the metabolic changes associated with cachexia and finally to induce wasting (for reviews see Drug Discov. Today, 8: 838 (2003); Int. J Cardiol., 85: 73 (2002)). Recent studies indicate that the ubiquitin-proteasome proteolytic pathway plays a role in wasting of skeletal muscle and the intracellular events and transcription factors are also involved (Nature-Review-Cancer, 2:862- 871 (2002)).

A variety of strategies have been tried to achieve these aims, which include use of nutritional supplementation with improved diet, administration of agents that can reduce energy expenditures, f-adrenergic blockers and nonsteroidal anti-inflammatory drugs such as COX inhibitors, appetite stimulants, progesterone and cannabinoids, anabolic stimulants, e.g., testosterone and IGF-1, anticytokines, f3-2 agonist such as clenbuterol and WO 2005/013949 PCT/US2004/025564 -26analogues, omega-3 fatty acids, melatonin, and thalidomide, and miscellaneous agents, Ghrelin, anadamide, ponalrestat, ATP, cyclic plasma perfusion, IL-1 receptor agonist A, IL-15 and decoy nuclear factor KB (Current Oncology Reports, 4:264-274 (2002)). There are currently four approved drug products for the treatment of wasting and some of them are used for AIDS-related cachexia: Oxandrolone, Dronabinol, Megestrol acetate and growth hormone. (for a review, see J. Nutrition, 129: 303S (1999)).

Oxandrolone is an anabolic steroid being a synthetic derivative of testosterone. The indications for Oxandrolone include use as an adjunctive therapy to promote weight gain following weight loss after extensive surgery, chronic infections, or severe trauma; for patients with unexplained weight loss; and to offset protein catabolism associated with prolonged corticosteroid use. Dronabinol is an orally active cannabinoid first approved for the treatment of nausea and vomiting and were extended in 1992 to the treatment of anorexia associated with AIDS. The third drug approved for a wasting related indication was megestrol acetate, a synthetic progesterone derivative. It is approved for the treatment of anorexia, cachexia or weight loss in patients with AIDS and hormone-sensitive malignancies.

Growth hormone has been approved for the treatment of AIDS wasting and cachexia. This drug received accelerated approval for wasting based on a positive change in lean body mass.

Despite of the numerous efforts in developing treatments for cachexia, few efficacious therapeutic solutions are known. In randomized clinical trials, dietary counseling and use of nutritional supplements have failed to ameliorate the symptoms of cachexia in chronically ill, nonmalignant patients (for reviews, see Am.

J Clin. Nutr., 74: 6 (2001); J Nutrition, 129: S290 (1999)). Furthermore, artificial and aggressive feeding does not appear to have an impact on the overall survival of advanced cancer patients (J Clin. Oncol., 2: 534 (1984)) and the global quality of life remains unaffected. Drugs that enhance appetite and anabolic therapies, despite the demonstrated efficacy in randomized clinical trials, do not have a major longterm impact on the vast majority of patients. For example, Dronabinol treatment was associated with improved appetite but had no effect on mood and body weight improvement Clin. Oncol., 20: 567 (2002)). On the other hand, Oxandrolone WO 2005/013949 PCT/US2004/025564 -27treatment resulted in a moderate increase of body weight that might have represented primary edema (Proc. Am. Soc. Clin. Oncol., 21: 363a (2002)).

Megestrol acetate treatment resulted in body weight gain of at least five pounds in AIDS as well as cancer patients (AIDS Res. Hum. Retrov., 13: 305 (1997); J. Clin.

Oncol., 11: 762 (1993); Annals Oncol., 12: 289 (2001)). However, the primary body component that increased was fat, but not lean body mass.

Therefore, taken together, it is difficult to determine the actual clinical relevance, impact on morbidity, mortality, or quality of life, of the pharmacological therapies in cachectic patients. As such, there is a need for improved methods for the treatment of cachexia. In a preferred embodiment of the invention, the cachexia being treated is associated with one or more diseases, conditions and disorders selected from the group consisting of cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In one particularly preferred embodiment, the cachexia is associated with one or more of AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In another particularly preferred embodiment, the cachexia is associated with one or more of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In yet another preferred embodiment, the cachexia is associated with one or more of AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia. In a specific embodiment, the cachexia is associated with cancer. In another specific embodiment, the cachexia is associated with AIDS.

WO 2005/013949 PCT/US2004/025564 -28-

CANCER

As used herein, cancer refers to tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, leukemias and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human Tcell lymphotropic virus (HTLV), for example, adult T-cell leukemia/lymphoma (ATLL), acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non- Hodgkin's lymphomas, and multiple myeloma, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' Tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers oral, laryngeal and esophageal), genitourinary cancers prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, liver cancer, biliary cancer, gastrointestinal cancers small intestinal, gastric) and thyroid cancer.

RETINOID X RECEPTOR (RXR) AGONISTS There are two main types ofretinoid receptors that have been identified in mammals (and other organisms). The two main types or families of receptors are respectively designated the Retinoid Acid Receptors (RARs) and Retinoid X Receptors (RXRs).

The Retinoid X Receptor (RXR) is a member of the nuclear hormone receptor family of proteins. RXR contains two signature domains of nuclear receptor family proteins, the DNA-binding domain and ligand binding domain (LBD). RXR is a ligand-dependent transcription factor. The endogenous ligand for RXR is 9-cis retinoic acid. RXR plays an important role in many fundamental biological processes such as reproduction, cellular differentiation, bone development, hematopoiesis and pattern formation during embryogenesis (Mangelsdorf, D.J. et al., Cell, 83: 841-850 (1995)). RXR is also implicated in some pathological conditions as neoplastic formation and it is a potential target for cancer therapy (Nagy, et al., Cell Death and Diff 5: 11-19 (1998)).

WO 2005/013949 PCT/US2004/025564 -29- The mammalian RXR includes at least three distinct genes, RXR RXRB and RXR,y (RXR alpha, beta and gamma) which give rise to a large number of protein products through differential promoter usage and alternative splicing. Compounds useful in treating cachexia can be agonists for the RXR, RXRa or RXR, receptor.

Besides acting as a homodimer, RXR plays a central role in regulating the activity of other nuclear hormone receptors by acting as a partner for heterodimers. RXR forms a functional heterodimer with retinoic acid receptor (RAR), thyroid hormone receptor, vitamin D receptor, NGFI-B and many other nuclear receptors. The different binding partners of the RXR render a different DNA-binding specificity of the heterodimer.

As used herein, RXR refers to naturally occurring RXRs mammalian RXRs human (Homo sapien) RXRs, murine rat, mouse) RXRs) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring RXR recombinant proteins). The term includes naturally occurring variants, such as polymorphic or allelic variants and splice variants.

As used herein, the term an RXR agonist refers to a substance a molecule, a compound) which promotes (induces or enhances) at least one function characteristic of an RXR. In one embodiment, the RXR agonist binds the RXR. In certain embodiments, the agonist is a partial agonist. Partial agonist, as used herein, refers to an agonist which no matter how high of a concentration is used, is unable to produce maximal activation of the RXR. Some RXR agonists may have mixed agonist-antagonist activity.

An RXR agonist can be identified and activity assessed by any suitable method. For example a chimeric receptor transactivation assay that tests for agonist-like activity in the RAR, RARR, RAR,, RXRa receptor subtypes, and that is based on work published by Feigner P. L. and Holm M. Focus, 112, (1989), is described in detail in United States Patent No. 5,455,265, which is hereby incorporated by reference. In addition, a holoreceptor transactivation assay and a ligand binding assay that measure the antagonist/agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in WO 93/11755 (particularly on pages 30-33 and 37-41) published on June 24, 1993, the content of which is also incorporated WO 2005/013949 PCT/US2004/025564 herein by reference. A detailed experimental procedure for holoreceptor transactivations has been described by Heyman et al., Cell 68: 397-406, (1992); Allegretto et al., J. Biol. Chem, 268: 26625-26633, and Mangelsdorf et al., The Retinoids: Biology, Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York, which are incorporated herein by reference. The results obtained in this assay and the chimeric receptor transactivation assay, are expressed as EC 5 0 values. Still another transactivation assay, the "PGR assay" is described in Klein et al., J. Biol.

Chem. 271: 22692-22696 (1996), which is incorporated herein by reference.

In a particular embodiment, the RXR agonists are described, for example, in United States Patent Nos. 6,403,638; 6,388,105; 6,313,163; 6,147,224; 6,114,533; 6,048,873; 6,048,873; 6,034,242; 5,917,082; 5,817,836; 5,780,647; 5,675,033; 5,663,367; 6,320,074; 6,162,815; 5,977,125; 5,801,253; 6,326,397 and 6,043,279 the entire contents of which are expressly incorporated herein by reference. RXR agonist compounds that can be administered in accordance with the present invention are also described, for example, in the following PCT Published Patent Applications: WO 97/12853; WO 01/19770; WO 00/53562; WO 01/70668 and WO/02/071827, the entire contents of which are expressly incorporated herein by reference.

Preferably, RXR agonists having the structures described in United States Patent Nos. 5,675,033, 5,917,082 and 6,320,074 are used in the pharmaceutical compositions and methods of the present invention. Even more preferably, RXR agonist compounds of United States Patent Nos. 5,675,033 and 5,917,082 are used.

Examples of RXR agonist compounds disclosed in United States Patent Nos.

5,675,033 and 5,917,082 are represented by Structural Formula

R

1

R

1 Z B RI R where: Z is represented by Structural Formula (II) or Structural Formula (III) POPER\ASl2 M12M2I2U st Is sp amendmcns do0c-5fOl09 -31- IC2 R2

R

3 R2 3 \O R1(I); Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two R4 groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CR 1 =CRI-CRI=CRI- groups on adjacent carbons; preferably, Y is cyclopropyl, phenyl, pyridyl, thienyl or furyl; more preferably, Y is cyclopropyl or phenyl; and even more preferably, Y is a cyclopropyl substituted with a methyl group at the carbon atom nearest to Z, thereby forming a quaternary carbon; n is l or 2; RI and R 2 independently are H, lower alkyl or fluoroalkyl; preferably, R 1 is H or methyl;

R

3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, Cl or Br;

R

4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs,

-CONR

9 RIo, -CH 2 OH, -CH 2 0R 1

-CH

2 0CORI 1 -CHO, -CH(OR 1 2 2

-CHOR

1 30, -COR 7

-CR

7

(OR

1 2 2

-CR

7 0R 1 3 0, or tri(lower alkyl)silyl; preferably, B is -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 or -CONR 9 Rio;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; P \O ERLASU2MMU272SSS la spa -rdnd-/0l(2X N -32- Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

In one preferred embodiment, Z is represented by Structural Formula (II) and n is 2.

In a particular embodiment, Z is represented by Structural Formula Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CR 1 =CRI-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs,

CONR

9 Rio, -CH20H, -CH 2 0R 1 I, -CH 2 OCORiI, -CHO, -CH(ORI 2 2

-CHOR

1 30, -COR 7

-CR

7

(ORI

2 2

-CR

7 0RI 3 0, or tri(lower alkyl)silyl; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl;

R

11 is lower alkyl, phenyl or lower alkylphenyl; RI 2 is lower alkyl; and Ri3 is a divalent alkyl radical of 2 to 5 carbons.

P OPERkAS%0 I92729MS Ist spa -dsisu docM)IfSPE9 33 In a further particular embodiment of compounds represented by Structural Formula Z is represented by Structural Formula Y is selected from thienyl P OPERMAS\20212 72 8 19 Tm.i -rImdo.5/I201109 -34or furyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRI=CRI-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, CI or Br; R4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio,

-CH

2 0H, -CH 2 0RII, -CH 2 0CORII, -CHO, -CH(ORI 2 2

-CHOR

1 30, -COR 7

-CR

7

(ORI

2 2

-CR

7 0RI 3 0, or tri(lower alkyl)silyl; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rg is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; R 1 1 is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and R 13 is divalent alkyl radical of 2 to 5 carbons.

P XOPERUS'2t9\ 21288O I 51 Va Wmsdx./OCl/0In Still more preferably, compounds of the general structure shown by Structural Formula (IV) are used:

H

(IV),

Compounds 1, 2 and 3, the chemical formulas of which are shown below, are specific examples of RXR agonists that can be used, either as a free acid or as a pharmaceutically acceptable salt, in accordance with the present invention to treat mammals, including human beings, to prevent, inhibit or reduce (partially or completely) cachexia. Among all RXR agonists, Compounds 1 and 2 are presently WO 2005/013949 PCT/US2004/025564 -36the most preferred to be used in the present invention. Compounds 1 and 2 are within the scope of Structural Formula (IV).

COOH

Compound 1 United States Patent No. 5,917,082 Compound 2 United States Patent No. 5,917,082

CH

2

COOH

Compound 3 United States Patent No. 6,320,074 Compounds 1 and 2 can be obtained in accordance with the synthetic procedures described in United States Patent Nos. 5,917,082. Compound 3 can be obtained in accordance with the synthetic procedure described in United States Patent No. 6,320,714. The entire contents of both of these patents are expressly incorporated herein by reference.

WO 2005/013949 PCT/US2004/025564 -37- Further preferred compounds disclosed by U.S. Patent No. 5,917,082 are represented by Structural Formula R2 R2

B

R2 R2 R where:

R

2 is hydrogen or lower alkyl;

R

3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0Ri -CH 2 OCOR 1, -CHO, -CH(OR 1 2 2

-CHOR

13 0, -COR 7

-CR

7

(ORI

2 2 -CR7OR130, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl' group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl;

R

12 is lower alkyl; and

R

13 is divalent alkyl radical of 2 to 5 carbons.

Other preferred compounds encompassed by U.S. Patent No. 5,917,082 are represented by Structural Formula (VI): R 2 R4 R2-- R, R 1 n(H2C)

B

2 2 R 3 R 1 R 1 R2 (VI), where: WO 2005/013949 PCT/US2004/025564 -38n is 1 or 2;

R

1 and R 2 independently are H, lower alkyl or fluoroalkyl;

R

3 is hydrogen, lower alkyl, -Cl or -Br;

R

4 is H, lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0Rin, -CH20COR 11 -CHO, -CH(ORI 2 2

-CHOR

1 30, -COR 7

-CR

7

(OR

1 2 2

-CR

7 0R 13 0, or tri-lower alkylsilyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; Rn is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and

R

1 3 is divalent alkyl radical of 2 to 5 carbons.

Another group of preferred compounds disclosed by U.S. Patent No.

5,917,082 is represented by Structural Formula (VII):

B(VII),

where:

R

4 is lower alkyl of 1 to 6 carbons; B is -COOH or -COORs; and R8 is lower alkyl of 1 to 6 carbons; and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of said double bonds, and pharmaceutically acceptable salts thereof.

WO 2005/013949 PCT/US2004/025564 -39- Yet another group of preferred compounds disclosed by U.S. Patent No.

5,917,082 is represented by Structural Formula (VIII): R2 R2 x

RB

(VIII),

wherein: X is S or 0; alternatively, X is NRs;

R

2 is hydrogen or lower alkyl;

R

3 is hydrogen or lower alkyl;

R

5 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0RI 1

-CH

2 0CORIn, -CHO, -CH(OR 12 2

-CHOR

13 0, -COR 7

-CR

7 (OR12)2, -CR 7 OR130, ortri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, such as an alkyl of 1 to 5 carbons, a cycloalkyl of 3 to 5 carbons or an alkenyl group containing 2 to 5 carbons; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl;

R

9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; Rn is lower alkyl, phenyl or lower alkylphenyl;

R

12 is lower alkyl; and

R

13 is divalent alkyl radical of 2 to 5 carbons.

Particularly preferred compounds encompassed by Structural Formula are represented by Structural Formulas and (XI): WO 2005/013949 PCT/US2004/025564

B

R3

(X)

R

3

(X)

B

x R3

(XI),

where: B is -COOH or -COOR 8

R

3 is hydrogen, lower alkyl, -Cl or -Br;

R

8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; and X is S or O.

When the compound is represented by Structural Formula R 3 is preferably H or methyl and B is preferably -COOH or -COOCH 2

CH

3 Particularly preferred compounds are represented by Structural Formula wherein R 3 is B is -COOH or -COOR, and R is lower alkyl of 1 to 6 carbons, and pharmaceutically acceptable salts thereof.

When the compound is represented by Structural Formula it is preferred that R 3 is -H and B is -COOH or -COOCH 2

CH

3 WO 2005/013949 PCT/US2004/025564 -41- When the compound is represented by Structural Formula it is preferred that R 3 is B is -COOH or -COOCH 2

CH

3 and X is O or S.

Additional compounds useful for treating cachexia, without limitation to the disease, disorder or condition with the cachexia is associated, are shown below.

One group of compounds useful in treating cachexia is represented by Structural Formulas (XIII), (XIV) or (XV):

(XIII)

(XIV)

(XV),

where: X is O, S, or (CRIRi)n; n is 0, 1 or 2; WO 2005/013949 PCT/US2004/025564 -42- Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:

(CRIR

1 )p RC--CRi

(XVII)

or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1- 6 alkyl or with 1 to 3 Ci- 6 fluoroalkyl groups; X is O, S or NH;

R

2 is independently lower alkyl of 1 to 6 carbons, -OR 1 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R 2 groups jointly represent an oxo group;

R

3 is hydrogen, lower alkyl of 1 to 6 carbons, -OR 1 fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2

-NH

2 -NHCO(Ci-C 6 )alkyl, or -NHCO(C 1

C

6 )alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CHzOR 1 1

-CH

2 0COR 1 1 -CHO, -CH(OR 1 2 2

-CH(OR

13

-COR

7

-CR

7

(OR

12 2

-CR

7

(OR

3 or -Si(C.-6 alkyl) 3

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl;

R

11 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl; WO 2005/013949 PCT/US2004/025564 -43-

R

1 3 is divalent alkyl radical of 2-5 carbons; and

R

1 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C 1 -Clo-alkylphenyl, naphthyl, Ci-Cio-alkylnaphthyl, phenyl-C 1 -Clo alkyl, naphthyl-C 1 -Co alkyl, C 1 -Clo-alkenylphenyl having 1 to 3 double bonds, Ci-Cloalkynylphenyl having 1 to 3 triple bonds, phenyl-C 1 -Clo alkenyl having 1 to 3 double bonds, phenyl-Ci-Clo alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by CORs, or R 14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C 1 to C 1 0 alkyl group, with a C 1 to Clo fluoroalkyl group, or with halogen, and the dashed line in Structural Formula (XVI) represents a bond or absence of a bond.

Another group of compounds suitable for treating cachexia is represented by Structural Formula (XVIII): R1 R1 Y(P) R R

(XVIII),

wherein: X is O, NR' or S; R' is alkyl of 1 to 6 carbons; Y is a bivalent cyclopropyl radical optionally substituted with one or two R 4 groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups optionally substituted with 1 to 4 R 4 groups; WO 2005/013949 PCT/US2004/025564 -44-

R

1 is independently alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons;

R

2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;

R'

2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;

R

3 is hydrogen, alkyl of 1 to 6 carbons, fluoro substituted alkyl of 1 to 6 carbons, halogen, alkoxy of 1 to 8 carbons, or alkylthio of 1 to 6 carbons, -NO 2 -NH2, -NHCO(Ci-C 6 )alkyl, -NHCO(C 1

-C

6 )alkenyl, -NR 1 H or -N(R 1 2 benzyloxy or Ci-C 6 alkyl-substituted benzyloxy;

R

4 is -H or alkyl of 1 to 6 carbons, or fluoro substituted alkyl of 1 to 6 carbons; m is an integer having the values of 0 to 3, and B is -COOH or a pharmaceutically acceptable salt thereof, -COOR s

-COOCH

2

COR

7 -CONRgRio, -CH 2 OH, -CH 2 0R 1

-CH

2 0COR 1

-CHO,

-CH(OR

12 2 -CH(ORi 3

-COR

7

-CR

7

(ORI

2 2

-CR

7

(OR

1 3 0),

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a group of 5 to 10 phenyl or lower alkylphenyl;

R

11 is lower alkyl, phenyl or lower alkylphenyl;

R

12 is lower alkyl; and

R

13 is divalent alkyl radical of 2-5 carbons.

Yet another group of compounds useful for treating cachexia is represented by Structural Formula (XIX): R2 R2 R2 R2

X,

I R3

A

(XIX),

WO 2005/013949 PCT/US2004/025564 wherein: Y is a bivalent radical having Formula or Formula (CRRi),p 0

R

1 C CR 1 RiC- CRI (b) or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1-6 alkyl or with 1 to 3 Ci-6 fluoroalkyl groups; p is an integer from 1 to 4; the two Xi groups jointly represent an oxo or thione function, or Xi is independently selected from H or alkyl of 1 to 6 carbons; the two X 2 groups jointly represent an oxo or a thione function, or X 2 is independently selected from H or alkyl of 1 to 6 carbons, with the proviso that one of the joint X 1 grouping or of the joint X 2 grouping represents an oxo or a thione function; W is H, O, C(RI) 2 phenyl, naphthyl, or 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with a C 1 to Clo alkyl group, with a C 1 to Clo fluoroalkyl group, or with halogen;

R

-NH

2

-NHCO(C

1

-C

6 alkyl, or vNHCO(Ci-

C

6 )alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9

R

1 o, -CH 2 OH, -CH 2 0R 1 -CH20COR 11 -CHO, -CH(OR 2 2

-CH(OR

13

-COR

7

-CR

7

(OR

12 2

-CR

7 (ORI30), or -Si(C- 6 alkyl) 3

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, WO 2005/013949 PCT/US2004/025564 -46-

R

8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl;

R

11 is lower alkyl, phenyl or lower alkylphenyl;

R

1 2 is lower alkyl;

R

1 3 is divalent alkyl radical of 2-5 carbons;

R

1 4 is H, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 -Clo-alkylphenyl, naphthyl, Ci-Clo-alkylnaphthyl, phenyl-Ci-Clo alkyl, naphthyl-C 1 -Clo-alkyl, C 1 -Clo-alkenylphenyl having 1 to 3 double bonds, CI-Cloalkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Co1 alkenyl having 1 to 3 double bonds, phenyl-C1-Clo alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by CORs, or R 1 4 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said carbocyclic aryl and heteroaryl groups being unsubstituted or substituted with a C 1 to C 1 o alkyl group, with a C 1 to Clo fluoroalkyl group, or with halogen; and the dashed line in Formula represents a bond or absence of a bond, provided that when the dashed line represents a bond then there are no Ri substituents on the carbons connected by said bond.

A further group of compounds suitable for treating cachexia is represented by Structural Formula (XX):

(XX),

WO 2005/013949 PCT/US2004/025564 -47wherein: X is O, S, or C(R)2; R is -H or alkyl of 1 to 6 carbons;

R

1 is alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-Ci-C 6 alkyl, or Ci-C 6 -alkylphenyl;

R

2 is alkyl of 1 to 6 carbons, -Cl, -Br, -CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, -Cl, -Br, -CF3, fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, benxyloxy, Ci-C 6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, C 1

-C

6 alkyl substituted phenyloxy, or halogen substituted phenyloxy;

R

4 is independently alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; m is an integer having the values 0 to 3; p is an integer having the values 0 to 4; A is -(CH2)q- where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, -COOH, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0RIt,

-CH

2

OCOR

11 -CHO, -CH(OR 12 2

-CHOR

1 30, -COR 7

-CR

7

(OR

12 2 -CR70R 13 0, or tri-lower alkylsilyl;

R

7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, Rs is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or Rs is phenyl or lower alkylphenyl;

R

1 1 is lower alkyl, phenyl or lower alkylphenyl; WO 2005/013949 PCT/US20041025564 48

R

12 is lower alkyl; and R1 3 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof.

Another group of compounds for treating cachexia is represented by Structural Formnulas (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVI1a) or (XXVIlIb): zx

R

3 R4

(XXI)

(XXIII)

WO 2005/013949 WO 2005013949PCIIUS200I/02556I 49 (XXI V)

(XXV)

(XXVI)

(XX VJ2D WO 2005/013949 PCT/US2004/025564

R

13 (XXVIIa) RI Ro R' R" R2\ R z R12 R18

I

R12 (XXVIab), wherein: RI and R2 each independently is hydrogen or lower alkyl or acyl having 1-4 carbon atoms; Y is C, O, S, N, CHOH, CO, SO, SO 2 or a pharmaceutically acceptable salt; R3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N; R4 is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, R 4 does not exist if Y is N, or neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO 2 R' and R" are hydrogen, lower alkyl or acyl having 1-4 carbon atoms, -OH, alkoxy having 1-4 carbon atoms, thiol or thioether, or amino, or R' or R" taken together form an oxo(keto), methano, thioketo, HO-N=, NC-N=, (R 7 Rs)N-N=,

R

17

R

17 epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or'halogen; R" and are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or and taken together form a cycloalkyl group having 3carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen; R5 is hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR 7

-NR

7 Rs, or -(CF)nCF 3 but R5 is not hydrogen if R6, Rio, Ri 1 R12 and RI 3 are all WO 2005/013949 PCT/US2004/025564 -51 hydrogen, Z, and are all carbon, and R' and R" represent H, OH, C 1

C

4 alkoxy or C 1

-C

4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group;

R

6 Rio, R 1 1

R

1 2 and R 1 3 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR 7

-SR

7

-NR

7 R or (CF)nCF 3 and exist only if the Z, or from which R 6 Rio, R 11 R1 or R 13 originates is C, or R 6 Rio, R 11

R

12 and R3 each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, or from which R 6 Rio, RI 1

R

12 or R13 originates is N, and where one of Rs, Rio, RI, Rt2 or R 1 3 is X;

R

7 represents hydrogen or a lower alkyl having 1-6 carbons; Rs represents hydrogen or a lower alkyl having 1-6 carbons; R9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or qhydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2- 4 R1 4 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;

R

1 7 is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyl, -OR 7 or -SR7, -R 9 alkyl carboxylic acid optionally substituted with halogen, acyl, -OR 7 or -SR 7 substituted, alkenyl carboxylic acid optionally substituted with halogen, acyl, -OR 7 or -SR, alkyl amine optionally substituted with halogen, acyl, -OR 7 or -SR7, or alkenyl amine optionally substituted with halogen, acryl, -OR 7 or -SR7; Rig represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro,

-OR

7

-SR

7

-NR

7

R

s or -(CF)nCF 3 X is -COOH, tetrazole, -PO 3 H, -SO 3 H, -CHO, -CH20H, -CONH2, -COSH,

-COOR

9 -COSR, -CONHR 9 or -COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or N on the ring; Z, and each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, and are not O or S if Z, or is attached by a double bond to one of Z, or or if one or more of Z, or is attached to one of Z, or that is O or S, and provided that one or more of Z, and are not N if one of Z, WO 2005/013949 PCT/US2004/025564 -52and is attached by a single bond to one of Z, and that is

N;

n is 0 to 3; and the dashed lines are optional double bonds.

In a particular embodiment, compounds of Structural Formula (XXI)- (XXVII) are administered to subjects having cachexia associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and sarcopenia.

Described below are additional groups of compounds that can be used in treating cachexia, without limitation as to the primary disease, disorder or condition with which the cachexia is associated.

A first group of compounds useful in treating cachexia is represented by Structural Formula (XXVIII): R7 R1 R2 COR3 CH3 Rs Rio R4 (XXVIII), where: the dotted bond is optional, provided that when: a) the dotted bond is present, R 1 is lower alkyl and R 2 is halogen, or R 1 and R 2 taken together with the carbon atoms to which they are attached form a 5 to 8 membered carbocyclic ring or a 5 to 8 membered heterocyclic ring containing one sulfur, oxygen or nitrogen atom, wherein when said ring is aromatic, the dotted bond is part of a mesomeric system, and b) the dotted bond is absent, R 1 and R 2 taken together are methylene, thereby forming a cis-substituted cyclopropyl ring; WO 2005/013949 PCT/US2004/025564 -53-

R

3 is hydroxy or lower alkoxy;

R

4

R

5 R and R 7 are, independently, hydrogen or lower alkyl; X is (>CRsR 9 )n; n is 1,2 or 3; Rg and R 9 are, independently, hydrogen or lower alkyl; and Rl 0 is hydrogen, alkyl or alkoxy; and pharmaceutically acceptable salts of carboxylic acids of Structural Formula

(XXVIII).

A second group of compounds useful in treating cachexia is represented by Structural Formula (XXIX): RI R2 R6 TCORa CH3 R4

R

(XXIX),

where: the dotted bond is either hydrogenated or forms a double bond, provided that: a) when the dotted bond forms a double bond, R 1 is lower alkyl and R 2 is hydrogen; and b) when the dotted bond is hydrogenated, R 1 and R 2 taken together are methylene to form a cis-substituted cyclopropyl ring;

R

3 is hydroxy or lower alkoxy;

R

4 is alkyl or alkoxy; and

R

5 and R 6 are, independently, a C4- 1 2 alkyl or a C5- 1 2 cycloalkyl substituent containing from 1-3 rings which are either unsubstituted or substituted with from 1-3 lower alkyl groups, with the carbon atom of Rs and R 6 being linked to the remainder of the molecule to form a quaternary carbon atom; or WO 2005/013949 PCT/US2004/025564 -54-

R

5 and Re are independently a C 4 1 2 alkyl group or a mono- or polycyclic 1 2 hydrocarbon group that are linked to the phenyl ring through a quaternary carbon atom, and pharmaceutically acceptable salts thereof.

A third group of compounds useful for treating cachexia are represented by Structural Formula (XXX): Y R2 I Ar z x

(XXX),

wherein:

R

1 is a hydrogen atom, a -CH3 radical, a -CH 2

OR

3 radical, a -CH20COR 4 radical, an -OR 5 radical, an -O(CH 2 )m(CO)nR 6 radical, a -COR 7 radical, a -COORs radical or an -S(O)pR 9 radical;

R

2 is a hydrogen atom or a halogen atom, a lower alkyl radical, an -NO 2 radical, an -OCOR 4 radical, an -OR 9 radical or a -NR 9 Rio radical; Ar is a radical selected from among those of the following formulae R2 (a) (b) 0 (c) 1 WO 2005/013949 PCT/US2004/025564

N

R X is or an -NR 9 radical; Y and Z are each or a radical -CR 1 IR1 2 m is an integer equal to 1, 2 or 3; n is an integer equal to 0 or 1; p is an integer equal to 0, 1, 2 or 3; t is an integer equal to 0, 1 or 2;

R

3 is a hydrogen atom or a lower alkyl radical; R4 is a lower alkyl radical; Rs is a hydrogen atom or a lower alkyl radical;

R

6 is a lower alkyl radical or a heterocycle;

R

7 is a hydrogen atom, a lower alkyl radical or an -NR'R" radical; R' and R" are identical or different, and are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical, or an amino acid or peptide or sugar residue, or R' and R" together form, with the nitrogen atom from which they depend, a nitrogen-containing heterocycle;

R

8 is a hydrogen atom, a linear or branched alkyl radical having from 1 to carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, or a sugar residue or an amino acid or peptide residue; R9 is a hydrogen atom or a lower alkyl radical; Rio is a hydrogen atom or a lower alkyl radical;

R

11 is a hydrogen atom or a lower alkyl radical;

R

1 2 is a hydrogen atom or a lower alkyl radical, with the proviso that Y and Z are not simultaneously each an oxygen atom or an radical.

A fourth group of compounds useful for treating cachexia are represented by Structural Formula (XXXI):

Z-(CR

3

=CR

2 ),-COOR' (XXXI) WO 2005/013949 PCT/US2004/025564 -56where: R' is hydrogen or a carboxyl-protecting group;

R

2 and R 3 are each independently hydrogen atom, halogen, linear lower alkyl, branched lower alkyl, linear lower alkoxy, branched lower alkoxy or aryl; n is an integer of 1 to 3; nR 2 's or nR 3 's are the same or different from one another; and Z is a group represented by one of the following formulas: X, A 1 -D

YB

X2N

E

Y ,and

X

3

Y

3 A, B and D are each carbon, nitrogen, sulfur or oxygen, where the carbon or nitrogen atoms are optionally substituted; Xi and Y 1 are each independently hydrogen, -NR 4

R

5

-CR

6

R

7

R

8

-OR

9

-SR

1 o, -S(O)R 1 or -S(O)2R12, or alternatively XI and Yi together with the carbon atoms to which they are bonded form an optionally substituted, saturated or unsaturated ring optionally containing oxygen, sulfur and/or nitrogen, and the substituents on the saturated or unsaturated ring are optionally united to form a saturated or unsaturated ring optionally containing oxygen, sulfur and/or nitrogen;

R

4 and R s are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl, or optionally when A or B is a carbon atom optionally bearing a substituent, R 4 or R 5 together with the substituent of A or B form a ring; WO 2005/013949 PCT/US2004/025564 -57-

R

6

R

7 and R 8 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and

R

9

R

1 0 R" and R 12 are each independently hydrogen, linear lower alkyl or branched lower alkyl; E is a carbon or nitrogen; F and G are each independently carbon, nitrogen, sulfur or oxygen, where the carbon or nitrogen atoms are optionally substituted;

X

2 and Y 2 are each independently hydrogen, -NR" 3

R

14 -CR R1 6 R17, -OR 18

-SR

19

-S(O)R

20 or -S(0) 2

R

21 or alternatively X 2 and Y 2 taken together form an optionally substituted, saturated or unsaturated ring optionally containing oxygen, sulfur and/or nitrogen;

R

1 3 and R 1 4 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R 1 5

R

1 6 and R 17 are each independently hydrogen, linear lower alkyl or branched lower alkyl; R R 20 and R 21 are each independently hydrogen, linear lower alkyl or branched lower alkyl;

X

3 and Y 3 are each independently hydrogen, linear or branched lower alkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl, fluoroalkyl or halogeno; and the symbol represents a single bond or a double bond, with the proviso that where Z is not

F

SG or

G

A fifth group of compounds suitable for treating cachexia are represented by Structural Formula (XXXII): WO 2005/013949 PCT/US2004/025564 -58-

(XXXII),

where:

R

1 and R 2 are each independently hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, or alternatively R 1 and R 2 are united to form a 5- to 7-membered cycloalkyl group which is substituted with a lower alkyl group and optionally contains sulfur, oxygen, sulfinyl, sulfonyl or NR 3

R

3 is hydrogen or lower alkyl; the broken line moiety represents a single bond or a double bond; A represents R, N R2

N

R1 2' o^

R,

R2A N S 2

N

R3 B represents WO 2005/013949 PCT/US2004/025564 59

R

6 R 6

R

1 3 NN N R7/- N-

RR

R3R 6 \R 7 N N

R

6 is hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R

13 is hydrogen, lower alkyl or lower alkoxy;

R

7 is -EC(=0)R8; E is aryl, heteroaryl or

R

12 RIand RI 2 are each hydrogen or lower alkyl;

N--F

WO 2005/013949 PCT/US2004/025564 60 M isan integer ofi1 to 3;

R

8 is hydrogen, hydroxyl, lower alkoxy or -NR 9 RIO; and

R

9 and Ric are each independently hydrogen, hydroxyl, lower alkyl, lower alkoxy, hydroxyalkyl, aryl, hydroxyaryl or heteroaryl, or alternatively R 9 and RIO together with the nitrogen atom to which they are bonded may form a ring optionally containing nitrogen, oxygen or sulfur.

Additional compounds useful for the treatment of cachexia are represented by Structural Formulas (XXXIII)-(XXXVI): mn(R36 111111 I-~WxR

R

37

R

3 8\ 5QO 2 R31

I

R3

(XXXV)

WO 2005/013949 PCT/US2004/025564 61 R(3 2

R

4 4 5 9

R

63 M 1 C0R 40

R

65 R 67 H64

(XX-XVI)

R R2 R 9 R44R4

R

37

R

3 R4 R 10 (XXXVII), where: RI through R 4 each independently are hydrogen, a CI-C 6 alkyl or a C-I arylalkyl or heteroarylalkyl;

R

5 is a C 5 -CIO alkyl, heteroalkyl, aryl, heteroaryl, a C 7

-C

15 arylalkyl or heteroarylalkyl, -NR 6

R

7 or -ORs, where R 6 and R 7 each independently are a C 7 -Clo alkyl, heteroalkyl, a C 7

-C

1 5 arylalkyl or heteroarylalkyl, a C 3 -Cl 0 acyl, provided that only one of Rr, or R 7 is acyl, or R 6 and R 7 taken together are C 3

-C

6 cycloalkyl, and where Rs is a C 7 -Cl 0 alkyl, heteroaficyl, aryl, heteroaryl, or a C 7

-CI

1 5 arylalkyl or heteroarylalkyl;

R

9 and RIO each independently are hydrogen, a C 1 -Clo alkyl, halogen, heteroarylalkyl, -INR 1 1

R

1 2

NO

2 or -OR 13 where R, I and R12 each independently are hydrogen, a C I-C 10 alkyl, heteroalkyl, a C 7 -C 15 arylalkyl or heteroarylalkyl, a C I- Cg acyl, provided that only one of R, I or RI 2 is acyl, or R, 1 and RI 2 taken together are a C 3

-C

6 cycloalkyl, and where R13 is hydrogen or a CI-Clo alkyl, heteroalkyl or a arylalkyl or heteroarylalkyl;

R

14 and R 15 each independently are hydrogen, a C 1

-C

10 alkyl, a CI-C8 acyl, or

OR

1 6 where R 16 is hydrogen or a C 1 -Cj 0 alkyl; or R 14 and R13 taken together are keto, methano, optionally substituted oxime, optionally substituted hydrazine, optionally substituted epoxy, 1 ,3-dioxolane, 1 ,3-dioxane, 1 ,3-dithiolane, 1,3dithiane, oxazolidine or: WO 2005/013949 PCT/US2004/025564 -62

R

1 7

R

18 R1 o \R 21 I111,R23) k where the dashed lines crossing the bonds indicate the attachment bonds to the rings adjacent to R(14 and R 15

R.

17 and R.

1 8 each independently are hydrogen, a CI-Cio alkyl, heteroalkyl, aryl, a C7-CI 5 arylalkyl or heteroarylalkyl. or R17 and R 18 taken together are a C 3

-C

6 cycloalkyl;

R

19 is hydrogen, a CI-CI 0 alkyl, heteroalkyl, aryl, heteroaryl, a C 7

-C

1 arylalkyl or heteroarylalkyl;

R

20 through R.

23 each independently are hydrogen, halogen, a C, -CIO alkyl, heteroalkyl, aryl, heteroaryl, a C?-C 15 arylalkyl or heteroarylalkyl, -NR 2 4R 25

-NO

2 or -OR 2 6 where R.

24 and R(25 each independently are hydrogen, a C 1

-C

10 alkyl, heteroalkyl, a C 7

-CI

5 arylalkyl or heteroarylalkyl or a Cl-CR acyl, provided that only one of R24 orRP 25 is acyl, and where R 26 is hydrogen or a CI-C 10 alkyl, heteroalkyl, aryl, heteroaryl, or a C 7

-CI

5 arylalkyl or heteroarylalkyl; R27 through R31 each independently are hydrogen, a CI-Cio alkyl, heteroalkyl, halogen, -NR 32

R

33

-NO

2 or -OR 34 where R 32 and R(33 each independently are hydrogen, a CI-Cio alkyl, a C 7

-C

15 arylalkyl or heteroarylalkyl, a C I-C 8 acyl, provided that only one of R(32 or R(33 is acyl, or R(32 and R(33 taken together are a C 3

-C

6 cycloalkyl, and where R 34 is hydrogen or a CI-CIO alkyl, heteroalkyl or a C 7

-C

1 5 arylalkyl or heteroarylalkyl and exist only when W is C; through R 38 each independently are hydrogen, a CI-C 2 alkyl or -OR 39 where R(39 is hydrogen or a CI-Clo alkyl, or R(35 and R(36 or R 37 and 1(3g taken together are keto, or R 35 and 1R36, R 37 and 1(38, R(35 and R(37 or R 36 and R(38 taken together are epoxy; C0R 40 can originate from any W when the originating W is C, and R.

40 is

-OR

41 or -NR 42

R

43 with R(41 being hydrogen, a CI-C 6 alkyl or a C 7

-CI

5 arylailkyl or heteroarylalkyl, and with R4 and R43 each independently being hydrogen, a CI -C 6 alkyl, a C 7 -CIS arylalkyl or heteroarylalkyl, aryl, ortho-, meta, or para-substituted hydroxyari, or taken together are a C 3

-C

6 cycloalkyl; WO 2005/013949 PCT/US2004/025564 63

R

44 and R45 each independently are hydrogen, a CI-C 4 alkyl or -CH 2 0R 46 where R 46 is hydrogen or a CI-C 6 alkyl, or R44 and R45 taken together are a 3C cycloalkyl or cycloheteroalkyl;,

R

4 7 is hydrogen, a CI-C 4 alkyl, or when R47 taken together with R 44 or

R

45 is a C 3

-C

6 cycloalkyl or cycloheteroalkyl; R~s and R49 each independently are CI-C 4 alkyl;

R

50 is a C 4

-CI

0 alkyl, keteroalkyl, aryl, heteroaryl, a C 7

-C

1 5 arylalkyl or heteroarylalkyl, -NR 51

R

52 or -OR 53 where R 51 and R 52 each independently are a C 2 CIO alkyl, heteroalkyl, a C 7

-CI

5 arylailkyl or heteroarylalkyl, a C 3 -Clo acyl, provided that only one of R 51 or R 52 is acyl, or R 51 and R 52 taken together are C 3

-C

6 cycloalkyl, and where R 5 3 is a C 7 -Cio alkyl, heteroalkyl, aryl, heteroaryl, a C 3

-C

6 alkyl, heteroalkyl, aryl or heteroalkyl. or a C 7

-C

15 arylalkyl or heteroarylalkyl;

R

54 represents:

WW

I

1 C0R 40 where R 9 Rio, R 14

R

15 and R 40 have the definitions given above;

R

55 through R 5 g each independently are hydrogen, halogen, a Cl-C 10 alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -Cls arylalkyl or heteroarylalkyl, -NRs 9

R

6 o or

-OR

61 where R 59 and R 6 o each independently are hydrogen, a C 1 -Clo alkyl or heteroalkyl, a C 7 -CI 5 arylalkyl or heteroarylalkyl, a C, -C 8 acyl, provided that only one of R 5 9 or R 6 o is acyl, or R 59 and R 60 taken together are C 3

-C

6 cycloalkyl, and where R 61 is hydrogen or a Ci-C 10 alkyl, hecteroalkyl, aryl, heteroaryl, or a C-I arylalkyl or heteroarylalkyl, or where R 55 and R 56 or R 57 and R 58 taken together are keto, methano, a Cl-Cio alkyl methylene, a C 1 -Clo dialkylmnethylene, C 7

-C

1 arylalkyl or heteroarylalkylmethylene, oxime, 0-alkyl oxime, hydrazone, 1,3dioxolane, 1,3-dioxane, 1,3-dithiolane, 1 ,3-dithiane, oxazolidine, or R 5 5 and R 57 or R56 and R 5 S taken together are epoxy; WO 2005/013949 PCT/US2004/025564 -64-

R

62 through R 6 4 each independently are hydrogen, aryl, heteroaryl, -CF3, a C2-C6 alkyl, C 2

-C

6 heteroalkyl or -NRs 5

R

52 where R 5 l and R 5 2 have the definitions given above;

R

65 is hydrogen, a C 1

-C

2 alkyl or -OR 66 where R 66 is a C 1

-C

2 alkyl;

R

67 is a C 4

-C

10 alkyl, heteroalkyl, aryl, heteroaryl, a C 7

-C

15 arylalkyl or heteroarylalkyl, -NR 5 sR 52 or -OR6, where R51 and R 5 2 have the definitions described above, and where R 6 8 is a C 3 -Co1 alkyl, heteroalkyl, aryl, heteroaryl, or a

C

7

-C

1 5 arylalkyl or heteroarylalkyl; X and Y each independently represent C, O, S, N, SO or SO 2 provided, however, that when X or Y are O, S, SO or SO 2 then either Ri and R 2 or R3 and R 4 respectively do not exist, and further provided, that when X or Y is N, then one each of Ri and R2 or R 3 and R 4 respectively, does not exist; M is N or C; Q is N or C; Z is O, S, SO, SO 2

CR

69

R

70 or NR 7 1 where R 69 through R71 each independently are hydrogen or a C-Co alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, or R 69 and R70 each independently are -OR 71 or R 6 9 and R7o taken together are a cycloalkyl; each W is independently C, N, S or O, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another W or if attached to another such W which is O or S, and is not N if attached by a single bond to another such W which is N; m is 0, 1 or 2 carbon atoms; n is 0 or 1 carbon atoms; k is 1 to 5 carbon atoms; the dashed lines in the structures, other than at R 14 and Ris, represent optional double bonds, provided, however, that the double bonds are not contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and the wavy lines represent olefin geometry that is either cis or trans and unless otherwise indicated, for substituents Ri through R71, all olefin geometric isomers cis or trans of the above compounds are included.

WO 2005/013949 PCT/US20041025564 65 Yet another group of compounds suitable for treating cachexia is represented' by Structural Formula (XXXVIII):

R

2

R

9

R

14

R

15 R2 R 3 R R 0

R

0

XXVI)

where: al vrible i th srucurs ae s dfind bov fr Sruturl ormla (XX)(XVwtthexetoofnwvralR 7 ,wihiaC-C 0 ak, hetrolky, Ry37eeorl 15 ayaklo eeorlakl R 3 7 ,o R l aibe ntesrcue r sdfndaoefrStructural Fornulas(XI) V\54 ~(XXIX), where: R44 through R 47 and R 62 through R 68 M, W and n each have the definitions given above for Structural Formulas (XXIII)-(XXXVID, or R 62 and R 63 R6 3 and

R

65 or R 65 and R64 taken together are: WO 2005/013949 PCT/US2004/025564 -66- R3 R2

R

36 R 3

X

R38

R

3 R" where R 1 through R 4 R35 through R 39 X, Y and m have the definitions given above for Structural Formulas (XXXIII)-(XXXVII) and the dashed lines crossing the bonds adjacent to X and Y indicate the points of attachment at R 62 and Re3, R 6 3 and

R

65 or R 65 and R 64

R

76 is:

R

27 'W eR2 8 R49 W

R

31 W COR40R29

COR

40

I

or

R

3 0 where R 27 through R 3 4

R

40 through R4 3

R

49 W and n have the same definitions given above for Structural Formulas (XXXIII)-(XXXVII) and the dashed lines crossing the bonds adjacent to R 49 and R 27

/R

31 indicate the points of attachment at R76; other than as indicated above for points of attachment, the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency; and the wavy lines represent olefin geometry that is either cis or trans and unless otherwise indicated, for substituents R 1 through R 76 all olefin geometric isomers cis or trans of the above compounds are included.

Yet another group of compounds useful in treating cachexia are represented by Structural Formulas (LX) and (LXI): WO 2005/013949 PCT/US2004/025564 67 H0 2 C R Ra R6 R2

R

3

OR

7 P-4

(LX)

H0 2 C R 9

R

8 Y R 6 R 3

OR

7

R

4 (LXI), where: R, is selected from the group of hydrogen, -Cl, -Br, C I-C 3 alkyl, C 1

-C

3 haloalkyl, C 2

-G

3 alkenyl, C 2

-G

3 haloalkenyl, C 2

-C

3 alkynyl, C 2

-C

3 haloalkynyl, and

CI-C

3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, halo alkenyl, alkynyl, haloalkynyl, and alkoxy groups are optionally substituted;

R

2 and R 4 are independently selected from the group of hydrogen, -NRI 0 RI 1

CI-C

6 alkyl, CI-C 6 haloalkyl, C 3 -CS cycloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 haloalkenyl,

C

2

-C

6 alkynyl, C 2

-C

6 haloalkynyl, aryl, heteroaryl, C1-C 6 alkoxy, and aryloxy, WO 2005/013949 PCT/US2004/025564 -68wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups are optionally substituted;

R

3 is selected from the group of hydrogen, Ci-C 6 alkyl, C 1

-C

6 haloalkyl, C 3 Cs cycloalkyl, C 2

-C

6 alkenyl, Cz-C 6 haloalkenyl, C 2

-C

6 alkynyl, C 2

-C

6 haloalkynyl, aryl, heteroaryl, C 1

-C

6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups are optionally substituted;

R

5 and R6 are independently selected from the group of hydrogen, -Cl, -Br, -CN, -NH 2 -OH, -SH, C 1

-C

6 alkyl, Ci-C 6 haloalkyl, C 2

-C

6 alkenyl, C 1

-C

6 haloalkenyl, C 1

-C

6 alkoxy, and aryloxy wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups are optionally substituted; or

R

5 and R 6 taken together form a three- to eight-membered carbocyclic ring, a three- to eight-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein said carbocyclic ring, heterocyclic ring, aryl and heteroaryl groups are optionally substituted;

R

7 is selected from the group of C 2

-C

6 alkyl, C 2

-C

6 alkenyl, and C 2

-C

6 haloalkyl, wherein said alkyl, alkenyl, and haloalkyl groups are optionally substituted; Rs is selected from the group of hydrogen, -Cl, -Br, I, -CN, Ci-C 6 alkyl,

C

1

-C

6 haloalkyl, C 2

-C

6 alkenyl, C 2

-C

6 haloalkenyl, C 2

-C

6 alkynyl, C 1

-C

6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups are optionally substituted;

R

9 is selected from the group of hydrogen, -Cl, -Br, methyl, and optionally substituted methyl; Rio and R 11 each independently is hydrogen or optionally substituted CI-C 6 alkyl; or Rio and Rn taken together with nitrogen form an optionally substituted fiveor six-membered heterocyclic ring; Y is selected from the group ofNR 12 O and S; and

R

1 2 is selected from the group of hydrogen, optionally substituted C 1

-C

6 alkyl, and optionally substituted C 1

-C

6 haloalkyl; and pharmaceutically acceptable salts thereof WO 2005/013949 PCT/US2004/025564 -69- Additional compounds suitable for treating cachexia are represented by Structural Formula (LXII), including pharmaceutically acceptable salts, solvates and hydrates thereof:

R

R A R 6 0 R2 R4 R5 R1 R R (LXII) In Structural Formula (LXII), R is selected from the group of hydrogen, -F, -Cl, -Br, Ci-C 3 alkyl, Ci-C 3 haloalkyl, C 2

-C

3 alkenyl, C 2

-C

3 haloalkenyl, C 2

-C

3 alkynyl, C 2

-C

3 haloalkynyl, and CI-C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups are optionally substituted;

R

1 and R 2 are each, independently, a halo, a Ci-Clo alkyl, a C 3

-C

10 cycloalkyl, a C 5 -Clo cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1

-C

6 -alkyl, or an amino group represented by the formula

-NR

14

R

1 5 wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1

-C

3 alkyl, Ci-C 3 haloalkyl or C1-

C

3 alkoxy; or Ri and R 2 taken together with the carbon atoms to which they are attached form a five or six membered carbocyclic ring which is optionally substituted with one or more halo or C 1

-C

6 alkyl groups. R 14 and R 1 5 are each, independently, H, a C 1

-C

6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 heterocycle.

Alternatively, R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a Cs-Cs cycloalkyl or C 5 -Cs cycloalkenyl ring in which the aryl, heteroaryl, C 5 -C cycloalkyl or C 5

-C

8 cyclolkenyl are optionally substituted with one or more halo, C 1

-C

3 alkyl, Ci-C 3 haloalkyl or C1-C3 alkoxy substituents. Preferably, when R and R 1 together with the carbon atoms to which they are attached form an aryl or a heteroaryl, the aryl and heteroaryl have from five to six atoms.

R

3 is a halo, a CI-C 1 o alkyl, a C 3

-C

10 cycloalkyl, C 5

-C

1 o cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-Ci-C6-alkyl, or an WO 2005/013949 PCT/US2004/025564 amino group represented by the formula NR 1 4

R

15 wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1

-C

3 alkyl, Ci-C 3 haloalkyl or C 1

-C

3 alkoxy.

R4 is a halo, an aryl-C1-C 6 -alkyl, a Ci-Clo alkyl or a Ci-Clo alkoxy group wherein the arylalkyl, alkyl, and alkoxy are optionally substituted with one or more substituents selected from halo, C 1

-C

6 alkyl, aryl, heteroaryl, a C 1

-C

6 alkoxy, an amino group represented by the formula -NR 1 4

R

1 5 Preferably, the aryl and the heteroaryl substituents each, independently, have from five to ten atoms.

Alternatively, R. and R 4 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5

-C

8 cycloalkyl or a C 5

-C

8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1

-C

3 alkyl, C 1

-C

3 haloalkyl or C 1

-C

3 alkoxy substituents. Preferably, when R 3 and R 4 together with the carbon atoms to which they are attached form an aryl or a heteroaryl, the aryl and heteroaryl have from five to ten atoms.

R

5 is a halo, or a CI-C 3 alkyl group which is optionally substituted with one or more halo.

R

6 is -H or halo.

R

16 is -OR 17

-OCH(R

17 )OC(O)Ris, -NR 1 9

R

20 or an aminoalkyl.

Ri7, R 19 and R 2 0 are each, independently, -H or a C 1

-C

6 alkyl.

RIs is a C 1

-C

6 alkyl.

Ring A is a heteroaryl group represented by the following structural formula: In ring A, Xi and X 2 are each, independently, 0, S, N, NH, or CH.

X

3 is N or C.

X

4 is CH or N.

p is 0 or 1.

However, when Xi is O or S, then X 2 is CH or N and p is 0.

WO 2005/013949 PCT/US2004/025564 -71- Ring A is optionally substituted with one or more substituents selected from a halo, a CI-C 6 alkyl, or a C 1

-C

6 alkoxy.

Additional compounds for use in treating cachexia, without limitation as to the disease, disorder or condition with which it is associated, are disclosed in the following documents: U.S. Patent Nos. 5,770,378, 5,770,382, 5,770,383, 5,917,082, 6,048,873, 6,093,838, 6,403,638, 6,534,545 and 6,624,154; U.S. Patent Application Publication No. 20030166932; Published International Applications WO 93/21146, WO 94/12880, WO 94/17796, WO 97/12853; WO 98/22423, WO 99/06036, WO 99/58486, WO 99/58487, WO 00/020370; WO 01/070662, WO 02/071827 and WO 03/027090; and European Patent Application No. 947496, the contents of which are incorporated herein by reference. Also, the following documents disclose compounds for use in treating cachexia: V.R. Atigadda, et al. Abstracts ofPapers, 226th ACS National Meeting, New York, NY, United States, September 7-11, 2003 (2003); P.Y. Michellys, et al., Journal ofMedicinal Chemistry (2003), 46(13), 2683- 2696; L.J. Farmer, et al., Bioorganic Medicinal Chemistry Letters (2003), 13(2), 261-264; B. Dominguez, et al., Bioorganic Medicinal Chemistry Letters (2002), 12(18), 2607-2609; B.M. Forman, et al., Journal of Biological Chemistry (2002), 277(15), 12503-12506; M.I. Dawson, et al., Current Medicinal Chemistry (2002), 623-637; V.R. Atigadda, et al., Abstracts ofPapers, 223rdACS National Meeting, Orlando, FL, United States, April 7-11, 2002 (2002); A.M. Standeven, et al., Biochemical Pharmacology (2001), 62(11), 1501-1509; M.M. Faul, et al., Abstracts ofPapers, 222nd A CS National Meeting, Chicago, IL, United States, August 26-30, 2001 (2001); V. Vuligonda, et al., Journal of Medicinal Chemistry (2001), 44(14), 2298-2303; M. Ebisawa, et al., Chemical Pharmaceutical Bulletin (2001), 49(4), 501-503; K. Ohta, et al., Chemical Pharmaceutical Bulletin (2000), 48(10), 1504-1513; M.I. Dawson, Bioorganic Medicinal Chemistry Letters (2000), 10(12), 1311-1313; S.S. Koch, et al., Journal ofMedicinal Chemistry (1999), 42(4), 742-750; S. Hibi, et al., Journal ofMedicinal Chemistry (1998), 41(17), 3245-3252; L.J. Farmer, et al., Bioorganic Medicinal Chemistry Letters (1997), 7(21), 2747-2752; L.J. Farmer, et al., Bioorganic Medicinal Chemisty Letters (1997), 7(18), 2393-2398; A.M. Standeven, et al., Biochemical Pharmacology (1997), 54(4), 517-524; R.L. Beard, et al., Journal of Medicinal Chemistry (1996), WO 2005/013949 PCT/US2004/025564 -72- 39(18), 3556-3563; V. Vuligonda, et al., Bioorganic Medicinal Chemistry Letters (1996), 213-18; Y. Katsuta, et al., Chemical Pharmaceutical Bulletin (1994), 42(12), 2659-61; M.F. Boehm, et al., Journal ofMedicinal Chemistry (1994), 37(18), 2930-41; and M.F. Boehm, et al., Journal ofMedicinal Chemistry (1995), 38(16), 3146-55, the contents of which are incorporated herein by reference.

Examples of compounds disclosed in the documents listed in the above paragraph include:

OH

Bu-t Et (R 4) (R 3)m CO 2H N- Y(R 2

)AB

X 1 Me Me

II

where: X is O, S, or C(R)2; R is H or alkyl of 1 to 6 carbons;

R

1 is H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-C 1

-C

6 alkyl, or Ci-C 6 -alkylphenyl;

R

2 is H, alkyl of 1 to 6 carbons, -dl, -Br, -CF 3 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, -Cl, -Br, -CF3, fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons; benxyloxy, Ci-C 6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, C 1

-C

6 alkyl substituted phenyloxy, or halogen substituted phenyloxy;

R

4 is independently alkyl of 1 to 6 carbons, or -F; WO 2005/013949 PCT/US2004/025564 -73- Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; m is an integer having the values 0 to 3; n is an integer having the values 0 to 4; A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is hydrogen, -COOH, -COOR 8

-CONRR

10

-CH

2 0H, -CH 2

OR

1 -CHO, -CH(OR 12 2

-CHOR

30

-COR

7

-CR(OR

12 z

-CR

7

OR

13 0, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R 9 and R 1 0 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R" is lower alkyl, phenyl or lower alkylphenyl, R 2 is lower alkyl, and

R

1 3 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts.

R

COOH

where the R groups attached directly to the phenyl ring are isopropyl or 1,1 dimethylpropyl and the R group attached to oxygen is methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl or butyl.

WO 2005/013949 WO 2005013949PCIIUS200I/02556I -74- ~:iix z

R

2 2

R

3

R

21

R

2

G

R zI R16 R17 R1

R'R

R111 R'I I me R6R 1 7

D

III

IV

R

1 8

V

E RN R 1 8

R

1 8 0 CO02H V I VII including salts, solvates, and physiologically functional derivatives thereof, where: WO 2005/013949 PCT/US2004/025564 X is CR' or N, where R' is halogen, H, or CH3; Z is O, S, or NH; M is N, C, or CR 2 when M is N, the ring in which M is located is nonaromatic, when M is C, the ring in which N is located is aromatic, when M is CR 2 then R 2 is H or Y(CH 2 )nR 6 and the A ring is non-aromatic; Y is O or CH2; when n is 0 to 6, R 6 is alkyl, or -CF 3 but when n is 2 to

R

6 is H, alkyl, -CF 3

-SO

2

NHR

23

-NHSO

2

R

23 or -NR23R 24 where R 23 is alkyl, aryl optionally substituted, heteroaryl optionally substituted or combined with R 24 to form a ring of 3-7 atoms; and R 24 is alkyl, cycloalkyl or combined with R 23 to form a ring of 3 to 7 atoms; G is -C0 2

R

7

-SOR

7 -P0 3

R

7 -CONHOH, or (R)z (R)y where the broken line represents an optional double bond; J is -CHO, -C0 2

R

7

-SO

3

R

7

-PO

3

R

7 -CONHOH, or J forms a thiazolidinedione ring with R8; R 7 is -H or alkyl;

R

8 and R 9 are independently halogen, alkyl, or -CF3; y and z are each 0, 1, or 2; Q is CR 4

CR

4

R

5 0, NR, or S, where R 4 and R 5 are independently H or alkyl, provided that when Q is CR 4 the A ring is aromatic; Ro 1 is alkyl, -COR", -CONHR", -CO 2

R

11

-CONR"R

1 2

-SO

2

R

1 aryl, or cycloalkyl;

R"

1 and R 1 2 are independently alkyl or cycloalkyl;

R

3 is wherein D is CRR 1 4 O, S, NR1 5 CHOH, CO, SO,S0 2 where R 1 3 and R 14 are independently H, alkyl, or cycloalkyl; and where R15 is H, alkyl, or cycloalkyl; D' is (CH 2

R'

6 and R 1 7 independently are C1-4 alkyl, cycloalkyl, or together form a carbocyclic ring having from 3 to 7 atoms; R is is -OR, halogen, -CF 3 alkenyl, -SR 1 6 C.4 alkyl, -CO2R 16

-COR

1 or -NR 6 R 17 where R 16 and R 1 7 are as above defined; m is 0 or 1; or R3 is where R 1 8 is as defined above; or WO 2005/013949 PCT/US2004/025564 -76-

R

3 is where M 2 is C or N, provided however that the optional double bond represented by the broken line is optionally present only when M 2 is C; each

R

19 is, independently, H or alkyl; y and z are as defined above; or

R

3 is where each R 1 8 is, independently, as defined above; and M 3 is

C(R

6 3 or N(R 16 2 when M 3 is N(R 6 2 an R 1 6 may combine with an R' 8 to form a or 6-membered ring; and G' and E react to form a bond.

XYR 1 in which: X represents: either a divalent radical of following formula: (a) and Y then represents a divalent radical of following formula: (ii) or a divalent radical of formula: (c) and Y then represents either a divalent radical corresponding to the divalent radical of formula above or one of the divalent radicals of following formula: WO 2005/013949 PCT/US2004/025564 -77-

OR

3 (d) (f Z being or >N-R 3

R

1 represents -CH 3

-(CH

2 )p-OR 4

-(CH

2

),-COR

5 or -S(O)t-R 6 p being 0, 1, 2 or 3, t being 0, 1 or 2,

R

2 represents H or lower alkyl,

R

3 represents H, lower alkoxy or -OCOR 7

R

4 represents H, lower alkyl, -COR 7 aryl, aralkyl, mono- or polyhydroxyalkyl, or a polyether radical, Rs represents H, lower alkyl, -OR 8 or -Nr'r",

R

6 represents H or lower alkyl,

R

7 represents lower alkyl, Rs represents H, alkyl, alkenyl, alkynyl, aryl, aralkyl, mono- or polyhydroxyalkyl, a sugar residue or an amino acid residue, r' and identical or different, represent H, lower alkyl, -COR 7 aryl, a sugar residue or an amino acid residue or r' and taken together, form a heterocycle, and the salts of the compounds of formula when Ri represents a carboxylic acid group, and the geometrical and optical isomers of the compounds of formula WO 2005/013949 WO 2005013949PCIIUS200I/02556I -78me Me CO 2H I Me OH CO 2 H where the left hand compound corresponds to Structural Formula (LXII) above CH 2 WO 2005/013949 WO 205/03949PCT/US2004/025564 79 t -Bu CO 2 R Bu- t CO 2 R

III

where R is a salt of the carboxylic acid or lower alkyl; and R 1 is methyl, ethyl or n-propyl OPr-n 'CO 2 H 11 Me CO2 H Me Me WO 2005/013949 PCT/US2004/025564 CO 2 If Me Me

K-

Me me CO 2 H Me meN Me Me Me x

R

3

R

4 having 1-4 carbon atoms; Y represents C, 0, S, N, CHOH, GO, SO, SO 2 or a pharmaceutically acceptable salt; WO 2005/013949 PCT/US2004/025564 -81-

R

3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;

R

4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R 4 does not exist ifY is N, and neither R 3 or R 4 exist ifY is S, O, CHOH, CO, SO, or SO2; R' and R" represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino, or R' or R" taken together form an oxo (keto), methano, thioketo, HO-N=, NC-N=, (R 7

R

8 epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;

R

5 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro,

-OR

7

-SR

7

-NR

7

R

8 or -(CF)nCF 3

R

6 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro,

-OR

7

-SR

7 -NR7R or -(CF)nCF3;

R

7 represents hydrogen or a lower alkyl having 1-6 carbons;

R

8 represents hydrogen or a lower alkyl having 1-6 carbons; X is -COOH, tetrazole, -PO 3 H, -SO 3 H, -CHO, -CH20H, -CONH 2

-COSH,

-COOR

9

-COSR

9

-CONHR

9 or -COOW where R 9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, qchlorophenyl, q- fluorophenyl, or q-iodophenyl, where q=2-4, where W is a pharmaceutically acceptable salt; and n 0-3.

Me Me S Me CO 2 H Me Me WO 2005/013949 WO 2005013949PCIIUS200I/02556I 82 HO 2C.

R

2

H

1 i CO 2 R1 me Me H "N.c

R

1

R

4 Me Me Me Me

III

where: R is a carboxylic acid salt or lower alkyl;

R

2 is methyl, ethyl or propyl;

R

3 is methyl, ethyl or propyl;

R

4 is lower alkyl; and

R

5 is lower alkyl.

WO 2005/013949 WO 2005013949PCIIUS200I/02556-I 83 CO 2 H I CO 2H 11 Me Me CO 2 H Mee Me Me where Y is -OH, -0C11 3 -N11N11 2 or -H and Z is -NHC(O)NH- or Me. me n- Pr CO 2 H Me Me WO 2005/013949 PCT/US2004/025564 84- [R 3] [R 2]1 I l: N-Y(R 2

-A-B

0 11I [Rn 2] 0 J N-Y(R 2 -A-B3

II

Me Me MeI

N

o CO 2 H Pr-i I where:

R

1 is H, alkyl of 1 to 10 carbons, phenyl, heteroaryl, phenyl-C 1

-C

6 alkyl, Cj- C6-alkylphenyl, heteroaryl-C 1

-C

6 alkyl, Cl-CG-alkylheteroaryl where heteroaryl is selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl;

R

2 is independently H, alkyl of 1 to 6 carbons, -Cl, -Br, -CF 3 fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of I to 6 carbons, or alkylthio of 1 to 6 carbons; m is an integer having the values of 0 to 3; Ris independently alkyl of 1 to 6 carbons, or -F; o is in an integer having the values of 0 to 4; Y is a phenyl or naplithyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, WO 2005/013949 PCT/US2004/025564 oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, -COOH, -COOR 8

-CONRR

1 0

-CH

2 OH, -CH 2

OR",

-CH

2 0COR", -CHO, -CH(OR1 2 2

-CHOR

3 O, -COR 7

-CR

7

(OR

2 2

-CR

7

OR'

3 0, tri-lower alkylsilyl, -OH, -OR 8 or -OCOR 8 where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of I to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 1 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R" is lower alkyl, phenyl or lower alkylphenyl, R 1 2 is lower alkyl, and R 1 3 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof WO 2005/013949 WO 2005013949PCIIUS200I/02556I -86- R14R

R

2 iy

R

2

X

R3

R

R I

R

1 y

A

I II Me3C,

Y

2 Me 3C me CO 2H~

IV

where: X is 0, S, or (CR'R 1 where nais 0, 1 or 2; WO 2005/013949 PCT/US2004/025564 -87- Y is Y 1 or Y2 where Z is (CRR )o and o is an integer from 1 to 4, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and 0, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C 1 -6 alkyl or with 1 to 3 C1- 6 fluoroalkyl groups; X is O, S or NH; R' is independently lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;

R

2 is independently lower alkyl of 1 to 6 carbons, OR 1 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R 2 groups jointly represent an oxo group;

R

3 is hydrogen, lower alkyl of 1 to 6 carbons, OR 1 fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2

-NH

2

-NHCO(CI-C

6 alkyl, or

-NHCO(C

1

-C

6 alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,

-COOR

8

-CONRR'O

1 -CH20H, -CH 2 0R 1 1 -CH20COR", -CHO, -CH(OR 12 2

-CH(OR'

3

-COR

7

-CR

7 (OR1 2 2

-CR

7 (OR0O), or -Si(Cl-6alkyl) 3 where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl,

R

11 is lower alkyl, phenyl or lower alkylphenyl, R 1 2 is lower alkyl, and R 1 3 is divalent alkyl radical of 2-5 carbons, and R 14 is alkyl of 1 to 10 carbons, fluorosubstituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C 1 -Clo-alkylphenyl, naphthyl, C 1 Clo-alkylnaphthyl, phenyl-C 1 -Cioalkyl, naphthyl-Ci-Cloalkyl, C1-C 1 0 -alkenylphenyl having 1 to 3 double bonds, C 1 -Clo-alkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Clo-alkenyl having 1 to 3 double bonds, phenyl-Ci-Clo-alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons WO 2005/013949 PCT/US2004/025564 -88and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR 8 or R 1 4 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C 1 to Clo alkyl group, with a C 1 to Clo fluoroalkyl group, or with halogen, and the dashed line in Y' represents a bond or absence of a bond.

R

1

R

2 CO H

R

5

I

where:

R

1 and R 2 are independently hydrogen or C1- 6 alkyl; W is C(R 3

)R

4 0, NR 3 S, SO or SO 2 wherein R 3 and R 4 are independently hydrogen or CI-6 alkyl;

R

5 is hydrogen, C 1 -6 alkyl, halogen, -OR 1 -OCOR", -NH 2

-NHR

11

-NR"R

12 -NHCOR", -NR' 1 -COR1 2 where R 1 and R 12 are independently C1- 6 alkyl, phenyl or alkyl phenyl; Xis WO 2005/013949 PCT/US2004/025564 89 R is hydrogen, or taken together with R7 forms a double bond, or taken together with R7 is methylene to form a cyclopropyl ring; W7 is hydrogen, or taken together with RP formns a double bond, or taken together with R 6 is methylene to form a cyclopropyl ring, or taken to gether with R9 forms a double bond, or taken together with R9 is methylene to form a cyclopropyl ring;

R

8 is hydrogen, or taken together with R9 forms a double bond, or taken together with R9 is methylene to form a cyclopropyl ring;

R

9 ishydrogen, hydroxy, -OCOR.", or taken together with R7 forms a double bond, or taken together with R7 is methylene to form a cyclopropyl ring, or taken together with R8 forms a double bond, or taken together with R8 is methylene to form a cyclopropyl ring, where R 1 3 is 6 alkyl, phenyl or alkyl phenyl; Z is -X-Y-R1 0 wherein X is'a valence bond, phenyl or pyridyl, optionally substituted with C 1 3 alkyl, halogen, hydroxy, C1- 3 alkoxy, CI- 3 acyloxy, C,- 3 alkyl halide, thiol, C 1 3 substituted thiol, Y is C, alkyl, C 2 -6 alkenyl or C 2 6 alkynyl and R1 0 is -CO 2 H, tetrazole, -PO 3 H, -SO 3 H, -COR' 5

-CONR'

6

R'

7

-CH

2 OH, -CHO,

-CH

2 OR', -CH(OR' 9 2 -HC(0P7 0

-CR

20 (OR1 9 2

-CR

21 (0P7 0 0), wherein R1 5 is C 1 6 alkyl, phenyl or alkyl phenyl; or Z is '=Y-Rl 0 wherein Y is -CR'1 4

-CR'

4 6 alkyl, -CR' 4 phenyl,

-CR'

4 pyridyl, -CR 1 4

CI-

3 alkYlaryl, -CR'1 4

_C

2 5 alkenyl or 4

_C

2 5 alkynyl, wherein R. 4 is H or C 1 3 alkyl and R1 0 is-CO 2 H, tetrazole, -PO 3 H, -SO 3 H, -CO 2 R1 5 -CONR R -CH 2 OH, -CH0, -CH 2 OR", -CH(OR 9 2 -HC(0R 20

-COW'

-CR

20

(OR'

9 2

-CR

21 (0R 20 wherein R' 5 is C1..

6 alkyl, phenyl. or alkyl phenyl; R. 6 and R. 7 are independently hydrogen, C1p 6 -alkyl, C 5 5 cycloalkyl, phenyl or 6 -alkyl phenyl; R1 8 is 6 -alkyl, phenyl or C 1 6 -alkyl phenyl; R 19 is C 1 6 alkyl; R 0 is C 24 alkyl; P7' is 6 alkyl phenyl or C 3 -5 cycloalkyl; and salts thereof with a pharnaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.

WO 2005/013949 WO 2005013949PCIIUS200I/02556I OMe t -Bu t -BU Me CO 2

R

CO 2H I Me Me where: Z is or

A

in which Q, X and Y are each indepenrdently 0, S or CH 2 A is -(CR 2 where n is an integer of from. 1 to 3; T and T' are each independently 0, S, CH 2 or C(C11 3 2 and R1 is hydrogen or CI-C 6 alkyl, and pharmaceutically acceptable salts thereof WO 2005/013949 PCT/US2004/025564 91 CO 2H~ Me Me Me Me Me

N

R

4 where R 4 is methyl, ethyl, n-propyl or n-butyl.

R IR 2 R 1 0 R1 Y z R R 8 R 3 R 4 R 9 where: R' through R 4 each independently are hydrogen, a 01-06 alkyl, or a C-1 arylalkyl; Ri through R 8 each independently are hydrogen, a CI-C 6 alkyl, or at least two of R 5 through Ri taken together are a 03-06 cycloalkyl; WO 2005/013949 PCT/US2004/025564 -92-

R

9 and R 10 each independently are hydrogen, a CI-C 6 alkyl, -Cl, -Br, -NR R 12

-NO

2 or -OR 3 where R 1 and R 12 each independently are hydrogen, a C1-

C

8 alkyl, a C 7

-C

15 arylalkyl, a CI-Cs acyl, provided that only one R 1 or R 1 2 can be acyl, or R" and R 1 2 taken together are a C 3

-C

6 cycloalkyl, and where R 1 3 is hydrogen or a C 1

-C

8 alkyl or a C 7 -C15 arylalkyl;

R

14 represents: S COR

-COR

CO

R

1

R

19 N N--N /CORM C O R1 A A G rG

-COR

1 5 V COR' where R' 5 is -OR 1 6 or -NR"R 8 with R 1 6 being hydrogen, a C1-C 6 alkyl or a C7-C15 arylalkyl, and with R 1 7 and R 1 8 each independently being hydrogen, a C 1

-C

6 alkyl, a

C

7

-C

1 5 arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C 3

-C

6 cycloalkyl, provided that R 18 must be hydrogen when R 1 7 is aryl or hydroxyaryl, R 1 9 is a Ci-C 5 alkyl, and A is O, S or NR 2 0 where R 2 0 is a hydrogen, C1-C 6 alkyl or a C 7 -C15 arylalky; W is (CH 2 )m; X and Y each independently represent C, 0, S, N, SO or SO 2 provided, however, that when X or Y are 0, S, SO or SO 2 then either R' and R 2 or R and R 4 respectively do not exist, and further provided, that when X or Y is N, then one each of R' and R 2 or R 3 and R 4 respectively, do not exist; Z is O, S, CR 22

R

2 3 or NR 24 where R 22 through R 2 4 each independently are hydrogen or a CI-C 6 alkyl or R 2 2 and R 23 taken together are a C 3

-C

6 cycloalkyl; V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V; G is C or N, provided G cannot be C when W is C; WO 2005/013949 PCT/US2004/025564 -93m is 0 or 1 carbon atoms; and n is 0, 1 or 2 carbon atoms; the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each ofR 5 and R 6 or R 7 and R 8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis or trans configuration.

1 10 11 R R

R

1

R

12 T R 2 I Rs X W R

R

1 3

R

1 4 1 J- J7 1 5 Y Z R R i R8

R

3

R

4

R

9

I

where:

R

1 through R 4 each independently are hydrogen, a C 1

-C

6 alkyl, or a C7-C15 arylalkyl;

R

5 through R 8 each independently are hydrogen, a Ci-C6 alkyl, or at least two ofR 5 through R 8 taken together are a C 3

-C

6 cycloalkyl;

R

9 and R 1 0 each independently are hydrogen, a CI-C 6 alkyl, -Cl, -Br,

-NR

1

"R

2

-NO

2 or -OR 1 3 where R 11 and R 1 2 each independently are hydrogen, a C 1 Cg alkyl, a C 7

-C

1 5 arylalkyl, a Ci-Cs acyl, provided that only one R 1 1 or R 1 2 can be acyl, or R 1 and R 1 2 taken together are a C 3

-C

6 cycloalkyl, and where R 1 3 is hydrogen or a C 1

-C

8 alkyl or a C 7

-C

1 5 arylalkyl; R" represents: COR

CR

R

1 9 WO 2005/013949 PCT/US2004/025564 -94- N N-N

COR

15 COR's A4

-A

G G

COR

5 V where R" is -OR' 1 or -NR 7

R"

8 with R 16 being hydrogen, a Ci-C 6 alkyl or a C 7

-C

1 arylalkyl, and with R 1 7 and R 1 8 each independently being hydrogen, a Ci-C 6 alkyl, a

C

7 -C15 arylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C 3

-C

6 cycloalkyl, provided that R 1 8 must be hydrogen when R 1 7 is aryl or hydroxyaryl, R 1 9 is a C 1

-C

5 alkyl, and A is O, S or NR 2 0 where R 20 is a hydrogen,

C

1

-C

6 alkyl or a C 7 -Ci 5 arylalky;

R

1 2 through R' i attached to the tricyclic ring each independently are hydrogen or a Ci-C 6 alkyl, or taken together then one each of R 1 2 and R 1 3 or R 1 4 and

R

15 respectively, form a carbonyl group; X and Y each independently represent C, O, S, N, SO or SO 2 provided, however, that when X or Y are O, S, SO or SO2, then either R' and R 2 or R 3 and R 4 respectively do not exist, and further provided, that when X or Y is N, then one each ofR 1 and R 2 or R 3 and R 4 respectively, do not exist; Z is O, S, CR 22

R

23 or NR 24 where R 22 through R 24 each independently are hydrogen or a C 1

-C

6 alkyl or R 22 and R 23 taken together are a C 3

-C

6 cycloalkyl; W is N or CR 25 where R 25 is hydrogen or a Ci-C 6 alkyl; V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V; and G is C or N, provided G cannot be C when W is C; the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each ofR 5 and R 6 or R 7 and R 8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis or trans configuration.

WO 2005/013949 PCT/US2004/025564 95 R I R 2

U

x V KI R14

R

3

R

4

R

9

I

where: R1 through R 4 each independently are hydrogen, a Cl-C 6 alkyl, or a C 7

-C

1 arylalkyl;

R

9 and R 10 each independently are hydrogen, a Cl-C 6 alkyl, -Cl, -Br, -NR 11

R

12

-NO

2 or where R1 and R 12each independently are hydrogen, a Cl- C8 alkyl, a C 7 -Cl 5 arylalkyl, a C 1

-C

8 acyl, provided that only one R 1 1 or R 12 can be acyl, or R 1 1 and R 12 taken together are a C 3

-C

6 cycloalkyl, and where R 13 is hydrogen or a Cl-C 8 alkyl or a C7-CI5 arylalkyl; R 1 4 represents: C0R 15 N \N-N -_CORI' G rG -C0R 15 V -CR 1 where R" 5 is -OR 16 or _NRl 7 RB, with R" 6 being hydrogen, a CI-C 6 alkyl or a C 7

-C

1 arylalkyl, and with R'1 7 and R's each independently being hydrogen, a Cl-C 6 alkyl, a

C

7

-C

1 5 arylailkyl, aryl, ortho-, meta-, or p ar-substituted hydroxyaryl, or taken together are a C 3

-C

6 cycloalkyl, provided that R1 8 must be hydrogen when W7 1 is aryl.

or hydroxyaryl, R1 9 is a C 5 alkyl, and A is 0, S or NR? 20 where is a hydrogen,

C

1

-C

6 alkyl or a C7-Cl 5 arylalky; WO 2005/013949 PCT/US2004/025564 -96- X and Y each independently represent C, O, S, N, SO or SO 2 provided, however, that when X or Y are 0, S, SO or SO 2 then either R' and R 2 or R 3 and R 4 respectively do not exist, and further provided, that when X or Y is N, then one each ofR 1 and R 2 or R 3 and R 4 respectively, do not exist; U is (CH 2 )n where n is 0, 1 or 2 carbon atoms; V is C or N, provided, however, that when V is N, then no double bond exists adjacent to V; W is (CH2)m where m is 0 or 1 carbon atoms G is C or N, provided G cannot be C when W is C; the dashed lines in the structures represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then one each ofR 5 and R 6 or R 7 and R 8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis or trans configuration.

R3 4 SX Y I Me Me

O

CO 2H Me Me II where: R' represents: the radical -CH 3 (ii) the radical -CH 2

-O-R

5 (iii) the radical -O-R 5 (iv) the radical -CO-R 6

R

5 and R 6 having the meanings given below, Y represents a radical chosen from the radicals of formulae and (b) below: WO 2005/013949 PCT/US2004/025564 -97- (b)

R

7 and R' 7 having the meanings given below, Ar represents a radical chosen from the radicals of formulae to below: XY

X

(f) in which the radical Y is in an ortho or meta position relative to the radical X, X and Y of these formulae corresponding to X and Y represented in formula R 8 having the meaning given below, X represents an oxygen or sulphur atom, a radical -SO 2

-N(R

9 or a radical chosen from the radicals of formulae to below: Y Y H) C (k) oi H H H 5

SH

3 C "CH 3 0 0 S S (n m (n) (n) NOR5 (o) (p) (p) SR(q) H R 12 H NHOH H NHOH

R

5

R

9

R

1 2 and n having the meanings given below,

R

2 and R 3 which may be identical or different, are chosen from the group consisting of: WO 2005/013949 PCT/US2004/025564 -98a hydrogen atom, (ii) an alkyl radical having at least 3 carbon atoms, among which the carbon attached to the phenyl radical of formula is substituted with at least two carbon atoms, (iii) a linear or branched alkyl radical, (iv) a radical -OR 5 a radical -SR 5 S(vi) a polyether radical,

R

5 having the meaning given below, it being understood that R 2 and R 3 taken together, can form, with the adjacent aromatic ring, a 5- or 6-membered ring, optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulphur atom, it being understood that, when R 2 and R 3 do not form a ring, at least one of the radicals R 2 and R 3 has a meaning (ii) mentioned above,

R

4 and R 8 which may be identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, or a radical -OR 5 a polyether radical,

R

5 represents a hydrogen atom, a lower alkyl radical or a radical -COR 1 0

R

1 having the meaning given below,

R

6 represents: a hydrogen atom a lower alkyl radical a radical of formula R' and R" having the meanings given below, a radical -OR' R 1 having the meaning given below,

R

7

R

a and R 9 which may be identical or different, represent a hydrogen atom or a lower alkyl radical, n is an integer equal to 0 or 1,

R

1 represents a lower alkyl radical, R" represents a hydrogen atom, a linear or branched alkyl radical, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an aryl or aralkyl radical, optionally substituted, a sugar residue or an amino acid or peptide residue,

R

1 2 represents a lower alkyl radical, WO 2005/013949 PCT/US2004/025564 -99- R' and which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid, peptide or sugar residue, or alternatively, taken together, form a heterocycle, and the optical and geometrical isomers of the said compounds of formula as well as their salts.

Me Me Me Me Me CO 2 H Me Me CH

C

Me

H

3

C

CO 2 H I WO 2005/013949 PCIIUS200I/02556I 100 Me Me Na MeCO 2e Me Me e Me Me MeHMe -CC22H Me me WO 2005/013949 PCTI.S2001102556-I Me ~CO2 H He Me me X3: E -o HO 2 C ,O 2 H me me HO 2 Me me me me WO 2005/013949 PCT/US2004/025564 -102- Me Me CH 2 Me CO 2H Me Me Me Me Me CO 2H Me Me

TREATMENT

Treating, as used herein, refers to a reduction in (alleviation of) at least one symptom of cachexia in a patient suffering from (in need of treatment for) cachexia.

Treating, as used herein, also refers to preventing the onset of at least one symptom of cachexia in a subject at risk of developing cachexia a subject suffering from one or more of the diseases, disorders or conditions named above). Treating, as used herein, further refers to inhibiting the progression of at least one symptom of cachexia in a subject. Preferably, as with any multisymptom disorder, a reduction in or inhibition or prevention of more than one symptom is desired. The symptoms of cachexia can include loss of appetite, loss of body weight, elevation of resting energy expenditures, glucose intolerance, insulin resistance, increased fat oxidation rates, increased whole body protein turnover, decreased quality of life decreased mobility, energy and/or stamina) and decreased life span. As such, treating of cachexia can include prevention or inhibition of appetite loss or return of appetite, prevention or inhibition of loss of body weight or an increase in body weight as a result of preservation or restoration of lean body mass and the energy store of fat and glycogen), improvement in the patients quality of life and increased life span.

WO 2005/013949 PCT/US2004/025564 103 Quality of Life can be assessed by objective measurements which include nutritional and metabolic endpoints, physical function (muscle strength) and endurance (exercise tolerance). Quality of Life can also be evaluated by completing patient and caregiver questionnaires, which include standard forms such as the functional living index-cancer (FLIC), functional assessment of cancer therapy index (FACT) and the European Organization for Research and Treatment of Cancer (RORTC). The questionnaires are designed to give information regarding the effect of the drug product from a patient's and caregiver's perspective.

For the prevention or treatment ofcachexia cachexia resulting from a cancerous condition or other malignancies) it is likely that a compound of the invention is to be administered systemically. Suitable routes of administration include, but are not limited to, orally, intraperitoneally, subcutaneously, intramuscularly, intradermally, transdermally, rectally, sublingually, intravenously, buccally or via inhalation. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection. Oral admininistration of a compound in accordance with the present invention is presently preferred.

Forms suitable for oral administration include powders, pills, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum or the like prepared by art recognized procedures. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.

The pharmaceutical compositions of the invention preferably contain a pharmaceutically acceptable carrier or diluent suitable for rendering the compound or mixture administrable orally, parenterally, intravenously, intradermally, intramuscularly or subcutaneously, rectally, via inhalation or via buccal administration, or transdermally. The active ingredients may be admixed or compounded with a conventional, pharmaceutically acceptable carrier or diluent. It will be understood by those skilled in the art that any mode of administration, vehicle or carrier conventionally employed and which is inert with respect to the active agent may be utilized for preparing and administering the pharmaceutical compositions of WO 2005/013949 PCT/US2004/025564 -104the present invention. Illustrative of such methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (1990), the disclosure of which is incorporated herein by reference.

The formulations of the present invention for use in a subject comprise the agent, together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carriers or diluents must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the agent with the carrier or diluent which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the agent with the carriers and then, if necessary, dividing the product into unit dosages thereof.

Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the agents that are preferably isotonic with the blood of the recipient. Suitable carrier solutions include phosphate buffered saline, saline, water, lactated ringers or dextrose in water). Such formulations can be conveniently prepared by admixing the agent with water to produce a solution or suspension, which is filled into a sterile container and sealed against bacterial contamination. Preferably, sterile materials are used under aseptic manufacturing conditions to avoid the need for terminal sterilization.

Such formulations can optionally contain one or more additional ingredients, which can include preservatives such as methyl hydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride. Such materials are of special value when the formulations are presented in multidose containers.

Buffers can also be included to provide a suitable pH value for the formulation. Suitable buffer materials include sodium phosphate and acetate. Sodium chloride or glycerin can be used to render a formulation isotonic with the blood.

If desired, a formulation can be filled into containers under an inert atmosphere such as nitrogen and can be conveniently presented in unit dose or multidose form, for example, in a sealed ampoule.

WO 2005/013949 PCT/US2004/025564 -105- Those skilled in the art will be aware that the amounts of the various components of the compositions of the invention to be administered in accordance with the method of the invention to a subject will depend upon those factors noted above.

The compositions of the invention when given orally or via buccal administration can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent. Where the composition is in the form of a tablet, one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose. Where the composition is in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

A typical suppository formulation includes the conjugate or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example, polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.

Typical transdermal formulations include a conventional aqueous or nonaqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated plastic, patch or membrane.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that can be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

A "subject" is typically a human, but can also be an animal in need of treatment, companion animals dogs, cats, and the like), farm animals cows, pigs, horses, sheep, goats and the like) and laboratory animals rats, mice, guinea pigs and the like).

WO 2005/013949 PCT/US2004/025564 -106- The therapeutically effective amount of a compound of the invention depends, in each case, upon several factors, the health, age, gender, size and condition of the subject to be treated, the intended mode of administration, and the capacity of the subject to incorporate the intended dosage form, among others. A therapeutically effective amount of an active agent is an amount sufficient to have the desired effect for the condition being treated. Desired treatment effects are discussed in detail above. A useful therapeutic or prophylactic concentration may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated.

Such concentrations can be arrived at through routine experimentation.

A suitable dose for mammals humans or mammals other than humans) can range from about 0.01 to about 100 mg per kg of body weight per day, such as from about 0.1 to about 75 mg per kg of body weight per day, for example, from about 1 to about 50 mg per kg of body weight per day. More preferably, the daily dose can be from about 2 to about 25 mg per kg body weight of the mammal. In a preferred embodiment, the subject is a human and a suitable dose is about 10 to about 4000 mg per day per subject, such as about 20 to about 2000 mg per day per subject, for example, about 50 to about 1000 mg per day per subject, assuming an average human of about 70 kg. More preferably, a suitable amount is in the range from about 100 to about 500 mg per day per subject.

The method of the invention can further comprise administering an additional therapeutic agent. Preferably, the additional therapeutic agent does not diminish the effects of the primary agent(s) and/or potentiates the effect of the primary agent(s).

In one embodiment, the additional therapeutic agent can be one that is useful for treating cachexia. For example, the additional therapeutic agent can be an anticachetic agent that has a primary mechanism of action which is different from the RXR agonists described herein. Suitable anticachetic agents include, but are not limited to, progesterone derivatives megestrol acetate and medroxyprogesterone acetate), growth hormone Serostim®), growth hormone secretagogues ghrelin, GHRP-1, GHRP-2, GHRP-6, NN703, Ipamorelin, WO 2005/013949 PCT/US20041025564 -107- Campromorelin, MK-677 and those described in U.S. Patent Nos. 6,303,620, 6,576,648, 5,977,178, 6,566,337, 6,083,908, 6,274,584 and published Inteniational Application No. WO 00/01726), cannabinoids dronabinol), anabolic steroids oxandrolone), corticosteroids dexamethasone), monoclonal antibodies entanercept (ENBREL® and REMICADE®)), f-Adrenergic blockers, NSAIDS, anticytokines fl-2 agonist such as clenbuterol, omega-3 fatty acids, melatonin and thalidomide), metoclopramide, insulin-like growth factor-i (see WO 96/37216), tumor necrosis factor converting enzyme inhibitors, matrix metalloproteinase inhibitors (see WO 03/090777), appetite stimulants, melanocortin receptors, serotonin receptor inhibitors and hydrazine sulfate.

In another embodiment, the additional therapeutic agent can reduce side effects associated with the administration of the RXR agonist. For example, the additional therapeutic agent can be an antihyperlipidemic agent. Suitable antihyperlipidemic agents include, but are not limited to, bile acid sequestrants WELCHOLO, Cholestryramine, Colestipol and Polidexide), Fibrates Beclobrate, Bezafibrate, Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid, Etofibrate, Fenofibrate, Genfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Simfibrate and Theofibrate), HMG CoA Reductase Inhibitors Atorvastatin, Fluvastatin, Lovastatin, Provastatin and Simvastatin), Nicotinic acid and derivatives Acipimox, Aluminum Nicotinate, Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid), Thyroid Hormone/Analogs Etiroxate, Thyropropic Acid and Thyroxine), and others agents such as, Acitran, Azacosterol, Benfluorex, 0- Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, y-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, a-Phenylbutyramide, Pirozadil, Probucol, g-Sitosterol, Sultosilic Acid (Piperazine Salt), Tiadenol, Cholesterol Absorption Inhibitors (Zetia or ezetimibe) Triparanol and Xenbucin.

The term alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenyl refers to and covers normal alkenyl, branch chain alkenyl and cycloalkenyl groups having one or WO 2005/013949 PCT/US2004/025564 -108more sites ofunsaturation. Similarly, the term alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition ofalkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.

The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters.

Unless stated otherwise in this application, preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.

Amide has the meaning classically accorded that term in organic chemistry.

In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides. Unless stated otherwise in this application, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the substituted and unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula -CK where K is

(-OR)

2 Here, R is lower alkyl. Also, K may be -ORO 7 where R 7 is lower alkyl of 2carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capable of forming such salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the WO 2005/013949 PCT/US2004/025564 -109activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered. Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may by be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.

Certain compounds of the present invention have trans and cis (E and Z) isomers. In addition, the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. In the present application when no specific mention is made of the configuration (cis, trans or R or S) of a compound (or of an asymmetric carbon) then a mixture of such isomers, or either one of the isomers is intended. In a similar vein, when in the chemical structural formulas of this application a straight line representing a valence bond is drawn to an asymmetric carbon, then isomers of both R and S configuration, as well as their mixtures are intended. A straight horizontal single line or a wavy single line drawn to a carbon with a double bond denotes either cis or trans or both orientations of the substituent on the double-bond. Specific orientation of substituents relative to a double bond is indicated in the name of the respective compound, and/or by specifically showing in the structural formula the orientation of the substituents relative to the double bond.

WO 2005/013949 PCT/US2004/025564 -110-

EXEMPLIFICATION

FIGS. 1-5 comprise charts or graphs disclosing the results of tests obtained with experimental animals that have been inoculated with a xenograft of non-small cell lung cancer cells H292 or with small cell lung cancer cells H446, and which were then orally administered the RXR agonist Compound 1 referred to above.

FIGS. 6 and 7 disclose results of tests obtained with experimental animals that have been inoculated with a xenograft of non-small cell lung cancer cells H292 and which were then orally administered the RXR agonist Compound 2 referred to above.

Specifically, in the experiment shown in FIG. 1 nude mice were subcutaneously transplanted with non-small cell lung cancer cells H292. A group of the animals was given a daily oral dose of 10 mg per kilogram body weight of Compound 1 in a suitable pharmaceutically acceptable vehicle. A group of the control animals was given the vehicle only. The graph shows the body weight of the animals in grams. It can be seen that the animals treated with Compound 1 have significantly greater body weights than the animals which received the vehicle only.

FIG. 2 shows the percentage of survival of nude mice from a similar experiment as the one described in connection with FIG. 1, and demonstrates significantly better survival rate for the animals that received Compound 1 in a daily oral dose of 10 mg per kg body weight of the animal.

In the experiment shown in FIG. 3, SCID mice were subcutaneously transplanted with small cell lung cancer cells H446. A first group of the animals was given a daily oral dose of 3 mg per kilogram body weight of Compound 1 in a suitable pharmaceutically acceptable vehicle, and a second group was given a daily oral dose of 10 mg per kilogram body weight in the same vehicle. A group of the control animals was given the vehicle only. The graph shows the body weight of the animals in grams. It can be seen that the animals treated with Compound 1 have significantly greater body weights than the animals that received the vehicle only.

In the experiment shown in FIG. 4 the right gastrocnemius muscle of the control animals and of the animals treated with Compound 1 in a daily dose of mg/kg, as described in connection with FIG. 1, was weighed after the animals had WO 2005/013949 PCT/US2004/025564 -Illbeen sacrificed. It can be seen that treatment in accordance with the invention prevents muscle wasting.

In the experiment shown in FIG. 5, the food intake of nude mice with and without H292 xenografts was evaluated. Mice with H292 xenografls had reduced appetite compared with normal control. Mice treated with Compound 1 in a daily dose of 10 mg/kg body weight had equal amount of food intake as normal mice.

Therefore, adminstration of Compound 1 reverses poor appetite in cachectic animals.

In the experiment shown in FIG. 6, nude mice were subcutaneously transplanted with non-small cell lung cancer cells H292. A group of the animals was given a daily oral dose of 50 mg per kilogram body weight of Compound 2 in a suitable pharmaceutically acceptable vehicle. A group of the control animals was given the vehicle only. The graph shows the body weight of the animals in grams. It can be seen that the animals treated with Compound 2 have significantly greater body weights than the animals which received the vehicle only.

In the experiment shown in FIG. 7, the food intake of nude mice bearing H292 xenografts was evaluated. Mice treated with Compound 2 in a daily dose of mg/kg body weight had significantly larger food intake than the tumor bearing mice which received only vehicle. Therefore, adminstration of Compound 2 significantly increases the appetite of tumor bearing animals.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

PAOPERASUtNO 272SflO IM W. -mn1tsd.5 -1OW(NJ9 8 -112- SThroughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group IN of integers or steps but not the exclusion of any other integer or step or group of integers or 5 steps.

The reference in this specification to any prior publication (or information derived Sfrom it), or to any matter which is known, is not, and should not be taken as an

O

CI acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula R1 R1 Z B R1 R1 wherein: Z is represented by Structural Formula (II) R2 R2 n(H 2 C) R 2 R3 R2 (II); Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two R 4 groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRi=CRI-CRi=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH 2 0H, -CH 2 0R, 1 -CH 2 OCOR 1 -CHO, -CH(ORI 2 2 -CHORi 3 0, -COR 7 -CR 7 (ORI 2 2 or -CR 7 0RI 3 0; P %0PERkASU09272801t1 4. d M d.51012009 C-114- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is Sphenyl or lower alkylphenyl; c 5 R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, C or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; RII is lower alkyl, phenyl or lower alkylphenyl; O CI Ri2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons.

2. The method of Claim 1, wherein Y is cyclopropyl, phenyl, pyridyl, thienyl or furyl.

3. The method of Claim 2, wherein Y is cyclopropyl or phenyl.

4. The method of Claim 3, wherein Y is The method of Claim 1, wherein RI is H or methyl.

6. The method of Claim 1, wherein B is -COOH or a pharmaceutically acceptable salt thereof, -COORs or -CONR 9 Rio.

7. The method of Claim 1, wherein Z is represented by Structural Formula (II) and n is 2.

8. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (IV): P AOPERXASUO&I 272MO I u s -d Sd=-"MO9 -115- (IV), wherein: R 20 is alkyl of 1 to 6 carbons; B is -COOH, or -COOR 21 and R 2 1 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.

9. The method of Claim 8, wherein the compound is represented by the formula: CH3 H 'COOH or a pharmaceutically acceptable salt of said compound. The method of Claim 8, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt of said compound. P OPER\AS\29\1272880 ISt spasc rdandox./O-lOO9 V -116-

11. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula l R 2 R2 B SoR3 R 2 R 2 R 3 M wherein: R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 -CONR 9 Rio, -CH 2 0H, -CH 2 0RI -CH 2 0COR I, -CHO, -CH(ORI 2 2 -CHORi 3 0, -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; R I is lower alkyl, phenyl or lower alkylphenyl; Rl 2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons.

12. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (VI): P \OPER129\ 2I2812&W II spa ,,csdoc.%l~m510120 -117- R2 R4 R2 R, R, n(H 2 C) R2RR3 R2 R1 R1 (VI), wherein: nis 1 or 2; R, and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, -Cl or -Br; R4 is H, lower alkyl, trifluoromethyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 -CONR 9 Rio, -CH 2 0H, -CH 2 0R 11 -CH 2 0CORII, -CHO, -CH(ORI 2 2 -CHOR 1 30, -COR 7 -CR 7 (ORI 2 2 or -CR 7 ORi 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; R i is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons.

13. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (VII): P.\OPERMASVWA12728SS Ist spa saIndmsasc-5/01109 -118- R4 B B (VII), wherein: SR4 is lower alkyl of 1 to 6 carbons; B is -COOH or -COORs; and R 8 is lower alkyl of 1 to 6 carbons; and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of said double bonds, or a pharmaceutically acceptable salt of said compound.

14. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula R1 R1 Z B R1 R, wherein: Z is represented by Structural Formula (II) R2 R2 n(H 2 C) R2 R3 R2 (II); P MAPER SUO&9\212SO Is sp ancndmascdoc-sIfl)9 -119- Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRi=CRi-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH 2 0H, -CH 2 0R 1 -CH 2 0CORIi, -CHO, -CH(OR 2 2 -COR 7 -CR 7 (ORI 2 2 or -CR 7 0RI 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; RIt is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and Ri3 is a divalent alkyl radical of 2 to 5 carbons. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an RXR agonist compound represented by Structural Formula RZ R P \OPERASUNOMI272SSO Is [sp adl dw-oc MIf009 -120- wherein: Z is represented by Structural Formula (II) R2 R 2 R2 R2 (II); Y is selected from thienyl or furyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRI=CRI-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 -CONR 9 Rio, -CH20H, -CH 2 0R 1 -CH 2 0COR 1 l, -CHO, -CH(OR 1 2 2 -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; RIi is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons.

16. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (IX) or P OPER\ASU)9\I272UU Is( spa mdoCts mi5ALf20(qI 121 R3 (IX), R3 wherein: B is -COOH or -COORs; R 3 is hydrogen, lower alkyl, Cl or Br; Rg is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R is phenyl or lower alkylphenyl.

17. The method of Claim 16, wherein the compound is represented by Structural Formula R 3 is H or methyl and B is -COOH or -COOCH 2 CH 3

18. The method of Claim 16, wherein the compound is represented by Structural Formula R 3 is H and B is -COOH or -COOCH 2 CH 3

19. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XII): P \OPERAS\200'P1272SSS Ia spa -do3 )wf2)Wa9 -122- ,-O C02R (XII), wherein R is hydrogen or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof.

20. The method of any one of Claims 1 to 19, wherein the cachexia is associated with cancer.

21. The method of Claim 20, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.

22. The method of any one of Claims 1 to 19, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointenstinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.

23. The method any one of Claims 1 to 19, wherein the therapeutically effective amount of the compound is from about 1 to about 50 mg per kg body weight of the subject per day.

24. The method of any one of Claims 1 to 19, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg. P XOPMAS120M 1272980 1 ga W. au-1.-m O-5 O9

123- The method of any one of Claims 1 to 19, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent. 26. The method of Claim 25, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG CoA Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterol, Benfluorex, p-Benzalbutyramide, Camitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaeonic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, y-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, a-Phenylbutyramide, Pirozadil, Probucol, p-Sitosterol, Sultosilic Acid, Tiadenol, Cholesterol Absorption Inhibitors Triparanol and Xenbucin. 27. The method of any one of Claims 1 to 19, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist. 28. The method of any one of Claims 1 to 19, wherein the compound is orally administered. 29. The method of Claim 1, wherein the therapeutically effective amount of the compound is from about 2 to about 25 mg per kg body weight of the subject per day. 30. The method of Claim 1, wherein the compound is administered to a human subject at a daily dose of from about 100 to about 500 mg. ?A0PERA201272W8M Ist spa lsd-tsI x )5/01/2 -124- 31. Use of a compound represented by Structural Formula Ri R 1 Z B R1 R1 wherein: Z is represented by Structural Formula (II) R2 n(H 2 C) R2 R3 2 (II); Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two R 4 groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRI=CRi-CRI=CRI- groups on adjacent carbons; n is 1 or 2; RI and R 2 independently are lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, COORs, -CONR 9 Rio, -CH 2 OH, -CH 2 0RI -CH20COR I, -CHO, -CH(OR 12 2 CHOR 1 30, -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; P.\OPER\AS2OOI 272888) I9 nd doc.SA/ IM)

125- R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; R I is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and Ri3 is divalent alkyl radical of 2 to 5 carbons in the manufacture of a medicament for treating cachexia. 32. Use of a compound represented by Structural Formula (IV): (IV), wherein: is alkyl of 1 to 6 carbons; B is -COOH, or -COOR 21 and R21 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound in the manufacture of a medicament for treating cachexia. 33. Use of a compound represented by Structural Formula wherein: R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; P \OERAS\200\IZ7298M ISI Spa am mnoc-510ltN29 -126- B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 -CONR 9 Rio, -CH 2 0H, -CH 2 OR i, -CH20COR 1 -CHO, -CH(ORI 2 2 -COR 7 -CR 7 (ORI 2 2 or -CR 7 0RI 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or Rs is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; RIi is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and Ri 3 is divalent alkyl radical of 2 to 5 carbons in the manufacture of a medicament for treating cachexia. 34. Use of a compound represented by Structural Formula (VI): R2 R4 R2 R 1 R, n(H 2 C) B R2RR3 R2 R, Ri (VI), wherein: n is 1 or 2; RI and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, -Cl or -Br; R 4 is H, lower alkyl, trifluoromethyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, COOR s -CONR 9 Rio, -CH 2 0H, -CH 2 0R, -CH 2 0CORil, -CHO, -CH(OR 1 2 2 -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to P XOPERASgV0,2729ISO sp -d-d-5/01/2009

127- carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; RI 1 is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons in the manufacture of a medicament for treating cachexia. 35. Use of a compound represented by Structural Formula (VII): R4 (VII), wherein: R 4 is lower alkyl of 1 to 6 carbons; B is -COOH or -COOR 8 and R 8 is lower alkyl of 1 to 6 carbons; and the configuration about the cyclopropane ring is cis, and the configuration about the double bonds in the pentadienoic acid or ester chain attached to the cyclopropane ring is trans in each of said double bonds, or a pharmaceutically acceptable salt of said compound in the manufacture of a medicament for treating cachexia. P.XOPERASU2OO1272S8 I% rp. ff-A-.d-5MI/2009

128- 36. Use of a compound represented by Structural Formula R1 R1 Z I B R1 R, wherein: Z is represented by Structural Formula (II) R2 R2 n(H 2 C) I R2 R3 R2 (II); Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRI=CRI.CRi=CRi- groups on adjacent carbons; nis or 2; R, and R 2 independently are lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH 2 OH, -CH 2 0RI -CH 2 0CORII, -CHO, -CH(ORI 2 2 -CHOR 1 3 0, -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri30; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; P\OPER\AS\209\1272R8? I sp a rn docm.51O/2009 -129- R I is lower alkyl, phenyl or lower alkylphenyl; R 1 2 is lower alkyl; and Ri 3 is a divalent alkyl radical of 2 to 5 carbons in the manufacture of a medicament for treating cachexia. 37. Use of an RXR agonist compound represented by Structural Formula R, R, Z Y B R1 R1 wherein: Z is represented by Structural Formula (II) R2 R2 n(H 2 C) R2 R 3 R2 Y is selected from thienyl or furyl, said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and -CRi=CRI-CRI=CRI- groups on adjacent carbons; n is 1 or 2; Ri and R 2 independently are lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -Cl or -Br; R 4 is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 Rio, -CH20H, -CH 2 0R 1 -CH 2 0CORII, -CHO, -CH(ORi 2 2 -CHORi30, -COR 7 -CR 7 (ORI 2 2 or -CR 7 0Ri 3 0; R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; PAOPERASUOO9\12728M Is pa h ndsts dx5oc. 1009 IN -130- R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl; R, is lower alkyl, phenyl or lower alkylphenyl; R i2 is lower alkyl; and R 1 3 is divalent alkyl radical of 2 to 5 carbons in the manufacture of a medicament for treating cachexia. 38. Use of a compound represented by Structural Formula (IX) or (IX), wherein: B is -COOH or -COORg; R 3 is hydrogen, lower alkyl, Cl or Br; R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to carbons or trimethylsilylalkyl, where the alkyl group has 1 to 10 carbons, or Rg is phenyl or lower alkylphenyl in the manufacture of a medicament for treating cachexia. P \OPRMASUO\D)\ 1728R I gs pa c-ls dow-5u12(X)9 131 39. Use of a compound represented by Structural Formula (XII): S/ CO 2 R (XII), wherein R is hydrogen or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cachexia. Method according to any one of Claims 1 to 30 or use according to any one of Claims 31 to 39 substantially as hereinbefore described.