WO2005013949A2 - Method for treating cachexia with retinoid ligands - Google Patents

Method for treating cachexia with retinoid ligands Download PDF

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Publication number
WO2005013949A2
WO2005013949A2 PCT/US2004/025564 US2004025564W WO2005013949A2 WO 2005013949 A2 WO2005013949 A2 WO 2005013949A2 US 2004025564 W US2004025564 W US 2004025564W WO 2005013949 A2 WO2005013949 A2 WO 2005013949A2
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carbons
cancer
alkyl
group
compound
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PCT/US2004/025564
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French (fr)
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WO2005013949A3 (en
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Guang Liang Jiang
Yang-Dar Yuan
Roshantha A. Chandraratna
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Allergan, Inc.
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Priority to EP04780406A priority Critical patent/EP1653939A2/en
Priority to AU2004263156A priority patent/AU2004263156B2/en
Priority to CA002535260A priority patent/CA2535260A1/en
Priority to JP2006522776A priority patent/JP2007501800A/en
Publication of WO2005013949A2 publication Critical patent/WO2005013949A2/en
Publication of WO2005013949A3 publication Critical patent/WO2005013949A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • 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.
  • 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 impetus for the search into underlying mechanisms and therapies that might prevent or reverse cachexia. However, this need has gone largely unmet.
  • 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.
  • RXRs retinoid X receptors
  • 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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, dementia, major depression, anorexia nervosa, an aged condition and sarcopenia.
  • cancer AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel
  • 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.
  • the cachexia is associated with one or more of cancer, ALDS, 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.
  • 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.
  • the cachexia is associated with cancer.
  • the cachexia is associated with ALDS.
  • 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 (I): where: Z is represented by Structural Formula (II) or Structural Formula (III)
  • X is S, O, or NR 5 ;
  • n is 1 or 2;
  • Ri and R 2 independently are -H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, -CI or -Br;
  • Rt is lower alkyb fluoroalky
  • Z is represented by Structural Formula (II) or (III);
  • Y is selected from pyridyl, pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and and R 2 independently are -H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyl, -CI or -Br;
  • R 4 is lower alkyl, fluoroalkyl or halogen;
  • R 5 is -H or lower alkyl;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 , -CONR R ⁇ o, -CH 2 OH, -CH 2 OR 11 , -CH 2 OCOR ⁇ , -CHO, -CH(OR 12 ) 2 ,
  • Z is represented by Structural Formula (III); Y is thienyl or furyb said thienyl or furyl groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and groups on adjacent carbons;
  • X is NR 5 ;
  • n is 1 or 2;
  • Ri and R 2 independently are -H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyb -CI or -Br;
  • R ⁇ is lower alkyb fluoroalkyl or halogen;
  • R 5 is H or lower alkyl;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 , -CONR 9 R 10 , -CH 2 OH, -CH 2 OR 11 , -CH 2 OCOR11, -CHO, -CH(OR 12 ) 2 , -CHOR 13 O, -COR 7 , -CR 7 (OR
  • Z is represented by Strucutural Formula (III);
  • Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two t groups, or Y is selected from phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and groups on adjacent carbons;
  • X is S or O;
  • n is 1 or 2;
  • R ⁇ and R 2 independently are H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyb CI or Br;
  • j is lower alkyb fluoroalkyl or halogen;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,
  • Z is represented by Structural Formula (II); Y is selected from thienyl or furyb said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and groups on adjacent carbons; n is 1 or 2; R 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, -COOR 8 , -CONR 9 R 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO,
  • 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 trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyb R 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 alkylphenyb R ⁇ is lower alkyb phenyl or lower alkylphenyb R 12 is lower alkyl; and R 13 is divalent alkyl radical of 2 to 5 carbons.
  • Structural Formula (I) Another group of compounds encompassed by Structural Formula (I) include those where Z is represented by Structural Formula (III); 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 phenyb said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and groups on adjacent carbons; X is NR 5 ; R ⁇ and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, CI or Br; R 4 is lower alkyb fluoroalkyl or halogen; R 5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 , -CONR Rio, -CH 2 OH, -CH 2 OR
  • R 2 o is alkyl of 1 to 6 carbons
  • B is -COOH, or -COOR 21 where R 21 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
  • a therapeutically effect amount of a compound represented by Structural Formula (V) is used in a method of treating cachexia in a subject in need of treatment therefor:
  • 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 R 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR 12 ) 2 , -CHOR 13 O, -COR 7 , -CR 7 (OR 12 ) 2 , -CR 7 OR 13 O, or tri-lower alkylsilyl;
  • R 7 is an alkyb 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 alkylphenyb
  • R 10 independently are hydrogen, an alkyl group
  • n is 1 or 2; Ri and R 2 independently are -H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyb -CI or -Br; R t is H, lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 R 10 , -CH 2 OH, -CH 2 OR n , -CH 2 OCOR n , -CHO, -CH(OR 12 ) 2 , -CHOR 13 O, -COR 7 , -CR 7 (OR 12 ) 2 , -CR 7 OR 13 O, 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 trimethylsilylal
  • R 4 is lower alkyl of 1 to 6 carbons
  • B is -COOH or -COOR 8
  • Rs is lower alkyl of 1 to 6 carbons
  • 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.
  • the compounds administered for treating cachexia in a subject in need thereof are represented by Structural Formula (VIII):
  • X is S or O; 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, -CONR 9 R 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR 12 ) 2 , -CHOR 13 O, -COR 7 , -CR 7 (OR 12 ) 2 , -CR 7 OR 13 O, 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
  • B is -COOH or -COOR 8 ;
  • R 3 is hydrogen, lower alkyb -CI or -Br;
  • R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or
  • R 8 is phenyl or lower alkylphenyb and
  • X is S or O.
  • 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):
  • X is O, S, or (CRiR r,; n is 0, 1 or 2; Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
  • Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C ⁇ - 6 alkyl or with 1 to 3 -e; fluoroalkyl groups;
  • X is O, S or NH;
  • Rt is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
  • R2 is independently -H, lower alkyl of 1 to 6 carbons, -OR 1?
  • R 3 is hydrogen, lower alkyl of 1 to 6 carbons, -OR l5 fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2 , -NH 2 , -NHCO(C,-C 6 )alkyb or -NHCO(d- C 6 )alkenyl;
  • A is hydrogen, COOH or a pharmaceutically acceptable salt thereob
  • R 7 is an alkyb 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
  • R 8 is phenyl or lower alkylphenyb R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphen
  • 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 t groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 t groups; R ⁇ is independently -H, 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
  • Y is a bivalent radical having Formula (a) or Formula (b): or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 d- 6 alkyl or with 1 to 3 d- 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 Xi grouping or of the joint X 2 grouping represents an oxo or a thione function;
  • W is -H, -O-
  • R 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(d-C 6 alkyb or -NHCO(d- C 6 )alkenyl;
  • A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,
  • 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 R 8 is phenyl or lower alkylphenyl
  • R 9 and R ⁇ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5- 10 carbons, or phenyb hydroxyphenyl or lower
  • 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): wherein: X is O, S, or C(R) 2 ; R is -H or alkyl of 1 to 6 carbons; Ri is -H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-d-C ⁇ alkyl, or C ⁇ -C 6 -alkylphenyl; R 2 is H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, -F, -CI, -Br, -I, -CF 3 , fluoro substituted
  • 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), (XXfll), (XXIV), (XXN), (XXXVI), (XXXVII), (XXVIIa) or (XXVIIb):
  • R 5 is not hydrogen if Re, Rio, Rn, R 12 and R 13 are all hydrogen, Z, Z', Z", Z'", and Z"" are all carbon, and R* and R" represent -H, -OH, C 1 -C 4 alkoxy or Ci-C 4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group;
  • R 6 , Rio, R ⁇ , R 12 and R 13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR 7 , -SR 7 , -NR R 8 or - (CF) n CF 3 , and exist only ifthe Z, Z', Z", Z"', or Z"" from which R 6 , R 10 , R u , R 12 or R 13 originates is C, or R 6 , R .
  • R 11 , R 12 and R 13 each independently represent hydrogen or a lower alkyl having 1-4 carbons ifthe Z, Z', Z", Z"', or Z"" from which R 6 , R 10 , R ⁇ , R1 2 or R 13 originates is N, and where one of R 6 , R ⁇ , R ⁇ , R12 or R ⁇ 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;
  • R 14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thi
  • Z, Z', Z", Z'" and Z" each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z', Z", Z" 1 and Z"" are not O or S if Z, Z', Z", Z"' or Z"" is attached by a double bond to one of Z, Z', Z", Z"* or Z"" or if one or more of Z, Z', Z", Z'" or Z”" is attached to one of Z, Z', Z", Z'" or Z”” that is O or S, and provided that one or more of Z, Z 1 , Z", Z'" and Z"" are not N if one of Z, Z', Z", Z'" and Z"" is attached by a single bond to one of Z, Z*,
  • the invention also includes the use of the compounds disclosed (e.g., 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 (e.g., an RXR agonist) disclosed herein.
  • 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
  • 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. 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.
  • 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.
  • 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.
  • 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.
  • 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, chrome renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, dementia, major depression, anorexia nervosa, an aged condition and sarcopenia.
  • cancer AIDS, liver cirrhosis, diabetes mellitus, chrome renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel
  • 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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and 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.
  • 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
  • cytokines such as TNF-o interleukin- 1, interleukin-6, interferon- ⁇ , 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 DrugDiscov. Today, 8: 838 (2003); Int. J. Cardiol., 85: 73 (2002)).
  • cytokines such as TNF-o interleukin- 1, interleukin-6, interferon- ⁇ , leukemia inhibitory factor, and ciliary neurotrophic factor
  • 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 ALDS 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., IA: 6 (2001); J. Nutrition, 129: S290 (1999)).
  • 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)).
  • 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, e.g., 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.
  • 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.
  • 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.
  • 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.
  • the cachexia is associated with one or more of ALDS, 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.
  • the cachexia is associated with cancer.
  • the cachexia is associated with ALDS.
  • cancer refers to tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
  • 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 T- cell 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
  • RXR RETINOID X RECEPTOR AGONISTS
  • RARs Retinoid Acid Receptors
  • Retinoid X Retinoid X
  • 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, DJ. 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
  • the mammalian RXR includes at least three distinct genes, RXR ⁇ , RXR ⁇ 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 ⁇ , RXR ⁇ or RXRy 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.
  • RAR retinoic acid receptor
  • the different binding partners of the RXR render a different DNA-binding specificity of the heterodimer.
  • RXR refers to naturally occurring RXRs (e.g., mammalian RXRs (e.g., human (Homo sapien) RXRs, murine (e.g., rat, mouse) RXRs) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring RXR (e.g., recombinant proteins).
  • an RXR agonist refers to a substance (e.g., a molecule, a compound) which promotes (induces or enhances) at least one function characteristic of an RXR.
  • the RXR agonist binds the RXR.
  • 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.
  • 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 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.
  • 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.
  • 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 (I):
  • Z is represented by Structural Formula (II) or Structural Formula (III)
  • Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two groups, or Y is selected from phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R- t groups, and wherein Y is substituted by the Z and groups on adjacent carbons; preferably, Y is cyclopropyb phenyb 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
  • 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 trimethylsilylalkyb where the alkyl group has 1 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 to 10 carbons, or phenyl or lower alkylphenyl
  • R ⁇ is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • Z is represented by Structural Formula (II) and n is 2.
  • Z is represented by Structural Formula (III) and X is S or O.
  • Z is represented by Structural Formula (II) or (III);
  • Y is selected from pyridyl, pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and groups on adjacent carbons;
  • X is NR 5 ;
  • 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;
  • R* is lower alkyl, fluoroalkyl or halogen;
  • R 5
  • X is NR 5 ; n is 1 or 2; Rj and R 2 independently are -H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, -CI or -Br; 4 is lower alkyb fluoroalkyl or halogen;
  • R 5 is H or lower alkyl;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COOR 8 , -CONR 9 R ⁇ o, -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(
  • Z is represented by Strucutural Formula (III);
  • 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 phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyb pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R 4 groups, and wherein Y is substituted by the Z and groups on adjacent carbons;
  • X is S or O;
  • 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;
  • R 4 is lower alkyl, fluoroalkyl or halogen;
  • B is hydrogen
  • Z is represented by Structural Formula (II);
  • n is 1 or 2;
  • Ri and R 2 independently are H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, CI or Br;
  • j is lower alkyb fluoroalkyl or halogen;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR 8 , -CONR 9 R ⁇ 0 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR ⁇ 2 ) , -CHOR ⁇ 3 O, -COR 7
  • X is NR 5 ;
  • Ri and R 2 independently are H, lower alkyl or fluoroalkyl;
  • R 3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; t is lower alkyl, fluoroalkyl or halogen;
  • R 5 is -H or lower alkyl;
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COORs, -CONR R ⁇ o, -CH 2 OH, -CH2OR11, -CH2OCOR11,
  • R 2 o is alkyl of 1 to 6 carbons
  • B is -COOH, or -COOR 21 where R 2 ⁇ is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
  • 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.
  • Compounds 1 and 2 are presently the most preferred to be used in the present invention.
  • Compounds 1 and 2 are within the scope of Structural Formula (TV).
  • R 3 is hydrogen or lower alkyl
  • B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR ⁇ Rio, -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR 12 ) 2 , -CHORoO, -COR 7 , -CR 7 (OR ⁇ 2 ) 2 , -CR 7 OR ⁇ 3 O, or tri-lower alkylsilyl;
  • R is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;
  • Rs is an alkyl 1 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 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons
  • n is 1 or 2; Ri and R 2 independently are H, lower alkyl or fluoroalkyl; R 3 is hydrogen, lower alkyb -CI or -Br; R t is H, lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR 9 R ⁇ o, -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR ⁇ 2 ) 2 , -CHOR ⁇ 3 O, -COR 7 , -CR 7 (OR ⁇ 2 ) 2 , -CR 7 OR ⁇ 3 O, or tri-lower alkylsilyl; R is an alkyb 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;
  • R t is lower alkyl of 1 to 6 carbons
  • B is -COOH or -COOR 8
  • R 8 is lower alkyl of 1 to 6 carbons
  • 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.
  • Yet another group of preferred compounds disclosed by U.S. Patent No. 5,917,082 is represented by Structural Formula (VIII):
  • X is S or O; 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, -CONR 9 R 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR ⁇ 2 ) , -CHOR 13 O, -COR 7 , -CR 7 (OR ⁇ 2 ) 2 , -CR 7 OR ⁇ 3 O, or tri-lower alkylsilyl;
  • R 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;
  • Rs is an
  • B is -COOH or -COOR 8 ;
  • R 3 is hydrogen, lower alkyb -CI or -Br;
  • R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl; and
  • X is S or O.
  • R 3 is preferably H or methyl and B is preferably -COOH or -COOCH 2 CH 3 .
  • Structural Formula (IX) Particularly preferred compounds are represented by Structural Formula (IX), wherein R 3 is -H, B is -COOH or -COOR, and R is lower alkyl of 1 to 6 carbons, and pharmaceutically acceptable salts thereof.
  • R 3 When the compound is represented by Structural Formula (X), it is preferred that R 3 is -H and B is -COOH or -COOCH 2 CH 3 .
  • Structural Formula (XI) it is preferred that R 3 is -H, 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):
  • X is O, S, or (CR,R ⁇ )neigarchal; n is 0, 1 or 2; Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
  • Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C ⁇ - 6 alkyl or with 1 to 3 C ⁇ - 6 fluoroalkyl groups;
  • X is O, S orNH;
  • Ri is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of
  • R 2 is independently -H, lower alkyl of 1 to 6 carbons, -ORi, 1-adamantyb 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, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO 2 , -NH 2 , -NHCO(C ⁇ -C 6 )alkyl, or -NHCO(C ⁇ -
  • A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,
  • 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 Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphen
  • 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 groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 R t groups; Ri is independently -H, 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
  • Y is a bivalent radical having Formula (a) or Formula (b):
  • Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 , heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C ⁇ - 6 alkyl or with 1 to 3 C ⁇ - 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 Xi grouping or of the joint X 2 grouping represents an oxo or a thione function;
  • W is H, O, C(R ⁇ ) 2 , phenyb naphthyl, or 5 or 6 membered hetero
  • R 2 is independently -H, 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(C ⁇ -C 6 alkyl, or vNHCO(C ⁇ - C 6 )alkenyl
  • A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRgRio, -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , -CHO, -CH(OR ⁇ 2 ) 2 , -CH(OR ⁇ 3 O), -COR 7 , -CR 7 (OR 12 ) 2 , -CR 7 (OR ⁇ 3 O), or -Si(C ⁇ - 6 alkyl) 3 ;
  • R 7 is an
  • X is O, S, or C(R) 2 ;
  • R is -H or alkyl of 1 to 6 carbons ;
  • Ri is -H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-C ⁇ -C 6 alkyl, or Q-C 6 -alkylphenyl;
  • 2 is -H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, -F, -CI, -Br, -I, -CF 3 , fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons
  • R 5 is not hydrogen if R 6 , Rio, R ⁇ , R1 2 and R ⁇ 3 are all hydrogen, Z, Z', Z", Z"', and Z"" are all carbon, and R' and R" represent H, OH, Ci- C 4 alkoxy or C ⁇ -C 4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group;
  • R 6 , Rio, R ⁇ , R 12 and R ⁇ 3 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR 7 , -SR 7 , -NR R 8 or - (CF) n CF 3 , and exist only ifthe Z, Z', Z", Z'", or Z"" from which R 6 , R ⁇ 0 , R ⁇ , R12 or R ⁇ 3 originates is C, or R(5, Rio, R ⁇ , R 12 and R ⁇ each independently
  • Z, Z', Z", Z"' and Z" each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z', Z", Z'" and Z"" are not O or S if Z, Z', Z", Z'" or Z"" is attached by a double bond to one of Z, Z', Z", Z'" or Z"" or if one or more of Z, Z', Z", Z"' or Z”" is attached to one of Z, Z', Z", Z'" or Z”” that is O or S, and provided that one or more of Z, Z', Z", Z'" and Z"" are not N if one of Z, Z', Z", Z"' and Z”" is attached by a single bond to one of Z, Z * ,
  • 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, ADDS, 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.
  • diseases, disorders or conditions selected from the group consisting of cancer, ADDS, 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.
  • diseases, disorders or conditions selected from the group consisting of cancer, ADDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, an aged condition and
  • dotted bond is optional, provided that when: a) the dotted bond is present, Ri is lower alkyl and R 2 is halogen, or Ri 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, Ri and R 2 taken together are methylene, thereby forming a cis-substituted cyclopropyl ring; R is hydroxy or lower alkoxy; R t , R 5 , 5 and R 7 are, independently, hydrogen or lower alkyl; X is (>CR 8 R 9 ) classroom ; n is 1,2 or 3; Rs and R are, independently, hydrogen or lower alkyl; and Rio is hydrogen, alkyl or alkoxy; and
  • the dotted bond is either hydrogenated or forms a double bond, provided that: a) when the dotted bond forms a double bond, Ri is lower alkyl and R 2 is hydrogen; and b) when the dotted bond is hydrogenated, Ri and R 2 taken together are methylene to form a cis-substituted cyclopropyl ring;
  • R 3 is hydroxy or lower alkoxy;
  • R t is alkyl or alkoxy;
  • R 5 and Re are, independently, a C - ⁇ 2 alkyl or a C 5 - ⁇ 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 R 5 and Re being linked to the remainder of the molecule to form a quaternary carbon atom; or
  • R 5 and Re are independently a C 4 - ⁇ 2 alkyl group or a mono- or polycyclic C 5 - ⁇ 2 hydrocarbon group that are linked
  • Ri is a hydrogen atom, a -CH 3 radical, a -CH 2 OR 3 radical, a -CH 2 OCOR t radical, an -OR 5 radical, an -O(CH 2 ) m (CO) n R 6 radical, a -COR 7 radical, a -COOR 8 radical or an -S(O) p R 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 R ⁇ o radical;
  • Ar is a radical selected from among those of the following formulae (a)-(e):
  • X is -O-, -S(O) t - or an -NR - radical; Y and Z are each -O-, -S(O) t - or a radical -CR ⁇ R ⁇ 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; R-t is a lower alkyl radical; R 5 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
  • R 1 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
  • Z is a group represented by one of the following formulas:
  • A, B and D are each carbon, nitrogen, sulfur or oxygen, where the carbon or nitrogen atoms are optionally substituted;
  • Xi and Yi are each independently hydrogen, -NR 4TC>5, -CR >6 0 RT)7'R- ⁇ ,8 ⁇ , -OR , -SR 10 , -S(O)R ⁇ 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 5 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
  • a fifth group of compounds suitable for treating cachexia are represented by
  • Ri and R 2 are each independently hydrogen, lower alkyb alkenylalkyb alkynylalkyb cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryb heteroaryl or arylalkyb or alternatively Ri 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
  • B represents Re is hydrogen, lower alkyb alkenylalkyb alkynylalkyb cycloalkyl, cycloalkylalkyb lower alkoxyalkyl, aryb heteroaryl, arylalkyl or heteroarylalkyl;
  • R ⁇ 3 is hydrogen, lower alkyl or lower alkoxy;
  • E is aryb heteroaryl or
  • R ⁇ and R ⁇ 2 are each hydrogen or lower alkyl; m is an integer of 1 to 3; R 8 is hydrogen, hydroxyl, lower alkoxy or -NR 9 R ⁇ 0 ; and R and Rio are each independently hydrogen, hydroxyl, lower alkyb lower alkoxy, hydroxyalkyb aryb hydroxyaryl or heteroaryl, or alternatively R 9 and R 10 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)-(XXXVII):
  • Ri through t each independently are hydrogen, a C ⁇ -C 6 alkyl or a C 7 -C ⁇ 5 arylalkyl or heteroarylalkyl;
  • R 5 is a C 5 -C 10 alkyb heteroalkyl, aryb heteroaryl, a C 7 -C ⁇ 5 arylalkyl or heteroaryialkyb -NR 6 R 7 , or -OR 8 , where R 6 and R 7 each independently are a C- 7 -C 10 alkyb heteroalkyl, a C -C ⁇ 5 arylalkyl or heteroaryialkyb a C 3 -C ⁇ o acyb provided that only one of Re or R 7 is acyb or R 6 and R 7 taken together are C 3 -C 6 cycloalkyl, and where R 8 is a C- 7 -C 10 alkyb heteroalkyl, aryb heteroaryl, or a C -C ⁇ s arylalkyl or heteroarylalkyl;
  • R 41 being hydrogen, a C ⁇ -C 6 alkyl or a C 7 -C ⁇ s arylalkyl or heteroarylalkyl
  • t2 and R « each independently being hydrogen, a C ⁇ -C 6 alkyl, a C 7 -C ⁇ s arylalkyl or heteroaryialkyb aryb ortho-, meta, or para-substituted hydroxyarl, or taken together are a C 3 -C 6 cycloalkyl
  • R 44 and Ris each independently are hydrogen, a C 1 -C 4 alkyl or -CH 2 OR t6 , where R 46 is hydrogen or a C ⁇ -C 6 alkyb or t4 and t 5 taken together are a C 3 -C 6 cycloalkyl or cycloheteroalkyl
  • R 55 through R 58 each independently are hydrogen, halogen, a C 1 -C 10 alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C ⁇ 5 arylalkyl or heteroarylalkyl, -NRsgReo or -OR 6 ⁇ , where R 59 and R 50 each independently are hydrogen, a C 1 -C 10 alkyl or heteroalkyl, a C 7 -C ⁇ 5 arylalkyl or heteroarylalkyl, a C ⁇ -C 8 acyl, provided that only one of R 59 or Reo is acyl, or R 5 and Reo taken together are C 3 -C 6 cycloalkyl, and where R ⁇ i is hydrogen or a C1-C 10 alkyl, heteroalkyl, aryl, heteroaryl, or a C 7 -C ⁇ 5 arylalkyl or heteroaryialky
  • R 72 which is a C 3 -C ⁇ o alkyl, heteroalkyl, aryl, heteroaryl, a C 7 -C ⁇ 5 arylalkyl or heteroaryialkyb ⁇ R 7 R 74 , or OR 75 , where R 73 and R 74 each independently are a C 7 -C ⁇ o alkyb heteroalkyl, a C -C ⁇ 5 arylalkyl or heteroaryialkyb a C 3 -C ⁇ o acyb provided that only one of R 73 or R 74 is acyb or R 73 and R 74 taken together are C 3 -C 6 cycloalkyl, and where R 75 is a d-Cio alkyb heteroalkyl, aryb heteroaryl, or a C -C ⁇ 5 arylalky
  • (XXXIX) where: R 4 4 through R4- 7 and R 6 2 through R 68 , M, W and n each have the definitions given above for Structural Formulas (XXXIII)-(XXXVII), or Re 2 and R 63 , R ⁇ and R 65 , or R ⁇ 5 and R 6 taken together are: where Ri through Rt, R 35 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 Re, R 63 and
  • R 27 through R 4 , R 4 0 through R-t 3 , Rj , W and n have the same definitions given above for Structural Formulas (XXXIII)-(XXXNII) and the dashed lines crossing the bonds adjacent to - and R 2 7/R3 1 indicate the points of attachment at
  • 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 (Z) or trans (E), and unless otherwise indicated, for substituents Ri through R 76 , all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.
  • R is selected from the group of hydrogen, -F,
  • Ri and R 2 are each, independently, -H, a halo, a C1-C1 0 alkyl, a C 3 -C ⁇ o cycloalkyl, a C 5 -C ⁇ o cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-Ci-C ⁇ -alkyl, or an amino group represented by the formula
  • R ⁇ 4 and R 15 are each, independently, H, a C ⁇ -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 heterocycle.
  • R and Ri taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring in which the aryl, heteroaryl, C 5 -C 8 cycloalkyl or Cs-C 8 cyclolkenyl are optionally substituted with one or more halo, C ⁇ -C 3 alkyl, C ⁇ -C 3 haloalkyl or C 1 -C 3 alkoxy substituents.
  • R and Ri 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 -H, a halo, a C 1 -C1 0 alkyl, a C 3 -C ⁇ o cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-Ci-C ⁇ -alkyb or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy.
  • R t is -H, a halo, an aryl-C ⁇ -C 6 -alkyb a C 1 -C10 alkyl or a C1-C1 0 alkoxy group wherein the arylalkyb alkyb and alkoxy are optionally substituted with one or more substituents selected from halo, C ⁇ -C 6 alkyl, aryl, heteroaryl, a C ⁇ -C 6 alkoxy, an amino group represented by the formula -NR ⁇ 4 R ⁇ 5 .
  • the aryl and the heteroaryl substituents each, independently, have from five to ten atoms.
  • R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -Cs 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.
  • the aryl and heteroaryl have from five to ten atoms.
  • R 5 is -H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo.
  • R 6 is -H or halo.
  • Ri6 is -OR17, -OCH(R ⁇ 7 )OC(O)R ⁇ s, -NR ⁇ 9 R 20 , or an aminoalkyl.
  • R ⁇ , R ⁇ 9 and R 2 o are each, independently, -H or a C ⁇ -C 6 alkyl.
  • Ris is a Ci-C ⁇ alkyl.
  • Ring A is a heteroaryl group represented by the following structural formula:
  • Xi and X are each, independently, O, S, N, NH, or CH.
  • X 3 is N or C.
  • Xt is CH orN.
  • p is 0 or 1.
  • Ring A is optionally substituted with one or more substituents selected from a halo, a C ⁇ -C 6 alkyb or a C ⁇ -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.
  • 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 ⁇ -C 6 alkyl, or C ⁇ -C 6 -alkylphenyl;
  • R 2 is H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF 3 , fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
  • R is independently alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF 3 , fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons, alkylthi
  • 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.
  • X is CR 1 or N, where R 1 is halogen, H, or CH 3 ; 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 non- aromatic, 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 ) n R 6 , and the A ring is non-aromatic; Y is O or CH 2 ; when n is 0 to 6, R 6 is -H, alkyb or -CF 3 , but when n is 2 to 5, R 6 is H, alkyb -CF 3 , -SO 2 NHR 23 , -NHSO 2 R 23 , or -NR 23 R 24 , where R 23 is alkyb aryl optionally substituted, heteroaryl optionally substituted or combined with R 24 to form a ring of 3
  • R 8 (R 8 ) y where the broken line represents an optional double bond; J is -CHO, -CO 2 R 7 , -SO 3 R 7 , -PO 3 R 7 , -CONHOH, or J forms a thiazolidinedione ring with R 8 ;
  • R 7 is -H or alkyl;
  • R 8 and R 9 are independently -H, halogen, alkyl, or -CF 3 ;
  • 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 alkyb provided that when Q is CR 4 , the A ring is aromatic;
  • R 10 is alkyb -COR 11 , -CONHR 11 , -CO 2 R n , -CONR n R 12 , -SO 2 R ⁇ , aryb or cycloalkyl;
  • R 11 and R 12 are independently al
  • X represents: (i) either. a divalent radical of following formula:
  • Y represents a divalent radical of following formula:
  • Y then represents either a divalent radical corresponding to the divalent radical of formula (b) above or one of the divalent radicals of following formula: Z being -O-, -S- or >N-R 3 ; Ri represents -CH 3 , -(CH 2 ) p -OR 4 , -(CH ) p -COR 5 or -S(O) t -R 5 , 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, R 5 represents H, lower alkyl, -OR 8 or -Nr'r", R 6 represents H or lower alkyl, R 7 represents lower alkyl, R 8 represents H, alkyl, alkenyb alkynyb aryb
  • R is -H, a salt of the carboxylic acid or lower alkyl; and R 1 is methyl, ethyl or n-propyl
  • R is -H, 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
  • R 5 is lower alkyl
  • Y is -OH, -OCH 3 , -NHNH 2 or -H and Z is -C(O)NH-, -NHC(O)NH- or
  • R 1 is H, alkyl of 1 to 10 carbons, phenyb heteroaryl, phenyl-C ⁇ -C 6 alkyb Ci- C 6 -alkylphenyb heteroaryl-C ⁇ -C 6 alkyb Ci-C 6 -alkylheteroaryl where heteroaryl is selected from the group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyl; R is independently H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF 3 , fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; m is an integer having the values of 0 to 3; R is independently -H, alkyl
  • X is O, S, where n is 0,1 or 2; Y is Y 1 or Y 2 where Z is (CR ⁇ , 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 O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C ⁇ - 6 alkyl or with 1 to 3 C ⁇ - 6 fluoroalkyl groups;
  • R 7 is an o alkyb cycloalkyl or alkenyl group contaimng 1 to 5 carbons
  • R 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
  • R is phenyl or lower alkylphenyb
  • R and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyb
  • R 11 is lower alkyb phenyl or lower alkylphenyb
  • R 12 is lower alkyb and R 13 is divalent alkyl radical of 2-5 carbons
  • R 14 is alkyl radical of 2-5 carbons
  • R 1 and R 2 are independently hydrogen or C ⁇ - 6 alkyl
  • W is C(R 3 )R 4 , O, NR 3 , S, SO or SO 2 wherein R 3 and R 4 are independently hydrogen or C ⁇ - 6 alkyl
  • R 5 is hydrogen, C ⁇ - 6 alkyl, halogen, -OR 11 , -SR 11 , -OCOR 11 , -NH 2 , -NHR 11 , -NR ⁇ R 12 , -NHCOR 11 , -NR ⁇ -COR 12 where R 11 and R 12 are independently Ci-e alkyb phenyl or alkyl phenyl
  • X is
  • R 6 is hydrogen, or taken together with R 7 forms a double bond, or taken together with R 7 is methylene to form a cyclopropyl ring
  • R 7 is hydrogen, or taken together with R 6 forms a double bond, or taken together with R 6 is methylene to form a cyclopropyl ring, or taken together with R 9 forms a double bond, or taken together with R 9 is methylene to form a cyclopropyl ring
  • R 8 is hydrogen, or taken together with R 9 forms a double bond, or taken together with R 9 is methylene to form a cyclopropyl ring
  • R is hydrogen, hydroxy, -OR , -OCOR , or taken together with R forms a double bond, or taken together with R is methylene to form a cyclopropyl ring, or taken together with R 8 forms a double bond, or taken together with R 8 is methylene 1 " to form a cyclopropyl ring, where R is C ⁇ - 6 al
  • Q, X and Y are each independently O, S or CH 2 ;
  • A is -(CR 2 ) consult- where n is an integer of from 1 to 3;
  • T and T 1 are each independently O, S, CH 2 , or C(CH 3 ) 2 ; and
  • R 1 is hydrogen or C ⁇ -C 6 alkyb and pharmaceutically acceptable salts thereof.
  • R is methyl, ethyl, n-propyl or n-butyb
  • R 1 through R 4 each independently are hydrogen, a C ⁇ -C 6 alkyb or a C 7 -C 15 arylalkyl
  • R 5 through R 8 each independently are hydrogen, a C ⁇ -C 6 alkyb or at least two of R 5 through R 8 taken together are a C 3 -C 6 cycloalkyl
  • R 9 and R 10 each independently are hydrogen, a Ci- alkyb -F, -Cb -Br, -NR n R 12 , -NO 2 or -OR 13
  • R 11 and R 12 each independently are hydrogen, a C r C 8 alkyb a C 7 -C ⁇ 5 arylalkyb a C C 8 acyb provided that only one R 11 or R 12 can be acyl, or R 11 and R 12 taken together are a C 3 -C 6 cycloalkyl
  • R 13 is hydrogen or a C ⁇ -C 8 alkyl or a C -Ci5 arylalkyl
  • R 15 is -OR 16 or -NR 17 R 18 , with R 16 being hydrogen, a C ⁇ -C 6 alkyl or a C 7 -C ]5 arylalkyb and with R 17 and R 18 each independently being hydrogen, a C ⁇ -C 6 alkyl, a C 7 -Ci 5 arylalkyb aryb 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 . 17 .
  • R 19 is aryl or hydroxyaryl
  • R 19 is a C 1 -C 5 alkyl
  • A is O, S or NR 20 , where R 20 is a hydrogen, C ⁇ -C 6 alkyl or a C 7 -Ci 5 arylalky
  • W is (CH 2 ) m
  • 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 R 1 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 of R 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 Ci-C ⁇ alkyl or R and R taken together are a C 3 -C 6 cycloalkyl
  • V is C or N, provided, however, that when
  • R 1 through R 4 each independently are hydrogen, a C ⁇ -C 6 alkyl, or a C 7 -C ⁇ 5 arylalkyl
  • R 5 through R 8 each independently are hydrogen, a C ⁇ -C 6 alkyl, or at least two of R 5 through R 8 taken together are a C 3 -C 6 cycloalkyl
  • R 9 and R 10 each independently are hydrogen, a C ⁇ -C 6 alkyl, -F, -CI, -Br, -NR ⁇ R 12 , -NO 2 or -OR 13
  • R 11 and R 12 each independently are hydrogen, a Ci- 11 1
  • R 15 is -OR 16 or -NR 17 R 18 , with R 16 being hydrogen, a C ⁇ -C 6 alkyl or a C 7 -C ⁇ 5 arylalkyb and with R 17 and R 18 each independently being hydrogen, a C ⁇ -C 6 alkyl, a C 7 -Ci 5 arylalkyb aryb ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a -C ⁇ cycloalkyl, provided that R 18 must be hydrogen when R 17 is aryl or hydroxyaryl, R 19 is a C 1 -C 5 alkyl, and A is O, S or NR 20 , where R 20 is a hydrogen, C ⁇ -C 6 alkyl or a C 7 -C ⁇ 5 arylalky; R 12 through R 15 attached to the tricyclic ring each independently are hydrogen or a C ⁇ -C 6 alkyb or taken together then one each of R 12 and R 13 or R 14 and R 15 respectively, form
  • R 1 through R 4 each independently are hydrogen, a C ⁇ -C 6 alkyb or a C 7 -C 15 arylalkyl
  • R 9 and R 10 each independently are hydrogen, a C ⁇ -C 6 alkyb -F, -Cb -Br, -NR ⁇ R 12 , -NO 2 or -OR 13
  • R 11 and R 12 each independently are hydrogen, a C r C 8 alkyb a C- 7 -C 15 arylalkyb a C ⁇ -C 8 acyb provided that only one R 11 or R 12 can be acyl, or R 11 and R 12 taken together are a d-C 6 cycloalkyl
  • R 13 is hydrogen or a C ⁇ -C 8 alkyl or a C -C ⁇ 5 arylalkyl
  • R .14 represents:
  • R 15 is -OR 16 or -NR 17 R 18 , with R 16 being hydrogen, a C ⁇ -C 6 alkyl or a C 7 -Ci 5 arylalkyb and with R 17 and R 18 each independently being hydrogen, a C ⁇ -C 6 alkyl, a C 7 -Ci 5 arylalkyb aryb 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 17 is aryl or hydroxyaryl, R 19 is a C 1 -C5 alkyl, and A is O, S or NR 20 , where R 20 is a hydrogen, C ⁇ -C 6 alkyl or a C 7 -C ⁇ 5 arylalky; 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
  • R 1 represents: (i) 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 (a) and (b) below: (a) (b)
  • Ar represents a radical chosen from the radicals of formulae (c) to (f) below:
  • R 5 , R 9 , R 12 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: (i) a hydrogen atom, (ii) an alkyl radical having at least 3 carbon atoms, among which the carbon attached to the phenyl radical of formula (I) is substituted with at least two carbon atoms, (iii) a linear or branched alkyl radical, (iv) a radical -OR 5 , (v) a radical -SR 5 , > (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 nng, at least one of the radicals R 2 and R has a meaning (
  • TREATMENT Treating 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 (e.g., 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 (e.g., decreased mobility, energy and/or stamina) and decreased life span.
  • 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 (e.g., 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.
  • 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.
  • FLIC functional living index-cancer
  • FACT functional assessment of cancer therapy index
  • RORTC European Organization for Research and Treatment of Cancer
  • the questionnaires are designed to give information regarding the effect of the drug product from a patient's and caregiver's perspective.
  • cachexia e.g., cachexia resulting from a cancerous condition or other malignancies
  • Suitable routes of administration include, but are not limited to, orally, intraperitoneally, subcutaneously, intramuscularly, intradermally, transdermally, rectally, sublingually, intravenously, buccally or via inhalation.
  • 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 admministration 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.
  • 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 the present invention. Illustrative of such methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18th ed.
  • 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 (5% 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.
  • 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, metacresob phenol and benzalkonium chloride.
  • 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.
  • a formulation can be filled into containers under an inert atmosphere such as nitrogen and can be conveniently presented in unit dose or multi- dose form, for example, in a sealed ampoule.
  • 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.
  • a liquid carrier for example, ethanol, glycerine or water
  • a flavoring or coloring agent for example, ethanol, glycerine or water
  • a flavoring or coloring agent for example, ethanol, glycerine or water
  • a flavoring or coloring agent for example, ethanol, glycerine or water
  • 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.
  • routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.
  • compositions are 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 non- aqueous 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, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the therapeutically effective amount of a compound of the invention depends, in each case, upon several factors, e.g., 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.
  • 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 e.g., humans or mammals other than humans
  • 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.
  • the additional therapeutic agent does not diminish the effects of the primary agent(s) and/or potentiates the effect of the primary agent(s).
  • the additional therapeutic agent can be one that is useful for treating cachexia.
  • 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 (e.g., megestrol acetate and medroxyprogesterone acetate), growth hormone (e.g,. Serostim®), growth hormone secretagogues (e.g., ghrelin, GHRP-1, GHRP-2, GHRP-6, NN703, Ipamorelin, Campromorelin, MK-677 and those described in U.S. Patent Nos.
  • progesterone derivatives e.g., megestrol acetate and medroxyprogesterone acetate
  • growth hormone e.g,. Serostim®
  • growth hormone secretagogues e.g., ghrelin, GHRP-1, GHRP-2, GHRP-6, NN703, Ipamorel
  • cannabinoids e.g., dronabinol
  • anabolic steroids e.g., oxandrolone
  • corticosteroids e.g., dexamethasone
  • monoclonal antibodies e.g., entanercept (ENBREL® and REMICADE®)
  • ⁇ -Adrenergic blockers e.g., dronabinol
  • cannabinoids e.g., dronabinol
  • anabolic steroids e.g., oxandrolone
  • corticosteroids e.g., dexamethasone
  • monoclonal antibodies e.g., entanercept (ENBREL® and REMICADE®)
  • ⁇ -Adrenergic blockers e.g., entanercept (ENBREL® and REMICADE®
  • the additional therapeutic agent can reduce side effects associated with the administration of the RXR agonist.
  • the additional therapeutic agent can be an antihyperlipidemic agent. Suitable antihyperlipidemic agents include, but are not limited to, bile acid sequestrants (e.g., WELCHOL®, Cholestryramine, Colestipol and Polidexide), Fibrates (e.g.,
  • Oxiniacic Acid Thyroid Hormone/ Analogs (e.g., Etiroxate, Thyropropic Acid and Thyroxine), and others agents such as, Acitran, Azacosterol, Benfluorex, ⁇ - Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, ⁇ -Oryzanol, Pantethine,
  • Thyroid Hormone/ Analogs e.g., Etiroxate, Thyropropic Acid and Thyroxine
  • others agents such as, Acitran, Azacosterol, Benfluorex, ⁇ - Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone
  • alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl.
  • alkenyl refers to and covers normal alkenyb branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation.
  • alkynyl refers to and covers normal alkynyb and branch chain alkynyl groups having one or more triple bonds.
  • Lower alkyl means the above-defined broad definition of alkyl 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.
  • esters 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 often 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.
  • amides include the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides.
  • preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic- cyclic radicals of 5 to 10 carbon atoms.
  • Particularly preferred amides are those derived from substituted and unsubstituted lower alkyl amines.
  • 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 .
  • R is lower alkyl.
  • K may be -OR 7 O- where R 7 is lower alkyl of 2- 5 carbon 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 activity 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.
  • 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. Prefe ⁇ ed 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.
  • 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.
  • a mixture of such isomers, or either one of the isomers is intended.
  • 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 refened 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.
  • 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.
  • 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 sigmficantly greater body weights than the animals which received the vehicle only.
  • the food intake of nude mice bearing H292 xenografts was evaluated. Mice treated with Compound 2 in a daily dose of 50 mg/kg body weight had significantly larger food intake than the tumor bearing mice which received only vehicle. Therefore, adminsfration of Compound 2 significantly increases the appetite of tumor bearing animals.

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Abstract

The present invention relates to a method of treatment 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 treatment 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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.

Description

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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., 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 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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., 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, ALDS, 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 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 ALDS. 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 (I):
Figure imgf000004_0001
where: Z is represented by Structural Formula (II) or Structural Formula (III)
Figure imgf000004_0002
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 phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two i groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is S, O, or NR5; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, -CI or -Br; Rt is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb 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 alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. In a particular embodiment, Z is represented by Structural Formula (II) or (III); Y is selected from pyridyl, pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000005_0001
and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, -CI or -Br; R4 is lower alkyl, fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR Rιo, -CH2OH, -CH2OR11, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR1 O, or tri(lower alkyl)silyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb R 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 alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is a divalent alkyl radical of 2 to 5 carbons. In another particular embodiment, Z is represented by Structural Formula (III); Y is thienyl or furyb said thienyl or furyl groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000005_0002
groups on adjacent carbons; X is NR5; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb -CI or -Br; R^ is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9R10, -CH2OH, -CH2OR11, -CH2OCOR11, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb R and R^ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyb Ri 1 is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is a divalent alkyl radical of 2 to 5 carbons. In yet another particular embodiment, Z is represented by Strucutural Formula (III); Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two t groups, or Y is selected from phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000006_0001
groups on adjacent carbons; X is S or O; n is 1 or 2; R\ and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb CI or Br; j is lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9R10, -CH2OH, -CH2ORn, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb R and RJO independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. In a further particular embodiment of compounds represented by Structural
Formula (I), Z is represented by Structural Formula (II); Y is selected from thienyl or furyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000007_0001
groups on adjacent carbons; n is 1 or 2; R and R2 independently are H, lower alkyl or fluoroalkyl; R3 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, -COOR8, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO,
-CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb R 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 alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. Another group of compounds encompassed by Structural Formula (I) include those where Z is represented by Structural Formula (III); 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 phenyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000007_0002
groups on adjacent carbons; X is NR5; R\ and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, CI or Br; R4 is lower alkyb fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR Rio, -CH2OH, -CH2ORπ, -CH2OCORn, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb 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 alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R1 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. Yet another group of compounds encompassed by Structural Formula (I) include those where Z is represented by Structural Formula (III); Y is cyclopropyb said Y group being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRι=CRι-CRl=CRι- groups on adjacent carbons; X is NR5; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, CI or Br; l^t is lower alkyl, fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCOR11, -CHO, -CH(OR1 )2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R is an alkyl of 1 to 5 carbons, cycloalkyl of 3 to 5 carbons or alkenyl group containing 2 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb R9 and R^ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. In another embodiment, the invention includes a method of treating cachexia in a subject in need of treatment comprising administering a therapeutically effect amount of a compound represented by Structural Formula (IV):
Figure imgf000008_0001
where R2o is alkyl of 1 to 6 carbons, and B is -COOH, or -COOR21 where R21 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound. Another aspect of the invention is where a therapeutically effect amount of a compound represented by Structural Formula (V) is used in a method of treating cachexia in a subject in need of treatment therefor:
Figure imgf000009_0001
where: R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri-lower alkylsilyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 is phenyl or lower alkylphenyb R and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 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):
Figure imgf000009_0002
where: n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb -CI or -Br; Rt is H, lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10, -CH2OH, -CH2ORn, -CH2OCORn, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri-lower alkylsilyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 is phenyl or lower alkylphenyb R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and (' R13 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):
Figure imgf000010_0001
where: R4 is lower alkyl of 1 to 6 carbons; B is -COOH or -COOR8; and Rs 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. - 10 -
In yet another embodiment, the compounds administered for treating cachexia in a subject in need thereof are represented by Structural Formula (VIII):
Figure imgf000011_0001
wherein: X is S or O; alternatively, X is NR5; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri-lower alkylsilyl; R7 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; R8 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 R8 is phenyl or lower alkylphenyb 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 alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. In a preferred embodiment, compounds of Structural Formula (I) for treating cachexia are represented by Structural Formulas (LX), (X) and (XI): 11
Figure imgf000012_0001
where: B is -COOH or -COOR8; R3 is hydrogen, lower alkyb -CI or -Br; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyb and X is S or O. 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):
Figure imgf000013_0001
where: X is O, S, or (CRiR r,; n is 0, 1 or 2; Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
Figure imgf000013_0002
Figure imgf000014_0001
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 -e; fluoroalkyl groups; X is O, S or NH; Rt is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, -OR1? 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, -ORl5 fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(C,-C6)alkyb or -NHCO(d- C6)alkenyl; A is hydrogen, COOH or a pharmaceutically acceptable salt thereob
-COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORn, -CHO, -CH(OR12)2, -CH(OR13O), -COR7, -CR7(OR12)2, -CR7(OR13O), or Si(Cw alkyl)3; R7 is an alkyb 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 R8 is phenyl or lower alkylphenyb R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyb Rπ is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyl; R1 is divalent alkyl radical of 2-5 carbons; and Ri4 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb C 1 -C 1 o-alkylphenyb naphthyl, C 1 -C 1 o-alkylnaphthyb phenyl-C 1 -C 10 alkyb naphthyl-Ci-Cio alkyb d-do-alkenylphenyl having 1 to 3 double bonds, Ci-Cio- alkynylphenyl having 1 to 3 triple bonds, phenyl-d-C10 alkenyl having 1 to 3 double bonds, phenyl-d-do 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 COR8, or R14 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 Ci to do alkyl group, with a d to o 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):
Figure imgf000015_0001
(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 Rt groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 t groups; R\ is independently -H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons; R2 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; R3 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 , -NH2, -NHCO(d-C6)alkyb -NHCO(C,-C6)alkenyb -NRiR or -N(Rι)2, benzyloxy or d-C6 alkyl-substituted benzyloxy; R4 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 thereob -COORs, -COOCH2COR7, -CONR9R10, -CH2OH, -CH2ORu, -CH2OCORn, -CHO, -CH(OR12)2, -CH(OR13O), -COR7, -CR7(OR12)2, -CR7(OR13O), R7 is an alkyb 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; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rπ is lower alkyb phenyl or lower alkylphenyl; Ri2 is lower alkyl; and Rι3 is divalent alkyl radical of 2-5 carbons. Yet another aspect of the invention is a method of treating cachexia in a subj ect in need thereof with a therapeutically effective amount of a compound represented by Structural Formula (XIX):
Figure imgf000016_0001
wherein: Y is a bivalent radical having Formula (a) or Formula (b):
Figure imgf000017_0001
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 d-6 alkyl or with 1 to 3 d-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 X2 groups jointly represent an oxo or a thione function, or X2 is independently selected from -H or alkyl of 1 to 6 carbons, with the proviso that one of the joint Xi grouping or of the joint X2 grouping represents an oxo or a thione function; W is -H, -O-, -C(Ri)2-, phenyb 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 phenyb naphthyl or heteroaryl groups being unsubstituted or substituted with a d to do alkyl group, with a Ci to do fluoroalkyl group, or with halogen; Ri is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of
1 to 6 carbons; R is hydrogen, lower alkyl of 1 to 6 carbons, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(d-C6 alkyb or -NHCO(d- C6)alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,
-COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORH, -CHO, -CH(OR12)2, -CH(OR13O), -COR7, -CR7(OR12)2, -CR7(OR13O), or -81(0,-6 alkyl)3; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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; R9 and R^ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5- 10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rπ is lower alkyb phenyl or lower alkylphenyl; Rπ is lower alkyl; R13 is divalent alkyl radical of 2-5 carbons; R14 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb d-Cio-alkylphenyb naphthyl, d-do-alkylnaphthyb phenyl- Ci-Cio alkyb naphthyl-Cι-C10-alkyb Ci-Cio-alkenylphenyl having 1 to 3 double bonds, d-do-alkynylphenyl having 1 to 3 triple bonds, phenyl-d-do alkenyl having 1 to 3 double bonds, ρhenyl-Cι-Cιo 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 COR8, or R14 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 Cι to Cio alkyl group, with a d to o fluoroalkyl group, or with halogen; and the dashed line in Formula (a) represents a bond or absence of a bond, provided that when the dashed line represents a bond then there are no Rt 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):
Figure imgf000019_0001
wherein: X is O, S, or C(R)2; R is -H or alkyl of 1 to 6 carbons; Ri is -H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-d-Cό alkyl, or Cι-C6-alkylphenyl; R2 is H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, d-C6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, Cι-C6 alkyl substituted phenyloxy, or halogen substituted phenyloxy; Rt is independently -H, alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyb 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, -COOR8, -CONR9R10, -CH2OH, -CH2ORn, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri-lower alkylsilyl; R is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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; R9 and R^ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl; Rπ is lower alkyl, phenyl or lower alkylphenyl; Ri2 is lower alkyl; and R13 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), (XXfll), (XXIV), (XXN), (XXXVI), (XXXVII), (XXVIIa) or (XXVIIb):
Figure imgf000020_0001
Figure imgf000021_0001
(XXNIIa)
Figure imgf000022_0001
(XXVIIb), wherein: Ri and R2 each independently is hydrogen or lower alkyl or acyl having 1-4 carbon atoms; Y is C, O, S, Ν, CHOH, CO, SO, SO2, or a pharmaceutically acceptable salt; R3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or Ν; Rt is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, t does not exist if Y is Ν, or neither R3 or t exist if Y is S, O, CHOH, CO, SO, or SO2; 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-Ν=, NC-N^, (R7R8)N-N=, R17O- N=, R17N=, epoxy, cyclopropyb or cycloalkyl group and wherein the epoxy, cyclopropyb and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or halogen; R'" and R"" are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or R"1 and R"" taken together form a cycloalkyl group having 3- 10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen; R is hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7,
-NR7R8, or -(CF)nCF3, but R5 is not hydrogen if Re, Rio, Rn, R12 and R13 are all hydrogen, Z, Z', Z", Z'", and Z"" are all carbon, and R* and R" represent -H, -OH, C1-C4 alkoxy or Ci-C4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group; R6, Rio, Rπ, R12 and R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR R8 or - (CF)nCF3, and exist only ifthe Z, Z', Z", Z"', or Z"" from which R6, R10, Ru, R12 or R13 originates is C, or R6, R.o, R11, R12 and R13 each independently represent hydrogen or a lower alkyl having 1-4 carbons ifthe Z, Z', Z", Z"', or Z"" from which R6, R10, Rπ, R12 or R13 originates is N, and where one of R6, R^, Rπ, R12 or Rι3 is X; R7 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, phenyb aromatic alkyb or q- hydroxyphenyb q-bromophenyb q-chlorophenyb q-fluorophenyb or q-iodophenyb where q=2-4; R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone; R17 is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyb -OR7 or -SR , -R , alkyl carboxylic acid optionally substituted with halogen, acyb -OR7 or -SR , alkenyl carboxylic acid optionally substituted with halogen, acyl, -OR7 or -SR , alkyl amine optionally substituted with halogen, acyl, -OR7 or -SR7, or alkenyl amine optionally substituted with halogen, acryb -OR or -SR7; R18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8, or -(CF)nCF3; X is -COOH, tetrazole, -PO3H, -SO3H, -CHO, -CH2OH, -CONH2, -COSH,
-COOR9, -COSR9, -CONHR9, or -COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or N on the ring; Z, Z', Z", Z'" and Z"" each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z', Z", Z"1 and Z"" are not O or S if Z, Z', Z", Z"' or Z"" is attached by a double bond to one of Z, Z', Z", Z"* or Z"" or if one or more of Z, Z', Z", Z'" or Z"" is attached to one of Z, Z', Z", Z'" or Z"" that is O or S, and provided that one or more of Z, Z1, Z", Z'" and Z"" are not N if one of Z, Z', Z", Z'" and Z"" is attached by a single bond to one of Z, Z*, Z", Z"' and Z"" that is N; n is O to 3; and the dashed lines are optional double bonds. The invention also includes the use of the compounds disclosed (e.g., 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 (e.g., 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. 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, chrome renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., 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 (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and 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-o interleukin- 1, interleukin-6, interferon-γ, 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 DrugDiscov. 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 (1) use of nutritional supplementation with improved diet, (2) administration of agents that can reduce energy expenditures, e.g., -adrenergic blockers and nonsteroidal anti-inflammatory drugs such as COX inhibitors, (3) appetite stimulants, e.g., progesterone and cannabinoids, (4) anabolic stimulants, e.g., testosterone and IGF-1, (5) anticytokines, e.g., β-2 agonist such as clenbuterol and analogues, omega-3 fatty acids, melatonin, and thalidomide, and (5) miscellaneous agents, e.g., Ghrelin, anadamide, ponahestat, ATP, cyclic plasma perfusion, JX-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 ALDS 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., IA: 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 long- term 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 (J. Clin. Oncol, 20: 567 (2002)). On the other hand, Oxandrolone treatment 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, e.g., 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 ALDS, 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 ALDS. 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 T- cell 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 (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., 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 (e.g., small intestinal, gastric) and thyroid cancer.
RETINOID X RECEPTOR (RXR) AGONISTS There are two main types of retinoid 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, DJ. 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, L., et al, Cell Death andDiff., 5: 11-19 (1998)). The mammalian RXR includes at least three distinct genes, RXRα, RXRβ and RXRy (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 RXRα, RXRβ or RXRy 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 (e.g., mammalian RXRs (e.g., human (Homo sapien) RXRs, murine (e.g., rat, mouse) RXRs) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring RXR (e.g., 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 (e.g., 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^, RARβ, RARγ, RXRQ. 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 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 EC5o 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 (I):
Figure imgf000031_0001
where: Z is represented by Structural Formula (II) or Structural Formula (III)
Figure imgf000032_0001
Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two groups, or Y is selected from phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R-t groups, and wherein Y is substituted by the Z and
Figure imgf000032_0002
groups on adjacent carbons; preferably, Y is cyclopropyb phenyb 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; X is S, O, orNR5; n is 1 or 2; Ri and R independently are H, lower alkyl or fluoroalkyl; preferably, Ri is H or methyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, CI or Br; R<t is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10. -CH2OH, -CH2ORι j , -CH OCORι ., -CHO, -CH(OR12)2,
-CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; preferably, B is -COOH or a pharmaceutically acceptable salt thereof, -COOR8 or -CONR R10; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R9 and R10 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 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 another preferred embodiment, Z is represented by Structural Formula (III) and X is S or O. In a particular embodiment, Z is represented by Structural Formula (II) or (III); Y is selected from pyridyl, pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and
Figure imgf000033_0001
groups on adjacent carbons; X is NR5; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; R* is lower alkyl, fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHORπO, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; Rπ is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is a divalent alkyl radical of 2 to 5 carbons. In another particular embodiment, Z is represented by Structural Formula (III); Y is thienyl or furyb said thienyl or furyl groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRr groups on adjacent carbons; X is NR5; n is 1 or 2; Rj and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, -CI or -Br; 4 is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COOR8, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7ORι3O, or tri(lower alkyl)silyl; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; Rπ is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; and Rι3 is a divalent alkyl radical of 2 to 5 carbons. In yet another particular embodiment, Z is represented by Strucutural Formula (III); 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 phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyb pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000034_0001
groups on adjacent carbons; X is S or O; n is 1 or 2; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 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, -COOR8, -CONRgRio, -CH2OH, -CH2ORπ, -CH2OCORn, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R9 and R10 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; Rπ is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons. In a further particular embodiment of compounds represented by Structural Formula (I), Z is represented by Structural Formula (II); Y is selected from thienyl or furyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; n is 1 or 2; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, CI or Br; j is lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9Rι0, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2) , -CHORι3O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri(lower alkyl)silyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R 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 alkyb phenyl or lower alkylphenyl; Rι2 is lower alkyl; and Rι3 is divalent alkyl radical of 2 to 5 carbons. Another group of compounds represented by Structural Formula (I) include those where Z is represented by Structural Formula (III); Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two Rt groups, or Y is phenyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is NR5; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; Rt is lower alkyb fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR Rιo, -CH2OH, -CH2ORii, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORi2)2, -CR ORι3O, or tri(lower alkyl)silyl; R is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R 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; Rι2 is lower alkyl; and Rι is divalent alkyl radical of 2 to 5 carbons. Yet another group of compounds represented by Structural Formula (I) include those where Z is represented by Structural Formula (111); Y is cyclopropyb said Y group being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is NR5; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; t is lower alkyl, fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COORs, -CONR Rιo, -CH2OH, -CH2OR11, -CH2OCOR11, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2, -CR7ORι3O, or tri(lower alkyl)silyl; R7 is an alkyl of 1 to 5 carbons, cycloalkyl of 3 to 5 carbons or alkenyl group containing 2 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; Rπ is lower alkyb phenyl or lower alkylphenyl; Rι2 is lower alkyl; and Rι3 is divalent alkyl radical of 2 to 5 ( carbons. Still more preferably, compounds of the general structure shown by Structural Formula (IV) are used:
Figure imgf000036_0001
where R2o is alkyl of 1 to 6 carbons, and B is -COOH, or -COOR21 where R2ι is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound. 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 the most preferred to be used in the present invention. Compounds 1 and 2 are within the scope of Structural Formula (TV).
Figure imgf000037_0001
Compound 1 United States Patent No. 5,917,082
Figure imgf000037_0002
Compound 2 United States Patent No. 5,917,082
Figure imgf000037_0003
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. Further preferred compounds disclosed by U.S. Patent No. 5,917,082 are represented by Structural Formula (V):
Figure imgf000038_0001
where: 2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRαRio, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHORoO, -COR7, -CR7(ORι2)2, -CR7ORι3O, or tri-lower alkylsilyl; R is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; Rs is an alkyl1 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 R8 is phenyl or lower alkylphenyl; R 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; R11 is lower alkyl, phenyl or lower alkylphenyl; Ri2 is lower alkyl; and Rι3 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) :
Figure imgf000038_0002
where: n is 1 or 2; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb -CI or -Br; Rt is H, lower alkyb fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2, -CR7ORι3O, or tri-lower alkylsilyl; R is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 is phenyl or lower alkylphenyl; R 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; Ri2 is lower alkyl; and Rι3 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):
Figure imgf000039_0001
where: Rt is lower alkyl of 1 to 6 carbons; B is -COOH or -COOR8; 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. Yet another group of preferred compounds disclosed by U.S. Patent No. 5,917,082 is represented by Structural Formula (VIII):
Figure imgf000040_0001
wherein: X is S or O; alternatively, X is NR5; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2) , -CHOR13O, -COR7, -CR7(ORι2)2, -CR7ORι3O, or tri-lower alkylsilyl; R 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; 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 R8 is phenyl or lower alkylphenyl; R 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; Ri2 is lower alkyl; and Rι3 is divalent alkyl radical of 2 to 5 carbons. Particularly preferred compounds encompassed by Structural Formula (I) are represented by Structural Formulas (IX), (X) and (XI):
Figure imgf000041_0001
where: B is -COOH or -COOR8; R3 is hydrogen, lower alkyb -CI or -Br; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; and X is S or O. When the compound is represented by Structural Formula (IX), R3 is preferably H or methyl and B is preferably -COOH or -COOCH2CH3. Particularly preferred compounds are represented by Structural Formula (IX), wherein R3 is -H, 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 (X), it is preferred that R3 is -H and B is -COOH or -COOCH2CH3. When the compound is represented by Structural Formula (XI), it is preferred that R3 is -H, B is -COOH or -COOCH2CH3 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):
Figure imgf000042_0001
where: X is O, S, or (CR,Rι)„; n is 0, 1 or 2; Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
Figure imgf000043_0001
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 Cι-6 fluoroalkyl groups; X is O, S orNH; Ri is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of
1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, -ORi, 1-adamantyb 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, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(Cι-C6)alkyl, or -NHCO(Cι-
C6)alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof,
-COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CH(ORι3O), -COR7, -CR7(ORι2)2, -CR7(ORι3O), or -Si(Cι-6 alkyl)3; R7 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 cycloalkyl group of 5 to 10 carbons, or R8 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 phenyb hydroxyphenyl or lower alkylphenyl; R11 is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; Rι3 is divalent alkyl radical of 2-5 carbons; and Rι4 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb Ci-Cio-alkylphenyb naphthyl, Ci-Cio-alkylnaphthyb phenyl-Ci-Cio alkyb naphthyl-Cι-Cιo alkyb Ci-Cio-alkenylphenyl having 1 to 3 double bonds, Ci-Cio- alkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Cio alkenyl having 1 to 3 double bonds, phenyl-Ci-Cio 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 COR8, or Rι4 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 Ci to Cio alkyl group, with a Ci to Cio 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):
Figure imgf000044_0001
(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 groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 Rt groups; Ri is independently -H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons; R2 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; R3 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 , -NH2, -NHCO(Cι-C6)alkyb -NHCO(d-C6)alkenyb -NRiH or -N(Rι)2, benzyloxy or Cι-C6 alkyl-substituted benzyloxy; R-t 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, -COOR8, -COOCH2COR7, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CH(ORι3O), -COR7, -CR7(ORι2)2, -CR7(ORι3O), R7 is an alkyl, cycloalkyl or alkenyl grou 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; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rπ is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; and Rι3 is divalent alkyl radical of 2-5 carbons. Yet another group of compounds useful for treating cachexia is represented by Structural Formula (XIX):
Figure imgf000045_0001
wherein: Y is a bivalent radical having Formula (a) or Formula (b):
Figure imgf000046_0001
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 , heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 Cι-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 X2 groups jointly represent an oxo or a thione function, or X2 is independently selected from H or alkyl of 1 to 6 carbons, with the proviso that one of the joint Xi grouping or of the joint X2 grouping represents an oxo or a thione function; W is H, O, C(Rι)2, phenyb 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 phenyb naphthyl or heteroaryl groups being unsubstituted or substituted with a Ci to Cio alkyl group, with a Ci to Cio fluoroalkyl group, or with halogen; Ri is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of
1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(Cι-C6 alkyl, or vNHCO(Cι- C6)alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRgRio, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CH(ORι3O), -COR7, -CR7(OR12)2, -CR7(ORι3O), or -Si(Cι-6 alkyl)3; R7 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 cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rπ is lower alkyb phenyl or lower alkylphenyl; Rι is lower alkyl; Ri3 is divalent alkyl radical of 2-5 carbons; Rι4 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb Ci-Cio-alkylphenyb naphthyl, Ci-Cio-alkylnaphthyb phenyl-Ci-Cio alkyb naphthyl-Cι-Cιo-alkyb Ci-Cio-alkenylphenyl having 1 to 3 double bonds, Ci-Cio- alkynylphenyl having 1 to 3 triple bonds, phenyl-C i -Cio alkenyl having 1 to 3 double bonds, phenyl-Ci-Cio 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 COR8, or Rι 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 Cio alkyl group, with a Ci to Cio fluoroalkyl group, or with halogen; and the dashed line in Formula (a) 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):
Figure imgf000047_0001
wherein: X is O, S, or C(R)2; R is -H or alkyl of 1 to 6 carbons ; Ri is -H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-Cι-C6 alkyl, or Q-C6-alkylphenyl; 2 is -H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, d-C6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, Cι-C6 alkyl substituted phenyloxy, or halogen substituted phenyloxy; Rt is independently -H, alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl groμp, or heteroaryl selected from a group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyb 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, -COOR8, -CONR9Rι0, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2, -CR7ORι3O, or tri-lower alkylsilyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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; R9 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; R11 is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof. Another group of compounds for treating cachexia is represented by Structural Formulas (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIIa) or (XXVIIIb):
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
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, SO2, or a pharmaceutically acceptable salt; R3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N; Rt is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, R4 does not exist if Y is N, or neither R3 or exist if Y is S, O, CHOH, CO, SO, or SO2; 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=, (R7R8)N-N=, Rι7O-N=, Rι7N=, epoxy, cyclopropyb or cycloalkyl group and wherein the epoxy, cyclopropyb and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or halogen; R'" and R"" are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or R"' and R"" taken together form a cycloalkyl group having 3- 10 carbons, 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, -SR7,
-NR R8, or -(CF)nCF3, but R5 is not hydrogen if R6, Rio, Rπ, R12 and Rϊ3 are all hydrogen, Z, Z', Z", Z"', and Z"" are all carbon, and R' and R" represent H, OH, Ci- C4 alkoxy or Cι-C4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group; R6, Rio, Rπ, R12 and Rι3 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR R8 or - (CF)nCF3, and exist only ifthe Z, Z', Z", Z'", or Z"" from which R6, Rι0, Rπ, R12 or Rι3 originates is C, or R(5, Rio, Rπ, R12 and Rι each independently represent hydrogen or a lower alkyl having 1-4 carbons ifthe Z, Z«, Z", Z'", or Z"" from which R6, Rι0, Rπ, R12 or > Rι3 originates is N, and where one of R6, Rio, Rπ, Rι2 or Rι3 is X; R7 represents hydrogen or a lower alkyl having 1-6 carbons; R8 represents hydrogen or a lower alkyl having 1-6 carbons; R represents a lower alkyl having 1-4 carbons, phenyb aromatic alkyb or q- hydroxyphenyb q-bromophenyb q-chlorophenyb q-florophenyb or q-iodophenyb where q=2-4; Rι4 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone; Rπ is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyl, -OR7 or -SR7, -R9, alkyl carboxylic acid optionally substituted with halogen, acyb -OR or -SR7 substituted, alkenyl carboxylic acid optionally substituted with halogen, acyl, -OR7 or -SR7, alkyl amine optionally substituted with halogen, acyb -OR or -SR , or alkenyl amine optionally substituted with halogen, acryl, -OR7 or -SR7; Ris represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8, or-(CF)nCF3; X is -COOH, tetrazole, -PO3H, -SO3H, -CHO, -CH2OH, -CONH2, -COSH,
-COOR9, -COSR9, -CONHR9, or -COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or N on the ring; Z, Z', Z", Z"' and Z"" each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z', Z", Z'" and Z"" are not O or S if Z, Z', Z", Z'" or Z"" is attached by a double bond to one of Z, Z', Z", Z'" or Z"" or if one or more of Z, Z', Z", Z"' or Z"" is attached to one of Z, Z', Z", Z'" or Z"" that is O or S, and provided that one or more of Z, Z', Z", Z'" and Z"" are not N if one of Z, Z', Z", Z"' and Z"" is attached by a single bond to one of Z, Z*, Z", Z'" and Z"" 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, ADDS, 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 (XXVIIT):
Figure imgf000053_0001
(XXVIII), where: the dotted bond is optional, provided that when: a) the dotted bond is present, Ri is lower alkyl and R2 is halogen, or Ri and R2 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, Ri and R2 taken together are methylene, thereby forming a cis-substituted cyclopropyl ring; R is hydroxy or lower alkoxy; Rt, R5, 5 and R7 are, independently, hydrogen or lower alkyl; X is (>CR8R9)„ ; n is 1,2 or 3; Rs and R are, independently, hydrogen or lower alkyl; and Rio is hydrogen, alkyl or alkoxy; and phaπnaceutically acceptable salts of carboxylic acids of Structural Formula (XXVIII). A second group of compounds useful in treating cachexia is represented by Structural Formula (XXIX):
Figure imgf000054_0001
where: the dotted bond is either hydrogenated or forms a double bond, provided that: a) when the dotted bond forms a double bond, Ri is lower alkyl and R2 is hydrogen; and b) when the dotted bond is hydrogenated, Ri and R2 taken together are methylene to form a cis-substituted cyclopropyl ring; R3 is hydroxy or lower alkoxy; Rt is alkyl or alkoxy; and R5 and Re are, independently, a C -ι2 alkyl or a C5-ι2 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 R5 and Re being linked to the remainder of the molecule to form a quaternary carbon atom; or R5 and Re are independently a C4-ι2 alkyl group or a mono- or polycyclic C5-ι2 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):
Figure imgf000055_0001
wherein: Ri is a hydrogen atom, a -CH3 radical, a -CH2OR3 radical, a -CH2OCORt radical, an -OR5 radical, an -O(CH2)m(CO)nR6 radical, a -COR7 radical, a -COOR8 radical or an -S(O)pR radical; R2 is a hydrogen atom or a halogen atom, a lower alkyl radical, an -NO2 radical, an -OCOR4 radical, an -OR9 radical or a -NR9Rιo radical; Ar is a radical selected from among those of the following formulae (a)-(e):
Figure imgf000055_0002
Figure imgf000056_0001
X is -O-, -S(O)t- or an -NR - radical; Y and Z are each -O-, -S(O)t- or a radical -CRπRι2; 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; R3 is a hydrogen atom or a lower alkyl radical; R-t is a lower alkyl radical; R5 is a hydrogen atom or a lower alkyl radical; R6 is a lower alkyl radical or a heterocycle; R7 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; Rs is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 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; Rπ is a hydrogen atom or a lower alkyl radical; R12 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 -S(O)r radical. A fourth group of compounds useful for treating cachexia are represented by Structural Formula (XXXI):
Z-(CR3=CR2)n-COOR1 (XXXI) where: R1 is hydrogen or a carboxyl-protecting group; R2 and R3 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; nR2's or nR3's are the same or different from one another; and Z is a group represented by one of the following formulas:
Figure imgf000057_0001
A, B and D are each carbon, nitrogen, sulfur or oxygen, where the carbon or nitrogen atoms are optionally substituted; Xi and Yi are each independently hydrogen, -NR 4TC>5, -CR >60RT)7'R-Γ,8β, -OR , -SR10, -S(O)Rπ 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; R4 and R5 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, R4 or R5 together with the substituent of A or B form a ring; R6, R7 and R8 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and R9, R10, R11 and R12 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; X2 and Y2 are each independently hydrogen, -NR13R14, -CR15R16R17, -OR18, -SR19, -S(O)R20 or -S(O)2R21, or alternatively X2 and Y2 taken together form an optionally substituted, saturated or unsaturated ring optionally containing oxygen, sulfur and/or nitrogen; R13 and R14 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R , R and R are each independently hydrogen, linear lower alkyl or branched lower alkyl; R , R , R and R are each independently hydrogen, linear lower alkyl or branched lower alkyl; X and Y 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
Figure imgf000058_0001
A fifth group of compounds suitable for treating cachexia are represented by
Structural Formula (XXXII):
Figure imgf000059_0001
(XXXII), where: Ri and R2 are each independently hydrogen, lower alkyb alkenylalkyb alkynylalkyb cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryb heteroaryl or arylalkyb or alternatively Ri and R2 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 NR3; R3 is hydrogen or lower alkyl; the broken line moiety represents a single bond or a double bond; A represents
Figure imgf000059_0002
B represents
Figure imgf000060_0001
Re is hydrogen, lower alkyb alkenylalkyb alkynylalkyb cycloalkyl, cycloalkylalkyb lower alkoxyalkyl, aryb heteroaryl, arylalkyl or heteroarylalkyl; Rι3 is hydrogen, lower alkyl or lower alkoxy; R7 is -E-C(=O)R8; E is aryb heteroaryl or
Figure imgf000060_0002
Rπ and Rι2 are each hydrogen or lower alkyl; m is an integer of 1 to 3; R8 is hydrogen, hydroxyl, lower alkoxy or -NR9Rι0; and R and Rio are each independently hydrogen, hydroxyl, lower alkyb lower alkoxy, hydroxyalkyb aryb hydroxyaryl or heteroaryl, or alternatively R9 and R10 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)-(XXXVII):
Figure imgf000061_0001
Figure imgf000062_0001
where: Ri through t each independently are hydrogen, a Cι-C6 alkyl or a C7-Cι5 arylalkyl or heteroarylalkyl; R5 is a C5-C10 alkyb heteroalkyl, aryb heteroaryl, a C7-Cι5 arylalkyl or heteroaryialkyb -NR6R7, or -OR8, where R6 and R7 each independently are a C-7-C10 alkyb heteroalkyl, a C -Cι5 arylalkyl or heteroaryialkyb a C3-Cιo acyb provided that only one of Re or R7 is acyb or R6 and R7 taken together are C3-C6 cycloalkyl, and where R8 is a C-7-C10 alkyb heteroalkyl, aryb heteroaryl, or a C -Cιs arylalkyl or heteroarylalkyl; R9 and Rio each independently are hydrogen, a C1-C10 alkyb halogen, heteroaryialkyb -NRπRι2, - NO2 or -ORι3, where Rπ and R12 each independently are hydrogen, a C1-C10 alkyb heteroalkyl, a C7-Cι5 arylalkyl or heteroaryialkyb a Ci- Cs acyb provided that only one of Rπ or Rι2 is acyb or Rπ and R12 taken together are a C3-C6 cycloalkyl, and where R13 is hydrogen or a C1-C10 alkyb heteroalkyl or a C7-Ci5 arylalkyl or heteroarylalkyl; Rι and Rι5 each independently are hydrogen, a C1-C10 alkyb a Cι-C8 acyb or ORι6 where Rι6 is hydrogen or a C1-C10 alkyl; or Rι4 and RJ5 taken together are keto, methano, optionally substituted oxime, optionally substituted hydrazine, optionally substituted epoxy, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3- dithiane, oxazolidine or:
Figure imgf000063_0001
where the dashed lines crossing the bonds indicate the attachment bonds to the rings adjacent to Rι4 and Rι5; Ri7 and Ris each independently are hydrogen, a Ci-Cio alkyl, heteroalkyl, aryl, a C7-C15 arylalkyl or heteroarylalkyl or Rι7 and Ris taken together are a C3-C6 cycloalkyl; Rι9 is hydrogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-Cι5 arylalkyl or heteroarylalkyl; R2o through R23 each independently are hydrogen, halogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-Ci5 arylalkyl or heteroaryialkyb -NR24R25, -NO2, or -OR26, where R24 and R25 each independently are hydrogen, a C1-C10 alkyb heteroalkyl, a C7-Cι5 arylalkyl or heteroarylalkyl or a d-C8 acyb provided that only one of R2 or R25 is acyb and where R26 is hydrogen or a C1-C10 alkyb heteroalkyl, aryb heteroaryl, or a C -Cι5 arylalkyl or heteroarylalkyl; R27 through R3 each independently are hydrogen, a C1-C10 alkyb heteroalkyl, halogen, -NR32R33, -NO2 or -OR34, where R32 and R33 each independently are hydrogen, a C1-C10 alkyb a C7-Cι5 arylalkyl or heteroaryialkyb a Cι-C8 acyb provided that only one of R32 or R33 is acyb or R32 and R33 taken together are a C3-C6 cycloalkyl, and where R34 is hydrogen or a Ci -Cio alkyb heteroalkyl or a C7-Cι5 arylalkyl or heteroarylalkyl and exist only when W is C; R35 through R38 each independently are hydrogen, a C1-C2 alkyl or -OR39 where R39 is hydrogen or a C1-C10 alkyb or R35 and R36 or R37 and R38 taken together are keto, or R35 and R36, R37 and R38, R35 and R37 or R36 and R38 taken together are epoxy; COR4o can originate from any W when the originating W is C, and R40 is
-OR41 or -N t2R43, with R41 being hydrogen, a Cι-C6 alkyl or a C7-Cιs arylalkyl or heteroarylalkyl, and with t2 and R« each independently being hydrogen, a Cι-C6 alkyl, a C7-Cιs arylalkyl or heteroaryialkyb aryb ortho-, meta, or para-substituted hydroxyarl, or taken together are a C3-C6 cycloalkyl; R44 and Ris each independently are hydrogen, a C1-C4 alkyl or -CH2ORt6, where R46 is hydrogen or a Cι-C6 alkyb or t4 and t5 taken together are a C3-C6 cycloalkyl or cycloheteroalkyl; R47 is hydrogen, a C1-C4 alkyb or when n=l, R47 taken together with t4 or R45 is a C3-C6 cycloalkyl or cycloheteroalkyl; Rt8 and R49 each independently are C1-C4 alkyl; R50 is a C4-Cιo alkyb keteroalkyb aryb heteroaryl, a C7-Cι5 arylalkyl or heteroaryialkyb -NR51R52, or -OR53, where R51 and R52 each independently are a C2- C10 alkyb heteroalkyl, a C7-Cι5 arylalkyl or heteroaryialkyb a C3-Cιo acyb provided that only one of R5ι or R52 is acyb or R51 and R52 taken together are C -C6 cycloalkyl, and where R53 is a C -Cιo alkyb heteroalkyl, aryb heteroaryl, a C3-C6 alkyb heteroalkyl, aryl or heteroalkyl or a C7-Cι5 arylalkyl or heteroarylalkyl; R54 represents:
Figure imgf000064_0001
where R , Rio, Rι4, R15 and to have the definitions given above; R55 through R58 each independently are hydrogen, halogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-Cι5 arylalkyl or heteroarylalkyl, -NRsgReo or -OR6ι, where R59 and R50 each independently are hydrogen, a C1-C10 alkyl or heteroalkyl, a C7-Cι5 arylalkyl or heteroarylalkyl, a Cι-C8 acyl, provided that only one of R59 or Reo is acyl, or R5 and Reo taken together are C3-C6 cycloalkyl, and where Rόi is hydrogen or a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, or a C7-Cι5 arylalkyl or heteroaryialkyb or where R55 and R56 or R57 and R58 taken together are keto, methano, a C1-C10 alkyl methylene, a C1-C10 dialkylmethylene, C7-C15 arylalkyl or heteroarylalkylmethylene, oxime, O-alkyl oxime, hydrazone, 1,3- dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine, or R55 and R57 or R56 and R58 taken together are epoxy; R62 through g4 each independently are hydrogen, aryb heteroaryl, -CF3, a C2-C6 alkyb C2-C6 heteroalkyl or -NR51R52, where R51 and R52 have the definitions given above; R65 is hydrogen, a Cι-C2 alkyl or -OR66, where Rδ6 is a C1-C2 alkyl; R6 is a C -Cιo alkyl, heteroalkyl, aryb heteroaryl, a C7-Cι5 arylalkyl or heteroaryialkyb -NR51R52, or -OR6s, where R51 and R52 have the definitions described above, and where Res is a C3-Cιo alkyl, heteroalkyl, aryl, heteroaryl, or a C7-Ci5 arylalkyl or heteroarylalkyl; X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either Ri and R2 or R3 and R-t, respectively do not exist, and further provided, that when X or Y is N, then one each of Ri and R2 or R3 and Rt, respectively, does not exist; M is N or C; Q is N or C; Z is O, S, SO, SO2, CR59R70 or NR71, where R® through R71 each independently are hydrogen or a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-Cι5 arylalkyl or heteroarylalkyl, or R<5 and R7o each independently are -OR71, or R69 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 Rι4 and Rι5, 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 (Z) or trans (E), and unless otherwise indicated, for substituents Ri through R7ι, all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included. Yet another group of compounds suitable for treating cachexia is represented by Structural Formula (XXXVIII):
Figure imgf000066_0001
(XXXVIII), where: all variables in the structures are as defined above for Structural Formulas (XXX)-(XXX1N), with the exception of new variable R72, which is a C3-Cιo alkyl, heteroalkyl, aryl, heteroaryl, a C7-Cι5 arylalkyl or heteroaryialkyb ΝR7 R74, or OR75, where R73 and R74 each independently are a C7-Cιo alkyb heteroalkyl, a C -Cι5 arylalkyl or heteroaryialkyb a C3-Cιo acyb provided that only one of R73 or R74 is acyb or R73 and R74 taken together are C3-C6 cycloalkyl, and where R75 is a d-Cio alkyb heteroalkyl, aryb heteroaryl, or a C -Cι5 arylalkyl or heteroaryialkyb A further group of compounds useful for treating cachexia are represented by Structural Formula (XXXIX):
Figure imgf000066_0002
(XXXIX), where: R44 through R4-7 and R62 through R68, M, W and n each have the definitions given above for Structural Formulas (XXXIII)-(XXXVII), or Re2 and R63, R^ and R65, or Rό5 and R6 taken together are:
Figure imgf000067_0001
where Ri through Rt, R35 through R39, 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 R62 and Re, R63 and
Figure imgf000067_0002
where R27 through R 4, R40 through R-t3, Rj , W and n have the same definitions given above for Structural Formulas (XXXIII)-(XXXNII) and the dashed lines crossing the bonds adjacent to - and R27/R31 indicate the points of attachment at
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 (Z) or trans (E), and unless otherwise indicated, for substituents Ri through R76, all olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above compounds are included. Yet another group of compounds useful in treating cachexia are represented by Structural Formulas (LX) and (LXI):
Figure imgf000068_0001
where: Ri is selected from the group of hydrogen, -F, -CI, -Br, -I, C1-C3 alkyb C C3 haloalkyb C2-C3 alkenyb C2-C3 haloalkenyb C2-C3 alkynyb C2-C3 haloalkynyb and Cι-C3 alkoxy, wherein said alkyb haloalkyb alkenyb haloalkenyb alkynyb haloalkynyb and alkoxy groups are optionally substituted; R2 and t are independently selected from the group of hydrogen, -NRioRn, Cι-C6 alkyb d-C6 haloalkyb C3-Cg cycloalkyl, C2-C6 alkenyb C -C6 haloalkenyb C2-C6 alkynyb C2-C6 haloalkynyb aryb heteroaryl, Cι-C6 alkoxy, and aryloxy, wherein said alkyb haloalkyb cycloalkyl, alkenyb haloalkenyb alkynyb haloalkynyb aryb heteroaryl, alkoxy, aryloxy groups are optionally substituted; R3 is selected from the group of hydrogen, Cι-C6 alkyb Cι-C6 haloalkyb C3- C8 cycloalkyl, C2-C6 alkenyb C2-C6 haloalkenyb C2-C6 alkynyb C2-C6 haloalkynyb aryb heteroaryl, Cι-C6 alkoxy, and aryloxy, wherein said alkyb haloalkyb cycloalkyl, alkenyb haloalkenyb alkynyb haloalkynyb aryb heteroaryl, alkoxy, aryloxy groups are optionally substituted; R5 and Rό are independently selected from the group of hydrogen, -F, -CI, -Br, -I, -CN, -NH2, -OH, -SH, Cι-C6 alkyl, Cι-C6 haloalkyb C2-C6 alkenyb Cι-C6 haloalkenyb Cι-C6 alkoxy, and aryloxy wherein said alkyb haloalkyb alkenyb haloalkenyb alkoxy and aryloxy groups are optionally substituted; or R5 and Re 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; R7 is selected from the group of C2-C6 alkyl, C2-C alkenyb and C2-C6 haloalkyb wherein said alkyb alkenyb and haloalkyl groups are optionally substituted; R8 is selected from the group of hydrogen, -F, -CI, -Br, - 1, -CN, Cι-C6 alkyb Cι-C6 haloalkyb C2-C6 alkenyb C2-C6 haloalkenyb C2-C6 alkynyb Cι-C6 alkoxy, and aryloxy, wherein said alkyb haloalkyb alkenyb haloalkenyb alkynyb alkoxy, and aryloxy groups are optionally substituted; ' R is selected from the group of hydrogen, -F, -CI, -Br, -I, methyl, and optionally substituted methyl; Rio and Rπ each independently is hydrogen or optionally substituted Cι-C6 alkyl; or Rio and Rπ taken together with nitrogen form an optionally substituted five- or six-membered heterocyclic ring; Y is selected from the group of NR12, O and S; and R12 is selected from the group of hydrogen, optionally substituted Cι-C6 alkyl, and optionally substituted Cι-C6 haloalkyl; and pharmaceutically acceptable salts thereof. Additional compounds suitable for treating cachexia are represented by Structural Formula (LXII), including pharmaceutically acceptable salts, solvates and hydrates thereof:
Figure imgf000070_0001
In Structural Fonnula (LXII), R is selected from the group of hydrogen, -F,
-CI, -Br, -I, C1-C3 alkyl, C1-C3 haloalkyb C2-C3 alkenyb C2-C3 haloalkenyb C2-C3 alkynyb C2-C3 haloalkynyb and C1-C3 alkoxy, wherein said alkyb haloalkyb alkenyb haloalkenyb alkynyb haloalkynyb and alkoxy groups are optionally substituted; Ri and R2 are each, independently, -H, a halo, a C1-C10 alkyl, a C3-Cιo cycloalkyl, a C5-Cιo cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-Ci-Cό-alkyl, or an amino group represented by the formula -NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or Ci- C3 alkoxy; or Ri and R2 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 Cι-C6 alkyl groups. Rι4 and R15 are each, independently, H, a Cι-C6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 heterocycle. Alternatively, R and Ri taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-C8 cycloalkyl or C5-C8 cycloalkenyl ring in which the aryl, heteroaryl, C5-C8 cycloalkyl or Cs-C8 cyclolkenyl are optionally substituted with one or more halo, Cι-C3 alkyl, Cι-C3 haloalkyl or C1-C3 alkoxy substituents. Preferably, when R and Ri 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. R3 is -H, a halo, a C1-C10 alkyl, a C3-Cιo cycloalkyl, C5-C10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-Ci-Cβ-alkyb or an amino group represented by the formula NR14R15, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy. Rt is -H, a halo, an aryl-Cι-C6-alkyb a C1-C10 alkyl or a C1-C10 alkoxy group wherein the arylalkyb alkyb and alkoxy are optionally substituted with one or more substituents selected from halo, Cι-C6 alkyl, aryl, heteroaryl, a Cι-C6 alkoxy, an amino group represented by the formula -NRι4Rι5. Preferably, the aryl and the heteroaryl substituents each, independently, have from five to ten atoms. Alternatively, R3 and R4 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C5-Cs cycloalkyl or a C5-C8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy substituents. Preferably, when R3 and R4 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. R5 is -H, a halo, or a C1-C3 alkyl group which is optionally substituted with one or more halo. R6 is -H or halo. Ri6 is -OR17, -OCH(Rι7)OC(O)Rιs, -NRι9R20, or an aminoalkyl. Rπ, Rι9 and R2o are each, independently, -H or a Cι-C6 alkyl. Ris is a Ci-Cβ alkyl. Ring A is a heteroaryl group represented by the following structural formula:
Figure imgf000071_0001
In ring A, Xi and X are each, independently, O, S, N, NH, or CH. X3 is N or C. Xt is CH orN. p is 0 or 1. However, when Xi is O or S, then X2 is CH or N and p is 0. Ring A is optionally substituted with one or more substituents selected from a halo, a Cι-C6 alkyb or a Cι-C6 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 of Papers, 226th ACS National Meeting, New York, NY, United States, September 7-11, 2003 (2003); P.Y. Michellys, et ab, Journal of Medicinal Chemistry (2003), 46(13), 2683- 2696; LJ. Farmer, et ab, Bioorganic & Medicinal Chemistry Letters (2003), 13(2), 261-264; B. Dominguez, et ab, Bioorganic & Medicinal Chemistry Letters (2002), 12(18), 2607-2609; B.M. Forman, et ab, Journal of Biological Chemistry (2002), 277(15), 12503-12506; M.I. Dawson, et ab, Current Medicinal Chemistry (2002), 9(6), 623-637; V.R. Atigadda, et ab, Abstracts of Papers, 223rd ACS National Meeting, Orlando, FL, United States, April 7-11, 2002 (2002); A.M. Standeven, et ab, Biochemical Pharmacology (2001), 62(11), 1501-1509; M.M. Faub et ab, Abstracts of Papers, 222nd ACS National Meeting, Chicago, IL, United States, August 26-30, 2001 (2001); V. Vuligonda, et ab, Journal of Medicinal Chemistry (2001), 44(14), 2298-2303; M. Ebisawa, et ab, Chemical & Pharmaceutical Bulletin (2001), 49(4), 501-503; K. Ohta, et ab, Chemical & Pharmaceutical Bulletin (2000), 48(10), 1504-1513; M.I. Dawson, Bioorganic & Medicinal Chemistry Letters (2000), 10(12), 1311-1313; S.S. Koch, et ab, Journal of Medicinal Chemistry (1999), 42(4), 742-750; S. Hibi, et ab, Journal of Medicinal Chemistry (1998), 41(17), 3245-3252; LJ. Farmer, et ab, Bioorganic & Medicinal Chemistry Letters (1997), 7(21), 2747-2752; L.J. Farmer, et ab, Bioorganic & Medicinal Chemistry Letters (1997), 7(18), 2393-2398; A.M. Standeven, et ab, Biochemical Pharmacology (1997), 54(4), 517-524; R.L. Beard, et ab, Journal of Medicinal Chemistry (1996), 39(18), 3556-3563; V. Vuligonda, et ab, Bioorganic & Medicinal Chemistry Letters (1996), 6(2), 213-18; Y. Katsuta, et ab, Chemical & Pharmaceutical Bulletin (1994), 42(12), 2659-61; M.F. Boehm, et ab, Journal of Medicinal Chemistry (1994), 37(18), 2930-41; and M.F. Boehm, et ab, Journal of Medicinal 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:
Figure imgf000073_0001
where: X is O, S, or C(R)2; R is H or alkyl of 1 to 6 carbons; R1 is H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-Cι-C6 alkyl, or Cι-C6-alkylphenyl; R2 is H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R is independently alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, Cι-C6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, Cι-C6 alkyl substituted phenyloxy, or halogen substituted phenyloxy; R4 is independently -H, alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyb said phenyl and heteroaryl groups being optionally substituted with one or two R 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, -COOR8, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the ft alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R is phenyl or lower alkylphenyb R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyb R is lower alkyb phenyl or lower alkylphenyb R is lower alkyb and R is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts.
Figure imgf000074_0001
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.
Figure imgf000075_0001
II
Figure imgf000075_0002
III IV V
Figure imgf000075_0003
including salts, solvates, and physiologically functional derivatives thereof, where: X is CR1 or N, where R1 is halogen, H, or CH3; Z is O, S, or NH; M is N, C, or CR2, when M is N, the ring in which M is located is non- aromatic, when M is C, the ring in which N is located is aromatic, when M is CR2, then R2 is H or Y(CH2)nR6, and the A ring is non-aromatic; Y is O or CH2; when n is 0 to 6, R6 is -H, alkyb or -CF3, but when n is 2 to 5, R6 is H, alkyb -CF3, -SO2NHR23, -NHSO2R23, or -NR23R24, where R23 is alkyb aryl optionally substituted, heteroaryl optionally substituted or combined with R24 to form a ring of 3-7 atoms; and R24 is -H, alkyl, cycloalkyl or combined with R23 to form a ring of 3 to 7 atoms; G is -CO2R7, -SOR7, -PO3R7, -CONHOH, or (R9)2
(R8)y where the broken line represents an optional double bond; J is -CHO, -CO2R7, -SO3R7, -PO3R7, -CONHOH, or J forms a thiazolidinedione ring with R8; R7 is -H or alkyl; R8 and R9 are independently -H, halogen, alkyl, or -CF3; y and z are each 0, 1, or 2; Q is CR4, CR4R5, 0, NR, or S, where R4 and R5 are independently H or alkyb provided that when Q is CR4, the A ring is aromatic; R10 is alkyb -COR11, -CONHR11, -CO2Rn, -CONRnR12, -SO2Rπ, aryb or cycloalkyl; R11 and R12 are independently alkyl or cycloalkyl; R3 is R', wherein D is CR13R14, O, S, NR15, CHOH, CO, SO,SO2, where R13 and R14 are independently H, alkyb or cycloalkyl; and where R15 is H, alkyb or cycloalkyl; D' is (CH2)m; R16 and R17 independently are -H, Cl-4 alkyb cycloalkyl, or together form a carbocyclic ring having from 3 to 7 atoms; R18 is -H, -OR6, halogen, -CF3, alkenyb -SR16, C alkyb -CO2R16, -COR11, or -NR16R17, where R16 and R17 are as above defined; m is 0 or 1; or R3 is R", where R18 is as defined above; or R3 is R'", where M2 is C or N, provided however that the optional double bond represented by the broken line is optionally present only when M2 is C; each R19 is, independently, H or alkyl; y and z are as defined above; or R3 is R"", where each R18 is, independently, as defined above; and M3 is C(R16)3 or N(R16)2, when M3 is N(R16)2, an R16 may combine with an R18 to form a 5- or 6-membered ring; and G' and E react to form a bond.
Figure imgf000077_0001
in which: X represents: (i) either. a divalent radical of following formula:
Figure imgf000077_0002
and Y then represents a divalent radical of following formula:
Figure imgf000077_0003
(ii) or a divalent radical of formula:
Figure imgf000077_0004
and Y then represents either a divalent radical corresponding to the divalent radical of formula (b) above or one of the divalent radicals of following formula:
Figure imgf000078_0001
Z being -O-, -S- or >N-R3; Ri represents -CH3, -(CH2)p-OR4, -(CH )p-COR5 or -S(O)t-R5, p being 0, 1, 2 or 3, t being 0, 1 or 2, R2 represents H or lower alkyl, R3 represents H, lower alkoxy or -OCOR7, , R4 represents H, lower alkyl, -COR7, aryl, aralkyl, mono- or polyhydroxyalkyl, or a polyether radical, R5 represents H, lower alkyl, -OR8 or -Nr'r", R6 represents H or lower alkyl, R7 represents lower alkyl, R8 represents H, alkyl, alkenyb alkynyb aryb aralkyl, mono- or polyhydroxyalkyl, a sugar residue or an amino acid residue, r' and r", identical or different, represent H, lower alkyb -COR , aryb a sugar residue or an amino acid residue or r' and r", taken together, form a heterocycle, and the salts of the compounds of formula (I), when Ri represents a carboxylic acid group, and the geometrical and optical isomers of the compounds of formula (I).
Figure imgf000079_0001
CO 2 H
Figure imgf000079_0002
where the left hand compound corresponds to Structural Formula (LXII) above
Figure imgf000079_0003
Figure imgf000080_0001
Bu- t
Figure imgf000080_0002
where R is -H, a salt of the carboxylic acid or lower alkyl; and R1 is methyl, ethyl or n-propyl
Figure imgf000080_0003
Figure imgf000080_0004
Me Me
Figure imgf000081_0001
where: R1 and R2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms; Y represents C, O, S, N, CHOH, CO, SO, SO2, or a pharmaceutically acceptable salt; R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C orN; R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y 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=, (R7R8)N-N=, epoxy, cyclopropyb or cycloalkyl group and wherein the epoxy, cyclopropyb and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen; R5 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8, or -(CF)nCF3; R6 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8 or -(CF)„CF3; R7 represents hydrogen or a lower alkyl having 1-6 carbons; R represents hydrogen or a lower alkyl having 1-6 carbons; X is -COOH, tetrazole, -PO3H, -SO3H, -CHO, -CH2OH, -CONH2, -COSH, -COOR9, -COSR9, -CONHR9, or -COOW where R9 represents a lower alkyl having 1-4 carbons, phenyb aromatic alkyb or q-hydroxyphenyb q-bromophenyb q- chlorophenyb q- fluorophenyl, or q-iodophenyb where q=2-4, where W is a pharmaceutically acceptable salt; and n = 0-3.
Figure imgf000082_0001
Me Me
Figure imgf000083_0001
Figure imgf000083_0002
where: R is -H, a carboxylic acid salt or lower alkyl; R2 is methyl, ethyl or propyl; R3 is methyl, ethyl or propyl; R4 is lower alkyl; and R5 is lower alkyl.
Figure imgf000084_0001
Figure imgf000084_0002
where Y is -OH, -OCH3, -NHNH2 or -H and Z is -C(O)NH-, -NHC(O)NH- or
-N=N-.
Figure imgf000084_0003
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003
where: R1 is H, alkyl of 1 to 10 carbons, phenyb heteroaryl, phenyl-Cι-C6 alkyb Ci- C6-alkylphenyb heteroaryl-Cι-C6 alkyb Ci-C6-alkylheteroaryl where heteroaryl is selected from the group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyl; R is independently H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF3, fluoro substituted alkyl of 1 to 6 carbons, -OH, -SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; m is an integer having the values of 0 to 3; R is independently -H, 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 naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyb said phenyl and heteroaryl groups being optionally substituted with one or two R2 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, -COOR8, -CONR9R10, -CH2OH, -CH2 OR11, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(OR12)2, -CR7OR13O, tri-lower alkylsilyl, -OH, -OR8 or -OCOR8 where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 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 alkylphenyb R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyb R11 is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyb and R13 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof.
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
where: X is O, S,
Figure imgf000087_0004
where n is 0,1 or 2; Y is Y1 or Y2 where Z is (CR^ , 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 O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 Cι-6 fluoroalkyl groups; X is O, S orNH; R1 is independently -H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, OR1, 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups jointly represent an oxo (=O) group; R3 is hydrogen, lower alkyl of 1 to 6 carbons, OR1, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(Cι-C6) alkyl, or -NHCO(Cι-C6) alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COOR8, -CONR9R10, -CH2OH, -CH2OR1 -CHzOCOR1 -CHO, -CH(OR12)2,
-CH(OR13O), -COR7, -CR7(OR12)2, -CR7(OR13O), or -Si(Cι-6alkyl)3, where R7 is an o alkyb cycloalkyl or alkenyl group contaimng 1 to 5 carbons, R 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 alkylphenyb R and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyb R11 is lower alkyb phenyl or lower alkylphenyb R12 is lower alkyb and R13 is divalent alkyl radical of 2-5 carbons, and R14 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb Ci-Cio-alkylphenyb naphthyl, Ci- Ci o-alkylnaphthyb phenyl-C l-Cioalkyb naphthyl-Ci-Cioalkyb Cl-Cio-alkenylphenyl having 1 to 3 double bonds, Ci-Cio-alkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Cio-alkenyl having 1 to 3 double bonds, phenyl-Ci-Cio-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 COR8, or R14 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 Ci to Cio alkyl group, with a Ci to Cio fluoroalkyl group, or with halogen, and the dashed line in Y1 represents a bond or absence of a bond.
Figure imgf000089_0001
Figure imgf000089_0002
where: R1 and R2 are independently hydrogen or Cι-6 alkyl; W is C(R3)R4, O, NR3, S, SO or SO2 wherein R3 and R4 are independently hydrogen or Cι-6 alkyl; R5 is hydrogen, Cι-6 alkyl, halogen, -OR11, -SR11, -OCOR11, -NH2, -NHR11, -NRπR12, -NHCOR11, -NRπ-COR12 where R11 and R12 are independently Ci-e alkyb phenyl or alkyl phenyl; X is
Figure imgf000089_0003
R6 is hydrogen, or taken together with R7 forms a double bond, or taken together with R7 is methylene to form a cyclopropyl ring; R7 is hydrogen, or taken together with R6 forms a double bond, or taken together with R6 is methylene to form a cyclopropyl ring, or taken together with R9 forms a double bond, or taken together with R9 is methylene to form a cyclopropyl ring; R8 is hydrogen, or taken together with R9 forms a double bond, or taken together with R9 is methylene to form a cyclopropyl ring; R is hydrogen, hydroxy, -OR , -OCOR , or taken together with R forms a double bond, or taken together with R is methylene to form a cyclopropyl ring, or taken together with R8 forms a double bond, or taken together with R8 is methylene 1 " to form a cyclopropyl ring, where R is Cι-6 alkyl, phenyl or alkyl phenyl; Z is -X-Y-R10, wherein X is a valence bond, phenyl or pyridyl, optionally substituted with Cι-3 alkyl, halogen, hydroxy, Cι-3 alkoxy, C1-3 acyloxy, C1-3 alkyl halide, thiol, C1-3 substituted thiol, Y is Cι-6-alkyl, C2.6 alkenyl or C2-6 alkynyl and R10 is -CO2H, tefrazole, -PO3H, -SO3H, -CO2R15, -CONR16R17, -CH2OH, -CHO, -CH2OR18, -CH(OR19)2, -HC(OR20O), -COR21, -CR20(OR19)2, -CR21(OR20O), wherein R15 is Cι-6 alkyl, phenyl or alkyl phenyl; or Z is =Y-R10, wherein Y is -CR14, -CR14-Cι-6 alkyl, -CR14phenyl, -CR14pyridyl, -CR14Cι-3alkylaryb -CR14-C2-5 alkenyl or -CR14-C2-5 alkynyb wherein R14 is H or C1-3 alkyl and R10 is -CO2H, tefrazole, -PO3H, -SO3H, -CO2R15, -CONR16R17, -CH2OH, -CHO, -CH2OR18, -CH(OR19)2, -HC(OR20O), -COR21, -CR20(OR19)2, -CR21(OR20O), wherein R15 is Cι-6 alkyb phenyl or alkyl phenyl; R16 and R17 are independently hydrogen, Cι-6-alkyb C5-8 cycloalkyl, phenyl or Cι-6-alkyl phenyl; R18 is Cι-6-alkyb phenyl or Cι-6-alkyl phenyl; R19 is Cι-6 alkyl; R20 is C2-4 alkyl; R21 is Cι-6 alkyl phenyl or C3-6 cycloalkyl; and salts thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
Figure imgf000091_0001
t-Bu
Figure imgf000091_0002
Figure imgf000091_0003
where: Z is -C(=Q)- or
Figure imgf000091_0004
in which Q, X and Y are each independently O, S or CH2; A is -(CR2)„- where n is an integer of from 1 to 3; T and T1 are each independently O, S, CH2, or C(CH3)2; and R1 is hydrogen or Cι-C6 alkyb and pharmaceutically acceptable salts thereof.
Figure imgf000092_0001
Figure imgf000092_0002
where R is methyl, ethyl, n-propyl or n-butyb
Figure imgf000092_0003
where: R1 through R4 each independently are hydrogen, a Cι-C6 alkyb or a C7-C15 arylalkyl; R5 through R8 each independently are hydrogen, a Cι-C6 alkyb or at least two of R5 through R8 taken together are a C3-C6 cycloalkyl; R9 and R10 each independently are hydrogen, a Ci- alkyb -F, -Cb -Br, -NRnR12, -NO2 or -OR13, where R11 and R12 each independently are hydrogen, a Cr C8 alkyb a C7-Cι5 arylalkyb a C C8 acyb provided that only one R11 or R12 can be acyl, or R11 and R12 taken together are a C3-C6 cycloalkyl, and where R13 is hydrogen or a Cι-C8 alkyl or a C -Ci5 arylalkyl; R , 14 represents:
Figure imgf000093_0001
where R15 is -OR16 or -NR17R18, with R16 being hydrogen, a Cι-C6 alkyl or a C7-C]5 arylalkyb and with R17 and R18 each independently being hydrogen, a Cι-C6 alkyl, a C7-Ci5 arylalkyb aryb ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3-C6 cycloalkyl, provided that R 18 . must be hydrogen when R . 17 . is aryl or hydroxyaryl, R19 is a C1-C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, Cι-C6 alkyl or a C7-Ci5 arylalky; W is (CH2)m; X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist; Z is O, S, CR22R23 or NR24, where R22 through R24 each independently are hydrogen or a Ci-Cβ alkyl or R and R taken together are a C3-C6 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; m 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 of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration.
Figure imgf000094_0001
where: R1 through R4 each independently are hydrogen, a Cι-C6 alkyl, or a C7-Cι5 arylalkyl; R5 through R8 each independently are hydrogen, a Cι-C6 alkyl, or at least two of R5 through R8 taken together are a C3-C6 cycloalkyl; R9 and R10 each independently are hydrogen, a Cι-C6 alkyl, -F, -CI, -Br, -NRπR12, -NO2 or -OR13, where R11 and R12 each independently are hydrogen, a Ci- 11 1
Cs alkyb a C7-Ci5 arylalkyb a Cι-C8 acyb provided that only one R or R can be acyb or R11 and R12 taken together are a C3-C6 cycloalkyl, and where R13 is hydrogen or a Cι-C8 alkyl or a C7-Cι5 arylalkyl; R i l l represents:
Figure imgf000094_0002
Figure imgf000095_0001
where R15 is -OR16 or -NR17R18, with R16 being hydrogen, a Cι-C6 alkyl or a C7-Cι5 arylalkyb and with R17 and R18 each independently being hydrogen, a Cι-C6 alkyl, a C7-Ci5 arylalkyb aryb ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a -Cό cycloalkyl, provided that R18 must be hydrogen when R17 is aryl or hydroxyaryl, R19 is a C1-C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, Cι-C6 alkyl or a C7-Cι5 arylalky; R12 through R15 attached to the tricyclic ring each independently are hydrogen or a Cι-C6 alkyb or taken together then one each of R12 and R13 or R14 and R15 respectively, form a carbonyl group; X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist; Z is O, S, CR22R23 or NR24, where R22 through R24 each independently are hydrogen or a Cι-C6 alkyl or R22 and R23 taken together are a d-C6 cycloalkyl; W is N or CR25, where R25 is hydrogen or a Cι-C6 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 of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration.
Figure imgf000096_0001
where: R1 through R4 each independently are hydrogen, a Cι-C6 alkyb or a C7-C15 arylalkyl; R9 and R10 each independently are hydrogen, a Cι-C6 alkyb -F, -Cb -Br, -NRπR12, -NO2 or -OR13, where R11 and R12 each independently are hydrogen, a Cr C8 alkyb a C-7-C15 arylalkyb a Cι-C8 acyb provided that only one R11 or R12 can be acyl, or R11 and R12 taken together are a d-C6 cycloalkyl, and where R13 is hydrogen or a Cι-C8 alkyl or a C -Cι5 arylalkyl; R .14 represents:
Figure imgf000096_0002
- COJRΓ 15
Figure imgf000096_0003
where R15 is -OR16 or -NR17R18, with R16 being hydrogen, a Cι-C6 alkyl or a C7-Ci5 arylalkyb and with R17 and R18 each independently being hydrogen, a Cι-C6 alkyl, a C7-Ci5 arylalkyb aryb ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3-C6 cycloalkyl, provided that R18 must be hydrogen when R17 is aryl or hydroxyaryl, R19 is a C1-C5 alkyl, and A is O, S or NR20, where R20 is a hydrogen, Cι-C6 alkyl or a C7-Cι5 arylalky; X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist; U is (CH2)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 of R5 and R6 or R7 and R8 respectively do not exist; and the wavy lines represent olefin bonds that are either in the cis (Z) or trans (E) configuration.
Figure imgf000097_0001
Me Me I I
where: R1 represents: (i) the radical -CH3, (ii) the radical -CH2-O-R5, (iii) the radical -O-R5, (iv) the radical -CO-R6, R5 and R6 having the meanings given below, Y represents a radical chosen from the radicals of formulae (a) and (b) below:
Figure imgf000098_0001
(a) (b)
R7 and R'7 having the meanings given below, Ar represents a radical chosen from the radicals of formulae (c) to (f) below:
Figure imgf000098_0002
(c) (d) (e) (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 (I), R8 having the meaning given below, X represents an oxygen or sulphur atom, a radical -SO-, -SO2-, -N(R9)- or a radical chosen from the radicals of formulae (g) to (r) below:
Figure imgf000098_0003
R5, R9, R12 and n having the meanings given below, R2 and R3, which may be identical or different, are chosen from the group consisting of: (i) a hydrogen atom, (ii) an alkyl radical having at least 3 carbon atoms, among which the carbon attached to the phenyl radical of formula (I) is substituted with at least two carbon atoms, (iii) a linear or branched alkyl radical, (iv) a radical -OR5, (v) a radical -SR5, > (vi) a polyether radical, R5 having the meaning given below, it being understood that R2 and R3, 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 R2 and R3 do not form a nng, at least one of the radicals R2 and R has a meaning (ii) mentioned above, R and R , which may be identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, or a radical -OR5, a polyether radical, R5 represents a hydrogen atom, a lower alkyl radical or a radical -COR10, R10 having the meaning given below, R6 represents: (a) a hydrogen atom (b) a lower alkyl radical (c) a radical of formula -NR'R", R' and R" having the meanings given below, (d) a radical -OR11, R11 having the meaning given below, R7, R'7 and R9, which may be identical or different, represent a hydrogen atom or a lower alkyl radical, n is an integer equal to 0 or 1, R10 represents a lower alkyl radical, R11 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, 1 R represents a lower alkyl radical, R' and R", 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 (I), as well as their salts.
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
Me Me
2H
Figure imgf000101_0002
Figure imgf000101_0003
Figure imgf000101_0004
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000102_0003
Figure imgf000102_0004
Figure imgf000103_0001
Me Me
Figure imgf000103_0002
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 (e.g., 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 (e.g., 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 (e.g., 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. 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 of cachexia (e.g., 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 admministration 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 the 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 (5% 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, metacresob 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 multi- dose form, for example, in a sealed ampoule. 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 non- aqueous 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, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). The therapeutically effective amount of a compound of the invention depends, in each case, upon several factors, e.g., 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 (e.g., 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 prefeπed 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 (e.g., megestrol acetate and medroxyprogesterone acetate), growth hormone (e.g,. Serostim®), growth hormone secretagogues (e.g., ghrelin, GHRP-1, GHRP-2, GHRP-6, NN703, Ipamorelin, 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 International Application No. WO 00/01726), cannabinoids (e.g., dronabinol), anabolic steroids (e.g., oxandrolone), corticosteroids (e.g., dexamethasone), monoclonal antibodies (e.g., entanercept (ENBREL® and REMICADE®)), β-Adrenergic blockers,
NSAIDS, anticytokines (e.g., β-2 agonist such as clenbuterol, omega-3 fatty acids, melatonin and thalidomide), metoclopramide, insulin-like growth factor- 1 (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 (e.g., WELCHOL®, Cholestryramine, Colestipol and Polidexide), Fibrates (e.g.,
Beclobrate, Bezafibrate, Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid, Etofibrate, Fenofibrate, Genfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Simfibrate and Theofibrate), HMG CoA Reductase Inhibitors (e.g., Atorvastatin, Fluvastatin, Lovastatin, Provastatin and Simvastatin), Nicotinic acid and derivatives (e.g., Acipimox, Aluminum Nicotinate, Niceritrol, Nicoclonate, Nicomol and
Oxiniacic Acid), Thyroid Hormone/ Analogs (e.g., Etiroxate, Thyropropic Acid and Thyroxine), and others agents such as, Acitran, Azacosterol, Benfluorex, β- Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine,
Pentaerythritol Tetraacetate, ce-Phenylbutyramide, Pirozadil, Probucol, jS-Sitosterob Sultosilic Acid (Piperazine Salt), Tiadenob Cholesterol Abso tion 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 alkenyb branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Similarly, the term alkynyl refers to and covers normal alkynyb and branch chain alkynyl groups having one or more triple bonds. Lower alkyl means the above-defined broad definition of alkyl 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 often 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 often or fewer carbon atoms or the cyclic or saturated aliphatic- cyclic 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 -OR7O- where R7 is lower alkyl of 2- 5 carbon 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 activity 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. Prefeπed 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. 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 refened 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 10 mg/kg, as described in connection with FIG. 1, was weighed after the animals had - Ill -
been 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 xenografts 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, adminsfration 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 sigmficantly 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 50 mg/kg body weight had significantly larger food intake than the tumor bearing mice which received only vehicle. Therefore, adminsfration of Compound 2 significantly increases the appetite of tumor bearing animals.
While this invention has been particularly shown and described with references to prefened 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.

Claims

What is claimed is:
A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (I):
Figure imgf000113_0001
wherein: Z is represented by Structural Formula (II) or Structural Formula (III)
Figure imgf000113_0002
Y is cycloalkyl of 3 to 8 carbons or cycloalkenyl of 5 to 8 carbons optionally substituted with one or two t groups, or Y is selected from phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRr groups on adjacent carbons; X is S, O, orNR5; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyb alkylamino, dialkylamino, cyano, -CI or -Br; R4 is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; R11 is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
2. The method of Claim 1 , wherein Y is cyclopropyb phenyb pyridyl, thienyl or furyb
3. The method of Claim 2, wherein Y is cyclopropyl or phenyb
4. The method of Claim 3, wherein Y is
Figure imgf000114_0001
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 thereob -COOR8 or -CONR9Rι0.
7. The method of Claim 1 , wherein Z is represented by Structural Formula (II) and n is 2.
8. The method of Claim 1 , wherein Z is represented by Structural Formula (III) and X is S or O.
9. The method of Claim , wherein the cachexia is associated with cancer.
10. The method of Claim 9, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
11. The method of Claim 1 , wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, ALDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
12. The method of Claim 1, 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.
13. The method of Claim 12, 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.
14. The method of Claim 1 , wherein the compound is administered to a human' subject at a daily dose of from about 10 to about 4000 mg.
15. The method of Claim 14, wherein the compound is administered to a human subject at a daily dose of from about 100 to about 500 mg.
16. The method of Claim 1 , further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
17. The method of Claim 16, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic Acid and Derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadib Probucob β- Sitosterob Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
18. The method of Claim 1 , further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
19. The method of Claim 1 , wherein the compound is orally administered.
20. 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 (JV):
Figure imgf000117_0001
wherein: R o is alkyl of 1 to 6 carbons; B is -COOH, or -COOR21; and R21 is alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
21. The method of Claim 20, wherein the cachexia is associated with cancer.
22. The method of Claim 21 , wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
23. The method of Claim 20, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
24. The method of Claim 20, 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.
25. The method of Claim 20, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
26. The method of Claim 20, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
27. The method of Claim 26, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
28. The method of Claim 20, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
29. The method of Claim 20, wherein the compound is orally administered.
30. The method of Claim 20, wherein the compound is represented by the formula:
Figure imgf000118_0001
or a pharmaceutically acceptable salt of said compound.
31. The method of Claim 20, wherein the compound is represented by the formula:
Figure imgf000119_0001
or a pharmaceutically acceptable salt of said compound.
32. 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 (V):
Figure imgf000119_0002
wherein: R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 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; Rπ is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
33. The method of Claim 32, wherein the cachexia is associated with cancer.
34. The method of Claim 33, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
35. The method of Claim 32, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system i diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
36. The method of Claim 32, 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.
37. The method of Claim 32, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
38. The method of Claim 32, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
39. The method of Claim 38, 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, Acifran, Azacosterob Benfluorex, j8-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabob Meflutob Melinamide, Mytatrienediob Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, c--Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
40. The method of Claim 32, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
41. The method of Claim 32, wherein the compound is orally administered.
42. 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):
Figure imgf000121_0001
wherein: n is 1 or 2; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, -CI or -Br; Rt is H, lower alkyl, trifluoromethyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONRgRio, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2)2, or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 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; Rii is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and Rι is divalent alkyl radical of 2 to 5 carbons.
43. The method of Claim 42, wherein the cachexia is associated with cancer.
44. The method of Claim 43, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
45. The method of Claim 42, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
46. The method of Claim 42, 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.
47. The method of Claim 42, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
48. The method of Claim 42, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
49. The method of Claim 42, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, H-MG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, c--Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
50. The method of Claim 42, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
51. The method of Claim 42, wherein the compound is orally administered.
52. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (VII):
Figure imgf000123_0001
wherein: Rt is lower alkyl of 1 to 6 carbons; B is -COOH or -COOR8; 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, or a pharmaceutically acceptable salt of said compound.
53. The method of Claim 52, wherein the cachexia is associated with cancer.
54. The method of Claim 53, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
55. The method of Claim 52, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
56. The method of Claim 52, 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.
57. The method of Claim 52, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
58. The method of Claim 52, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
59. The method of Claim 58, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tefraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absoφtion Inhibitors Triparanol and Xenbucin.
60. The method of Claim 52, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
61. The method of Claim 52, wherein the compound is orally administered.
62. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (I):
Figure imgf000125_0001
wherein: Z is represented by Structural Formula (II) or Structural Formula (III)
Figure imgf000125_0002
Y is selected from pyridyl, pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is NR5; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; Rt is lower alkyl, fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9Rιo, -CH2OH, -CH2ORn, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; R 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; Rι2 is lower alkyl; and Rι3 is a divalent alkyl radical of 2 to 5 carbons.
63. The method of Claim 62, wherein the cachexia is associated with cancer.
64. The method of Claim 63, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
65. The method of Claim 62, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, ah aged condition and sarcopenia.
66. The method of Claim 62, 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.
67. The method of Claim 62, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
68. The method of Claim 62, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
69. The method of Claim 68, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tefraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
70. The method of Claim 62, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
71. The method of Claim 62, wherein the compound is orally administered. 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 (I):
Figure imgf000128_0001
wherein: Z is represented by Structural Formula (III)
Figure imgf000128_0002
Y is thienyl or furyl, said thienyl or furyl groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is NR5; n is 1 or 2; Ri and R independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; Rt is lower alkyb fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9Rιo, -CH2OH, -CH2ORn, -CH2OCORπ, -CHO, -CH(OR12)2, -CHOR13O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; Rι2 is lower alkyl; and Rι3 is a divalent alkyl radical of 2 to 5 carbons.
73. The method of Claim 72, wherein the cachexia is associated with cancer.
74. The method of Claim 73, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
75. The method of Claim 72, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
76. The method of Claim 72, 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.
77. The method of Claim 72, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
78. The method of Claim 72, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
79. The method of Claim 78, 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, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, Tiadenol, Cholesterol Absorption Inhibitors Triparanol and Xenbucin.
80. The method of Claim 72, further comprising admimstering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
81. The method of Claim 72, wherein the compound is orally administered.
82. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (I):
Figure imgf000130_0001
ill. Z is represented by Structural Formula (III)
Figure imgf000130_0002
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 phenyb pyridyl, thienyb furyb pyrrolyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb and imidazolyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is S or O; n is 1 or 2; Ri and R2 independently are H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, CI or Br; Rt is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO,' -CH(ORι2)2, -CHORi3O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; R11 is lower alkyl, phenyl or lower alkylphenyl; Rι2 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
83. The method of Claim 82, wherein the cachexia is associated with cancer.
84. The method of Claim 83, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
85. The method of Claim 82, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
86. The method of Claim 82, 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.
87. The method of Claim 82, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
88. The method of Claim 82, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
89. The method of Claim 88, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11, 14, 17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
90. The method of Claim 82, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
91. The method of Claim 82, wherein the compound is orally administered.
92. 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 (VIII):
Figure imgf000133_0001
wherein: X is S or O; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 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 R8 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and Ri3 is divalent alkyl radical of 2 to 5 carbons.
93. The method of Claim 92, wherein the cachexia is associated with cancer.
94. The method of Claim 93, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
95. The method of Claim 92, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes melhtus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
96. The method of Claim 92, 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.
97. The method of Claim 92, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
98. The method of Claim 92, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
99. The method of Claim 98, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, c--Phenylbutyramide, Pirozadib Probucob β- Sitosterob Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
100. The method of Claim 92, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
101. The method of Claim 92, wherein the compound is orally administered.
102. 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 (I):
Figure imgf000135_0001
wherein: Z is represented by Structural Formula (II)
Figure imgf000135_0002
Y is selected from thienyl or furyb said groups being optionally substituted with one or two Rt groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; n is 1 or 2; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; Rt is lower alkyl, fluoroalkyl or halogen; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COOR8, -CONR9R10, -CH2OH, -CH2OR11, -CH2OCOR11, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; R11 is lower alkyl, phenyl or lower alkylphenyl; Rι2 is lower alkyl; and Rι3 is divalent alkyl radical of 2 to 5 carbons.
103. The method of Claim 102, wherein the cachexia is associated with cancer.
104. The method of Claim 103, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
105. The method of Claim 102, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, ALDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
106. The method of Claim 102, 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.
107. The method of Claim 102, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
108. The method of Claim 102, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
109. The method of Claim 108, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, o!-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, Tiadenol, Cholesterol Absorption Inhibitors Triparanol and Xenbucin.
110. The method of Claim 102, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
111. The method of Claim 102, wherein the compound is orally administered.
112. 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 (I) :
Figure imgf000137_0001
wherein: Z is represented by Structural Formula (III)
Figure imgf000138_0001
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 phenyb said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and
Figure imgf000138_0002
groups on adjacent carbons; X is NR5; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; R4 is lower alkyl, fluoroalkyl or halogen; R5 is H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHORι3O, -COR7, -CR7(OR12)2 or -CR7ORι3O; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; Rπ is lower alkyl, phenyl or lower alkylphenyl; Rι2 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
The method of Claim 112, wherein the cachexia is associated with cancer.
114. The method of Claim 113, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
115. The method of Claim 112, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
116. The method of Claim 112, 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.
117. The method of Claim 112, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
118. The method of Claim 112, further comprising admini stering a therapeutically effective amount of an antihyperlipidemic agent.
119. The method of Claim 118, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/ Analogs, Acifran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutob Melinamide, Mytatrienediob Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
120. The method of Claim 112, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
121. The method of Claim 112, wherein the compound is orally administered.
122. 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 (I):
Figure imgf000140_0001
wherein: Z is represented by Structural Formula (III)
Figure imgf000140_0002
Y is cyclopropyb said Y group being optionally substituted with one or two t groups, and wherein Y is substituted by the Z and -CRι=CRι-CRι=CRι- groups on adjacent carbons; X is NR5; Ri and R2 independently are -H, lower alkyl or fluoroalkyl; R3 is hydrogen, lower alkyl, alkylamino, dialkylamino, cyano, -CI or -Br; R4 is lower alkyl, fluoroalkyl or halogen; R5 is -H or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COOR8, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2)2 or -CR7OR13O; R7 is an alkyl of 1 to 5 carbons, cycloalkyl of 3 to 5 carbons or alkenyl group containing 2 to 5 carbons; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 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; R11 is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
123. The method of Claim 122, wherein the cachexia is associated with cancer.
124. The method of Claim 123, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
125. The method of Claim 122, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, ADDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
126. The method of Claim 122, 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.
127. The method of Claim 122, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
128. The method of Claim 122, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
129. The method of Claim 128, 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, Azacosterob Benfluorex, jS-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11, 14, 17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
130. The method of Claim 122, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
131. The method of Claim 122, wherein the compound is orally administered.
132. 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 (VIII):
Figure imgf000142_0001
wherein: X is NR5; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; B is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COOR8, -CONRgRio, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2)2 or -CR7ORι3O; R7 is an alkyl of 1 to 5 carbons, cycloalkyl of 3 to 5 carbons or alkenyl group containing 2 to 5 carbons; R8 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 R8 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; R11 is lower alkyl, phenyl or lower alkylphenyl; Rι2 is lower alkyl; and R13 is divalent alkyl radical of 2 to 5 carbons.
133. The method of Claim 132, wherein the cachexia is associated with cancer.
134. The method of Claim 133, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
135. The method of Claim 132, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
136. The method of Claim 132, 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.
137. The method of Claim 132, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
138. The method of Claim 132, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
139. The method of Claim 138, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase lnliibitors, Nicotinic acid and derivatives, Thyroid Hormone/ Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, c--Phenylbutyramide, Pirozadil, Probucob β- Sitosterob Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
140. The method of Claim 132, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
141. The method of Claim 132, wherein the compound is orally administered.
142. 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), (X) or (XI):
Figure imgf000145_0001
wherein: B is -COOH or -COOR8; R3 is hydrogen, lower alkyb CI or Br; R8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyb where the alkyl group has 1 to 10 carbons, or R8 is phenyl or lower alkylphenyl; and X is S or O.
143. The method of Claim 142, wherein the cachexia is associated with cancer.
144. The method of Claim 143, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
145. The method of Claim 142, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
146. The method of Claim 142, 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.
147. The method of Claim 142, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
148. The method of Claim 142, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
149. The method of Claim 148, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
150. The method of Claim 142, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
151. The method of Claim 142, wherein the compound is orally administered.
152. The method of Claim 142, wherein the compound is represented by Structural Formula (IX), R3 is H or methyl and B is -COOH or -COOCH2CH3.
153. The method of Claim 142, wherein the compound is represented by Structural Formula (X), R3 is H and B is -COOH or -COOCH2CH3.
154. The method of Claim 142, wherein the compound is represented by Structural Formula (XI), R3 is H, B is -COOH or -COOCH2CH3 and X is O or S.
155. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XII):
Figure imgf000147_0001
wherein R is hydrogen or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof.
156. The method of Claim 155, wherein the cachexia is associated with cancer.
157. The method of Claim 156, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
158. The method of Claim 155, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
159. The method of Claim 155, 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.
160. The method of Claim 155, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
161. The method of Claim 155, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
162. The method of Claim 161, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, jS-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
163. The method of Claim 155, further comprising admimstering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
164. The method of Claim 155, wherein the compound is orally administered. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIII), (XIV) or (XV):
Figure imgf000149_0001
wherein: X is O, S, or (CRιRι)n; n is 0, 1 or 2; Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
Figure imgf000150_0001
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 Cι-6 fluoroalkyl groups; X is O, S orNH; Ri is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently -H, lower alkyl of 1 to 6 carbons, -ORi, 1- adamantyb 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, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH , -NHCO(Cι-C6)alkyl, or -NHCO(Cι-C6)alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereof, -COORs, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORι2)2, -CH(ORι3O), -COR7, -CR7(ORι2)2, -CR7(OR13O), or -Si(Cι-6 alkyl)3; R7 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 cycloalkyl group of 5 to 10 carbons, or R8 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 phenyb hydroxyphenyl or lower alkylphenyl; R11 is lower alkyb phenyl or lower alkylphenyl; R12 is lower alkyl; Rι3 is divalent alkyl radical of 2-5 carbons; and Rι4 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb Cι-Cι o-alkylphenyb naphthyl, Ci-Cio- alkylnaphthyb phenyl-C i -Cio alkyb naphthyl-Cι-Cιo alkyb Ci-Cio- alkenylphenyl having 1 to 3 double bonds, Ci-Cio-alkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Cio alkenyl having 1 to 3 double bonds, phenyl-Ci- Cio 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 COR8, or Rι is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, andN, said heteroaryl group being unsubstituted or substituted with a Ci to Cio alkyl group, with a Ci to Cio fluoroalkyl group, or with halogen, and the dashed line in Structural Formula (XNI) represents a bond or absence of a bond.
166. The method of Claim 165, wherein the cachexia is associated with cancer.
167. The method of Claim 166, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
168. The method of Claim 165, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
169. The method of Claim 165, 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.
170. The method of Claim 165, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
171. The method of Claim 165, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
172. The method of Claim 171, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tefraacetate, c.-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
173. The method of Claim 165, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
174. The method of Claim 165, wherein the compound is orally administered.
175. 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 (XVIII):
Figure imgf000153_0001
(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 t groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 R4 groups; Ri is independently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons; R2 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; R3 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, -NO2, -NH2, -NHCO(Cι-C6)alkyl, -NHCO(C C6)alkenyb -NRiH or -N(Rι)2, benzyloxy or Cι-C6 alkyl-substituted benzyloxy; R4 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 thereob -COOR8, -COOCH2COR7, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCORπ, -CHO, -CH(ORi2)2, -CH(ORι3O), -COR7, -CR7(ORι2)2, -CR7(ORι3O), R7 is an alkyb 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; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rii is lower alkyb phenyl or lower alkylphenyl; Rι2 is lower alkyl; and Ri3 is divalent alkyl radical of 2-5 carbons.
176. The method of Claim 175, wherein the cachexia is associated with cancer.
177. The method of Claim 176, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
178. The method of Claim 175, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, ALDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
179. The method of Claim 175, 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.
180. The method of Claim 175, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
181. The method of Claim 175, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
182. The method of Claim 181, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/ Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabob Meflutob Melinamide, Mytatrienediob Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tefraacetate, c--Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
183. The method of Claim 175, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
184. The method of Claim 175, wherein the compound is orally administered.
185. A method of treating cachexia in a subject in need thereob the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIX):
Figure imgf000155_0001
wherein: Y is a bivalent radical having Formula (a) or Formula (b):
Figure imgf000155_0002
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 Cι-6 alkyl or with 1 to 3 Cι-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 X2 groups jointly represent an oxo or a thione function, or X2 is independently selected from H or alkyl of 1 to 6 carbons, with the proviso that one of the joint Xi grouping or of the joint X2 grouping represents an oxo or a thione function; W is H, O, C(Rι)2, phenyb 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 phenyb naphthyl or heteroaryl groups being unsubstituted or substituted with a Ci to Cio alkyl group, with a Ci to
Cio fluoroalkyl group, or with halogen; Ri is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R2 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons, -ORi, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, -NO2, -NH2, -NHCO(Cι-C6) alkyl, orNHCO(Cι-C6)alkenyl; A is hydrogen, -COOH or a pharmaceutically acceptable salt thereob -COORs, -CONR9Rιo, -CH2OH, -CH2ORπ, -CH2OCORn, -CHO,
-CH(ORι2)2, -CH(ORι3O), -COR7, -CR7(ORι2)2, -CR7(ORι3O), or -Si(Cι-6 alkyl)3; R7 is an alkyb cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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; R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyb hydroxyphenyl or lower alkylphenyl; Rπ is lower alkyb phenyl or lower alkylphenyl; Rι2 is lower alkyl; R13 is divalent alkyl radical of 2-5 carbons; Ri4 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 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyb Ci-d o-alkylphenyb naphthyl, Ci-Cio- alkylnaphthyb phenyl-Ci-Cio alkyb naphthyl-Ci-Cio-alkyb Ci-Cio- alkenylphenyl having 1 to 3 double bonds, Ci-Cio-alkynylphenyl having 1 to 3 triple bonds, phenyl-Ci-Cio alkenyl having 1 to 3 double bonds, phenyl-Ci- Cio 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 COR8, or Rι4 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 Cio alkyl group, with a Ci to Cio fluoroalkyl group, or with halogen; and the dashed line in Formula (a) 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.
186. The method of Claim 185, wherein the cachexia is associated with cancer.
187. The method of Claim 186, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
188. The method of Claim 185, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
189. The method of Claim 185, 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.
190. The method of Claim 185, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
191. The method of Claim 185, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
192. The method of Claim 191, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequesfrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Beιιzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutob Melinamide, Mytatrienediob Ornithine, γ-Oryzanob Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
193. The method of Claim 185, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
194. The method of Claim 185, wherein the compound is orally administered.
195. 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 (XX):
Figure imgf000159_0001
wherein: X is O, S, or C(R)2; R is H or alkyl of 1 to 6 carbons ; Ri is H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl- Cι-C6 alkyl, or Cι-C6-alkylphenyl; R2 is H, alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, -F, -CI, -Br, -I, -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, Cι-C6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, Ci- C6 alkyl substituted phenyloxy, or halogen substituted phenyloxy; Rt is independently -H, alkyl of 1 to 6 carbons, or -F; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyb furyb pyridazinyb pyrimidinyl, pyrazinyb thiazolyb oxazolyb imidazolyl and pyrrazolyb 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, -COOR8, -CONR9R10, -CH2OH, -CH2ORπ, -CH2OCOR11, -CHO, -CH(ORι2)2, -CHOR13O, -COR7, -CR7(ORι2) , -CR7OR13O, or tri-lower alkylsilyl; R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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; R9 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; R11 is lower alkyl, phenyl or lower alkylphenyl; R12 is lower alkyl; and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt thereof.
196. The method of Claim 195, wherein the cachexia is associated with cancer.
197. The method of Claim 196, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
198. The method of Claim 195, wherein the cachexia is associated with one or more diseases, disorders or conditions 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
199. The method of Claim 195, 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.
200. The method of Claim 195, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
201. The method of Claim 195, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
202. The method of Claim 201, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, /3-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytafrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
203. The method of Claim 195, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
204. The method of Claim 195, wherein the compound is orally administered.
205. A method of treating cachexia associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, ADDS, liver cinhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an RXR agonist compound.
206. The method of Claim 205, wherein cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of ALDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
207. The method of Claim 206, wherein cachexia is associated with AIDS.
208. The method of Claim 205, wherein cachexia is associated with cancer.
209. The method of Claim 208, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
210. The method of Claim 205, wherein the RXR agonist compound is a RXRQ, agonist compound.
211. The method of Claim 205, wherein the RXR agonist compound is a RXRø agonist compound.
212. The method of Claim 205, wherein the RXR agonist compound is a RXRr agonist compound.
213. The method of Claim 205, wherein the therapeutically effective amount of the compound is from about 1 to about 50 mg per kg body weight of the subj ect per day.
214. The method of Claim 205, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
215. The method of Claim 205, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
216. The method of Claim 215, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, jδ-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, Q!-Phenylbutyramide, Pirozadil, Probucol, β- '. Sitosterol, Sultosilic Acid, TiadenobCholesterol Absorption Inhibitors Triparanol and Xenbucin.
217. The method of Claim 205, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
218. The method of Claim 205, wherein the compound is orally administered.
219. A method of treating 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, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XXI), (XXII), (XXIH), (XXIV), (XXV), (XXVI), (XXVII), (XXVIIa) or (XXVIIb):
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
(XXVIlb), 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, SO2, or a pharmaceutically acceptable salt; R3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C orN; R4 is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, Rt does not exist if Y is N, or neither R3 or R exist if Y is S, O, CHOH, CO, SO, or SO2; 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=, (R7R8)N-N=, Rι7O-N=, Rι N=, epoxy, cyclopropyb or cycloalkyl group and wherein the epoxy, cyclopropyb and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or halogen; R'" and R"" are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or R'" and R"" taken together form a cycloalkyl group having 3-10 carbons, 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, -SR7, -NR7R8, or - (CF)nCF3, but R5 is not hydrogen if Re, Rio, Rπ, Rι2 and RB are all hydrogen, Z, Z', Z", Z'", and Z"" are all carbon, and R' and R" represent -H, -OH, Cι-C4 alkoxy or Cι-C4 acyloxy or R' and R" taken together form an oxo, methano, or hydroxyimino group; R6, Rio, Rii, R12 and R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8 or -(CF)nCF3, and exist only ifthe Z, Z', Z", Z'", or Z"" from which R6, Rio, R11, R12 or R13 originates is C, or R6, Rio, Rπ, R12 and R13 each independently represent hydrogen or a lower alkyl having 1-4 carbons ifthe Z, Z', Z", Z'", or Z"" from which R6, Rio, R11, R12 or R13 originates is N, and where one of R6, Rio, Rπ, R12 or R13 is X; R7 represents hydrogen or a lower alkyl having 1-6 carbons; R8 represents hydrogen or a lower alkyl having 1-6 carbons; R represents a lower alkyl having 1-4 carbons, phenyb aromatic alkyb or q-hydroxyphenyb q-bromophenyb q-chlorophenyb q-florophenyb or q-iodophenyb where q=2-4; Rι4 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone; Rι7 is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyl, -OR7 or -SR7, -R9, alkyl carboxylic acid optionally substituted with halogen, acyb -OR7 or -SR7, alkenyl carboxylic acid optionally substituted with halogen, acyl, -OR7 or -SR7, alkyl amine optionally substituted with halogen, acyl, -OR7 or -SR7, or alkenyl amine optionally substituted with halogen, acryl, -OR7 or -SR7; Ris represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, -OR7, -SR7, -NR7R8, or -(CF)nCF3; X is -COOH, tefrazole, -PO3H, -SO3H, -CHO, -CH2OH, -CONH2, -COSH, -COOR9, -COSR9, -CONHR9, or -COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or
N on the ring; Z, Z*, Z", Z'" and Z"" each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z', Z", Z'" and Z"" are not O or S if Z, Z', Z", Z"' or Z"" is attached by a double bond to one of Z, Z*, Z", Z'" or Z"" or if one or more of Z, Z', Z", Z*" or Z"" is attached to one of Z, Z', Z", Z'" or Z"" that is O or S, and provided that one or more of Z, Z*, Z", Z'" and Z"" are not N if one of Z, Z', Z", Z'" and Z"" is attached by a single bond to one of Z, Z', Z", Z*" and Z"" that is N; n is 0 to 3; and the dashed lines are optional double bonds.
220. The method of Claim 219, wherein the RXR agonist compound is represented by the formula:
Figure imgf000168_0001
or a pharmaceutically acceptable salt of said compound.
221. The method of Claim 219, wherein the cachexia is associated with cancer.
222. The method of Claim 221, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.
223. The method of Claim 219, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cinhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.
224. The method of Claim 219, 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.
225. The method of Claim 219, wherein the compound is administered to a human subject at a daily dose of from about 10 to about 4000 mg.
226. The method of Claim 219, further comprising administering a therapeutically effective amount of an antihyperlipidemic agent.
227. The method of Claim 226, wherein the antihyperlipidemic agent is selected from the group consisting of bile acid sequestrants, Fibrates, HMG Co A Reductase Inhibitors, Nicotinic acid and derivatives, Thyroid Hormone/Analogs, Acitran, Azacosterob Benfluorex, |8-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomesfrone, Detaxfran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meflutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, o--Phenylbutyramide, Pirozadil, Probucol, β- Sitosterol, Sultosilic Acid, Tiadenol, Cholesterol Absorption Inhibitors Triparanol and Xenbucin.
228. The method of Claim 219, further comprising administering a therapeutically effective amount of an anticachetic agent, which is not an RXR agonist.
229. The method of Claim 219, wherein the compound is orally administered.
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