WO2005013949A2 - Procédé de traitement de la cachexie au moyen de ligands de rétinoïdes - Google Patents

Procédé de traitement de la cachexie au moyen de ligands de rétinoïdes Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
carbons
cancer
alkyl
group
compound
Prior art date
Application number
PCT/US2004/025564
Other languages
English (en)
Other versions
WO2005013949A3 (fr
Inventor
Guang Liang Jiang
Yang-Dar Yuan
Roshantha A. Chandraratna
Original Assignee
Allergan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to JP2006522776A priority Critical patent/JP2007501800A/ja
Priority to AU2004263156A priority patent/AU2004263156B2/en
Priority to EP04780406A priority patent/EP1653939A2/fr
Priority to CA002535260A priority patent/CA2535260A1/fr
Publication of WO2005013949A2 publication Critical patent/WO2005013949A2/fr
Publication of WO2005013949A3 publication Critical patent/WO2005013949A3/fr

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un procédé de traitement de la cachexie chez un sujet nécessitant un traitement. L'invention concerne plus particulièrement l'utilisation de composés rétinoïdes agissant sur des récepteurs X de rétinoïdes (RXR) pour le traitement de la cachexie chez un sujet nécessitant un traitement. La cachexie est associée, c.-à-d. qu'elle est une complication, d'une maladie ou d'un trouble primaire. Les maladies ou troubles primaires peuvent inclure le cancer, le SIDA, la cirrhose du foie, le diabète sucré, l'insuffisance rénale chronique, la bronchopneumopathie chronique obstructive, l'insuffisance cardiaque chronique, des maladies du système immunitaire (par ex. l'arthrite rhumatoïde et le lupus érythémateux systémique), la tuberculose, la fibrose cystique, des troubles gastro-intestinaux (par ex. le syndrome du côlon irritable et le syndrome d'inflammation du côlon), la maladie de Parkinson, la névrose anorexique, la démence, la dépression majeure, les troubles de la vieillesse et la sarcopénie.
PCT/US2004/025564 2003-08-07 2004-08-06 Procédé de traitement de la cachexie au moyen de ligands de rétinoïdes WO2005013949A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2006522776A JP2007501800A (ja) 2003-08-07 2004-08-06 レチノイドリガンドを用いて悪液質を処置するための方法
AU2004263156A AU2004263156B2 (en) 2003-08-07 2004-08-06 Method for treating cachexia with retinoid ligands
EP04780406A EP1653939A2 (fr) 2003-08-07 2004-08-06 Procede de traitement de la cachexie au moyen de ligands de retinoides
CA002535260A CA2535260A1 (fr) 2003-08-07 2004-08-06 Procede de traitement de la cachexie au moyen de ligands de retinoides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US49313803P 2003-08-07 2003-08-07
US60/493,138 2003-08-07
US53373403P 2003-12-31 2003-12-31
US60/533,734 2003-12-31

Publications (2)

Publication Number Publication Date
WO2005013949A2 true WO2005013949A2 (fr) 2005-02-17
WO2005013949A3 WO2005013949A3 (fr) 2005-09-15

Family

ID=34138739

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/025564 WO2005013949A2 (fr) 2003-08-07 2004-08-06 Procédé de traitement de la cachexie au moyen de ligands de rétinoïdes

Country Status (5)

Country Link
EP (1) EP1653939A2 (fr)
JP (1) JP2007501800A (fr)
AU (1) AU2004263156B2 (fr)
CA (1) CA2535260A1 (fr)
WO (1) WO2005013949A2 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008020033A1 (fr) * 2006-08-16 2008-02-21 Action Medicines, S.L. Utilisation de dérivés de 2,5-dihydrobenzène pour le traitement de l'arthrite et de la douleur
EP2451455A2 (fr) * 2009-07-10 2012-05-16 Case Western Reserve University Composés agonistes de rxr et procédés associés
US20140329903A1 (en) * 2011-08-11 2014-11-06 Acadia Pharmaceuticals Inc. Treatment of neurodegenerative diseases
EP2910549A1 (fr) * 2011-09-15 2015-08-26 Arizona Board of Regents, a Body Corporate of the State of Arizona acting for and on behalf of Arizona State University Dérivés de 1,2,3,4-tétrahydro-1,1,4,4-tétraméthylnaphthalène en tant que modulateur du rxr utiles pour le traitement du cancer et de la maladie d'alzheimer
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
WO2017155577A1 (fr) 2016-03-10 2017-09-14 Io Therapeutics, Inc. Traitement de maladies auto-immunes à l'aide de combinaisons d'agonistes de rxr et d'hormones thyroïdiennes
US10231947B2 (en) 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10966950B2 (en) 2019-06-11 2021-04-06 Io Therapeutics, Inc. Use of an RXR agonist in treating HER2+ cancers
US10973788B2 (en) 2005-09-30 2021-04-13 Io Therapeutics, Inc. Treatment of cancer with specific RXR agonists
US11166927B2 (en) 2011-12-13 2021-11-09 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11517549B2 (en) 2017-09-20 2022-12-06 Io Therapeutics, Inc. Treatment of disease with esters of selective RXR agonists
US11896558B2 (en) 2021-12-07 2024-02-13 Io Therapeutics, Inc. Use of an RXR agonist and taxanes in treating Her2+ cancers
US11998521B2 (en) 2021-12-07 2024-06-04 Io Therapeutics, Inc. Use of an RXR agonist in treating drug resistant HER2+ cancers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10835507B2 (en) * 2016-03-10 2020-11-17 Io Therapeutics, Inc. Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0718285A2 (fr) * 1994-12-19 1996-06-26 American Cyanamid Company 9-cis-Rétinoides restreints
US5675033A (en) * 1995-06-06 1997-10-07 Allergan 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US5801253A (en) * 1994-08-10 1998-09-01 Hoffmann-La Roche Inc. Retinoic acid X-receptor ligands
US5917082A (en) * 1995-06-06 1999-06-29 Allergan Sales, Inc. 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US6320074B1 (en) * 1992-04-22 2001-11-20 Ligand Pharmaceuticals Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320074B1 (en) * 1992-04-22 2001-11-20 Ligand Pharmaceuticals Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
US5801253A (en) * 1994-08-10 1998-09-01 Hoffmann-La Roche Inc. Retinoic acid X-receptor ligands
EP0718285A2 (fr) * 1994-12-19 1996-06-26 American Cyanamid Company 9-cis-Rétinoides restreints
US5675033A (en) * 1995-06-06 1997-10-07 Allergan 2,4-pentadienoic acid derivatives having retinoid-like biological activity
US5917082A (en) * 1995-06-06 1999-06-29 Allergan Sales, Inc. 2,4-pentadienoic acid derivatives having retinoid-like biological activity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
APFEL C M ET AL: "ENHANCEMENT OF HL-60 DIFFERENTIATION BY A NEW CLASS OF RETINOIDS WITH SELECTIVE ACTIVITY ON RETINOID X RECEPTOR" JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 270, no. 51, 22 December 1995 (1995-12-22), pages 30765-30772, XP000601411 ISSN: 0021-9258 *
TANOSAKI S ET AL: "EFFECT OF LIGANDS OF NUCLEAR HORMONE RECEPTORS ON SODIUM/IODIDE SYMPORTER EXPRESSION AND ACTIVITY IN BREAST CANCER CELLS" BREAST CANCER RESEARCH AND TREATMENT, NIJHOFF, BOSTON, US, vol. 79, no. 3, June 2003 (2003-06), pages 335-345, XP009018337 ISSN: 0167-6806 *
VULIGONDA V ET AL: "ENANTIOSELECTIVE SYNTHESES OF POTENT RETINOID X RECEPTOR LIGANDS: DIFFERENTIAL BIOLOGICAL ACTIVITIES OF INDIVIDUAL ANTIPODES" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, no. 14, 2001, pages 2298-2303, XP008041053 ISSN: 0022-2623 *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973788B2 (en) 2005-09-30 2021-04-13 Io Therapeutics, Inc. Treatment of cancer with specific RXR agonists
WO2008020033A1 (fr) * 2006-08-16 2008-02-21 Action Medicines, S.L. Utilisation de dérivés de 2,5-dihydrobenzène pour le traitement de l'arthrite et de la douleur
EP2451455A2 (fr) * 2009-07-10 2012-05-16 Case Western Reserve University Composés agonistes de rxr et procédés associés
EP2451455A4 (fr) * 2009-07-10 2013-01-16 Univ Case Western Reserve Composés agonistes de rxr et procédés associés
US20140329903A1 (en) * 2011-08-11 2014-11-06 Acadia Pharmaceuticals Inc. Treatment of neurodegenerative diseases
US9573906B2 (en) 2011-09-15 2017-02-21 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University Therapeutic compounds
US10391093B2 (en) 2011-09-15 2019-08-27 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Therapeutic compounds
EP2910549A1 (fr) * 2011-09-15 2015-08-26 Arizona Board of Regents, a Body Corporate of the State of Arizona acting for and on behalf of Arizona State University Dérivés de 1,2,3,4-tétrahydro-1,1,4,4-tétraméthylnaphthalène en tant que modulateur du rxr utiles pour le traitement du cancer et de la maladie d'alzheimer
US11547684B2 (en) 2011-12-13 2023-01-10 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11576881B2 (en) 2011-12-13 2023-02-14 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11246845B2 (en) 2011-12-13 2022-02-15 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11793781B2 (en) 2011-12-13 2023-10-24 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11166927B2 (en) 2011-12-13 2021-11-09 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
IL261669B2 (en) * 2016-03-10 2023-12-01 Io Therapeutics Inc A combination of thyroid hormones and an RXR agonist for the treatment of autoimmune diseases
EP3426302A4 (fr) * 2016-03-10 2019-10-30 IO Therapeutics, Inc. Traitement de maladies auto-immunes à l'aide de combinaisons d'agonistes de rxr et d'hormones thyroïdiennes
US10946001B2 (en) 2016-03-10 2021-03-16 Io Therapeutics, Inc. Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
CN114470218A (zh) * 2016-03-10 2022-05-13 Io治疗公司 用rxr激动剂与甲状腺激素的组合的自身免疫疾病的治疗
CN115252789A (zh) * 2016-03-10 2022-11-01 Io治疗公司 Rxr激动剂和甲状腺激素在制备用于治疗自身免疫疾病的药物中的用途
WO2017155577A1 (fr) 2016-03-10 2017-09-14 Io Therapeutics, Inc. Traitement de maladies auto-immunes à l'aide de combinaisons d'agonistes de rxr et d'hormones thyroïdiennes
IL261669B1 (en) * 2016-03-10 2023-08-01 Io Therapeutics Inc A combination of thyroid hormones and a rxr agonist for the treatment of autoimmune diseases
EP4166160A1 (fr) * 2016-03-10 2023-04-19 IO Therapeutics, Inc. Traitement de maladies auto-immunes avec des combinaisons d'agonistes rxr et d'hormones thyroidiennes
US11690831B2 (en) 2016-03-10 2023-07-04 Io Therapeutics, Inc. Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US11690832B2 (en) 2016-03-10 2023-07-04 Io Therapeutics Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
US10231947B2 (en) 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US11517549B2 (en) 2017-09-20 2022-12-06 Io Therapeutics, Inc. Treatment of disease with esters of selective RXR agonists
US11224583B2 (en) 2019-06-11 2022-01-18 Io Therapeutics, Inc. Use of an RXR agonist in treating HER2+ cancers
US10966950B2 (en) 2019-06-11 2021-04-06 Io Therapeutics, Inc. Use of an RXR agonist in treating HER2+ cancers
US11896558B2 (en) 2021-12-07 2024-02-13 Io Therapeutics, Inc. Use of an RXR agonist and taxanes in treating Her2+ cancers
US11998521B2 (en) 2021-12-07 2024-06-04 Io Therapeutics, Inc. Use of an RXR agonist in treating drug resistant HER2+ cancers

Also Published As

Publication number Publication date
JP2007501800A (ja) 2007-02-01
WO2005013949A3 (fr) 2005-09-15
EP1653939A2 (fr) 2006-05-10
CA2535260A1 (fr) 2005-02-17
AU2004263156A1 (en) 2005-02-17
AU2004263156B2 (en) 2009-02-26

Similar Documents

Publication Publication Date Title
US20070185055A1 (en) Method for treating cachexia with retinoid ligands
EP1653939A2 (fr) Procede de traitement de la cachexie au moyen de ligands de retinoides
US5811449A (en) Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US20080214652A1 (en) Methods of treating hyperlipidemia
AU2016269491B2 (en) Systems, methods, and formulations for treating cancer
JP2012532892A (ja) Ｒｘｒアゴニスト化合物および方法
EP1746982A2 (fr) Inhibition des histone-desacetylases pour le traitement des hyperlipidemies et pour la prevention de l'atherosclerose et des maladies cardio-vasculaires
JP2009537540A (ja) 化学療法および／または放射線療法の副作用を処置するためのｒａｒアンタゴニストまたはｒａｒインバースアゴニストの使用
CA3028379A1 (fr) Procedes pour inhiber la conversion de la choline en trimethylamine (tma)
US6605639B1 (en) Ligands of nuclear receptor
US20030212074A1 (en) Phosphate transport inhibitors
WO2005063240A1 (fr) Methodes et compositions pour le traitement de l'hypertension
RU2011108587A (ru) Новые метилендиоксифенольные соединения и их применение для лечения заболеваний
JP2011530525A5 (fr)
RU2491065C2 (ru) Фармацевтическая композиция, содержащая производное 1,2-дитиолтиона, для предотвращения или лечения заболевания, обусловленного повышенной экспрессией lxr-альфа
US5234945A (en) Method of producing body weight and food intake using a dopamine D2 receptor agonist
US5369120A (en) Pharmaceutical composition of 7-((substituted)amino-8-((substituted)carbonyl)-(methylamino)-1-oxasp iro(4,5)decanes and L-dopa
EP1156795B1 (fr) Utilisation d'acide succinique ou de sels de cet acide et methode de traitement de l'insulino-resistance
CH631713A5 (fr) Derives de chromones a activite medicamenteuse et leur preparation.
RU2588133C2 (ru) Ниациновые миметики и способ их использования
AU709939B2 (en) Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
Kikuchi et al. Involvement of leukotrienes in allergic pleurisy in actively sensitized rats: Inhibition by the lipoxygenase inhibitor T-0757 of the increase in vascular permeability and leukotriene E 4 production
JPS62198616A (ja) 脳血流量改善・脳細胞保護剤
CN118203586A (zh) 姜黄素和tdo2抑制剂联用在预防和/或治疗非酒精性脂肪性肝病中的应用
AU733198B2 (en) Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006522776

Country of ref document: JP

ENP Entry into the national phase in:

Ref document number: 2535260

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004263156

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004780406

Country of ref document: EP

ENP Entry into the national phase in:

Ref document number: 2004263156

Country of ref document: AU

Date of ref document: 20040806

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004263156

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2004780406

Country of ref document: EP