Method for treating cachexia with retinoid ligands

A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIII), (XIV) or (XV):

• wherein:
• X is O, S, or (CR1R1)n;
• n is 0, 1 or 2;
• Y is a bivalent radical having Structural Formula (XVI) or Structural Formula (XVII) where p is an integer from 1 to 4:
• 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 C1-6 alkyl or with 1 to 3 C1-6 fluoroalkyl groups;
• X is O, S or NH;
• R1 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
• R2 is independently —H, lower alkyl of 1 to 6 carbons, —OR1, 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups jointly represent an oxo group;
• R3 is hydrogen, lower alkyl of 1 to 6 carbons, —OR1, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, —NO2, —NH2, —NHCO(C1-C6)alkyl, or —NHCO(C1-C6)alkenyl;
• A is hydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR8, —CONR9R10, —CH2OH, —CH2OR11, —CH2OCOR11, —CHO, —CH(OR12)2, —CH(OR13O), —COR7, —CR7(OR12)2, —CR7(OR13P), or —Si(C1-6 alkyl)3;
• R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;
• R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl;
• R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl;
• R11 is lower alkyl, phenyl or lower alkylphenyl;
• R12 is lower alkyl;
• R13 is divalent alkyl radical of 2-5 carbons;
• and
• R14 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10 alkyl, naphthyl-C1-C10 alkyl, C1-C10-alkenylphenyl having 1 to 3 double bonds, C1-C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1-C10 alkenyl having 1 to 3 double bonds, phenyl-C1-C10 alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR8, or R14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C1 to C10 alkyl group, with a C1 to C10 fluoroalkyl group, or with halogen, and the dashed line in Structural Formula (XVI) represents a bond or absence of a bond.

A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XVIII):

• 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 R4 groups, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 R4 groups;
• R1 is independently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons;
• R2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;
• R′2 is alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;
• R3 is hydrogen, alkyl of 1 to 6 carbons, fluoro substituted alkyl of 1 to 6 carbons, halogen, alkoxy of 1 to 8 carbons, or alkylthio of 1 to 6 carbons, —NO2, —NH2, —NHCO(C1-C6)alkyl, —NHCO(C1-C6)alkenyl, —NR1H or —N(R1)2, benzyloxy or C1-C6 alkyl-substituted benzyloxy;
• R4 is —H or alkyl of 1 to 6 carbons, or fluoro substituted alkyl of 1 to 6 carbons;
• m is an integer having the values of 0 to 3, and
• B is —COOH or a pharmaceutically acceptable salt thereof, —COOR8, —COOCH2COR7, —CONR9R10, —CH2OH, —CH2OR11, —CH2OCOR11, —CHO, —CH(OR12)2, —CH(OR13O), —COR7, —CR7(OR12)2, —CR7(OR13O),
• R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons;
• R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a group of 5 to 10 phenyl or lower alkylphenyl;
• R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl;
• R11 is lower alkyl, phenyl or lower alkylphenyl;
• R12 is lower alkyl;
• and
• R13 is divalent alkyl radical of 2-5 carbons.

A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIX):

• wherein:
• 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 C1-6 alkyl or with 1 to 3 C1-6 fluoroalkyl groups;
• p is an integer from 1 to 4;
• the two X1 groups jointly represent an oxo or thione function, or X1 is independently selected from H or alkyl of 1 to 6 carbons;
• the two X2 groups jointly represent an oxo or a thione function, or X2 is independently selected from H or alkyl of 1 to 6 carbons, with the proviso that one of the joint X1 grouping or of the joint X2 grouping represents an oxo or a thione function;
• W is H, O, C(R1)2, phenyl, naphthyl, or 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with a C1 to C10 alkyl group, with a C1 to C10 fluoroalkyl group, or with halogen;
• R1 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
• R2 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
• R3 is hydrogen, lower alkyl of 1 to 6 carbons, —OR1, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, —NO2, —NH2, —NHCO(C1-C6) alkyl, or NHCO(C1-C6)alkenyl;
• A is hydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR8, —CONR9R10, —CH2OH, —CH2OR11, —CH2OCOR11, —CHO, —CH(OR12)2, —CH(OR13O), —COR7, —CR7(OR12)2, —CR7(OR13O), or —Si(C1-6 alkyl)3;
• R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
• R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl;
• R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl;
• R11 is lower alkyl, phenyl or lower alkylphenyl;
• R12 is lower alkyl;
• R13 is divalent alkyl radical of 2-5 carbons;
• R14 is H, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10 alkyl, naphthyl-C1-C10-alkyl, C1-C10-alkenylphenyl having 1 to 3 double bonds, C1-C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1-C10 alkenyl having 1 to 3 double bonds, phenyl-C1-C10 alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR8, or R14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said carbocyclic aryl and heteroaryl groups being unsubstituted or substituted with a C1 to C10 alkyl group, with a C1 to C10 fluoroalkyl group, or with halogen;
• and the dashed line in Formula (a) represents a bond or absence of a bond, provided that when the dashed line represents a bond then there are no R1 substituents on the carbons connected by said bond.

A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XX):

• wherein:
• X is O, S, or C(R)2;
• R is H or alkyl of 1 to 6 carbons;
• R1 is H, alkyl of 1 to 10 carbons, alkenyl of 2 to 6 carbons, phenyl-C1-C6 alkyl, or C1-C6-alkylphenyl;
• R2 is H, alkyl of 1 to 6 carbons, —F, —Cl, —Br, —I, —CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
• R3 is independently alkyl of 1 to 6 carbons, —F, —Cl, —Br, —I, —CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, fluoroalkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, benxyloxy, C1-C6 alkyl substituted benzyloxy, halogen substituted benzyloxy, phenyloxy, C1-C6 alkyl substituted phenyloxy, or halogen substituted phenyloxy;
• R4 is independently —H, alkyl of 1 to 6 carbons, or —F;
• Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
• m is an integer having the values 0 to 3;
• p is an integer having the values 0 to 4;
• A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
• B is hydrogen, —COOH, —COOR8, —CONR9R10, —CH2OH, —CH2OR11, —CH2OCOR11, —CHO, —CH(OR12)2, —CHOR13O, —COR7, —CR7(OR12)2, —CR7OR13O, or tri-lower alkylsilyl;
• R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
• R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl;
• R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl;
• R11 is lower alkyl, phenyl or lower alkylphenyl;
• R12 is lower alkyl;
• and
• R13 is divalent alkyl radical of 2-5 carbons,
• or a pharmaceutically acceptable salt thereof.

A method of treating cachexia associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIIa) or (XXVIIb):

• wherein:
• R1 and R2 each independently is hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
• Y is C, O, S, N, CHOH, CO, SO, SO2, or a pharmaceutically acceptable salt;
• R3 is hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
• R4 is hydrogen or lower alkyl having 1-4 carbon atoms when Y is C, R4 does not exist if Y is N, or neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
• R′ and R″ are hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thioether, or amino, or R′ or R″ taken together form an oxo(keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups are optionally substituted with lower alkyl having 1-4 carbons or halogen;
• R′″ and R″″ are hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkylamino, or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
• R5 is hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, —OR7, —SR7, —NR7R8, or —(CF)nCF3, but R5 is not hydrogen if R6, R10, R11, R12 and R13 are all hydrogen, Z, Z′, Z″, Z′″, and Z″″ are all carbon, and R′ and R″ represent —H, —OH, C1-C4 alkoxy or C1-C4 acyloxy or R′ and R″ taken together form an oxo, methano, or hydroxyimino group;
• R6, R10, R11, R12 and R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, —OR7, —SR7, —NR7R8 or —(CF)nCF3, and exist only if the Z, Z′, Z″, Z′″, or Z″″ from which R6, R10, R11, R12 or R13 originates is C, or R6, R10, R11, R12 and R13 each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, Z′, Z′″, Z″, or Z″″ from which R6, R10, R11, R12 or R13 originates is N, and where one of R6, R10, R11, R12 or R13 is X;
• R7 represents hydrogen or a lower alkyl having 1-6 carbons;
• R8 represents hydrogen or a lower alkyl having 1-6 carbons;
• R9 represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
• R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
• R17 is hydrogen, lower alkyl having 1-8 carbons, alkenyl optionally substituted with halogen, acyl, —OR7 or —SR7, —R9, alkyl carboxylic acid optionally substituted with halogen, acyl, —OR7 or —SR7, alkenyl carboxylic acid optionally substituted with halogen, acyl, —OR7 or —SR7, alkyl amine optionally substituted with halogen, acyl, —OR7 or —SR7, or alkenyl amine optionally substituted with halogen, acryl, —OR7 or —SR7;
• R18 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, —OR7, —SR7, —NR7R8, or —(CF)nCF3;
• X is —COOH, tetrazole, —PO3H, —SO3H, —CHO, —CH2OH, —CONH2, —COSH, —COOR9, —COSR9, —CONHR9, or —COOW where W is a pharmaceutically acceptable salt, and wherein X can originate from any C or N on the ring;
• Z, Z′, Z″, Z′″ and Z″″ each independently is C, S, O, N, or a pharmaceutically acceptable salt, provided that one or more of Z, Z′, Z″, Z′″ and Z″″ are not O or S if Z, Z′, Z″, Z′″ or Z″″ is attached by a double bond to one of Z, Z′, Z″, Z′″ or Z″″ or if one or more of Z, Z′, Z″, Z′″ or Z″″ is attached to one of Z, Z′, Z″, Z′″ or Z″″ that is O or S, and provided that one or more of Z, Z′, Z″, Z′″ and Z″″ are not N if one of Z, Z′, Z″, Z′″ and Z″″ is attached by a single bond to one of Z, Z′, Z″, Z′″ and Z″″ that is N;
• n is 0 to 3;
• and
• the dashed lines are optional double bonds.