Small molecule pipecolic acid derivative hair growth compositions and uses

A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative of formula II

• 12
• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• A is O, NH, or N-(C1-C4 alkyl);
• B is hydrogen, CHL-Ar, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or
• 13
• wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
• and
• T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
• Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.
• D is hydrogen or U;
• E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U;
• U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7-cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-C4 alkyl or C2-C4 alkenyl) —Ar, or Ar;
• J is hydrogen, C1 or C2 alkyl, or benzyl;
• K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylethyl;
• or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2.

A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative of formula III

• 14
• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• n is 2;
• D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl;
• and
• B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4- (4-methoxyphenyl)butyl;
• provided that
• when D is phenyl, then B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl;
• when D is methoxy, then B is benzyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl;
• when D is 2-furyl, then B is benzyl;
• and
• when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexylbutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl) butyl.

A pharmaceutical composition which comprises:

• (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula I
• 16
• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• A is CH2, O, NH, or N—(C1-C4 alkyl);
• B and D are independently Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or
• 17
• wherein Q is hydrogen, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl;
• and
• T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
• Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms is independently selected from oxygen, nitrogen and sulfur;
• wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl) , O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
• L is either hydrogen or U;
• M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U;
• U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl) —Ar, or Ar;
• J is hydrogen, C1 or C2 alkyl, or benzyl;
• K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylmethyl;
• or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2;
• n is 0-3;
• and
• said pipecolic acid derivative has an affinity for FKBP-type immunophilins;
• and
• (ii) a pharmaceutically acceptable carrier.

A pharmaceutical composition which comprises:

• (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula II
• 18
• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• A is O, NH, or N-(C1-C4 alkyl);
• B is hydrogen, CHL-Ar, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or
• 19
• wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
• and
• T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
• Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.
• D is hydrogen or U;
• E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U;
• U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-C4 alkyl or C2-C4 alkenyl) —Ar, or Ar;
• J is hydrogen, C1 or C2 alkyl, or benzyl;
• K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylethyl;
• or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2;
• and
• (ii) a pharmaceutically acceptable carrier.

A pharmaceutical composition which comprises:

• (i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal, wherein the pipecolic acid derivative is a compound of formula III
• 20
• or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
• n is 2;
• D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl;
• and
• B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl) butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl;
• provided that
• when D is phenyl, then B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl;
• when D is methoxy, then B is benzyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl;
• when D is 2-furyl, then B is benzyl;
• and
• when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexylbutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl) butyl;
• and
• (ii) a pharmaceutically acceptable carrier.