Substituted melanocortin receptor-specific piperazine compounds

1. A compound of formula I:

or an enantomeric, stereoisomeric or diastereomeric form of the foregoing, and pharmaceutically acceptable salts thereof;

wherein

J is a substituted or unsubstituted monocyclic or bicyclic ring structure selected from the group consisting of

L is a bond, —(CH 2 ) q —, —(CH 2 ) q —O—, —(CH 2 ) q —O—(C═O)—, —(CH 2 ) q (C═O)— or —(CH 2 ) q —(C═O)—O—;

W is H or a substituted or unsubstituted aryl group;

Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl;

R 6 is H, ═O, ═S or CH 3 ;

R 7 is H, NH 2 , NH—R 8 , or

R 8 is a C 1 to C 6 linear or branched chain, an amine capping group, a natural or unnatural amino acid containing an aliphatic or aromatic side chain, or a natural or unnatural amino acid containing an aliphatic or aromatic side chain with a pendant amine capping group, and where there are two R 8 groups, each R 8 is independently a C 1 to C 6 linear or branched chain or an amine capping group, or one R 8 is a C 1 to C 6 linear or branched chain or an amine capping group and the remaining R 8 is a natural or unnatural amino acid containing an aliphatic or aromatic side chain or a natural or unnatural amino acid containing an aliphatic or aromatic side chain with a pendant amine capping group,

wherein the amine capping group is allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenyl acetyl, phenyl propinoyl, phenyl butanoyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, ring-substituted benzoyl, 4′-toluenesulfonyl, 4′-carboxy heptane, 12-Ado, 7r-amino heptanoyl, 6-Ahx, Amc, 8-Aoc, or polyethylene glycol with a formula molecular weight of between about 100 and about 10,000;

q is from 1 to 6;

y is from 0 to 6;

z is from 0 to 6; and

wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.

2. The compound of claim 1 wherein R 6 is H or ═O.

3. The compound of claim 1

wherein

J is phenyl, substituted phenyl, naphthyl or substituted naphthyl;

L is —CH 2 — or —(CH 2 ) 2 —;

Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl;

W is H or phenyl;

R 6 is H or ═O;

R 7 is NH 2 , NH—R 8 , or

y is 0 if W is H, and otherwise y is 1; and

z is 1 or 2.

4. The compound of claim 1 wherein R 7 is NH 2 , N(CH 3 ) 2 , NHCH 3 ,

5. The compound of claim 1 wherein the natural or unnatural amino acid containing an aliphatic or aromatic side chain is an L- or D-isomer of Phe, Phe(2-Cl), Phe(4-Cl), Phe(2,4-diCl), Phe(2,4-diF), Phe(3,4-diCl), Phe(4-NO 2 ), Phe(4-Me), Phe(4-Phenyl), HPhe, pF-Phe, Phe(4-Br), Phe(4-CF 3 ), Phe(3,4-diF), Phe(4-I), Phe(2-Cl, 4-Me), Phe(2-Me, 4-Cl), Phe(2-F, 4-CI), Phe(2,4-diMe), Phe(2-Cl, 4-CF 3 ), Phe(3,4-di-OMe), Phg, Trp, Nal 1, Nal 2, Bip, Dip, Bpa, Ser(Bzl), Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Tic, Tiq, Cys(Bzl), Tyr(2,6-DiCl-Bzl), Tyr(Bzl), Abu, 2-Abz, 3-Abz, 4-Abz, Ache, Acpe, Aib, Abn, Arg(Tos), Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBzA, B-Spa, GVA(Cl), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tle, Tiq, Atc, Igl, Hyp(O-2-Naphthyl), Hyp(O-Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl), Ser(O-2-Naphthyl), Ser(O-Phenyl), Ser(O-4-Cl-Phenyl), Ser(O-2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(O-2-Naphthyl), Thr(O-Phenyl), Thr(O-4-Cl-Phenyl), Thr(O-2-Cl-Phenyl), Nle, Leu, Ile, Val or Beta-Ala.

6. The compound of claim 1 wherein J is substituted at one or more positions with one or more hydroxyl, halogen, alkyl or aryl groups.

7. The compound of claim 1 wherein Q is:

wherein R 9a and R 9b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.

8. The compound of claim 1 of formula II:

and pharmaceutically acceptable salts thereof.

9. The compound of claim 8 of formula III:

and pharmaceutically acceptable salts thereof.

10. The compound of claim 9 of formula IV:

and pharmaceutically acceptable salts thereof,

wherein

J is phenyl, substituted phenyl, naphthyl or substituted naphthyl; and

R 9a and R 9b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.

11. The compound of claim 8 of formula V:

and pharmaceutically acceptable salts thereof.

12. The compound of claim 1 of formula VI:

and pharmaceutically acceptable salts thereof.

13. The compound of claim 1 of formula VII:

and pharmaceutically acceptable salts thereof.

14. The compound of claim 13 of formula VIII:

and pharmaceutically acceptable salts thereof,

wherein R 9a and R 9b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.

15. A compound of formula IX:

or an enantomeric, stereoisomeric or diastereomeric form of the foregoing, and pharmaceutically acceptable salts thereof;

wherein

J is a substituted or unsubstituted monocyclic or bicyclic ring structure selected from the group consisting of

L is a bond, —(CH 2 ) q —, —(CH 2 ) q —O—, —(CH 2 ) q —O—(C═O)—, —(CH 2 ) q —NH—, —(CH 2 ) q —NH—(C═O)—, —(CH 2 ) q —(C═O)—, —(CH 2 ) q —(C═O)—NH— and —(CH 2 ) q —(C═O)—O—;

A is a C 1 to C 6 linear or branched chain;

Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl;

R 6 is H, ═O, ═S or CH 3 ;

R 7 is H, NH 2 , NH—R 8 , or

R 8 is a C 1 to C 6 linear or branched chain, an amine capping group, a natural or unnatural amino acid containing an aliphatic or aromatic side chain, or a natural or unnatural amino acid containing an aliphatic or aromatic side chain with a pendant amine capping group, and where there are two R 8 groups, each R 8 is independently a C 1 to C 6 linear or branched chain or an amine capping group, or one R 8 is a C 1 to C 6 linear or branched chain or an amine capping group and the remaining R 8 is a natural or unnatural amino acid containing an aliphatic or aromatic side chain or a natural or unnatural amino acid containing an aliphatic or aromatic side chain with a pendant amine capping group,

wherein the amine capping group is allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenyl acetyl, phenyl propinoyl, phenyl butanoyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, ring-substituted benzoyl, 4′-toluenesulfonyl, 4′-carboxy heptane, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc, 8-Aoc, or polyethylene glycol with a formula molecular weight of between about 100 and about 10,000;

q is from 1 to 6;

y is from 0 to 6;

z is from 0 to 6; and

wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.

16. A pharmaceutical composition for treatment of a melanocortin receptor-associated disorder, comprising a compound of claim 1 and a pharmaceutically acceptable carrier, wherein the melanocortin receptor-associated disorder is cachexia, obesity, erectile dysfunction or female sexual dysfunction.

17. A method for treating a melanocortin receptor-associated disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 16 , wherein the melanocortin receptor-associated disorder is cachexia, obesity, erectile dysfunction or female sexual dysfunction.

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method for treating a melanocortin receptor-associated disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 18 , wherein the melanocortin receptor-associated disorder is cachexia, obesity, erectile dysfunction or female sexual dysfunction.