Melanocortin receptor-specific compounds

1. A compound having the formula of structure I:

or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

X is CH 2 ;

R 1 is —L 1 -J;

one of R 2a and R 2b is —L 2 —W and the remaining of R 2a and R 2b is hydrogen;

R 3 is —L 3 -Q;

L 1 is a linker unit selected from the group consisting of —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) y —C(═O)—, —C(═O)—CH 2 ) y — and —C(═O)—;

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

wherein, when substituted, J is substituted with one or more ring substituents independently selected from the group consisting of hydroxyl, halogen, sulfonamide, alkyl or aryl groups attached directly or through an ether linkage;

L 2 is —(CH 2 ) y —;

W is —NH—C(═NH)—NH 2 ;

L 3 is a linker unit selected from the group consisting of —(CH 2 ) y —CH(NR 6a R 6b )—(CH 2 ) y —, —(CH 2 ) y —C(═O)—CH(NR 6a R 6b )—(CH 2 ) y —, —(CH 2 ) y —C(═O)—, —(CH 2 ) y —CH(CH 3 )—C(═O)—, —C(═O)—CH 2 ) y —C(═O)—CH(NR 6a R 6b )—(CH 2 ) y —, —C(═O)—(CH 2 ) y —, —C(═O)—CH 2 ) y —CH(NR 6a R 6b )—, —C(═O)—(CH 2 ) y —CH(NR 6a R 6b )—(CH 2 ) y —, —C(═O)—(CH 2 ) y —CH(NHR 6a R 6b )—C(═O)— and —C(═O)—;

Q is naphthyl;

R 6a and R 6b are each independently selected from the group consisting of hydrogen and R 7 ;

R 7 is an amino acid residue or an amine capping group, wherein the amino acid residue is an L-amino acid and the amine capping group is selected from the group consisting of methyl, ethyl, isopropyl and acetyl;

one or two of R 4a , R 4b , R 5a , and R 5b are independently a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen, provided that at least one of R 4a and R 4b and at least one of R 5a and R 5b are hydrogen; and

y is from 1 to 6, provided that where any linker unit includes two y index values, the total of such y index values is from 2 to 6.

2. The compound of claim 1 wherein J is substituted.

3. The compound of claim 1 wherein y is between 1 and 4.

4. The compound of claim 1 wherein the L-amino acid is selected from the group consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, 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-Gpa, GVA(CI), His, hScr, Scr(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tle, Tiq, Atc, Igl, Hyp(2-Naphthyl), Hyp(Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl), Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(2-Naphthyl), Thr(Phenyl), Thr(4-Cl-Phenyl) and Thr(2-Cl-Phenyl), Nle, Lcu, Ilc, Val and Beta-Ala.

5. The compound of claim 1 wherein one of R 4a , R 4b , R 5a , and R 5b is a C 1 to C 6 aliphatic linear or branched chain.

6. The compound of claim 1 wherein one of R 4a , or R 4b and one of R 5a , and R 5b is a C 1 to C 6 aliphatic linear or branched chain.

7. The compound of claim 5 wherein the C 1 to C 6 aliphatic linear or branched chain is selected from the group consisting of methyl and isobutyl.

8. The compound of claim 1 wherein

one of R 4a , R 4b , R 5a , and R 5b is methyl or isobutyl, and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen; and

R 7 is selected from the group consisting of acetyl, methyl, ethyl, and isopropyl.

9. The compound of claim 1 and pharmaceutically acceptable salts thereof selected from the group consisting of:

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin -2(S)-yl]-propyl}-guanidine;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(3-phenyl-propyl)-piperazin-2 (S)-yl]-propyl}-guanidine;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-p-tolyl-ethyl)-piperazin-2 (S)-yl]-propyl }-guanidine;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4—(2-1H-indol-3-yl-acetyl)-5(R)-methyl-piperazin -2(S)-yl]-propyl}-guanidine;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-propionyl)-5(R)-methyl-piperazin -2(S)-yl]-propyl }-guanidine;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-butyryl)-5(R)-methyl-piperazin -2(S)-yl]-propyl }-guanidine;

N—(3—{1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4—[2—(1H-indol-3-yl)-ethyl]-5(R)-methyl-piperazin -2(S)-yl}-propyl)-guanidine;

N—(3—{1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4—[2—(2-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

N—(3—{1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4[—(1-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

N—{3—[1—[2(R)-Amino-3-naphthalen-2-yl-propionyl]-5(R)-isobutyl-4—(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

N—{2—[2(S)—(3-Guanidino-propyl)-5(R)-isobutyl-4—(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4—(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;

N—{2—[2(S)—(3-Guanidino-propyl)-5(R)-methyl-4—(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

N—{2—[4—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)—(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]—1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-ethanesulfonamide;

N—{2—[4—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)—(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide; and

N—{3—[1—(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-isobutyl-4—(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine.

10. The compound of claim 1 wherein one of R 5a and R 5b is an (R)-configuration C 1 to C 6 aliphatic linear or branched chain and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen.

11. The compound of claim 8 wherein one of R 5a and R 5b is (R)-methyl or (R)-isobutyl and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen.

12. The compound of claim 10 wherein L 1 is a linker unit selected from the group consisting of —(CH 2 ) 2 — and —(CH 2 ) 3 —.

13. A pharmaceutical composition, comprising a compound of any one of claim 10 , 11 or 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. A method of treating obesity or feeding-related disorders in an animal, comprising administering to the animal a therapeutically effective amount of a pharmaceutical composition of claim 13 .

15. The compound of claim 1 wherein one of R 5a and R 5b is an (R)-configuration C 1 to C 6 aliphatic linear or branched chain and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen and wherein L 1 is selected from the group consisting of —C(═O)—CH 2 —, —C(═O)—(CH 2 ) 2 — and —C(═O)—(CH 2 ) 3 —.

16. The compound of claim 8 wherein one of R 5a and R 5b is (R)-methyl or (R)-isobutyl and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen and wherein L 1 is selected from the group consisting of —C(═O)—CH 2 —, —C(═O)—(CH 2 ) 2 — and —C(═O)—(CH 2 ) 3 —.

17. A method of treating obesity or feeding-related disorders in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 1 wherein the compound binds to the melanocortin 4 receptor with high affinity and exhibits no intrinsic activity at the melanocortin 4 receptor.