Melanocortin receptor-specific compounds
A melanocortin receptor-specific compound of the general formula of structure I: where X, R 1 , R 2a , R 2b , R 3 , R 4a , R 4b , R 5a and R 5b are as defined in the specification, which compound binds with high affinity to one or more melanocortin receptors and is optionally an agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist, and may be employed for treatment of one or melanocortin receptor-associated conditions or disorders, and methods for the use of the compounds of the invention.
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)—, —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)—;
R 6a and R 6b are each hydrogen;
Q is
wherein R 9a and R 9b are ring substituents, wherein one or both are present and are the same or different and are independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage;
R 5a is a C 1 to C 6 aliphatic linear or branched chain;
R 5b is hydrogen; and
each of R 4a and R 4b is hydrogen; and
y is at each occurrence independently 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 for L 2 ,
y is from 1 to 4.
3. The compound of claim 1 wherein at least one Of R 9a and R 9b is selected from the group consisting of —CH 3 and —OCH 3 .
4. The compound of claim 1 wherein at least one of R 9a and R 9b is selected from the group consisting of —Cl and —CF 3 .
5. The compound of claim 1 wherein R 5a is selected from the group consisting of methyl and isobutyl.
6. The compound of claim 1 wherein
J is selected from the group consisting of naphthyl, phenyl, substituted phenyl, indole and substituted indole;
L 2 is (CH 2 ) 3 ;
L 3 is selected from the group consisting of —C(═O)—(C—NR 6a R 6b )—(CH 2 ) y —, —C(═O)—(CH 2 ) y — and —(CH 2 ) y —(C—NR 6a R 6b )—(CH 2 ) y —; and
is methyl or isobutyl.
7. The compound of claim 1 and pharmaceutically acceptable salts thereof selected from the group consisting of:
N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2 naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(2-chloro-4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-chloro-2-fluoro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(2-chloro-4-trifluoromethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(3,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl }-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-methyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-(3-{1-(2(R)-Amino-(4-chloro-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;
N-(3-{1-(2(R)-Amino-(4-chloro-2-methyl-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;
N-{3-[1-[2(R)-Amino-3-(phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-methoxy-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-{3-[1-[2(R)-Amino-3-(4-chloro-2-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;
N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine;
N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl}-propyl)-guanidine;
N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(4-phenyl-butyryl)-piperazin-2(S)-yl}-propyl)-guanidine;
N-(3-{1-[3-(2,4-Dichloro-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine; and
N-{3-[1-(2(R)-Amino-2-phenyl-acetyl)-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl]-propyl}-guanidine.
8. The compound of claim 1 wherein R 5a is an (R)-configuration C 1 to C 6 aliphatic linear or branched chain.
9. The compound of claim 1 wherein R 5a is (R)-methyl or (R)-isobutyl.
10. The compound of claim 8 wherein L 1 is selected from the group consisting of —(CH 2 ) 2 — and —(CH 2 ) 3 —.
11. A pharmaceutical composition, comprising a compound of any one of claims 1 , 7 and 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
12. A method of treating obesity or cachexia in a mammal, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of claim 11 .
13. The compound of claim 1 wherein R 5a is an (R)-configuration C 1 to C 6 aliphatic linear or branched chain 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 —.
14. The compound of claim 1 wherein R 5a is (R)-methyl or (R)-isobutyl 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 —.
15. A method of treating obesity or cachexia in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 , 7 and 8 .