Substituted melanocortin receptor-specific single acyl piperazine compounds
Melanocortin receptor-specific compounds of the general formula and pharmaceutically acceptable salts thereof, where J is a substituted or unsubstituted monocyclic or bicyclic ring structure, W is a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, Q is a substituted or unsubstituted aromatic carbocyclic ring group, L, R 2a , R 2b , R 3a , R 3b , r, x and y are as defined in the specification, and the carbon atoms marked with an asterisk can have any stereochemical configuration. Compounds disclosed herein bind to one or more melanocortin receptors and may be an agonist, a partial agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist as to one or more melanocortin receptors, and may be employed for treatment of one or more melanocortin receptor-associated conditions or disorders, including specifically treatment of obesity and related conditions.
1. A compound of formula I:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
J is selected from the group consisting of a substituted or unsubstituted aromatic carbocyclic ring and two substituted or unsubstituted aromatic carbocyclic rings wherein the two rings are joined by a bond, —CH 2 — or —O—, wherein in each instance each ring contains 5 or 6 ring atoms;
W is —NH—C(NH)—NH 2 or —NH 2 , wherein any NH or NH 2 may be replaced by N-Prg or NH-Prg, respectively, where each Prg is independently an amine protecting group;
Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
L is a C 1 to C 3 alkyl or a group of the formula
wherein R 1 is
one or two of R 2a , R 2b , R 3a , and R 3b are independently a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 2a , R 2b , R 3a , and R 3b are hydrogen, provided that at least one of R 2a and R 2b and at least one of R 3a and R 3b are hydrogen;
R 4a and R 4b are each independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl, or polyethylene glycol;
v is an index value from 0 to 5;
x is an index value from 0 to 6;
y is an index value from 0 to 4; and
r is an index value from 0 to 4;
wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.
2. The compound of claim 1 wherein J is:
unsubstituted or substituted with one or more ring substituents.
3. The compound of claim 2 wherein J is substituted with one or more ring substituents independently selected from the group consisting of hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, or —O-aryl groups.
4. The compound of claim 1 wherein the polyethylene glycol has a formula molecular weight of between 100 and 50,000.
5. The compound of claim 1 wherein Q is
wherein R 5a , R 5b and R 5c are each optional ring substituents, and when one or more are present, are the same or different and independently hydroxyl, halogen, alkyl, —O-alkyl, aryl, or —O-aryl groups.
6. The compound of claim 5 wherein at least one of R 5a , R 5b and R 5c is —CH 3 or —O—CH 3 .
7. The compound of claim 5 wherein at least one of R 5a , R 5b and R 5c is —Cl or —CF 3 .
8. The compound of claim 1 wherein one of R 3a and R 3b is a C 1 to C 6 aliphatic linear or branched chain, and R 2a and R 2b and the remaining of R 3a and R 3b are hydrogen.
9. The compound of claim 8 wherein the C 1 to C 6 aliphatic linear or branched chain is selected from the group consisting of methyl and isobutyl.
10. The compound of claim 1 wherein L is group of the formula
wherein R 1 is
11. The compound of claim 1 wherein each Prg independently is a nitro, urethane, arenesulfonyl or trityl group.
12. The compound of claim 1 wherein each Prg is independently acetyl, adamantyloxy, benzoyl, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, mesitylene-2-sulfonyl, 4-methoxy-2,3-6-trimethyl-benzenesulfonyl, 2,2,4,6,7-pentamethyldihydrobenzofurane-5-sulfonyl, 2,2,5,7,8-pentamethylchromane-6-sulfonyl, 9-fluorenylmethoxycarbonyl or tosyl.
13. The compound of claim 1 that is:
N-(3-{(2S,5R)-1-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propyl]-4-[3-(3,4-dichloro-phenyl)-propionyl]-5-isobutyl-piperazin-2-yl}-propyl)-guanidine,
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating a condition responsive to changes in melanocortin receptor function in a human or non-human mammal, comprising the step of administering a pharmaceutical composition of claim 14 , wherein the condition is selected from the group consisting of above-optimal body weight and obesity.