Substituted melanocortin receptor-specific piperazine compounds
Melanocortin receptor-specific compounds of the general formulas and pharmaceutically acceptable salts thereof, where J is a substituted or unsubstituted monocyclic or bicyclic ring structure, L is a linker, W is a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor, Q includes a substituted or unsubstituted aromatic carbocyclic ring, R 6 , R 7 , y and z are as defined in the specification, and the carbon atom marked with an asterisk can have any stereochemical configuration, and optionally with one or two additional ring substituents as defined, which compounds bind to one or more melanocortin receptors and are optionally an agonist, a partial agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist, and may be employed for treatment of one or more melanocortin receptor-associated conditions or disorders, and methods for the use of the compounds of the invention.
1. A compound of formula I or II:
and pharmaceutically acceptable salts thereof;
wherein
J is a substituted or unsubstituted monocyclic or bicyclic ring structure, wherein in each instance the ring or rings have 5 or 6 ring atoms;
L is a linker selected from the group consisting of —(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)—NH—, —(CH 2 ) q —(C═O)—O—, —NH—(C═O)—(CH 2 ) q —, —(C═O)—NH—(CH 2 ) q —, —NH—(CH 2 ) q —, —NH—(CH 2 ) q —O—, —(C═O)(CH 2 ) q —, —(CH 2 ) q —(C═O)—and —(C═O)—O—(CH 2 ) q —,
q is from 0 to 6;
W is a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr—I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —NH(C═O)NH 2 , —NH(C═O)NHCH 3 ,
Q represents a substituted or unsubstituted aromatic carbocyclic ring;
R 6 is H, ═O, ═S or CH 3 ;
R 7 is NH 2 , NH—R 8 , or
R 8 is a C 1 to C 6 linear or branched chain or an 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, wherein the amine capping group is allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 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;
y is from 0 to 6;
z is from 0 to 6; and
wherein the carbon atom 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 R 7 is NH2, N(CH 3 ) 2 , NHCH 3 ,
4. The compound of claim 1 wherein L is —CH 2 —, —(CH 2 ) 2 —, or —(C═O)(CH 2 ) 2 —.
5. The compound of claim 1 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of:
6. The compound of claim 5 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 W is selected from the group consisting of NH 2 and NH(C═NH)NH 2 .
8. The compound of claim 1 wherein Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl.
9. The compound of claim 1 wherein Q is an indole, substituted indole, quinoline, substituted quinoline, isoquinoline or substituted isoquinoline.
10. 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.
11. A compound of formula III or IV:
and pharmaceutically acceptable salts thereof
wherein
J is a substituted or unsubstituted monocyclic or bicyclic ring structure, wherein in each instance the ring or rings have 5 or 6 ring atoms;
L is a linker selected from the group consisting of —(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)—NH—, —CH 2 ) q —(C═O)—O—, —NH—(C═O)—(CH 2 ) q , —(C═O)—NH—(CH 2 ) q , —NH—(CH 2 ) q —, —NH—(CH 2 ) q —O—, —(C═O)(CH 2 ) q —, —CH 2 ) q —(C═O)—and —(C═O)—O—(CH 2 ) q —
q is from 0 to 6;
W is a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr-I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —NH(C═O)NH 2 , —NH(C═O)NHCH 3 ,
Q represents a substituted or unsubstituted aromatic carbocyclic ring;
R 4 is a C 1 to C 6 linear or branched chain or a C 1 to C 6 linear or branched chain with an aryl group;
R 6 is H, ═O, ═S or —CH 3 ;
R 7 is NH2, NH—R 8 , or
R 8 is a C 1 to C 6 linear or branched chain or an 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, wherein the amine capping group is allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 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;
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.
12. The compound of claim 11 of formula
13. The compound of claim 11 wherein R 6 is CH 3 ,
14. The compound of claim 11 wherein R 6 is H or ═O.
15. The compound of claim 11 wherein R 7 is NH 2 , N(CH 3 ) 2 , NHCH 3 ,
16. The compound of claim 11 wherein L is —CH 2 —, —(CH 2 ) 2 —, or —(C═O)(CH 2 ) 2 —.
17. The compound of claim 11 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of:
18. The compound of claim 17 wherein J is substituted at one or more positions with one or more hydroxyl, halogen, alkyl or aryl groups.
19. The compound of claim 11 wherein W is selected from the group consisting of —NH 2 and —NH(C═NH)NH 2 .
20. The compound of claim 11 wherein Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl.
21. The compound of claim 11 wherein Q is an indole, substituted indole, quinoline, substituted quinoline, isoquinoline or substituted isoquinoline.
22. The compound of claim 11 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.
23. A compound of formula V or VI:
and pharmaceutically acceptable salts thereof;
wherein
J is a substituted or unsubstituted monocyclic or bicyclic ring structure, wherein in each instance the ring or rings have 5 or 6 ring atoms;
L is a linker selected from the group consisting of —(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)—NH—, —CH 2 ) q —(C═O)—O—, —NH—(C═O)—(CH 2 ) q —, —C═O)—NH—(CH 2 ) q —, —NH—(CH 2 ) q —, —NH—CH 2 ) q —O—, —(C═O)(CH 2 ) q —, —(CH 2 ) q —(C═O)— and —(C═O)—O—(CH 2 ) q —
q is from 0 to 6;
W is a cationic center, hydrogen bond donor or hydrogen bond acceptor selected from the group consisting of NH2, NH(C═NH)NH2, —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr-I, —NH(C═NH)NH2, —NH(C═0)OCH 3 , —NH(C═0)CH 3 , —NH(C═0)NH2, —NH(C═0)NHCH 3 ,
Q represents a substituted or unsubstituted aromatic carbocyclic ring;
R 4 and R 5 are each independently a C 1 to C 6 linear or branched chain or a C 1 to C 6 linear or branched chain with an aryl group;
R 6 is H, ═O, ═S or —CH 3 ;
R 7 is NH 2 , NH—R 8 , or
R 8 is a C 1 to C 6 linear or branched chain or an 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, wherein the amine capping group is allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7′—amino heptanoyl, 6-Ahx, Ame, 8-Aoc or polyethylene glycol with a formula molecular weight of between about 100 and about 10,000;
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.
24. The compound of claim 23 of formula
25. The compound of claim 23 wherein R 4 and R 5 are each independently
26. The compound of claim 23 wherein R 6 is H or ═O.
27. The compound of claim 23 wherein R 7 is NH2, N(CH 3 ) 2 , NHCH 3 ,
28. The compound of claim 23 wherein L is —CH 2 —, —(CH 2 ) 2 —, or —(C═O)(CH 2 ) 2 —.
29. The compound of claim 23 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of:
30. The compound of claim 29 wherein J is substituted at one or more positions with one or more hydroxyl, halogen, alkyl or aryl groups.
31. The compound of claim 23 wherein W is selected from the group consisting of —NH 2 and —NH(C═NH)NH 2 .
32. The compound of claim 23 wherein Q is phenyl, substituted phenyl, naphthyl or substituted naphthyl.
33. The compound of claim 23 wherein Q is an indole, substituted indole, quinoline, substituted quinoline, isoquinoline or substituted isoquinoline.
34. The compound of claim 23 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.