Melanocortin receptor-specific piperazine and keto-piperazine compounds

1. A compound having the formula of structure I:

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

wherein

J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, two substituted or unsubstituted aromatic carbocyclic rings wherein the rings are joined by a bond, —CH 2 —, or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups, wherein in each instance the rings include 5 or 6 ring atoms;

W is

R 4 is

O,

CH 2 , provided that R 5 comprises N or O,

C 6 H 5 , provided that R 5 comprises N or O,

C(═O),

C(═O)—O, or

O—C(═O);

R 5 is

OH,

CH 3 , provided that R 4 comprises O,

NH—(CH 2 ) z where NH—(CH 2 ) z together with R 4 forms a ring,

NH—(CH 2 ) y —CH 3 ,

N(—(CH 2 ) y —CH 3 ) 2 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—NH 2 ,

N(—(CH 2 ) y —CH 3 )—C(═N((CH 2 ) y —CH 3 ))—NH 2 ,

NH—C(═NH)—NH 2 ,

NH—C(═N((CH 2 ) y —CH 3 ))—NH 2 ,

N(—(CH 2 ) y —CH 3 )—C(═N((CH 2 ) y —CH 3 ))—NH(CH 2 ) y —CH 3 ,

NH—C(═N((CH 2 ) y —CH 3 ))—NH—(CH 2 ) y —CH 3 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—NH(CH 2 ) y —CH 3 ,

NH—C(═N((CH 2 ) y —CH 3 ))—N((CH 2 ) y —CH 3 ) 2 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—N((CH 2 ) y —CH 3 ) 2 ,

O—(CH 2 ) y —CH 3 ,

SO 2 —NH 2 ,

SO 2 —NH—(CH 2 ) y —CH 3 ,

SO 2 —N(—(CH 2 ) y —CH 3 ) 2 or

SO 2 —(CH 2 ) y —CH 3 ,

wherein any NH or NH 2 in the foregoing may be substituted 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 1 is a bond or a linker unit consisting of from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;

L 2 is a bond or —(CH 2 ) z —;

L 3 is a bond or a linker unit consisting of from one to nine backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;

R 1a , R 1b , R 2a and R 2b are selected such that:

one of R 2a and R 2b are

 and the remaining of R 2a and R 2b is hydrogen and R 1a and R 1b are each hydrogen, R 1a and R 1b together form ═O, or one of R 1a and R 1b is a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 1a and R 2b is hydrogen,

or R 2a and R 2b are each hydrogen and one of R 1a and R 1b are

 and the remaining of R 1a and R 1b is hydrogen;

X is CH 2 , C═O or C═S;

t is an index value from 0 to 5; z is an index value from 1 to 6; and

each y is independently an index value from 0 to 5;

wherein the carbon atom 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, and —O-aryl.

4. The compound of claim 1 wherein Q is

and wherein R 3a , R 3b and R 3c are 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.

5. The compound of claim 4 wherein at least one of R 3a , R 3b or R 3c is —CH 3 or —O—CH 3 .

6. The compound of claim 4 wherein at least one of R 3a , R 3b or R 3c is —Cl or —CF 3 .

7. The compound of claim 1 wherein -L 3 -Q and -L 1 -J are the same, where Q and J are an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.

8. 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-fluorenylmethyloxycarbonyl, or tosyl.

9. The compound of claim 1 of a formula:

wherein

R 7 is H or ═O;

R 8 is hydrogen or N(R 9a R 9b );

R 9a and R 9b are each independently 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 in each instance independently an index value from 0 to 2; and

y is in each instance independently an index value from 0 to 5;

wherein if R 8 is not hydrogen, the adjacent carbon atom marked with an asterisk can have any stereochemical configuration.

10. The compound of claim 9 wherein the polyethylene glycol has a formula molecular weight of between 100 and 50,000.

11. The compound of claim 1 wherein one of R 2a and R 2b is

and the remaining of R 2a and R 2b and both R 1a and R 1b are hydrogen.

12. The compound of claim 1 wherein W comprises a single amine.

13. The compound of claim 1 wherein W comprises a single N and a single O.

14. The compound of claim 1 wherein W is —NH—C(═NH)—NH 2 .

15. The compound of claim 1 , wherein the compound is

N-{3-[(2S,5R)-1-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-benzyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-((R)-2-dimethylamino-3-naphthalen-2-yl-propionyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(4′-chloro-biphenyl-2-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(4′-chloro-biphenyl-3-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(4′-chloro-biphenyl-4-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-[2-(4′-chloro-biphenyl-2-yl)-acetyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(2′,4′-dichloro-biphenyl-2-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(3′,4′-dichloro-biphenyl-2-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(3′,5′-dichloro-biphenyl-2-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-1-((R)-2-amino-3-naphthalen-2-yl-propyl)-5-benzyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(2′,4′-dichloro-biphenyl-3-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(2′,4′-dichloro-biphenyl-3-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(3′,4′-dichloro-biphenyl-3-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(3′,5′-dichloro-biphenyl-3-carbonyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(3-iodo-benzoyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(2′,4′-dichloro-biphenyl-3-ylmethyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(4′-chloro-biphenyl-2-ylmethyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-(4′-chloro-biphenyl-3-ylmethyl)-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-5-benzyl-1-biphenyl-2-ylmethyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-1-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propyl]-5-benzyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5S)-1-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-benzyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2R,5R)-1-((R)-2-amino-3-naphthalen-2-yl-propionyl)-5-benzyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-1-[(R)-2-amino-3-(2,4-dimethyl-phenyl)-propyl]-5-cyclohexylmethyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

N-{3-[(2S,5R)-1-[(R)-2-amino-3-(2,4-dichloro-phenyl)-propyl]-5-cyclohexylmethyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine; or

N-{3-[(2S,5R)-5-cyclohexylmethyl-1-[(R)-3-(2,4-dichloro-phenyl)-2-dimethylamino-propyl]-4-(2-naphthalen-2-yl-acetyl)-piperazin-2-yl]-propyl}-guanidine;

or a pharmaceutically acceptable salt thereof.

16. A compound having the formula of structure II:

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

wherein

each J is independently a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, two substituted or unsubstituted aromatic carbocyclic rings wherein the rings are joined by a bond, —CH 2 —, or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups, wherein in each instance the rings include 5 or 6 ring atoms;

W is

R 4 is

O,

CH 2 , provided that R 5 comprises N or O,

C 6 H 5 , provided that R 5 comprises N or O,

C(═O),

C(═O)—NH

C(═O)—O, or

O—C(═O);

R 5 is

OH,

CH 3 , provided that R 4 comprises O,

NH—(CH 2 ) z where NH—(CH 2 ) z together with R 4 forms a ring,

NH—(CH 2 ) y —CH 3 ,

N(—(CH 2 ) y —CH 3 ) 2 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—NH 2 ,

N(—(CH 2 ) y —CH 3 )—C(═N((CH 2 ) y —CH 3 ))—NH 2 ,

NH—C(═NH)—NH 2 ,

NH—C(═N((CH 2 ) y —CH 3 ))—NH 2 ,

N(—(CH 2 ) y —CH 3 )—C(═N((CH 2 ) y —CH 3 ))—NH(CH 2 ) y —CH 3 ,

NH—C(═N((CH 2 ) y —CH 3 ))—NH—(CH 2 ) y —CH 3 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—NH(CH 2 ) y —CH 3 ,

NH—C(═N((CH 2 ) y —CH 3 ))—N((CH 2 ) y —CH 3 ) 2 ,

N(—(CH 2 ) y —CH 3 )—C(═NH)—N((CH 2 ) y —CH 3 ) 2 ,

NH—C(═O)—(CH 2 ) y —NH 2 ,

O—(CH 2 ) y —CH 3 ,

SO 2 —NH 2 ,

SO 2 —NH—(CH 2 ) y —CH 3 ,

SO 2 —N(—(CH 2 ) y —CH 3 ) 2 or

SO 2 —(CH 2 ) y —CH 3 ,

wherein any NH or NH 2 in the foregoing may be substituted by N-Prg or NH-Prg, respectively, where each Prg is independently an amine protecting group;

L 1 is a bond or a linker unit consisting of from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;

L 2 is a bond or —(CH 2 ) z —;

L 3 is a bond or a linker unit consisting of from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;

R 1a , R 1b , R 2a and R 2b are selected such that:

one of R 2a and R 2b are

 and the remaining of R 2a and R 2b is hydrogen and R 1a and R 1b are each hydrogen, R 1a and R 1b together form ═O, or one of R 1a and R 1b is a C 1 to C 6 aliphatic linear or branched chain and the remaining of R 1a and R 2b is hydrogen, or R 2a and R 2b are each hydrogen and one of R 1a and R 1b are

 and the remaining of R 1a and R 1b is hydrogen;

X is CH 2 , C═O or C═S;

t is an index value from 0 to 5;

z is an index value from 1 to 6; and

each y is independently an index value from 0 to 5;

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

17. The compound of claim 16 wherein each J is independently

unsubstituted or substituted with one or more ring substituents.

18. The compound of claim 17 wherein J is substituted with one or more ring substituents independently selected from the group consisting of hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, and —O-aryl.

19. The compound of claim 16 wherein -L 3 -J and -L 1 -J are the same.

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