Thieno [2,3-D]pyrimidine-2,4-dione melanocortin-specific compounds
A thienopyrimidine compound of the formula: wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, and methods of use of such compounds for the treatment of melanocortin receptor-associated disorders.
1. A compound of the formula:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
R 1 is -L 1 -J;
R 2 is -L 2 -W;
R 3 is -L 3 -T;
R 4 is -L 4 -Q;
L 1 is a bond or a linker unit comprising from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen and nitrogen;
J is a carbocyclic ring group comprising at least one aromatic ring;
L 2 is —(CX) m —;
W 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 or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance the rings include 5 or 6 ring atoms;
L 3 and L 4 are —(CH 2 ) m —;
T is —NH 2 , N(Z)(Z), —NH—C(=NH)—NH 2 or —N(Z)—C(=N(Z))—N(Z)(Z), where each Z is independently H or CH 3 ;
Q is a carbocyclic ring group comprising at least one aromatic ring;
X is at each occurrence independently H, H 2 , or a C 1 to C 12 linear or branched alkyl; and
m is at each occurrence independently from 1 to 6.
2. The compound of claim 1 wherein R 3 is
3. The compound of claim 1 wherein at least one aromatic ring of J or Q, or both, is substituted with one or more halogen, alkyl or aryl groups.
4. The compound of claim 2 wherein
R 1 is:
R 2 is:
R 4 is:
wherein R 5a and R 5b 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, but excluding F in the 2 and 6 position.
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A method for treating a melanocortin receptor-associated disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 5 , wherein the melanocortin receptor-associated disorder is sexual dysfunction or an energy homeostasis disorder.
7. The method of claim 6 wherein the melanocortin receptor-associated disorder is cachexia.
8. The method of claim 6 wherein the melanocortin receptor-associated disorder is obesity.
9. A method for treating a melanocortin receptor-associated disorder, comprising administering a therapeutically effective amount of a compound of the formula:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
R 1 is -L 1 -J;
R 2 is -L 2 -W;
R 3 is -L 3 -T
R 4 is -L 4 -Q;
L1 is a bond or a linker unit consisting of from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen and nitrogen;
J is a carbocyclic ring group consisting of at least one aromatic ring;
L 2 is a bond or —(CX) m —;
W is Y n , where each Y is independently N(CH 3 ) 2 , NH, N, CH 2 , or C=O and n has a value between 1 and 8, provided that any 5 or more Y units can be taken together to form an aromatic or non-aromatic carbocyclic or heterocyclic ring;
L 3 and L 4 are a bond or —(CH 2 ) m —;
T is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, and two substituted or unsubstituted aromatic carbocyclic rings wherein the rings are joined by a bond or —O—, wherein in each instance the rings include 5 or 6 ring atoms;
Q is a carbocyclic ring group consisting of at least one aromatic ring;
X is at each occurrence independently H, H 2 , or a C 1 to C 12 linear or branched alkyl;
m is at each occurrence independently from 1 to 6; and
a pharmaceutically acceptable carrier,
wherein the melanocortin receptor-associated disorder is sexual dysfunction or an energy homeostasis disorder.
10. The method of claim 9 wherein L 2 is —(CH 2 ) m — and W is N(CH 3 ) 2 .
11. The method of claim 10 wherein R 2 is
12. The method of claim 9 wherein at least one aromatic ring of J or Q, or both, is substituted with one or more halogen, alkyl or aryl groups.
13. The method of claim 11 wherein
R 1 and R 3 are:
R 4 is:
wherein R 5a and R 5b 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, but excluding F in the 2 and 6 position.
14. The method of claim 9 wherein the melanocortin receptor-associated disorder is cachexia.
15. The method of claim 9 wherein the melanocortin receptor-associated disorder is obesity.