Compositions and methods for reducing serum glucose and triglyceride levels in diabetic mammals
Diabetic mammals are treated with compounds that are significantly more efficacious as agonists of RXR β retinoid receptors than as agonists of RXR α or RXR γ retinoid receptors. The treatment reduces serum glucose and triglyceride levels of the mammals without the undesirable side effects of reducing serum thyroxine levels and a transient increase in serum triglyceride levels Compounds suitable for use in the methods of treatments of the present invention are selected by testing and identifying compounds of selective or specific efficacy as agonists of RXR β retinoid receptors in preference over RXR α and/or RXR γ retinoid receptors. Novel compounds used in the methods of the invention have Formula 1 where the variables are defined as disclosed in the specification.
1. A compound of the formula
where R 1 is H or alkyl of 1 to 6 carbons;
R 2 independently is H, alkyl of 1 to 6 carbons, or halogen;
m is an integer having the values 0 to 2;
R 3 is alkyl of 1 to 6 carbons;
R 4 is alkyl of 1 to 6 carbons;
R 5 is H or alkyl of 1 to 6 carbons;
R 6 is H or F, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound.
2. A compound in accordance with claim 1 where R 1 is alkyl of 1 to 3 carbons.
3. A compound in accordance with claim 1 where R 2 is H, or alkyl of 1 to 3 carbons.
4. A compound in accordance with claim 1 where R 3 is alkyl of 1 to 3 carbons and R 4 is alkyl of 1 to 3 carbons.
5. A compound in accordance with claim 1 where R 5 is H alkyl of 1 to 3 carbons.
6. A compound in accordance with claim 1 where R 7 is H, or alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
7. A compound of the formula
where R 1 is alkyl of 1 to 3 carbons;
R 3 is alkyl of 1 to 3 carbons;
R 4 is alkyl of 1 to 3 carbons;
R 5 is H or alkyl of 1 to 3 carbons, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound.
8. A compound in accordance with claim 7 where R 7 is H, alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
9. A compound in accordance with claim 7 where R 7 is H, or a pharmaceutically acceptable salt of said compound.
10. A compound of the formula
where R 3 is ethyl or n-propyl;
R 4 is methyl or ethyl, and
R 7 is H or alkyl of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound.
11. A compound in accordance with claim 10 where R 3 and R 4 are ethyl.
12. A compound in accordance with claim 11 where R 7 is H or a pharmaceutically acceptable salt of said compound.
13. A compound in accordance with claim 10 where R 3 is n-propyl and R 4 is methyl.
14. A compound in accordance with claim 13 where R 7 is H or a pharmaceutically acceptable salt of said compound.
15. A process for treating a diabetic Type II condition in a mammal comprising administering a compound of the formula to said mammal to reduce the serum glucose level of said mammal
where R 1 is H or alkyl of 1 to 6 carbons;
R 2 independently is H, alkyl of 1 to 6 carbons, or halogen;
m is an integer having the values 0 to 2;
R 3 is alkyl of 1 to 6 carbons;
R 4 is alkyl of 1 to 6 carbons;
R 5 is H or alkyl of 1 to 6 carbons;
R 6 is H or F, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound and wherein the compound is at least 1.5 times more efficacious as agonist of RXR β retinoid receptors than as agonists of RXR α or RXR γ retinoid receptors.
16. A process in accordance with claim 15 where the compound administered to the mammal is at least 2.0 times more efficacious as agonist of RXR β retinoid receptors than as agonist of RXR α or RXR γ retinoid receptors.
17. A process in accordance with claim 15 where the compound administered to the mammal is at least 3 more efficacious as agonist of RXR β retinoid receptors than as agonist of RXR α or RXR γ retinoid receptors.
18. A process in accordance with claim 15 where the compound has the formula
where R 1 is H or alkyl of 1 to 6 carbons;
R 2 independently is H, alkyl of 1 to 6 carbons, or halogen;
m is an integer having the values 0 to 2;
R 3 is alkyl of 1 to 6 carbons;
R 4 is alkyl of 1 to 6 carbons;
R 5 is H or alkyl of 1 to 6 carbons;
R 6 is H or F, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound.
19. A process in accordance with claim 15 where the compound has the formula
where R 1 is alkyl of 1 to 3 carbons;
R 3 is alkyl of 1 to 3 carbons;
R 4 is alkyl of 1 to 3 carbons;
R 5 is H alkyl of 1 to 3 carbons, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound.
20. A process in accordance with claim 15 where the compound has the formula
where R 3 is ethyl or n-propyl;
R 4 is methyl or ethyl, and
R 7 is H or alkyl of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound.
21. A process in accordance with claim 20 where in the formula of the compound R 3 and R 4 are ethyl.
22. A process in accordance with claim 21 where in the formula of the compound R 7 is H or a pharmaceutically acceptable salt of said compound.
23. A process in accordance with claim 20 where in the formula of the compound R 3 is n-propyl and R 4 is methyl.
24. A process in accordance with claim 23 where in the formula of the compound R 7 is H or a pharmaceutically acceptable salt of said compound.
25. A process in accordance with claim 15 where administration of the compound to the mammal also reduces serum triglyceride levels without reducing serum thyroxine levels.
26. A method of selecting a compound that is capable of reducing serum glucose level and serum triglyceride level in a mammal having Type II diabetes condition when said compound is administered to the mammal without reducing serum thyroxine level of the mammal, the method comprising the steps of:
assaying several compounds of the formula
as agonists of RXR α , RXR β and RXR γ retinoid receptors, and identifying the compound that is at least 1.5 times more efficacious as agonist of RXR β retinoid receptors than as agonist of RXR α or RXR γ retinoid receptors where in the formula of the compound
R 1 is H or alkyl of 1 to 6 carbons;
R 2 independently is H, alkyl of 1 to 6 carbons, or halogen;
m is an integer having the values 0 to 2;
R 3 is alkyl of 1 to 6 carbons;
R 4 is alkyl of 1 to 6 carbons;
R 5 is H or alkyl of 1 to 6 carbons;
R 6 is H or F, and
R 7 is H or alkyl of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound.
27. A method in accordance with claim 26 where the identified compound is at least 2.0 times more efficacious as agonist of RXR β retinoid receptors than as agonist of RXR α or RXR γ retinoid receptors.
28. A method in accordance with claim 26 where the identified compound is at least 3.0 times more efficacious as agonist of RXR β retinoid receptors than as agonist of RXR α or RXR γ retinoid receptors.