초록

Thyronamine derivatives and analogs, methods of using such compounds, and pharmaceutical compositions containing them are disclosed. Methods of preparing such compounds are also disclosed.

대표청구항 ▼

What is claimed: 1. A compound of formula I: or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof; wherein independently, R1 and R2 are: H, lower alkyl, cyclic alkyl, or benzyl; Y is--[CR8R9]--; where R8

What is claimed: 1. A compound of formula I: or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof; wherein independently, R1 and R2 are: H, lower alkyl, cyclic alkyl, or benzyl; Y is--[CR8R9]--; where R8 is H, and R9 is aryl optionally substituted with 1-3 substituents selected from the group consisting of lower alkyl, halo, hydroxy, and alkoxy; or benzyl wherein the phenyl portion thereof is optionally substituted with 1-3 substituents selected from the group consisting of lower alkyl, halo, hydroxy, and alkoxy; Z is:--[C(R)2]n--, CHOR, O, S, NR, CONH, or NHCO; R3, R4, R5, and R7 are: H, I, Br, Cl, F, CH3, CF3, CN, SR, OCH3, CH2CH3, or CH(CH3)2; R6 is: OR, H, SH, F, CF3, lower alkyl, or N(R)2; X is: O, S, SO, SO2, NR, C(R)2,-lower alkyl-O--,--O-lower alkyl-, COCH2O, or OCH2CO; R is H, lower alkyl, aryl optionally substituted with 1-3 substituents selected from the group consisting of lower alkyl, halo, hydroxy, and alkoxy; or benzyl wherein the phenyl portion thereof is optionally substituted with 1-3 substituents selected from the group consisting of lower alkyl, halo, hydroxy, and alkoxy; and n is 1 to 6. 2. The compound of claim 1, wherein R4 and R5 are H, CH3, CF3, CN, OCH3, CH2CH3, or CH(CH3)2. 3. The compound of claim 2, wherein R1 and R2 are H, R3 is I, R4, R5, and R7 are H, R6 is OH, X is O, and Z is CH2. 4. The compound of claim 1, wherein R4 is H, CH3, CF3, CN, OCH3, CH2CH3, or CH(CH3)2; and R5 is I, Br, Cl, or F. 5. The compound of claim 4, wherein R1 and R2 are H, R4 and R7 are H, R3 and R5 is I, R6 is OH, X is O, and Z is CH2. 6. The compound of claim 4, wherein R1 and R2 are H, R4 is H, R3, R5, and R7 are I, R6 is OH, X is O, and Z is CH2. 7. The compound of claim 1, wherein R1 is lower alkyl, R6 is OH or OR, and X is O. 8. The compound of claim 1, wherein R3 is a halogen, R6 is H, and X is O. 9. The compound of claim 1, wherein X is alkoxy. 10. The compound of claim 1, wherein R1 and R2 are H or lower alkyl, R6 is H or CF3, and X is alkoxy. 11. The compound of claim 1, wherein R1 is H or lower alkyl. 12. The compound of claim 1, wherein R1 and R2 are H or lower alkyl, R6 is H, X is O, and Z is alkyl. 13. The compound of claim 1, wherein R9 is aryl optionally substituted with 1-3 substituents selected from the group consisting of lower alkyl, halo, hydroxy, and alkoxy. 14. A pharmaceutical composition, comprising at least one pharmaceutically acceptable carrier or excipient and at least one compound of claim 1. 15. A method of exerting a positive inotropic effect on the heart without affecting the heart rate of a mammalian subject comprising the step of administering to said subject an effective amount of the compound of claim 1. 16. A method of lowering the core body temperature of a mammalian subject comprising the step of administering to said subject an effective amount of the compound of claim 1. 17. The method of claim 16, wherein administering the compound of claim 1 induces torpor or hibernation in said subject. 18. A method of treating a mammalian subject during surgery comprising administering to the subject a therapeutically effective amount of the compound of claim 1. 19. The method of claim 18, wherein said method reduces the core body temperature and induces anesthesia in the subject. 20. The method of claim 18, said method reduces blood loss of the subject. 21. A method for alleviating a disease state in a mammal believed to be responsive to treatment with a thyronamine agonist comprising the step of administering to the mammal a therapeutic amount of the compound of claim 1. 22. The method of claim 21, wherein the compound is an agonist of a G protein coupled receptor. 23. The method of claim 22, wherein the compound is an agonist of a trace amine receptor. 24. The method of claim 21, wherein the disease state is congestive heart failure, cardiac arrhythmia, or stroke. 25. The method of claim 21, wherein the disease state is diabetes, hyperglycemia, hypoglycemia, or obesity. 26. A method for alleviating a disease state in a mammal believed to be responsive to treatment with a thyronamine antagonist comprising the step of administering to the mammal a therapeutic amount of the compound of claim 1. 27. The method of claim 26, wherein the compound is an antagonist of a G protein coupled receptor. 28. The method of claim 27, wherein the compound is an antagonist of a trace amine receptor. 29. The method of claim 26, wherein the disease state is congestive heart failure, cardiac arrhythmia, or stroke. 30. The method of claim 26, wherein the disease state is diabetes, hyperglycemia, hypoglycemia, or obesity. 31. A method of treating a mammalian subject during open heart surgery believed to be responsive to treatment with a thyronamine antagonist comprising administering a therapeutically effective amount the compound of claim 1. 32. A method of treating a mammalian subject during trauma or blood loss believed to be responsive to treatment with a thyronamine antagonist comprising administering a therapeutically effective amount the compound of claim 1. 33. An isotopically labeled compound of claim 1. 34. The compound of claim 33 isotopically labeled with 3H, 2H, or 125I. 35. The compound of claim 1, wherein R9 is benzyl wherein the phenyl portion thereof is substituted with hydroxyl. 36. The compound of claim 35 wherein, R1, R2, R3, R5, and R7 are H, R4 is I, R6 is hydroxyl, X is O, and Z is CH2.