Hydrazide compounds as thyroid hormone receptor modulators and uses thereof
A method of identification of compounds that modulate thyroid hormone activity, and the use of such compounds and compositions thereof for such purposes are disclosed. The compounds may be selected from the group consisting of: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of conditions that are causally related to aberrant thyroid hormone activity, such as hyperthyroidism and thyrotoxicosis.
1. A compound of formula Ia:
or a pharmaceutically acceptable salt thereof, and stereoisomers, tautomers and thereof; and
wherein:
each of R 3 and R 4 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted amido, NHSO 2 -alkyl, halo, or nitro; and
each of m and m′ are independently selected from 0-4.
2. The compound of claim 1 wherein R 3 is alkyl, nitro, alkoxy, halo or haloalkyl.
3. The compound of claim 1 wherein R 4 is alkyl, alkoxy, halo or haloalkyl and m′ is 1.
4. The compound of claim 1 wherein each R 4 is independently alkyl, alkoxy, halo or haloalkyl and m′ is 2.
5. The compound of claim 1 wherein the compound is according to formula IIa:
or a pharmaceutically acceptable salt thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein:
each of R 3 and R 4 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted amido, NHSO 2 -alkyl, halo, or nitro; and m′ is selected from 0-4.
6. The compound of claim 5 wherein R 3 is alkyl, nitro, alkoxy, halo or haloalkyl.
7. The compound of claim 5 wherein R 4 is alkyl, alkoxy, halo or haloalkyl and m′ is 1.
8. The compound of claim 5 wherein each R 4 is independently alkyl, alkoxy, halo or haloalkyl and m′ is 2.
9. The compound of claim 1 wherein the compound is of formula III
or a pharmaceutically acceptable salt thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein:
each of R 3 and R 4a-e are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted amido, NHSO 2 -alkyl, halo, or nitro.
10. The compound of claim 9 wherein R 3 is alkyl, nitro, alkoxy, halo or haloalkyl.
11. The compound of claim 1 wherein the compound is according to formula IVa:
or a pharmaceutically acceptable salt thereof, and stereoisomers, tautomers and isotopic variants thereof; and wherein:
each of R 4a-e are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted amido, NHSO 2 -alkyl, halo, or nitro.
12. The compound of claim 1 wherein the compound is of formula V
or a pharmaceutically acceptable salt thereof, and stereoisomers, tautomers and thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .
14. The pharmaceutical composition of claim 13 wherein the carrier is a parenteral carrier, oral or topical carrier.
15. The compound of claim 1 , wherein each R 3 is independently H, NO 2 , CF 3 , F, Cl, or NHSO 2 Me.
16. The compound of claim 1 , wherein each R 4 is independently H, Me, Et, iso-Pr, CF 3 , OMe, F, or Cl.
17. The compound of claim 1 , wherein the compound is selected from