Thyrotropin-releasing hormone analogues and their therapeutic applications
View Patent ↗The present invention relates to novel metabolically stable and centrally active TRH analogues and prodrug forms of these analogues, wherein a functional portion of TRH is substituted with a pyridinium moiety or an ester moiety. Methods of synthesis and use of the TRH analogues and associated prodrugs are also provided.
1. A compound having the following structure
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is selected from the group consisting of H, alkyl, aryl, heterocycle, heteroaryl, hydroxyalkyl, alkylaryl, substituted aryl, COX, and COOX, wherein X is selected from the group consisting of alkyl, amine, alkylamino, aryl, substituted aryl, arylalkyl, and acyloxyalkyl;
R 3 is 3-(R 1 -)aminocarbonyl-pyridinium-1-yl, where carbon marker 2, 4, 5, or 6 of the pyridinium ring is independently and optionally attached to hydrogen, halogen, isopropyl, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, alkylamino, hydroxyalkyl, alkoxyalkyl, amide, CN, or a linear or branched hydrocarbon from 1–15 atoms carbon atoms in length, that can optionally include one or more heteroatoms in the chain;
R 5 is selected from the group consisting of alkyl, 1-Z, and 1H-imidazol-4-ylmethyl (or its tautomeric 1H-imidazol-5-ylmethyl), where Z is selected from the group consisting of H, alkyl, alkyloxycarbonyl, aryl, substituted aryl, arylalkyl, COX, or COOX; and
L is selected from the group consisting of alkyl including (CH 2 ) n , aryl, heterocycle, or heteroaryl, where n is an integer from 0 to 10.
2. A compound, wherein the compound has the following structure
3. A pharmaceutical composition comprising a compound having the following structure
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is selected from the group consisting of H, alkyl, aryl, heterocycle, heteroaryl, hydroxyalkyl, alkylaryl, substituted aryl, COX, and COOX, wherein X is selected from the group consisting of alkyl, amine, alkylamino, aryl, substituted aryl, arylalkyl, and acyloxyalkyl;
R 3 is 3-(R 1 -)aminocarbonyl-pyridinium-1-yl, where carbon marker 2, 4, 5, or 6 of the pyridinium ring is independently and optionally attached to hydrogen, halogen, isopropyl, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, alkylamino, hydroxyalkyl, alkoxyalkyl, amide, CN, or a linear or branched hydrocarbon from 1–15 atoms carbon atoms in length, that can optionally include one or more heteroatoms in the chain;
R 5 is selected from the group consisting of alkyl, 1-Z, and 1H-imidazol-4-ylmethyl (or its tautomeric 1H-imidazol-5-ylmethyl), where Z is selected from the group consisting of H, alkyl, alkyloxycarbonyl, aryl, substituted aryl, arylalkyl, COX, or COOX;
L is selected from the group consisting of alkyl including (CH 2 ) n , aryl, heterocycle, or heteroaryl, where n is an integer from 0 to 10; and
a pharmaceutically acceptable carrier or diluent.
4. A pharmaceutical composition comprising a compuond having the following structure