Pharmaceutical salts of macrocyclic modulators of the ghrelin receptor
View Patent ↗The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.
1. A pharmaceutically acceptable salt of a macrocyclic compound having the following structure:
2. The pharmaceutically acceptable salt of claim 1 , wherein the salt is an amorphous form.
3. The pharmaceutically acceptable salt of claim 1 , wherein the salt is a crystalline form.
4. The pharmaceutically acceptable salt of claim 1 , wherein the salt is a hydrochloride, hydrobromide or hydroiodide salt.
5. The pharmaceutically acceptable salt of claim 1 , wherein the salt is a hydrochloride salt.
6. A process for preparing a pharmaceutically acceptable salt of a compound having the following structure:
The process comprising:
(a) dissolving a macrocyclic compound having the following structure:
in a solution of an alcohol to form solution A;
(b) adding an acid to solution A to form acidified solution A;
(c) optionally cooling acidified solution A; and
(d) separating a precipitated salt from acidified solution A;
(e) dissolving the precipitated salt from (d) in a hot mixture of an alcohol and water to form solution C;
(f) cooling solution C; and
(g) separating a precipitated salt from solution C.
7. The process of claim 6 , wherein the alcohol is ethanol.
8. The process of claim 6 , wherein the acid is hydrochloric acid.
9. The process of claim 6 , wherein the precipitated salt is an amorphous form.
10. The process of claim 6 , wherein the precipitated salt is a hydrochloride salt.
11. The process of claim 6 , wherein the precipitated salt from solution C is a crystalline form.
12. A pharmaceutical composition comprising:
(a) a pharmaceutically acceptable salt of claim 1 ; and
(b) a pharmaceutically acceptable carrier, excipient or diluent.
13. The pharmaceutical composition of claim 12 further comprising a growth hormone secretagogue.
14. The pharmaceutical composition of claim 13 , wherein the growth hormone secretagogue is hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, RC-1291, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187, NNC-26-1291, growth hormone releasing factor, IGF-I or IGF-II.