Crystalline form III of melanocortin receptor agonist compound and preparation method therefor
The present invention relates to a crystalline form III represented by formula 1, a method for preparing the same, and a pharmaceutical composition comprising the same. The crystalline form III represented by formula 1 of the present invention may be characterized by XRPD patterns, TG/DTA profiles, an NMR spectrum, and/or DVS profiles.
1 . A crystalline form III of a compound of the following formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof,
wherein the X-ray powder diffraction (XRPD) pattern has 5 or more characteristic peaks selected from among peaks with the following diffraction angles (2θ values) of: 6.238±0.1°, 8.257±0.1°, 8.828±0.1°, 16.618±0.1°, 17.465±0.1°, 18.859±0.1°, 19.061±0.1°, 19.333±0.1°, 20.642±0.1°, 22.679±0.1°, and 25.985±0.1°,
wherein R 1 is C 2 -C 5 alkyl.
2 . The crystalline form III of claim 1 , wherein R 1 is C 2 -C 4 alkyl.
3 . The crystalline form III of claim 2 , wherein the compound of formula 1 is selected from the group consisting of:
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) isobutyramide;
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) propionamide; and
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) pivalamide.
4 . The crystalline form III of claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of: a hydrochloride, a sulfate, a nitrate, a phosphate, a hydrobromide, and a hydroiodide.
5 . The crystalline form III of claim 1 , which is a crystalline form of a formamide solvate of formula 1.
6 . A method for preparing the crystalline form III described in claim 1 , the method comprising the steps of: preparing a mixed solution by dissolving the compound of formula 1 in a crystallization solvent; and obtaining crystals from the mixed solution.
7 . The method for preparing the crystalline form III of claim 6 , wherein the crystals are obtained by anti-solvent crystallization.
8 . The method for preparing the crystalline form III of claim 6 , wherein the crystals are obtained by slurry method.
9 . The method for preparing the crystalline form III of claim 6 , wherein the crystallization solvent comprises a polar organic solvent.
10 . The method for preparing the crystalline form III of claim 9 , wherein the polar organic solvent comprises formamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, or mixtures thereof.
11 . The method for preparing the crystalline form III of claim 9 , wherein the crystallization solvent further comprises a non-polar organic solvent.
12 . The method for preparing the crystalline form III of claim 11 , wherein the non-polar organic solvent comprises hexane, heptane, cyclohexane, carbon tetrachloride, benzene, chloroform, or mixtures thereof.
13 . A pharmaceutical composition comprising the crystalline form III according to claim 1 and a pharmaceutically acceptable carrier.
14 . A method for agonizing the function of a melanocortin-4 receptor, the method comprising administering the crystalline form III according to claim 1 to a subject in need thereof.
15 . The method of claim 14 , which is for treating obesity, diabetes, or erectile dysfunction.
16 . A pharmaceutical composition comprising the crystalline form III according to claim 2 and a pharmaceutically acceptable carrier.
17 . A pharmaceutical composition comprising the crystalline form III according to claim 3 and a pharmaceutically acceptable carrier.
18 . A pharmaceutical composition comprising the crystalline form III according to claim 4 and a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition comprising the crystalline form III according to claim 5 and a pharmaceutically acceptable carrier.
20 . The crystalline form III of claim 1 , wherein R 1 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
21 . The crystalline form III of claim 2 , wherein R 1 is ethyl.
22 . The crystalline form III of claim 2 , wherein R 1 is n-propyl.
23 . The crystalline form III of claim 2 , wherein R 1 is isopropyl.
24 . The crystalline form III of claim 2 , wherein R 1 is n-butyl.
25 . The crystalline form III of claim 2 , wherein R 1 is isobutyl.
26 . The crystalline form III of claim 2 , wherein R 1 is sec-butyl.
27 . The crystalline form III of claim 3 , wherein the compound is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) isobutyramide.
28 . The crystalline form III of claim 3 , wherein the compound is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) propionamide.
29 . The crystalline form III of claim 3 , wherein the compound is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl) pivalamide.