CORTICOTROPIN RELEASING FACTOR RECEPTOR ANTAGONISTS
The present disclosure provides forms of CRF antagonists and methods using such CRF antagonists for treating diseases.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are independently ethyl or n-propyl;
R 3 is H, Cl, Br, methyl, trifluoromethyl or methoxy;
R 4 is H, Br, R a R b N—, methoxymethyl, n-butyl, acetamido, pyridin-4-yl, morpholin-4-yl,
R a and R b are independently hydrogen, C 1 -C 3 alkyl, H 2 NCH 2 CH 2 —,
(CH 3 ) 3 COC(O)NHCH 2 CH 2 —, or CH 3 CH 2 CH 2 NHCH 2 CH 2 ;
wherein the compound of Formula I contains at least one deuterium atom; and
wherein the deuterium enrichment content of the compound of Formula I is at least about 1%.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cl, Br, methyl or trifluoromethyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cl or Br.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R a R b N—, pyridin-4-yl, morpholin-4-yl, or
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is morpholin-4-yl or
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R a R b N— and R a and R b are independently C 1 -C 3 alkyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment in the compound of Formula I is at least about 2%.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is 3-[4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-2,5-dimethyl-7-(1-propyl-butyl)-pyrazolo[1,5-a]pyrimidine, wherein the 7-(1-propyl-butyl)moiety comprises at least one deuterium.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is 3-(4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine, wherein the 7-(1-ethyl-propyl) moiety comprises at least one deuterium.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethy-1-pyrazolo[1,5-a]pyrimidine wherein the 7-(1-ethyl-propyl) moiety comprises at least one deuterium.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine or 4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine, wherein the 7-(1-ethyl-propyl) moiety comprises at least one deuterium.
12 . A pharmaceutical composition comprising Compound 1:
or a pharmaceutically acceptable salt or solvate thereof, and Compound 2:
or a pharmaceutically acceptable salt or solvate thereof.
13 . A pharmaceutical composition of claim 12 , wherein the pharmaceutical composition comprises from about 0.5 ppm to about 5000 ppm of Compound 2, or a pharmaceutically acceptable salt or solvate thereof.
14 . A pharmaceutical composition of claim 12 , wherein the pharmaceutical composition comprises from about 0.00005 weight % to about 0.5 weight % of Compound 2, or a pharmaceutically acceptable salt or solvate thereof.
15 . A pharmaceutical composition comprising Compound 1:
or a pharmaceutically acceptable salt or solvate thereof, which has a D 90 from about 1 μm to about 20 μm.
16 . A pharmaceutical composition of claim 15 , wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof has a D 90 from about 5 μm to about 15 μm.
17 . A pharmaceutical composition of claim 16 , wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof has a D 90 of about 6 μm.
18 . A pharmaceutical composition of claim 16 , wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof has a D 90 of about 7 μm.
19 . A pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in an oral dosage form.
20 . A pharmaceutical composition of claim 19 , wherein the oral dosage form is selected from the group consisting of a tablet, a capsule, a buccal tablet, a sub-lingual table, an orally-disintegrating tablet, a thin film, a liquid solution, a liquid suspension, a syrup, a powder, solid crystals, minitabs, coated pellets and sachets.