Salts of nitrogen-containing heterocyclic compound, and solid forms of salts, pharmaceutical composition and use thereof
Provided are salts of a compound of formula (I) having an ATX inhibitory activity. The salts comprises inorganic acid salts or organic acid salts, and solid forms of the salts, such as crystal forms. The salts of the compound of formula (I) and their crystal forms according to the present disclosure have a good solubility, stability and hygroscopicity, and are more suitable for medicinal use. Moreover, their preparation methods are simple and convenient, and are suitable for large-scale production.
1 . A crystal form of a salt of a compound of formula (I),
(R)-2-((1-(1H-1,2,3-triazol-5-yl)propan-2-yl)oxy)-1-(2-((2,3-dihydro-1 H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one
wherein the crystal form is a crystal form A of hydrochloride of the compound of formula (I), wherein the crystal form A of hydrochloride has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 7.48±0.20°, 13.13±0.20°, 16.47±0.20° and 23.94±0.20°;
wherein the crystal form is a crystal form A of sulfate of the compound of formula (I), wherein the crystal form A of sulfate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.49±0.20°, 15.88±0.20°, 17.48±0.20° and 22.40±0.20°;
wherein the crystal form is a crystal form A of maleate of the compound of formula (I), wherein the crystal form A of maleate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 4.43±0.20°, 13.86±0.20°, 14.41±0.20°, 15.00±0.20°, 22.07±0.20°, 22.65±0.20°, 25.58±0.20° and 27.34±0.20°;
wherein the crystal form is a crystal form A of phosphate of the compound of formula (I), wherein the crystal form A of phosphate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.08±0.20°, 15.93±0.20°, 24.37±0.20° and 25.19±0.20°;
wherein the crystal form is a crystal form A of tartrate of the compound of formula (I), wherein the crystal form A of tartrate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.00±0.20° and 15.88±0.20°;
wherein the crystal form is a crystal form B of tartrate of the compound of formula (I), wherein the crystal form B of tartrate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.24±0.20° and 23.94±0.20°;
wherein the crystal form is a crystal form C of tartrate of the compound of formula (I), wherein the crystal form C of tartrate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 4.60±0.20°, 16.15±0.20° and 18.13±0.20°;
wherein the crystal form is a crystal form A of fumarate of the compound of formula (I), wherein the crystal form A of fumarate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 9.52±0.20°, 13.29±0.20°, 14.92±0.20° and 25.23±0.20°;
wherein the crystal form is a crystal form A of citrate of the compound of formula (I), wherein the crystal form A of citrate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 4.96±0.20° and 15.76±0.20°;
wherein the crystal form is a crystal form A of glycolate of the compound of formula (I), wherein the crystal form A of glycolate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.26±0.20°, 7.27±0.20°, 14.12±0.20°, 16.02±0.20° and 24.11±0.20°;
wherein the crystal form is a crystal form A of succinate of the compound of formula (I), wherein the crystal form A of succinate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 5.26±0.20°, 14.00±0.20°, 15.76±0.20°, 21.07±0.20°, 22.00±0.20° and 27.08±0.20°;
wherein the crystal form is a crystal form B of succinate of the compound of formula (I), wherein the crystal form B of succinate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 9.54±0.20°, 12.60±0.20°, 14.91±0.20°, 19.17±0.20°, 21.02±0.20° and 24.88±0.20°;
wherein the crystal form is a crystal form B of adipate of the compound of formula (I), wherein the crystal form B of adipate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 4.98±0.20°, 10.69±0.20°, 13.88±0.20°, 21.41±0.20°, 24.97±0.20° and 26.15±0.20°;
wherein the crystal form is a crystal form A of sebacate of the compound of formula (I), wherein the crystal form A of sebacate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 4.57±0.20°, 9.27±0.20°, 11.20±0.20°, 14.40±0.20°, 20.16±0.20°, 24.63±0.20° and 26.73±0.20°;
wherein the crystal form is a crystal form A of p-toluenesulfonate of the compound of formula (I), wherein the crystal form A of p-toluenesulfonate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 6.04±0.20°, 8.59±0.20°, 14.27±0.20°, 17.14±0.20° and 25.29±0.20°;
wherein the crystal form is a crystal form A of benzenesulfonate of the compound of formula (I), wherein the crystal form A of benzenesulfonate has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 6.16±0.20°, 8.98±0.20°, 14.22±0.20°, 16.90±0.20°, 18.31±0.20°, 20.92±0.20°, 25.11±0.20° and 26.29±0.20°;
wherein the crystal form is a crystal form A of hydrobromide of the compound of formula (I), wherein the crystal form A of hydrobromide has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 9.54±0.20° and 24.63±0.20°; or
wherein the crystal form is a crystal form B of hydrobromide of the compound of formula (I), wherein the crystal form B of hydrobromide has characteristic peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at the following 2θ angles: 9.48±0.20°, 15.89±0.20° and 23.98±0.20°.
2 . The crystal form according to claim 1 , wherein the crystal form A of hydrochloride has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 7.48±0.20°, 13.13±0.20°, 16.47±0.20°, 18.29±0.20°, 19.89±0.20° and 23.94±0.20°;
wherein the crystal form A of sulfate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 5.49±0.20°, 6.93±0.20°, 11.08±0.20°, 15.88±0.20°, 17.48±0.20°, 20.82±0.20° and 22.40±0.20°;
wherein the crystal form A of maleate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.43±0.20°, 9.92±0.20°, 13.86±0.20°, 14.41±0.20°, 15.00±0.20°, 17.82±0.20°, 22.07±0.20°, 22.65±0.20°, 25.58±0.20° and 27.34±0.20°;
wherein the crystal form A of tartrate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 5.00±0.20°, 7.34±0.20°, 8.59±0.20°, 15.88±0.20°, 19.54±0.20°, 21.46±0.20°, 23.43±0.20° and 25.08±0.20°;
wherein the crystal form C of tartrate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.60±0.20°, 7.58±0.20°, 14.39±0.20°, 16.15±0.20°, 18.13±0.20°, 22.32±0.20°, 24.44±0.20° and 26.69±0.20°;
wherein the crystal form A of fumarate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 9.52±0.20°, 13.29±0.20°, 14.92±0.20°, 19.02±0.20°, 21.39±0.20°, 25.23±0.20° and 28.07±0.20°;
wherein the crystal form A of succinate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 5.26±0.20°, 6.99±0.20°, 7.35±0.20°, 14.00±0.20°, 15.76±0.20°, 21.07±0.20°, 22.00±0.20° and 27.08±0.20°;
wherein the crystal form B of succinate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 9.54±0.20°, 12.60±0.20°, 13.28±0.20°, 14.91±0.20°, 15.20±0.20°, 19.17±0.20°, 21.02±0.20°, 24.88±0.20° and 28.15±0.20°;
wherein the crystal form B of adipate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.98±0.20°, 10.69±0.20°, 13.88±0.20°, 14.28±0.20°, 20.72±0.20°, 21.41±0.20°, 24.97±0.20° and 26.15±0.20°;
wherein the crystal form A of sebacate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.57±0.20°, 9.27±0.20°, 11.20±0.20°, 14.40±0.20°, 14.95±0.20°, 20.16±0.20°, 20.55±0.20°, 22.95±0.20°, 23.91±0.20°, 24.63±0.20° and 26.73±0.20°;
wherein the crystal form A of p-toluenesulfonate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 6.04±0.20°, 8.59±0.20°, 14.27±0.20°, 17.14±0.20°, 20.41±0.20°, 23.68±0.20°, 25.29±0.20° and 27.65±0.20°;
wherein the crystal form A of benzenesulfonate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 6.16±0.20°, 8.98±0.20°, 14.22±0.20°, 15.67±0.20°, 16.90±0.20°, 17.55±0.20°, 18.31±0.20°, 20.34±0.20°, 20.92±0.20°, 25.11±0.20°, 26.29±0.20° and 29.24±0.20°; or
wherein the crystal form B of hydrobromide has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 9.48±0.20°, 15.89±0.20°, 19.40±0.20°, 23.98±0.20°, 26.55±0.20° and 28.02±0.20°.
3 . The crystal form according to claim 1 , wherein the crystal form A of hydrochloride has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 7.48±0.20°, 13.13±0.20°, 14.86±0.20°, 16.47±0.20°, 18.29±0.20°, 19.89±0.20°, 23.94±0.20° and 26.92±0.20°;
wherein the crystal form A of maleate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.43±0.20°, 9.92±0.20°, 13.86±0.20°, 14.41±0.20°, 15.00±0.20°, 17.82±0.20°, 22.07±0.20°, 22.65±0.20°, 24.20±0.20°, 24.53±0.20°, 25.58±0.20°, 25.84±0.20° and 27.34±0.20°;
wherein the crystal form B of succinate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 9.54±0.20°, 12.60±0.20°, 13.28±0.20°, 14.91±0.20°, 15.20±0.20°, 19.17±0.20°, 19.77±0.20°, 21.02±0.20°, 21.44±0.20°, 24.88±0.20°, 25.22±0.20° and 28.15±0.20°;
wherein the crystal form B of adipate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.98±0.20°, 9.23±0.20°, 10.69±0.20°, 13.88±0.20°, 14.28±0.20°, 19.35±0.20°, 20.72±0.20°, 21.41±0.20°, 24.97±0.20° and 26.15±0.20°;
wherein the crystal form A of sebacate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 4.57±0.20°, 9.27±0.20°, 11.20±0.20°, 14.40±0.20°, 14.95±0.20°, 15.26±0.20°, 18.25±0.20°, 20.16±0.20°, 20.95±0.20°, 22.95±0.20°, 23.91±0.20°, 24.63±0.20° and 26.73±0.20°;
wherein the crystal form A of p-toluenesulfonate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 6.04±0.20°, 8.59±0.20°, 12.28±0.20°, 14.27±0.20°, 16.02±0.20°, 17.14±0.20°, 20.41±0.20°, 22.01±0.20°, 23.68±0.20°, 25.29±0.20° and 27.65±0.20°; or
wherein the crystal form A of benzenesulfonate has characteristic peaks in an X-ray powder diffraction pattern at the following 2θ angles: 6.16±0.20°, 8.98±0.20°, 14.22±0.20°, 15.67±0.20°, 16.90±0.20°, 17.55±0.20°, 18.31±0.20°, 20.34±0.20°, 20.92±0.20°, 23.54±0.20°, 24.65±0.20°, 25.11±0.20°, 26.29±0.20° and 29.24±0.20°.
4 . A pharmaceutical composition comprising the crystal form of the salt of the compound of formula (I) according to claim 1 .
5 . A method of treatment of an Autotaxin (ATX)-related disease, comprising administering to a patient in need thereof a therapeutically effective amount of the crystal form of the salt of the compound of formula (I) according to claim 1 or a pharmaceutical composition comprising the crystal form of the salt of the compound of formula (I) according to claim 1 .
6 . The method according to claim 5 , wherein the ATX-related disease comprises at least one selected from the following: cancer, metabolic diseases, renal diseases, hepatic diseases, fibrotic diseases, interstitial lung diseases, proliferative diseases, inflammatory diseases, pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and abnormal angiogenesis-related diseases.
7 . The method according to claim 5 , wherein the ATX-related disease comprises at least one selected from the following: interstitial lung diseases, pulmonary fibrosis, hepatic fibrosis and renal fibrosis.
8 . The method according to claim 5 , wherein the ATX-related disease comprises idiopathic pulmonary fibrosis, type II diabetes, non-alcoholic steatohepatitis, neuropathic pain and inflammatory pain.
9 . The method according to claim 5 , wherein the ATX-related disease comprises osteoarthritis-related pain.