JPWO2020010068A5 - - Google Patents

Claims (32)

2- (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl) oxy) phenyl) -3,5-dioxo-2,3,4,5 -A crystalline salt of tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A"). Characterized to have a counterion, the counterion is L-lysine, L-arginine, 2-hydroxy-N, N, N-trimethylethan-1-aminium, diethylamine, ethanolamine, ethanol-2-diethylamine, Na. The crystalline salt according to claim 1, which is selected from ⁺ , Mg ²⁺ , K ⁺ , Ca ²⁺ , diethanolamine, triethanolamine, L-histidine and meglumin. The counterion is K ^＋ The crystalline salt according to claim 2. The crystalline salt according to claim 3, which is a solvate. The crystalline salt according to claim 4, which is a tetrahydrofuran solvate or an acetic acid solvate. 3. Claim 3 characterized by an X-ray powder diffraction pattern containing peaks at about 4.13 and 11.97 ° 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα source (1.54 Å). The crystalline salt according to (Form 6-A). A claim characterized by an X-ray powder diffraction pattern containing peaks at about 4.15 and 6.73 ° 2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα source (1.54 Å). The crystalline salt according to No. 3 (form 6-B). Characterized by an X-ray powder diffraction pattern containing peaks at about 8.24, 10.91, and 22.17 ° 2θ, an X-ray powder diffraction pattern was obtained using a Cu Kα source (1.54 Å). The crystalline salt according to claim 3 (form 6-C). Characterized by an X-ray powder diffraction pattern containing peaks at about 8.91, 11.81, and 21.98 ° 2θ, an X-ray powder diffraction pattern was obtained using a Cu Kα source (1.54 Å). The crystalline salt according to claim 3 (form 6-D). The crystalline salt according to any one of claims 1 to 9 , which has compound A having a purity of more than 90% by weight. The crystalline salt according to any one of claims 1 to 9 , which has compound A having a purity of more than 95% by weight. The crystalline salt according to any one of claims 1 to 9 , which has compound A having a purity of more than 99% by weight. A pharmaceutical composition comprising the crystalline salt according to any one of claims 1 to 12 . 13. The crystalline salt according to any one of claims 1 to 12 or 13. Pharmaceutical composition . The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for use in the treatment of thyroid hormone refractory (RTH) disease in a subject having at least one TRβ mutation. .. Subjects are obesity, hyperlipidemia, hypercholesterolemia, heterozygous familial hypercholesterolemia, diabetes, non-alcoholic fatty hepatitis, fatty liver, fatty liver disease, bone disease, thyroid axis abnormalities, atherom Sexual arteriosclerosis, cardiovascular disorders, tachycardia, hyperactivity behavior, hypothyroidism, thyroidoma, attention deficit hyperactivity disorder, dyslipidemia, learning ability disorders, mental retardation, hearing loss, delayed bone age, The crystalline salt or pharmaceutical composition for use according to claim 14 or 15 , which has a neurological or mental illness or thyroid cancer. The TRβ mutation replaces the wild-type residue alanine (A) with threonine (T) at amino acid position 234 of SEQ ID NO: 1 (A234T); the wild-type residue arginine (R) at amino acid position 243 of SEQ ID NO: 1 to glutamine. Substitution with (Q) (R243Q); Wild-type residue at amino acid position 316 of SEQ ID NO: 1 Substitution of arginine (R) with histidine (H) (R316H); and wild-type residue at amino acid position 317 of SEQ ID NO: 1. The crystalline salt or pharmaceutical composition for use according to claim 14 or 15 , selected from the group consisting of the substitution of the group alanine (A) with threonine (T) (A317T). The crystalline salt or pharmaceutical composition for use according to any one of claims 14 to 17, wherein the crystalline salt or pharmaceutical composition is suitable for daily administration. The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for producing a drug for treating non-alcoholic steatohepatitis in a subject . The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for use in the treatment of non-alcoholic steatohepatitis in a subject . The crystalline salt or pharmaceutical composition for use according to claim 19 or 20, wherein the crystalline salt or pharmaceutical composition is suitable for daily administration. The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for producing a drug for treating familial hypercholesterolemia in a subject . The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for use in the treatment of familial hypercholesterolemia in a subject . The crystalline salt or pharmaceutical composition for use according to claim 22 or 23, wherein the familial hypercholesterolemia is homozygous or heterozygous. The crystalline salt or pharmaceutical composition for use according to any one of claims 22-24 , wherein the crystalline salt or pharmaceutical composition is suitable for daily administration. The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for producing a drug for treating fatty liver disease in a subject . The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for use in the treatment of fatty liver disease in a subject . The crystalline salt or pharmaceutical composition for use according to claim 26 or 27, wherein the crystalline salt or pharmaceutical composition is suitable for daily administration. The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for producing a drug for treating a lipid disorder in a subject . The crystalline salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for use in the treatment of dyslipidemia in a subject . The crystalline salt or pharmaceutical composition for use according to claim 29 or 30, wherein the crystalline salt or pharmaceutical composition is suitable for daily administration. The crystalline salt or pharmaceutical composition for use according to any one of claims 14 to 31 , wherein the subject is a human.