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CN-116867491-B - Salts of 3, 4-dihydro-isoquinoline compounds and application thereof

CN116867491BCN 116867491 BCN116867491 BCN 116867491BCN-116867491-B

Abstract

Salts of the compounds of formula (a), solid forms and crystalline forms thereof, pharmaceutical compositions comprising the same, uses thereof and methods of preparation are provided. Compared with the compound shown in the formula (A), the salt of the compound shown in the formula (A) has higher solubility in water and biological solvent medium, is easy to prepare into a solid form, is convenient to transfer and weigh, and has good application prospect.

Inventors

  • PENG XIAOSHI
  • LI PENGFEI
  • JIN GENGEN
  • LI CAN
  • YANG MIN
  • LIU XIAOZHENG
  • CUI QIAOLI
  • SI YAJUAN

Assignees

  • 石药集团中奇制药技术（石家庄）有限公司

Dates

Publication Date
20260505
Application Date
20221207
Priority Date
20211208

Claims (20)

  1. 1. A compound which is an inorganic acid addition salt or an organic acid addition salt of a compound represented by the formula (A), , Wherein the inorganic acid addition salt is sulfate or phosphate; The organic acid addition salt is selected from malate, oxalate, succinate, tartrate, adipate, citrate, gluconate, maleate, fumarate, lactate and gentisate.
  2. 2. The compound of claim 1, wherein the organic acid addition salt is selected from malate, oxalate, succinate, L-tartrate, L-lactate, adipate, citrate, and gluconate.
  3. 3. The compound of claim 1, wherein the organic acid addition salt is selected from the group consisting of L-malate and oxalate.
  4. 4. The compound according to any one of claims 1 to 3, wherein the chemical ratio of the compound represented by formula (a) to the organic acid or inorganic acid molecule is 1:1 to 1.5.
  5. 5. A compound according to any one of claims 1 to 3, wherein the chemical ratio of the compound of formula (a) to the organic or inorganic acid molecule is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.
  6. 6. A compound according to any one of claims 1 to 3, wherein the chemical ratio of the compound of formula (a) to the organic or inorganic acid molecule is 1:1.
  7. 7. A compound represented by the formula (B), , Wherein n is selected from 1 to 1.5.
  8. 8. The compound of claim 7, wherein n is 1, 1.1, 1.2, 1.3, 1.4, or 1.5.
  9. 9. The compound of claim 7, wherein n is 1 or 1.5.
  10. 10. The compound of claim 7, wherein the compound is in solid form and has an infrared spectrum comprising characteristic peaks at the following positions using KBr tabletting ：3301±4 cm -1 ,2940±4 cm -1 ,1611±4 cm -1 ,1528±4 cm -1 ,1456±4 cm -1 ,1368±4 cm -1 ,1045±4 cm -1 .
  11. 11. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form I and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.2 ± 0.2 °,6.5 ± 0.2 °,13.3 ± 0.2 °,19.1 ± 0.2 °,20.1 ± 0.2 °, and 22.0 ± 0.2 ° using Cu-ka radiation.
  12. 12. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form I and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.2 ± 0.2 °,6.5 ± 0.2 °,13.3 ± 0.2 °,18.3 ± 0.2 °,19.1 ± 0.2 °,20.1 ± 0.2 °, and 22.0 ± 0.2 ° using Cu-ka radiation.
  13. 13. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in crystalline form I and using Cu-ka radiation, the compound has an X-ray powder diffraction pattern substantially as shown in figure 1.
  14. 14. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form II and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.9 ± 0.2 °,6.6 ± 0.2 °,13.2 ± 0.2 °,18.7 ± 0.2 °, and 19.8 ± 0.2 ° using Cu-ka radiation.
  15. 15. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form II and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.9 ± 0.2 °,6.6 ± 0.2 °,13.2 ± 0.2 °,18.7 ± 0.2 °,19.8 ± 0.2 °,22.1 ± 0.2 °, and 26.5 ± 0.2 ° using Cu-ka radiation.
  16. 16. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form II and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.9 ± 0.2 °,6.6 ± 0.2 °,13.2 ± 0.2 °,18.7 ± 0.2 °,19.8 ± 0.2 °,22.1 ± 0.2 °,23.3 ± 0.2 °, and 26.5 ± 0.2 ° using Cu-ka radiation.
  17. 17. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in form II and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.9 ± 0.2 °,6.6 ± 0.2 °,13.2 ± 0.2 °,18.7 ± 0.2 °,19.8 ± 0.2 °,20.3 ± 0.2 °,22.1 ± 0.2 °,23.3 ± 0.2 °, and 26.5 ± 0.2 ° using Cu-ka radiation.
  18. 18. A compound according to any one of claims 7 to 10, wherein the compound is of formula (B) in crystalline form II and using Cu-ka radiation, the compound has an X-ray powder diffraction pattern substantially as shown in figure 2.
  19. 19. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in the form of crystalline form III and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.3 ± 0.2 °,6.9 ± 0.2 °,8.8 ± 0.2 °,20.3 ± 0.2 °, and 21.2 ± 0.2 ° using Cu-ka radiation.
  20. 20. A compound according to any one of claims 7 to 10, wherein the compound is a compound of formula (B) in the form of crystalline form III and the X-ray powder diffraction pattern of the compound has characteristic diffraction peaks at the following 2Θ angles, 4.3±0.2°,6.9±0.2°,8.8±0.2°,12.8±0.2°,13.3±0.2°,20.3±0.2°, and 21.2±0.2° using Cu-ka radiation.

Description

Salts of 3, 4-dihydro-isoquinoline compounds and application thereof The present invention claims priority from chinese patent application 202111494667.8, whose application date is 2021, 12, 8. The present invention incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention belongs to the technical field of medicines, and relates to a salt of a 3, 4-dihydroisoquinoline compound, a crystal form and a specific crystal form thereof, a pharmaceutical composition containing the salt and application of the salt in the field of medicines. Background Protein arginine methyltransferases (proteins ARGININE METHYLTRANSFERASES, PRMTs) are a class of S-adenosylmethionine (SAM or AdoMet) dependent methyltransferases that catalyze the methylation reaction of protein arginine, specifically responsible for the transfer of methyl groups from AdoMet to the guanidine nitrogen atom at the end of the arginine residue of histones or other proteins. PRMTs plays an important role in protein methylation, such as participation in variable cleavage, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis, and tumor formation, among others. Members of the PRMTs family can be classified into three classes, PRMT1-4, PRMT6, PRMT8 belonging to type I, the catalytic forms being monomethyl and asymmetric dimethyl, PRMT5 and PRMT9 belonging to type II, the catalytic forms being symmetric dimethyl, PRMT7 belonging to type III, capable of monomethyl catalysis, according to the different ways of catalyzing arginine methylation. PRMT5 was first isolated from the protein complex associated with Jak2 (Janus tyrosine kinase 2) in a yeast two-hybrid study by Pollock et al and is therefore also known as JBP1 (Jak-binding protein 1). PRMT5 can regulate gene transcription and protein modification, has the effect of regulating cell proliferation, differentiation and apoptosis in the growth process of tumor cells, and is a tumor treatment target with great potential. To date, development of PRMT5 inhibitors has been in an early stage, with the fastest growing GSK3326595 released by GSK corporation, which is in phase I/II clinic. JNJ-64619178, published by Janssen for the first time, PF-06939999, published by Pfizer, and PRT-543, published by Prelude Therapeutics, are all in phase I clinics. At present, PF-06939999 and PRT-543 have not yet published structural formulas. The structural formulas of GSK3326595 and JNJ-64619178 are as follows: In view of the fact that no PRMT5 inhibitor is currently available in the market, designing and synthesizing a novel PRMT5 inhibitor with good curative effect and good administration performance will have important clinical application value. Disclosure of Invention In a first aspect, the present invention provides a salt of a compound of formula (A), Wherein the salt is an inorganic acid addition salt or an organic acid addition salt. According to some embodiments of the invention, the inorganic acid addition salt is a sulfate or phosphate salt. According to some embodiments of the invention, the organic acid addition salt is selected from the group consisting of malate, oxalate, succinate, tartrate, adipate, citrate, gluconate, maleate, fumarate, lactate and gentisate, preferably malate, oxalate, succinate, L-tartrate, L-lactate, adipate, citrate or gluconate, preferably malate, oxalate, succinate, L-tartrate, adipate, citrate or gluconate, more preferably malate, oxalate, citrate or gluconate, still more preferably malate or oxalate, still more preferably L-malate or oxalate. According to some embodiments of the present invention, in the salt of the compound represented by formula (a), the chemical ratio of the compound represented by formula (a) to the organic acid or inorganic acid molecule is 1:0.5-2, preferably 1:1-1.5, more preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, more preferably 1:1 or 1:1.5, and even more preferably 1:1. According to some embodiments of the invention, the salt of the compound of formula (A) is a compound of formula (A-1), Wherein X is an inorganic or organic acid and n is selected from 0.5-2, preferably 1-1.5, more preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5, further preferably 1, 1.3, 1.4 or 1.5, further preferably 1:1 or 1:1.5, still further preferably 1. According to some embodiments of the invention, X is a mineral acid selected from sulfuric acid and phosphoric acid. According to some embodiments of the invention, X is an organic acid selected from the group consisting of malic acid, oxalic acid, succinic acid, tartaric acid, adipic acid, citric acid, gluconic acid, maleic acid, fumaric acid, lactic acid, and gentisic acid, preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, L-lactic acid, adipic acid, citric acid, or gluconic acid, preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, adipic acid, citric acid, or gluconic acid, more preferably malic acid, oxal