CN116265463A - Crystal form of aldose reductase inhibitor, and preparation method and application thereof - Google Patents
Crystal form of aldose reductase inhibitor, and preparation method and application thereof Download PDFInfo
- Publication number
- CN116265463A CN116265463A CN202211609540.0A CN202211609540A CN116265463A CN 116265463 A CN116265463 A CN 116265463A CN 202211609540 A CN202211609540 A CN 202211609540A CN 116265463 A CN116265463 A CN 116265463A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- radiation
- ray powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims description 27
- 239000003288 aldose reductase inhibitor Substances 0.000 title abstract description 6
- 229940118148 Aldose reductase inhibitor Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 230000005855 radiation Effects 0.000 claims description 9
- 102000016912 Aldehyde Reductase Human genes 0.000 claims description 7
- 108010053754 Aldehyde reductase Proteins 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 206010040872 skin infection Diseases 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- SYVJUAZBRVPJJO-UHFFFAOYSA-N 1,2-dimethoxyethane;2-methoxyethanol Chemical compound COCCO.COCCOC SYVJUAZBRVPJJO-UHFFFAOYSA-N 0.000 claims description 2
- BVOBEKTUNHUKRO-UHFFFAOYSA-N 1,2-dimethoxyethane;methanol Chemical compound OC.COCCOC BVOBEKTUNHUKRO-UHFFFAOYSA-N 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 2
- 238000002411 thermogravimetry Methods 0.000 claims 1
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 239000000600 sorbitol Substances 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000002491 angiogenic effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000002860 competitive effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000007166 healthy aging Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides a crystalline form II of a salt of an aldose reductase inhibitor represented by formulas A-N. The crystal form is easy to dry, good in solubility, stable in quality, stable in thermodynamics, small in relative hygroscopicity and easy to prepare.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a salt of an aldose reductase inhibitor, and a preparation method and application thereof.
Background
Diabetes is one of the most common chronic conditions. High blood glucose levels result from a lack of insulin production and/or insulin sensitivity. Individuals with hyperglycemia metabolize more glucose in insulin-insensitive cells such as the lens, peripheral nerves, and glomeruli via the glucose-to-sorbitol-to-fructose pathway. This results in an excess of sorbitol in the cells, which does not readily diffuse through the cell membrane. The increased concentration of sorbitol triggers water flow into the cells, causing swelling and potential injury.
Aldose reductase, an enzyme present in many parts of the body, catalyzes the reduction of glucose to sorbitol, which is one of the steps in the sorbitol pathway responsible for the formation of fructose from glucose. When glucose concentration rises in diabetic conditions where the tissue is no longer insulin sensitive, aldose reductase activity increases. These tissues include, for example, the lens, peripheral nerves and glomeruli. Sorbitol cannot readily diffuse across the cell membrane and thus accumulate, causing osmotic damage, which in turn leads to retinopathy, neuropathy and nephropathy. Thus, inhibition of aldose reductase can prevent sorbitol accumulation in insulin-insensitive cells in diabetics, and new methods of preventing macrovascular and microvascular complications in diabetics have been proposed. Furthermore, aldose reductase inhibitors such as zopoloxostat may help treat or ameliorate such effects, and have shown efficacy in wound healing of the corneal epithelium of diabetic animal models.
Chinese patent No. CN201180034944.5 discloses aldose reductase inhibitors represented by the following formula I:
wherein examples 1 and 2 disclose compounds of the following structure:
the compound of formula A is insoluble in water and has poor drug properties, so that the applicant improves the structure of the compound of formula A to meet the pharmaceutical requirements.
PCT patent WO2020173495A filed by the applicant describes a compound of formula A-N and one of its crystalline forms, the crystalline form of the compound of formula A-N having characteristic peaks at 17.2.+ -. 0.2 °, 21.4.+ -. 0.2 °, 21.9.+ -. 0.2 °, 25.9.+ -. 0.2 ℃ using Cu-K alpha radiation, X-ray powder diffraction expressed in terms of 2 theta angle.
Disclosure of Invention
The inventors have found that the crystalline form of the compound of formula A-N described in WO2020173495A is obtained in water and is not easily dried. Accordingly, there is a need for further research into the crystalline forms of compounds of formulas A-N to meet the need for better pharmaceuticals.
In order to solve the problems, the invention provides a crystal form II of the compound shown in the formulas A-N,
the method is characterized in that: using Cu-ka radiation, X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 27.1±0.2°.
In some embodiments, form ii of the compound of formulas a-N, which uses Cu-ka radiation, has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2° by X-ray powder diffraction expressed in terms of 2θ.
In some embodiments, form ii of the compound of formulas a-N, using Cu-ka radiation, has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.3±0.2°, 18.0±0.2°, 21.6±0.2°, 22.5±0.2°, 23.2±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2°, 30.2±0.2°, 31.6±0.2°.
In some embodiments, form ii of the compound of formulas a-N has an X-ray powder diffraction pattern (XRPD) substantially as shown in figure 1.
In some embodiments, form II of the compound of formulas A-N loses 0.7-0.8% weight during heating to 150 ℃.
In some embodiments, form II of the compound of formulas A-N has a differential scanning calorimetry curve that is free of melting signals prior to 210 ℃.
In some embodiments, form II of the compound of formulas A-N has a TGA-DSC profile substantially as shown in FIG. 2.
In some embodiments, form ii of the compound of formulas a-N is a short rod crystal.
In some embodiments, form ii of the compound of formulas a-N has a PLM image substantially as shown in figure 3.
The invention also provides a preparation method of the crystal form II of the compound shown in the formulas A-N, which comprises the following steps:
suspending the crude product of the compound shown in the formula A-N in a single solvent or a binary solvent for 1-7 days, separating solids, and drying to obtain a crystal form II of the compound shown in the formula A-N.
The crude compounds of the formula A-N according to the invention can be prepared by the methods described in the examples of WO 2020173495A.
According to the preparation method of the invention, the single solvent is selected from: 4-methyl-2-pentanone, isopropyl acetate, methyl tert-butyl ether, ethyl acetate, chloroform, ethylene glycol dimethyl ether; the binary solvent is selected from: methanol-ethylene glycol dimethyl ether (volume ratio is 1:5), ethylene glycol monomethyl ether-ethylene glycol dimethyl ether (volume ratio is 1:5).
According to the preparation method of the invention, the suspension temperature is 20-50 ℃.
According to the preparation method of the present invention, the suspension time is preferably 3 to 7 days.
According to the preparation method of the invention, the separation step comprises the steps of separating the obtained crystal form II of the compound shown in the formulas A-N from the crystallization liquid by adopting a proper method such as filtration, centrifugation and the like.
According to the preparation method of the present invention, the drying method may employ any suitable known method, preferably reduced pressure (vacuum) drying. Specific drying conditions are, for example, a temperature of preferably 40 to 80 ℃; the pressure is preferably vacuum degree > 0.090Mpa; the drying time is preferably 1 to 50 hours, more preferably 2 to 40 hours. Regardless of the drying means, the residual solvent content in the obtained product is suitable for meeting the quality standard.
In another aspect, the invention also relates to pharmaceutical compositions comprising form II of the compounds of formulas A-N.
In a further aspect, the invention also relates to the use of form ii of a compound of formula a-N or a pharmaceutical composition comprising form ii of a compound of formula a-N for the manufacture of a medicament for inhibiting aldose reductase activity in a subject, e.g. for promoting healthy aging of skin, treating skin disorders, treating angiogenic disorders such as cancer, treating tissue damage, treating cardiovascular disorders, treating renal disorders, treating evolving myocardial infarction, treating various other disorders such as complications due to diabetes. Such conditions may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infection, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosylation and the like.
In a further aspect, the invention also relates to a pharmaceutical composition of form ii of the compound of formulas a-N as described above or of form ii of the compound of formulas a-N as described above for inhibiting aldose reductase activity in a subject, e.g., promoting healthy aging of the skin, treating skin disorders, treating angiogenic disorders such as cancer, treating tissue damage, treating cardiovascular disorders, treating renal disorders, treating myocardial infarction that is developing, treating complications resulting from various other disorders such as diabetes. Such conditions may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infection, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosylation and the like.
In yet another aspect, the invention also relates to a method of treating a disorder in a subject by administering to the subject form II of a compound of formulas A-N or a pharmaceutical composition comprising form II of a compound of formulas A-N as described above, e.g., inhibiting aldose reductase activity in a subject, e.g., promoting healthy aging of skin, treating a skin disorder, treating an angiogenic disorder, e.g., cancer, treating tissue damage, treating a cardiovascular disorder, treating a renal disorder, treating an evolving myocardial infarction, treating various other disorders, e.g., complications resulting from diabetes. Such conditions may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infection, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosylation and the like.
The above "subjects" and "patients" include all members of the animal kingdom including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.
Advantageous effects
The present invention provides crystalline form ii of a compound of formula a-N. The inventors have unexpectedly found that the crystalline form can be obtained in an organic solvent, is easy to dry and has good solubility, stable quality, stable thermodynamics, small relative hygroscopicity and easy to prepare into a medicament.
Drawings
FIG. 1 is an XRPD pattern for form II of a compound of formulae A-N.
FIG. 2 is a TGA-DSC spectrum of form II of the compound of formulas A-N.
FIG. 3 is a PLM graph of form II of a compound of formulas A-N.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. The following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
In the following examples, the detection method of XRPD, TGA, DSC, PLM, DVS is as follows:
1. XRPD detection method
Instrument: german BRUKER D8 advanced X-ray powder diffractometer (BRUKER GER)
Conditions are as follows: cu-K alpha radiation, tube pressure of 40kV, tube flow of 40mA,2 theta scanning range of 3-45 degrees, scanning step length of 0.02 degrees, exposure time of 0.12 seconds, and sample disc as zero background sample disc.
2. TGA detection method
Instrument: TA Discovery 55 thermogravimetric analyzer (TA, US)
The method comprises the following steps: 2-5mg of sample was placed in an equilibrated open aluminum sample pan and weighed automatically in a TGA furnace. The sample was warmed to the final temperature at a rate of 10 ℃/min with a nitrogen purge rate of 60mL/min at the sample and 40mL/min at the balance.
3. DSC detection method
Instrument: TA Discovery 2500 differential scanning calorimeter (TA, US)
The method comprises the following steps: 1-2mg of the sample was accurately weighed and placed in a perforated DSC Tzero sample pan, and the temperature was raised to the final temperature at a rate of 10 ℃/min, with a nitrogen purge rate in the oven of 50mL/min.
4. PLM detection method
Instrument: motic BA310Met polarizing microscope (Motic, CN)
The method comprises the following steps: a small amount of sample is placed on a glass slide, and a proper lens is selected to observe the appearance of the sample.
5. Dynamic moisture desorption analysis (DVS) detection method
Instrument: DVS Intrinsic (SMS, UK).
The method comprises the following steps: the test adopts a gradient mode, the humidity change is 50% -95% -0% -50%, the humidity change amount of each gradient is 10% in the range of 0% -90%, the gradient end point is judged in a dm/dt mode, and the dm/dt is less than 0.002% and maintained for 10 minutes to be the gradient end point.
Preparation example 1 preparation of Compounds of formula A-N
4.5g of crude compound of formula A-N was prepared by the method described in example 1 of WO 2020173495A.
PLM images showed that the crystalline forms of formulas A-N obtained in preparation example 1 were short rod-like crystals, generally smaller than 10 μm in particle size, and were easily aggregated. DVS results showed that the crystalline form of formula a-N obtained in preparation 1 increased by 20.91% at 95% humidity, 3.34% at 0% humidity, and 16.49% on moisture absorption back to 50% humidity.
Example 1: preparation of form II of the Compound of formulas A-N
Crude product (1.0432 g) of the compound of formula A-N obtained in preparation example 1 and 4-methyl-2-pentanone (75 mL) are added into a reaction bottle, stirred to form a suspension, heated to 50 ℃, stirred for 24h under suspension, centrifugally separated, and the obtained solid is dried in vacuum at 40 ℃ for 16h to obtain crystal form II (901 mg) of the compound of formula A-N.
The obtained crystal form II shows good crystallinity, the XRPD characterization spectrogram of the crystal form II is basically shown in figure 1, and the characterization data are shown in table 1. The DSC-TGA test results are shown in FIG. 2, and the test results show that the sample does not contain crystallization water or crystallization solvent, loses weight by 0.783% during heating to 150 ℃, has no obvious melting signal before 210 ℃ and can be decomposed above 210 ℃. The PLM image shows the result as shown in FIG. 3, and the image shows that the crystal form II is a short rod-shaped crystal, the particle size is generally smaller than 10 mu m, and the crystal form II is slightly aggregated. DVS results showed that form ii had a weight gain of 18.94% at 95% humidity, a weight loss of 1.73% at 0% humidity, and a hygroscopic weight gain of 2.27% at return to 50% humidity.
Table 1 example 1 form ii sample XRPD characterization data
Examples 2 to 6: preparation of crystalline form II of the Compound of formulas A-N (Single solvent)
A certain amount of crude compound of formula A-N obtained in preparation example 1 was weighed, suspended and stirred in a single solvent as listed in Table 2 to obtain crystal form II of compound of formula A-N.
TABLE 2 Single solvent preparation of Crystal form II of Compound of formulas A-N
| Examples | Sample size (mg) | Solvent(s) | Volume (mL) | Temperature (. Degree. C.) | Time | Results |
| 2 | 19.6 | 4-methyl-2- |
10 | Room temperature | For 7 days | Crystal form II |
| 3 | 20.1 | Acetic |
10 | Room temperature | For 7 days | Crystal form II |
| 4 | 20.0 | Methyl tert- |
10 | Room temperature | For 7 days | Crystal form II |
| 5 | 20.5 | Acetic acid ethyl ester | 3 | 50 | 1 day (24 h) | Crystal form II |
| 6 | 19.7 | Chloroform (chloroform) | 3 | 50 | 1 day (24 h) | Crystal form II |
Examples 7 to 8: preparation of crystalline form II of the Compound of formulas A-N (binary solvent)
A certain amount of crude compound of formula a-N obtained in preparation example 1 was weighed, suspended and stirred in a binary solvent as listed in table 3 to obtain crystal form ii of compound of formula a-N.
TABLE 3 binary solvent preparation of form II of the Compound of formulas A-N
Test example 1: stability study
20mg of the form II sample obtained in example 1 was weighed into a weighing flask, placed in a solid state stability study under conditions of high temperature (60 ℃) and light (25 ℃,4500 Lux), sampled at 7 days and 15 days for XRPD characterization, and the results are shown in Table 4.
TABLE 4 stability test results for form II
The results show that the crystal form II is unchanged under the conditions of high temperature (60 ℃) and illumination (25 ℃,4500 Lux) for 15 days, and the crystal form is stable.
Test example 2: solubility test
The form II sample obtained in example 1 and the form sample obtained in preparation example 1 were added with buffers of different pH (the preparation process of the pH buffers is shown in Table 5) and water to prepare suspensions, and after shaking at constant temperature of 25℃for 24 hours, the suspensions were centrifuged, the supernatants were filtered with a 0.22 μm aqueous filter, and the amounts of the dissolved samples and the amounts of the solvents were recorded to calculate the solubilities of the samples. The solubility test results are shown in Table 6.
TABLE 5 preparation of buffers
TABLE 6 solubility test results for form II and preparation example 1 forms
Test example 3: competitive suspension experiments
The crystal form II of the compound of the formula A-N obtained in example 1 and the crystal form of the compound of the formula A-N obtained in preparation were subjected to competitive suspension experiments in ethyl acetate and 4-methyl-2-pentanone at low temperature (10 ℃), room temperature (25 ℃) and high temperature (60 ℃), respectively, and the results are shown in Table 7:
TABLE 7 competitive suspension results
In conclusion, the crystal form II of the compound of the formula A-N has good solubility, stable quality, stable thermodynamics, small relative hygroscopicity and easy drug-taking.
Claims (10)
1. A crystalline form II of a compound of formula A-N,
the method is characterized in that: using Cu-ka radiation, X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 27.1±0.2°.
2. Form ii of the compound of formula a-N according to claim 1, characterized in that the X-ray powder diffraction expressed in terms of 2Θ has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2° using Cu-ka radiation, or
Using Cu-ka radiation, X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.3±0.2°, 18.0±0.2°, 21.6±0.2°, 22.5±0.2°, 23.2±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2°, 30.2±0.2°, 31.6±0.2°, or
Using Cu-ka radiation, an X-ray powder diffraction pattern substantially as shown in figure 1.
3. Form ii of the compound of formulae a-N according to claim 1, characterized in that its thermogravimetric analysis profile loses weight 0.7-0.8% during heating to 150 ℃, or
Having a TGA-DSC profile substantially as shown in figure 2.
4. Form ii of the compound of formulae a-N according to claim 1, characterized in that it is a short rod-like crystal.
5. The process for preparing crystalline form ii of a compound of formula a-N according to any one of claims 1-4, comprising the steps of: suspending the crude product of the compound shown in the formula A-N in a single solvent or a binary solvent for 1-7 days, separating solids, and drying to obtain a crystal form II of the compound shown in the formula A-N.
6. The method of claim 5, wherein the single solvent is selected from the group consisting of: 4-methyl-2-pentanone, isopropyl acetate, methyl tert-butyl ether, ethyl acetate, chloroform, ethylene glycol dimethyl ether; the binary solvent is selected from: methanol-ethylene glycol dimethyl ether (volume ratio is 1:5), ethylene glycol monomethyl ether-ethylene glycol dimethyl ether (volume ratio is 1:5).
7. The method according to claim 5, wherein the temperature of the suspension is 20 to 50 ℃.
8. The method according to claim 5, wherein the suspension is carried out for 3 to 7 days.
9. A pharmaceutical composition comprising form ii of a compound of formulae a-N according to any one of claims 1-4.
10. The use of a crystalline form II of a compound of formula A-N as claimed in any one of claims 1 to 4 or of a pharmaceutical composition as claimed in claim 9 for the preparation of a medicament for the treatment of diseases associated with inhibition of aldose reductase activity,
preferably, the disease comprises: atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infection, peripheral vascular disease, stroke, diabetic cardiomyopathy, and galactosylemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021115457490 | 2021-12-16 | ||
| CN202111545749 | 2021-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116265463A true CN116265463A (en) | 2023-06-20 |
Family
ID=86744351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211609540.0A Pending CN116265463A (en) | 2021-12-16 | 2022-12-13 | Crystal form of aldose reductase inhibitor, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116265463A (en) |
-
2022
- 2022-12-13 CN CN202211609540.0A patent/CN116265463A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2728541C (en) | Crystalline forms of thiazolidinedione compound and its manufacturing method | |
| EP3466958B1 (en) | New crystal forms of sodium-glucose co-transporter inhibitor, processes for preparation and use thereof | |
| CN106810582B (en) | Glucopyranosyl derivative compound, preparation method and application | |
| US11420942B2 (en) | Crystalline forms of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine | |
| CN102167715B (en) | Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals | |
| CN110204548B (en) | Pyridazino triazole medicine molecule with sterilization and disinfection effects and preparation method and application thereof | |
| CN108239123B (en) | Co-crystal of glucopyranosyl derivative, preparation method and application | |
| CN116265463A (en) | Crystal form of aldose reductase inhibitor, and preparation method and application thereof | |
| CN107778336B (en) | Crystalline forms of glucopyranosyl derivatives | |
| CA2976408C (en) | Crystal form a of a compound and preparation method thereof | |
| CN113454084B (en) | Salt of aldose reductase inhibitor, preparation method and application thereof | |
| CN109970678B (en) | Amorphous 4-phenylthiazole derivative, and preparation method and application thereof | |
| CA3018800C (en) | Salt form of dppiv inhibitor and preparation method for salt form | |
| CN106478616B (en) | Crystalline form of GPR40 agonist and preparation method thereof | |
| JP7356176B2 (en) | Treprostinil monohydrate crystals and method for producing the same | |
| CN106397413B (en) | 5-hydroxytryptamine receptor agonist and preparation method and application thereof | |
| CN116396305A (en) | Crystal form of condensed ring derivative, preparation method and application thereof | |
| CN117209480A (en) | Crystal form of thyroid hormone beta receptor regulator, and preparation method and application thereof | |
| CN112313202A (en) | Novel crystal form of treprostinil sodium salt and preparation method thereof | |
| CN114437042A (en) | Crystal form of phthalazine compound and preparation method thereof | |
| CZ200911A3 (en) | Novel form of desvenlafaxine and process for preparing thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |