CN118063433A - Deuterated vorexant salt as well as preparation method and application thereof - Google Patents
Deuterated vorexant salt as well as preparation method and application thereof Download PDFInfo
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- CN118063433A CN118063433A CN202211470396.7A CN202211470396A CN118063433A CN 118063433 A CN118063433 A CN 118063433A CN 202211470396 A CN202211470396 A CN 202211470396A CN 118063433 A CN118063433 A CN 118063433A
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- vorexant
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- 150000003839 salts Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 13
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 16
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 14
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 9
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011976 maleic acid Substances 0.000 claims abstract description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000019253 formic acid Nutrition 0.000 claims abstract description 8
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 20
- 210000004211 gastric acid Anatomy 0.000 claims description 15
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical class C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 230000002496 gastric effect Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 206010019375 Helicobacter infections Diseases 0.000 claims description 2
- 206010030216 Oesophagitis Diseases 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- 208000000718 duodenal ulcer Diseases 0.000 claims description 2
- 208000006881 esophagitis Diseases 0.000 claims description 2
- 201000005917 gastric ulcer Diseases 0.000 claims description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 230000027119 gastric acid secretion Effects 0.000 abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- 239000013642 negative control Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000004051 gastric juice Anatomy 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- 210000001187 pylorus Anatomy 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229950003825 vonoprazan Drugs 0.000 description 4
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical class OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001734 carboxylic acid salts Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- -1 deuterated Vonoprazan L-pyroglutamate Chemical class 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 238000002479 acid--base titration Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007921 solubility assay Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to deuterated vorexant salt, and a preparation method and application thereof. The deuterated vorexant salt of the technical scheme of the invention has the following structure: has a structure shown in formula (I): Wherein HA is selected from formic acid, maleic acid, L-pyroglutamic acid or propionic acid. The deuterated vorexant salt disclosed by the invention is better in stability, shows a strong and durable gastric acid secretion inhibition effect, and has the advantages of high solubility in water and good bioavailability.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical chemical crystals, and particularly relates to deuterated vorexant salt, a preparation method and application thereof.
Background
Vonoprazan belongs to a potassium ion (K +) competitive acid blocker (P-CAB), is a reversible proton pump inhibitor, and can stop secretion of gastric acid and achieve acid inhibition effect by inhibiting combination of K + with H +、K+ -ATPase (proton pump) in the final step of acid secretion of gastric parietal cells after entering a human body. However, many problems of poor metabolism of the drug may occur during the course of treatment with voronoi, and the resulting active metabolites may be toxic or have side effects on the human body. Dilute stool, diarrhea, bitter taste, epigastric pain, and macula may occur during the course of treatment with voronoi praise.
The applicant carries out structural innovation transformation on the basis of Vonoprazan, and the deuterated Vonoprazan is obtained by screening, wherein the national patent application number is CN201780065181.8, patent authorization is obtained in China, the United states and Europe at present, the patent reports the deuterated Vonoprazan fumarate, and the solubility (3.04 mg/mL) of the deuterated Vonoprazan fumarate in water is examined, so that the result shows that the solubility in water is smaller. Therefore, further research is needed to obtain more advantageous salts to meet the requirements of good solubility, good stability and good bioavailability at the same time.
Disclosure of Invention
The invention aims to provide deuterated vorexant acid salt with good solubility, good stability and good bioavailability, and a preparation method and application thereof, which are suitable for large-scale application in production and clinic.
In order to achieve the technical purpose, the invention provides the following technical scheme: a deuterated vorexant salt having a structure according to formula (I):
HA in the formula (I) is selected from formic acid, maleic acid, L-pyroglutamic acid or propionic acid.
Further, when HA is formic acid, its X-ray powder diffraction pattern HAs diffraction peaks at least three of the following 2θ angles: 9.62 ° ± 0.2, 10.34 ° ± 0.2, 10.62 ° ± 0.2, 12.09 ° ± 0.2, 15.53 ° ± 0.2, 18.11 ° ± 0.2, 22.68 ° ± 0.2, 24.41 ° ± 0.2;
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2θ angles: 9.62 ° ± 0.2, 10.34 ° ± 0.2, 10.62 ° ± 0.2, 12.09 ° ± 0.2, 15.53 ° ± 0.2, 18.11 ° ± 0.2, 22.68 ° ± 0.2, 24.41 ° ± 0.2.
Further, when HA is maleic acid, the X-ray powder diffraction pattern thereof HAs diffraction peaks at least three of the following 2-theta angles ：9.76°±0.2,9.94°±0.2,11.48°±0.2,15.04°±0.2,18.13°±0.2,19.25°±0.2,19.52°±0.2,20.75°±0.2,22.98°±0.2,23.27°±0.2;
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2 theta angles ：9.76°±0.2,9.94°±0.2,11.48°±0.2,15.04°±0.2,18.13°±0.2,19.25°±0.2,19.52°±0.2,20.75°±0.2,22.98°±0.2,23.27°±0.2.
Further, when HA is L-pyroglutamic acid, the X-ray powder diffraction pattern thereof HAs diffraction peaks at least three of the following 2-theta angles ：11.36°±0.2,12.47°±0.2,13.52°±0.2,14.44°±0.2,15.68°±0.2,17.77°±0.2,18.05°±0.2,18.56°±0.2,20.85°±0.2,22.47°±0.2,24.84°±0.2;
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2 theta angles ：11.36°±0.2,12.47°±0.2,13.52°±0.2,14.44°±0.2,15.68°±0.2,17.77°±0.2,18.05°±0.2,18.56°±0.2,20.85°±0.2,22.47°±0.2,24.84°±0.2.
Further, when HA is propionic acid, the X-ray powder diffraction pattern thereof HAs diffraction peaks at least three of the following 2-theta angles ：10.12°±0.2,10.91°±0.2,11.22°±0.2,13.41°±0.2,15.08°±0.2,19.46°±0.2,20.27°±0.2,21.86°±0.2,24.50°±0.2,25.59°±0.2;
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2 theta angles ：10.12°±0.2,10.91°±0.2,11.22°±0.2,13.41°±0.2,15.08°±0.2,19.46°±0.2,20.27°±0.2,21.86°±0.2,24.50°±0.2,25.59°±0.2.
The invention also discloses a preparation method of the deuterated vorexant salt, which comprises the steps of adding the deuterated vorexant into an aprotic solvent, adding HA, stirring, cooling, carrying out aftertreatment or no aftertreatment, filtering and drying to obtain the deuterated vorexant salt shown in the formula (I).
Further, the HA is selected from formic acid, maleic acid, L-pyroglutamic acid or propionic acid;
the aprotic solvent is ethyl acetate;
the mass volume ratio of the deuterated nuprazan to the aprotic solvent is 1-5:7-20;
further, the mass-to-volume ratio of the deuterated pranoprazan to the aprotic solvent is 1:10 or 1.5:20.
Further, the post-treatment is concentration to remove the solvent, and any one or a mixture of any 2-3 of ethyl acetate, methyl tertiary butyl ether or n-hexane is added.
The invention also discloses a pharmaceutical composition comprising an effective amount of deuterated vorexant salt as described above; preferably, the composition further comprises pharmaceutically acceptable auxiliary materials.
The invention also discloses the application of the deuterated vorexant salt or the pharmaceutical composition in preparing medicines for preventing and treating gastric acid related diseases;
preferably, the gastric acid related disease is selected from the group consisting of gastrointestinal mucosal injury, helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, and gastric ulcer.
By adopting the technology, compared with the prior art, the invention has the remarkable advantages that:
1) According to the technical scheme, the deuterated vorexant acid salt is prepared by taking the aprotic solvent as the solvent, and has the advantages of high solubility and good stability, especially, the solubility in water is improved to 0.66g/mL, even 4.1g/mL, the preparation method is suitable for being applied to the production process of a pharmaceutical preparation, and the inconvenience in the preparation and storage processes caused by the lower water solubility of the vorexant acid salt and the deuterated vorexant acid salt in the prior art is solved;
2) Compared with the conventional Vonoprazan acid salt and the deuterated Vonoprazan fumarate crystal form, the deuterated Vonoprazan acid salt has more excellent biological activity and is more suitable for clinical use.
Drawings
FIG. 1 is a 1 H-NMR spectrum of deuterated vorexant free base;
FIG. 2 is a 1 H-NMR spectrum of deuterated vorexant formate of the present invention;
FIG. 3 is an XRPD pattern for deuterated vorexant formate of the present invention;
FIG. 4 is a 1 H-NMR spectrum of deuterated vorexant maleate according to the invention;
FIG. 5 is an XRPD pattern for deuterated vorexant maleate salt according to the invention;
FIG. 6 is a 1 H-NMR spectrum of deuterated vorexant L-pyroglutamate of the present invention;
FIG. 7 is an XRPD pattern for deuterated vorexant L-pyroglutamate of the present invention;
FIG. 8 is a 1 H-NMR spectrum of deuterated vorexant propionate according to the present invention;
fig. 9 is an XRPD pattern of deuterated vorexant propionate according to the present invention.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
Preparation of deuterated vorexant formate:
To the reaction flask were added 1.5g of deuterated vorexant free base and 15mL of ethyl acetate, 0.22g of formic acid was added, stirring was completed for 1 hour, cooling in an ice-water bath, filtration and drying to obtain 1.6g of a white solid with a yield of 97%.
Solubility: 4.1g/mL.
Melting point: 123-125 DEG C
1HNMR(600MHz,DMSO-d6)δ8.88(dd,J＝4.8,1.5Hz,1H),8.57(d,J＝2.1Hz,1H),8.35(d,J＝1.0Hz,1H),7.89(ddd,J＝8.2,2.4,1.6Hz,1H),7.67(d,J＝1.7Hz,1H),7.62(ddd,J＝8.2,4.9,0.6Hz,1H),7.56-7.49(m,1H),7.26-7.21(m,2H),7.12(td,J＝7.5,1.7Hz,1H),6.46(d,J＝1.5Hz,1H),2.37(s,3H).
Example 2
Preparation of deuterated vorexant maleate:
1.5g of deuterated vorexant free base and 15mL of ethyl acetate are added into a reaction bottle and stirred for dissolution; 0.54g of maleic acid is added into 15mL of ethyl acetate, stirred and dissolved, maleic acid is added into free base, stirring is completed for 2 hours, cooling, filtering and drying are carried out, and 1.45g of white solid is obtained. The yield thereof was found to be 72%.
Solubility: 0.66g/mL.
Melting point: 85-87 DEG C
1HNMR(600MHz,DMSO-d6)δ8.91(dd,J＝4.8,1.5Hz,1H),8.67(s,2H),8.62-8.55(m,1H),7.88(ddd,J＝8.2,2.4,1.6Hz,1H),7.82(d,J＝1.8Hz,1H),7.64(ddd,J＝8.2,4.8,0.7Hz,1H),7.59-7.50(m,1H),7.24(t,J＝8.1Hz,2H),7.12(td,J＝7.4,1.6Hz,1H),6.50(d,J＝1.8Hz,1H),6.10-6.09(m,2H),3.33(s,1H),2.57(s,3H).
Example 3
Preparation of deuterated Vonoprazan L-pyroglutamate
1.5G of deuterated vorexant free base and 20mL of ethyl acetate are added into a reaction bottle, stirred and dissolved; 0.62g of L-pyroglutamic acid is added into 10mL of methanol, stirred and dissolved, L-pyroglutamic acid is added into free base, stirring is completed for 2 hours, the solvent is removed by concentration, 10mL of ethyl acetate is added, the temperature is reduced by ice water bath, filtration and drying are carried out, and 1.4g of white solid is obtained. The yield thereof was found to be 68%.
Solubility: 1.2g/mL.
Melting point: 161-164 DEG C
1HNMR(600MHz,DMSO-d6)δ8.88(dd,J＝4.8,1.4Hz,1H),8.57(d,J＝2.3Hz,1H),7.93-7.86(m,1H),7.72(d,J＝1.7Hz,1H),7.63(dd,J＝8.0,4.4Hz,2H),7.52(td,J＝7.3,1.6Hz,1H),7.26-7.19(m,2H),7.11(td,J＝7.5,1.5Hz,1H),6.49(d,J＝1.6Hz,1H),3.85(dd,J＝8.7,4.7Hz,1H),2.40(s,3H),2.24-2.15(m,1H),2.10-1.95(m,2H),1.99-1.86(m,1H).
Example 4
Preparation of deuterated Vonoprazan propionate
To the reaction flask, 1.5g of deuterated vorexant free base and 20mL of ethyl acetate were added, and the mixture was stirred and dissolved, 0.36g of propionic acid was added, and after stirring was completed for 2 hours, the solvent was removed by concentration, 10mL of ethyl acetate, 10mL of methyl t-butyl ether and 50mL of n-hexane were added, and filtration and drying were carried out to obtain 1.36g of a white solid. The yield thereof was found to be 75%.
Solubility: 1.1g/mL.
Melting point: 91-93 DEG C
1HNMR(600MHz,DMSO-d6)δ8.87(dd,J＝4.8,1.5Hz,1H),8.57(d,J＝2.3Hz,1H),7.88(ddd,J＝8.2,2.3,1.6Hz,1H),7.62(dd,J＝8.2,4.8Hz,1H),7.56-7.46(m,2H),7.27-7.20(m,2H),7.14(td,J＝7.5,1.7Hz,1H),6.39(d,J＝1.8Hz,1H),2.25(s,3H),2.19(q,J＝7.5Hz,2H),0.99(t,J＝7.5Hz,3H).
Example 5
Deuterated vorexant salt solubility assay:
Chromatographic conditions:
chromatographic column: CAPCELLPAKC18MG II 4.6X105 mm,3 μm
Column temperature: flow rate at 25 ℃): sample injection amount of 1.0 mL/min: detection wavelength of 10 μl): 230nm
Mobile phase: 0.05moL/L phosphate buffer (0.025 moL of potassium dihydrogen phosphate and 0.025moL of disodium hydrogen phosphate are weighed, dissolved and diluted to 1000mL by adding water, and the pH value is adjusted to 6.8 by phosphoric acid or sodium hydroxide test solution) -acetonitrile-methanol (17:7:6)
Preparing a reference substance solution: precisely weighing 50mg of deuterated vorexant fumarate, placing in a 50mL measuring flask, dissolving with a mobile phase and diluting to scale to obtain 1000 mug/mL mother liquor, and sequentially diluting the mother liquor by 2 times, 5 times, 10 times, 40 times and 200 times to obtain 500 mug/mL, 200 mug/mL, 100 mug/mL, 25 mug/mL and 5 mug/mL of serial solutions respectively; after conversion to the free base, the concentration of the series of solutions was 748.47 μg/mL, 374.23 μg/mL, 149.69 μg/mL, 74.85 μg/mL, 18.71 μg/mL, 3.74 μg/mL, respectively;
Preparing a test solution: because the solubility difference among deuterated vorexant carboxylic acid salt water of different species is relatively large, in the test process, generally, 0.25g is firstly taken and put into a 10mL test tube with a plug, 1mL of water is firstly added for observation, if the deuterated vorexant carboxylic acid salt water can be dissolved very quickly, the sample weighing amount is gradually increased, and the saturated solubility of the deuterated vorexant carboxylic acid salt water in water is calculated according to the final 1mL of soluble amount; if the solubility is poor, the water addition amount is increased to 5mL based on 1mL of water in the test, the mixture is respectively oscillated for 24 hours at 37 ℃ and 100 r/min, and then the mixture is filtered by a 0.45 mu m microporous filter membrane, and the subsequent filtrate is diluted by 200 to 500 times to be used as a test solution.
And (3) injecting the reference substance solution and the sample solution respectively under the chromatographic conditions, performing linear regression equation on the area of the reference substance solution and the concentration of the reference substance free alkali, obtaining the saturated solubility of the free alkali in water according to the peak area of the sample solution, and finally converting into the saturated solubility of the carboxylate in water.
Example 6
Effects of oral gavage administration of deuterated vorofacian or vorofacian on gastric acid secretion in pylorus ligation SD rats of different salts:
Total 110 SD rats (male and female halves) were included, fasted and not water-inhibited for 24 hours, and randomly divided into 11 groups according to body weight, respectively: the test groups of deuterated vorexant fumarate, formate, L-pyroglutamate, propionate, and maleate, and the test groups of vorexant fumarate, formate, L-pyroglutamate, propionate, and maleate were set, and negative control groups were set, as shown in the following table. Each test group was metered at a dose of 20 mg/day for clinical use of voronoi praziram fumarate, and the dose equivalent to the test dose of SD rats was set at 2mg/kg. Oral gavage 1h prior to surgery was given to different salt forms of deuterated vorofacian or vorofacian; the negative control group was given the same volume of solvent. After 1h, animals are anesthetized by isoflurane, the animals are conventionally disinfected, the joint of pylorus and duodenum is ligatured by opening abdomen, wounds are sutured, and the animals are kept in a cage after operation and are fasted and disabled. Ligature for 3h, anaesthetizing pentobarbital, opening abdominal cavity, ligating cardiac, picking whole stomach, bleeding, killing, collecting gastric content in centrifuge tube, centrifuging at 3000r/min for 10min, collecting supernatant, and measuring liquid volume to obtain gastric juice volume. 2mL of gastric juice is taken, 4mL of CO 2-free water is added for dilution, a basic burette is used for titration with 0.05N sodium hydroxide solution, 0.5% phenolphthalein indicator is used as a color indicator, titration is carried out until the color is light pink and does not fade within 30 seconds (pH value is 7) is used as an end point, the titration volume is measured, and the gastric acid concentration, the total acidity of gastric acid and the acid inhibition rate are calculated. Experimental data are expressed in average±sem and T-test analysis was used to compare the effect of deuterated vorofacin or vorofacin of different salt forms on SD rat gastric acid secretion. All data statistical analyses were performed using SPSS17.0 statistical software.
Gastric acid concentration: determination of the NaOH volume (V NaOH) at pH7 at the end of the gastric acid concentration by acid-base titration
Gastric acid concentration (μmol/mL) =v NaOH (mL) ×0.05nx1000/2 (mL)
Total acidity of gastric acid (μmol) =gastric volume (mL) ×gastric acid concentration (μmol/mL)
Acid inhibition rate = [ (GA negative control group -GA Test group )/GA negative control group ] ×100%
Note that: the acid inhibition rate is the inhibition rate of the test sample to the total acidity of gastric juice, GA negative control group is the average value of the total acidity of gastric juice of a negative control group, and GA Test group is the average value of the total acidity of gastric juice of each salt-type deuterated voroforprazan group
TABLE 1 SD group settings for the pyloric ligation gastric acid secretion consistency test in rats
* : As a negative control group, the same volume of solvent was administered
The test results show that each salt-type deuterated vorpran or each test product of the vorpran shows the effect of inhibiting gastric acid secretion of the pylorus ligation rat with statistical significance, and the inhibition effect of the deuterated vorpran of each salt type is superior to that of each salt type vorpran no matter the gastric acid volume of the pylorus ligation rat, the gastric acid concentration and the total acidity of the gastric acid, and the acid inhibition rate is also obviously superior to that of each salt type vorpran. Wherein, the acid inhibition rate of the deuterated vorexant propionate and the deuterated vorexant maleate respectively reach 77.41 percent and 80.24 percent, which is obviously stronger than other salt types.
TABLE 2 influence of deuterated Vonoprazan or Vonoprazan on gastric volume of gastric acid secretion model of pylorus ligation rats (mean+ -SEM)
The above embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the protection scope of the present invention should be defined by the claims, including the technical equivalents of the technical features in the claims, as the protection scope, that is, the equivalent replacement and improvement within the protection scope of the present invention.
Claims (10)
1. A deuterated vorexant salt, wherein the deuterated vorexant salt has the structure of formula (I):
HA in the formula (I) is selected from formic acid, maleic acid, L-pyroglutamic acid or propionic acid.
2. The deuterated vorexant salt according to claim 1, wherein when HA is formic acid, its X-ray powder diffraction pattern HAs diffraction peaks at least three of the following 2Θ angles: 9.62 ° ± 0.2, 10.34 ° ± 0.2, 10.62 ° ± 0.2, 12.09 ° ± 0.2, 15.53 ° ± 0.2, 18.11 ° ± 0.2, 22.68 ° ± 0.2, 24.41 ° ± 0.2;
Preferably, its X-ray powder diffraction pattern has diffraction peaks at least five of the following 2θ angles: 9.62 ° ± 0.2, 10.34 ° ± 0.2, 10.62 ° ± 0.2, 12.09 ° ± 0.2, 15.53 ° ± 0.2, 18.11 ° ± 0.2, 22.68 ° ± 0.2, 24.41 ° ± 0.2.
3. The deuterated vorexant salt according to claim 1, wherein when HA is maleic acid, its X-ray powder diffraction pattern HAs diffraction peaks at least three of the following 2Θ angles ：9.76°±0.2,9.94°±0.2,11.48°±0.2,15.04°±0.2,18.13°±0.2,19.25°±0.2,19.52°±0.2,20.75°±0.2,22.98°±0.2,23.27°±0.2;
Preferably, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2-theta angles ：9.76°±0.2,9.94°±0.2,11.48°±0.2,15.04°±0.2,18.13°±0.2,19.25°±0.2,19.52°±0.2,20.75°±0.2,22.98°±0.2,23.27°±0.2.
4. The deuterated vorexant salt according to claim 1, wherein when HA is L-pyroglutamic acid, its X-ray powder diffraction pattern HAs diffraction peaks at least three of the following 2Θ angles ：11.36°±0.2,12.47°±0.2,13.52°±0.2,14.44°±0.2,15.68°±0.2,17.77°±0.2,18.05°±0.2,18.56°±0.2,20.85°±0.2,22.47°±0.2,24.84°±0.2;
Preferably, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2-theta angles ：11.36°±0.2,12.47°±0.2,13.52°±0.2,14.44°±0.2,15.68°±0.2,17.77°±0.2,18.05°±0.2,18.56°±0.2,20.85°±0.2,22.47°±0.2,24.84°±0.2.
5. The deuterated vorexant salt according to claim 1, wherein when HA is propionic acid, its X-ray powder diffraction pattern HAs diffraction peaks at least three of the following 2Θ angles ：10.12°±0.2,10.91°±0.2,11.22°±0.2,13.41°±0.2,15.08°±0.2,19.46°±0.2,20.27°±0.2,21.86°±0.2,24.50°±0.2,25.59°±0.2;
Preferably, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2-theta angles ：10.12°±0.2,10.91°±0.2,11.22°±0.2,13.41°±0.2,15.08°±0.2,19.46°±0.2,20.27°±0.2,21.86°±0.2,24.50°±0.2,25.59°±0.2.
6. The process for preparing deuterated vonoprazan salt according to claim 1, characterized in that deuterated vonoprazan is added into an aprotic solvent, HA is added, the mixture is stirred and cooled, and the deuterated vonoprazan salt represented by formula (I) is obtained by post-treatment or not, filtration and drying.
7. The method of claim 6, wherein HA is selected from formic acid, maleic acid, L-pyroglutamic acid, or propionic acid;
the aprotic solvent is ethyl acetate;
the mass volume ratio of the deuterated nuprazan to the aprotic solvent is 1-5:7-20;
preferably, the mass-to-volume ratio of the deuterated pranoprazan to the aprotic solvent is 1:10 or 1.5:20.
8. The method according to claim 6, wherein the post-treatment is concentration to remove the solvent, and any one of ethyl acetate, methyl tert-butyl ether or n-hexane or a mixture of any 2 to 3 of them is added.
9. A pharmaceutical composition comprising an effective amount of the deuterated vorexant salt of any of claims 1-5; preferably, the composition further comprises pharmaceutically acceptable auxiliary materials.
10. Use of the deuterated vorexant salt of any of claims 1-5 or the pharmaceutical composition of claim 9 in the manufacture of a medicament for the prevention and treatment of gastric acid related diseases;
preferably, the gastric acid related disease is selected from the group consisting of gastrointestinal mucosal injury, helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, and gastric ulcer.
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