WO2014194741A1 - 一种jak激酶抑制剂的硫酸氢盐及其制备方法 - Google Patents
一种jak激酶抑制剂的硫酸氢盐及其制备方法 Download PDFInfo
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- WO2014194741A1 WO2014194741A1 PCT/CN2014/076794 CN2014076794W WO2014194741A1 WO 2014194741 A1 WO2014194741 A1 WO 2014194741A1 CN 2014076794 W CN2014076794 W CN 2014076794W WO 2014194741 A1 WO2014194741 A1 WO 2014194741A1
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- methyl
- formula
- pyrrole
- pyrrolo
- hexahydrocyclopenta
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- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 108010024121 Janus Kinases Proteins 0.000 title abstract description 15
- 102000015617 Janus Kinases Human genes 0.000 title abstract description 15
- 239000003112 inhibitor Substances 0.000 title abstract 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- -1 hydrogen cyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate Chemical compound 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YXMHRFATVRTKLW-UHFFFAOYSA-N S(=O)(=O)(O)O.CN(C=1C2=C(N=CN1)NC=C2)C2N(CC1C2CCC1)C(=O)N Chemical compound S(=O)(=O)(O)O.CN(C=1C2=C(N=CN1)NC=C2)C2N(CC1C2CCC1)C(=O)N YXMHRFATVRTKLW-UHFFFAOYSA-N 0.000 claims 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000552 rheumatic effect Effects 0.000 abstract 1
- 201000003068 rheumatic fever Diseases 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229940043355 kinase inhibitor Drugs 0.000 description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
- 229960001350 tofacitinib Drugs 0.000 description 6
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000004012 Tofacitinib Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 241000282560 Macaca mulatta Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- OBUMTUWKJRFJDH-UHFFFAOYSA-N formamide;sulfuric acid Chemical compound NC=O.OS(O)(=O)=O OBUMTUWKJRFJDH-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- WLFZBSSDZNVOJT-UHFFFAOYSA-N phenyl n-(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate Chemical compound COC1=NSC(NC(=O)OC=2C=CC=CC=2)=N1 WLFZBSSDZNVOJT-UHFFFAOYSA-N 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 2
- OJCCUUWVUOCZAA-UHFFFAOYSA-N 3-methoxy-1,2,4-thiadiazol-5-amine Chemical compound COC1=NSC(N)=N1 OJCCUUWVUOCZAA-UHFFFAOYSA-N 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- AXWBJJJQRJBTMI-UHFFFAOYSA-N CNc1c(cc[nH]2)c2ncn1 Chemical compound CNc1c(cc[nH]2)c2ncn1 AXWBJJJQRJBTMI-UHFFFAOYSA-N 0.000 description 1
- KHHLUGASAALFCZ-UHFFFAOYSA-N COc1n[s]c(NC(N2CC(CCC3)C3C2)=O)n1 Chemical compound COc1n[s]c(NC(N2CC(CCC3)C3C2)=O)n1 KHHLUGASAALFCZ-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000010250 cytokine signaling pathway Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- PMPYSSMGWFNAAQ-UHFFFAOYSA-N dichloromethane;n,n-diethylethanamine Chemical compound ClCCl.CCN(CC)CC PMPYSSMGWFNAAQ-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- XXHGDLJQCZLECB-UHFFFAOYSA-N pyrimidin-4-amine;hydrochloride Chemical compound Cl.NC1=CC=NC=N1 XXHGDLJQCZLECB-UHFFFAOYSA-N 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MUQNAPSBHXFMHT-UHFFFAOYSA-N tert-butylhydrazine Chemical compound CC(C)(C)NN MUQNAPSBHXFMHT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Definitions
- the present invention relates to a hydrogensulfate salt of a JAK kinase inhibitor and a process for the preparation thereof.
- the invention relates to (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrole[ 2,3-d]pyrimidin-4-yl:)amino:)hexahydrocyclopenta[c]pyrrole-2 (1 ⁇ carboxamide hydrogensulfate and preparation method thereof)
- RA rheumatoid arthritis
- JAK Janus kinase
- Tofacitinib (tasocitinib, CP-690550), currently developed by Pfizer, is a JAK1 inhibitor.
- Pfizer tofacitinib drug is significantly better than methotrexate (methotrexate;).
- methotrexate methotrexate
- the researchers randomized patients, one group taking 5 mg/10 mg of tofacitinib as monotherapy, and the other group taking 5 mg/10 mg of methotrexate (methotrexate: ).
- methotrexate methotrexate
- the object of the present invention is to provide a salt of a JAK kinase inhibitor which is more water-soluble and which can enhance its pharmacokinetic activity, and specifically provides a salt as shown in formula (I).
- Another aspect of the invention provides (3aR,5 S ,6aS:)-NP-methoxy-1,2,4-thiadiazol-5-yl)-5- (as shown in formula (I)
- Process for preparing methyl (7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2 1H formamide hydrogensulfate which comprises compound (IV) and Sulfuric acid salt
- the above reaction can be carried out in a solvent which is a mixed solvent of a halogenated anthracene and an alcohol having a carbon number of less than or equal to 3, preferably a mixed solution of dichloromethane and methanol.
- the reaction temperature of the above reaction is preferably from 10 to 30 ° C, and the reaction time is preferably from 0.5 to 4 hours.
- Another aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (3aR, 5s, 6aS)-N-(3-methoxy- 1 ,2,4-thiadiazole as shown in formula (I) -5-yl)-5-(methyl(7H-pyrrolo[2,3-d-mididin-4-yl:)amino:)hexahydrocyclopenta[c
- a pharmaceutically acceptable carrier comprising (3aR, 5s, 6aS)-N-(3-methoxy- 1 ,2,4-thiadiazole as shown in formula (I) -5-yl)-5-(methyl(7H-pyrrolo[2,3-d-mididin-4-yl:)amino:)hexahydrocyclopenta[c
- a pharmaceutically acceptable carrier comprising (3aR, 5s, 6aS)-N-(3-
- Another aspect of the invention provides (3aR,5 S ,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5 as shown in formula (I) - (methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2 1H;)-carboxamide hydrogensulfate or comprising the above hydrogen sulfate
- Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of rheumatoid arthritis and rheumatoid arthritis.
- the hydrogensulfate of the formula (I) prepared according to the process of the present invention does not contain or contains only a relatively low amount of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, and thus the hydrogen sulfate of the formula (I) of the present invention
- the salt can be preferably used as a pharmaceutically active ingredient.
- the reaction mixture was concentrated under reduced pressure to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
- the experimental animals were 4 rhesus monkeys, half male and half female.
- 0.5 mL was taken from the femoral vein, placed in heparin sodium anticoagulant tube, shaken, centrifuged at 3500 rpm for 10 min, plasma was separated, and stored at low temperature.
Landscapes
- 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)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及一种JAK激酶抑制剂的硫酸氢盐及其制备方法。更具体地，本发明涉及如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯 -2(1H)-甲酰胺硫酸氢盐及其制备方法和用途。如式(I)所示的硫酸氢盐可很好地作为JAK激酶抑制剂应用于临床，用来治疗风湿及类风湿性关节炎。
Description
一种 JAK激酶抑制剂的硫酸氢盐及其制备方法
技术领域
本发明涉及一种 JAK激酶抑制剂的硫酸氢盐及其制备方法。 具体 地说， 本发明涉及 (3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基：)氨基：)六氢环戊并 [c]吡咯 -2(1Η 甲酰胺硫 酸氢盐及其制备方法。 背景技术
关节炎是全世界最常见的慢性疾病， 导致关节炎的原因很多， 引 起关节损伤也各有不同。 目前， 治疗风湿性关节炎的主要药物有美国 雅培制药公司的阿达木单抗 (Hrnrnra;),辉瑞和安进公司共同研发的依那 西普 (Enbrel)以及 Janssen制药公司的英利昔单抗 (Remicade), 这些药物 都是当前医药市场的畅销药物， 但值得注意的是， 这些畅销药物都只 是注射型药物， 常用的口服药甲氨蝶呤 (methotrexate;), 虽然药效显著， 但毒性也非常大。
研究表明， 在类风湿性关节炎RA)病理生理学过程中， 多重细胞 因子信号通路失调发挥重要作用， 一系列失控的细胞因子介导的炎症 级联反应导致 RA相关的多种细胞， 包括 T细胞、 B细胞、 单核细胞、 巨噬细胞和破骨细胞处于长期激活状态， 从而引发持续炎症及关节结 构性损伤。 而 Janus激酶 (JAK)信号通路对 RA相关细胞的促炎活性有 调控作用， 其中 JAK是炎症细胞因子网络信号传导中枢蛋白， RA关 节滑膜组织中 JAK水平显著增高。 目前由辉瑞公司开发的 tofacitinib (tasocitinib, CP-690550)为 JAK1抑制剂。 经临床三期试验结果， 辉瑞 tofacitinib药物药效明显优于甲氨蝶呤 （methotrexate；)。在该实验中，研 究人员对患者进行随机分组， 其中一组患者服用 5 毫克 /10 毫克的 tofacitinib药物作为单一疗法， 另外一组患者则服用 5毫克 /10毫克剂 量的甲氨蝶呤 (methotrexate：)。 研究结果显示， 在六个月的时间里， tofacitinib 药物在抑制人体内部结构损伤方面的药效比甲氨蝶呤 (methotrexate)略胜一筹， 可以有效改善风湿性关节炎患者的各种综合 症。
我们从研制 JAK激酶抑制剂的思路出发， 紧跟国际上同类药物发 展方向， 基于 tofacitmib的结构， 开发出一系列具有体内、 外活性， 高 吸收的药物， 成功得到了 JAK激酶抑制剂化合物 （IV) , 关于式 （IV) 所示化合物， 其信息已完整记载于申请人与他人共同申请的 PCT专利 申请 PCT/CN2012/086922 在此全文引入作为参考。
本发明的目的是提供一种水溶性较好的、能增强其药代活性的 JAK 激酶抑制剂的盐， 具体来说是提供一种如式 （I ) 所示的
(3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d] 嘧啶 -4-基：)氨基：)六氢环戊并 [c]吡咯 -2 1H 甲酰胺硫酸氢盐及其制备方 法。
其中 (3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯 并 [2,3-d]嘧啶 -4-基：)氨基：)六氢环戊并 [c]吡咯 -2(：1¾-甲酰胺与硫酸的化
学配比为 1:1。
本发明的另一方面提供了如式 （I) 所示的 (3aR,5S,6aS:)-N-P-甲氧 基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基)氨基)六氢环 戊并 [c]吡咯 -2 1H 甲酰胺硫酸氢盐的制备方法， 其包括化合物 （IV) 与硫酸成盐的
(IV) (I)
上述反应可在溶剂中进行， 所述的反应溶剂为碳原子数小于或等 于 3的卤代垸类与醇类的混合溶剂， 优选二氯甲垸与甲醇的混合溶液。
上述反应的反应温度优选为 10 - 30°C， 反应时间优选为 0.5 - 4小 时。
本发明的另一方面提供了一种药物组合物， 其含有如式 （I) 所示 的（3aR,5s,6aS)-N-(3-甲氧基 - 1 ,2,4-噻二唑 -5-基 )-5-(甲基 (7H-吡咯并 [2,3-d 密啶 -4-基：)氨基：)六氢环戊并 [c|吡咯 -2 1H 甲酰胺硫酸氢盐及药 学上可接受的载体。
本发明的另一方面提供了如式 （I) 所示的 (3aR,5S,6aS)-N-(3-甲氧 基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基)氨基)六氢环 戊并 [c]吡咯 -2 1H;)-甲酰胺硫酸氢盐或包含上述硫酸氢盐的药物组合物 在制备治疗风湿及类风湿性关节炎的药物中的用途。
按照本发明的方法制备的式 （I) 硫酸氢盐不含有或仅含有较低含 量的残留溶剂， 符合国家药典规定的有关医药产品残留溶剂的限量要 求， 因而本发明的式（I)硫酸氢盐可以较好地作为医药活性成分使用。 具体实施方式
以下将结合实施例更详细地解释本发明， 本发明的实施例仅用于 说明本发明的技术方案， 并非限定本发明的实质和范围。
买施例 1 : 式 (IV) 化合物的制备 (引自 PCT/CN2012/086922) 式 （IV) 化合物可依如下路线制备：
IV
其中化合物 d的制备方法如下:
具体的， 式 （IV) 化合物的制备包括如下两个部分:
第一部分： 制备化合物 d
(3aR,5r,6aS)-5- (甲基磺酰氧基：)六氢环戊并 [c]吡咯 -2(1Η)-甲酸叔丁 酉'
将 (3aR,5r,6aS 5-羟基六氢环戊并 [c]吡咯 -2(1H 甲酸叔丁酯 Id (9 g， 40 mmol )溶于 150 mL二氯甲垸中，在 0°C下加入甲磺酰氯 (4.70 mL, 60 11111101 )和三乙胺(11.20 11^， 80 mmol ), 室温下反应 2小时。 向反应 液加入 200 mL饱和碳酸氢钠溶液， 分液， 有机相用饱和氯化钠溶液洗 涤 (200 mL), 无水硫酸钠干燥， 过滤， 减压浓缩滤液， 得到标题产物 (3aR,5r,6aS 5- (甲基磺酰氧基：)六氢环戊并 [c]吡咯 -2(1Η 甲酸叔丁酯 2d (12.00 g, 黄色液体)， 产率： 98.4%。
(3aR,5s,6aS)-5- (甲基氨基)六氢环戊并 [c]吡咯 -2(1Η)-甲酸叔丁酯 将 (3aR,5r,6aS)-5- (甲基磺酰氧基：)六氢环戊并 [c]吡咯 -2(1Η)-甲酸叔 丁酯 2d (60 mg， 0.2 mmol)溶解于 10 mL甲醇中， 加入 5 mL甲基胺， 于 40°C下反应 16 小时。 减压浓缩反应液， 得到粗品标题产物 (3aR,5s,6aS)-5- (甲基氨基)六氢环戊并 [c]吡咯 -2(1Η)-甲酸叔丁酯 3d (60 mg， 褐色油状物：)， 不经纯化直接用于下一歩反应。
MS m/z (ESI): 241.5 [M+l].
(3aR,5s,6aS)-5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基：)氨基)六氢环戊并 [c]吡咯 -2(：11¾-甲酸叔丁酯
将 (3aR,5s,6aS)-5- (甲基氨基)六氢环戊并 [c]吡咯 -2(1H)-甲酸叔丁酯 3d(200 mg， 0.8 mmol)和 4-氯 -7H-吡咯并 [2,3-d]嘧啶 4d (127 mg， 0.8 mmol)溶解于 5 mL正丁醇中，滴加三乙胺 (168 mg， 1.6 mmol),于 100°C 下反应 48小时。 减压浓缩反应液， 加入 10 mL水和 10 mL乙酸乙酯， 分液， 合并有机相， 无水硫酸钠干燥， 过滤， 减压浓缩滤液， 用 HPLC 制备得到标题产物3aR,5s,6aS;)-5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基:)氨 基:)六氢环戊并 [c]吡咯 -2(1Η)-甲酸叔丁酯 5d(5 mg， 白色固体：)， 产率： 5.0%。
MS m/z (ESI): 358.5[M+1]
¾ NM (400 MHz, CDC13): δ 10.07 (s, 1H), 8.31 (s, 1H), 7.50 (s,
1H), 6.55(s, 1H), 5.58-5.54 (m, 1H), 3.65-3.62 (m, 2H), 3.27-3.23 (m,5H), 2.86-2.81 (m, 2H), 2.06-2.02 (m, 2H), 1.93-1.91 (m, 2H), 1.49 (s, 6H).
第四歩
Ν·甲基 _N_((3aR,5s,6aS)-八氢环戊并 [c]吡咯 -5-基) -7H-吡咯并 [2,3-d] 嘧啶 -4-胺盐酸盐
将 (3aR,5s,6aS)-5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基：)氨基)六氢环戊 并 [c]吡咯 -2(1Η)-甲酸叔丁酯 5d(1.5 g， 4.2 mmol)溶解于 20 mL 1 M氯 化氢的甲醇溶液中， 反应 16小时。 减压浓缩反应液， 得到粗品标题产 物 N-甲基 -N-((3aR,5s,6aS)-八氢环戊并 [c]吡咯 -5-基) -7H-吡咯并 [2,3-d] 嘧啶 -4-胺盐酸盐 d (1.5 g， 褐色固体：)。
MS m/z (ESI): 258.1 [M+l].
第二部分： 式 （IV) 化合物的制备
3-甲氧基 -1 ,2,4-噻二唑 -5-基氨基甲酸苯酯
将 3-甲氧基 -1,2,4-噻二唑 -5-胺 a (500 mg， 3.82 mmol)和氯甲酸苯 酯 b (600 mg， 3.82 mmol)溶解于 20 mL二氯甲垸中， 滴加三乙胺 (0.8 mL, 5.73 mmol), 滴毕反应 16小时。 向反应液中加入 30 mL水稀释， 分液， 水相用二氯甲垸萃取 (20 mLx2)， 合并有机相， 无水硫酸钠干燥， 过滤， 减压浓缩反应液， 用硅胶柱色谱法以洗脱剂体系 A纯化所得残 余物， 得到标题产物 3-甲氧基 -1,2,4-噻二唑 -5-基氨基甲酸苯酯 C (200 mg， 白色固体：)， 产率： 20.8%。
MS m/z (ESI): 252.0 [M+l].
(3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-yl)胺)六氢环戊并 [c]吡咯 -2(1H)-甲酰胺
将根据第一部分所述方法制备得到的化合物 d (120 mg， 0.47 mmol) 溶解于 15 mL四氢呋喃中， 加入 3-甲氧基 -1,2,4-噻二唑 -5-基氨基甲酸 苯酯 c (117 mg， 0.47 mmol), 滴加三乙胺 (0.13 mL， 0.94 mmol), 滴毕 于 60°C下反应 5小时。 向反应液中加入 30 mL水， 用二氯甲垸萃取 (50 mLx3), 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2), 无水硫酸钠 干燥， 过滤， 减压浓缩滤液， 用硅胶柱色谱法以洗脱剂体系 A纯化所 得残余物， 得到标题产物 (3aR,5s,6aS)-N-P-甲氧基 -1 ,2,4-噻二唑 -5- 基) -5- (甲基 (7H-吡咯并 [2,3 -d]嘧啶 -4-基） 氨基))六氢环戊并 [c]吡咯 -2(1H)-甲酰胺 (IV) (50 mg, 白色固体)， 产率： 25.9%。
MS m/z (ESI): 412.9 [M-l].
¾ NM (400 MHz, DMSO-d6): δ 11.60 (m, 2H), 8.08 (s, 1H), 7.06-7.05 (m, 1H), 6.53-6.51 (m, 1H), 5.48-5.44 (m, 1H), 3.90 (s, 3H), 3.69-3.65 (m, 2H), 3.37-3.32 (m, 2H), 3.16 (s, 3H), 2.90-2.88 (m, 2H), 2.02-1.99 (m, 2H), 1.80-1.77 (m, 2H). 实施例 2: (3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡 咯并 [2,3-d]嘧啶 -4-基：)氨基：)六氢环戊并 [c]吡咯 -2(1Η 甲酰胺硫酸氢盐 的制备 (式 I)
在 10L反应瓶中投入化合物 （IV) 140g(0.34mol), 加入无水甲醇
350g，二氯甲垸 2.0kg，悬浮搅拌，室温下缓慢滴加硫酸 34.8g(0.36moi;)， 反应液溶清， 搅拌反应 30min。 过滤除去不溶物， 滤液减压浓缩干， 干 燥， 得目标产物 135g〜168g， 产率： 80〜90%。
MS m/z (ESI): 415.1651 [M+l].
¾ NM (400 MHz, DMSO-d6): 512.75 (s, IH), 11.04 (s, IH), 8.37 (s;
IH), 7.41-7.42 (t, IH), 6.89 (s, IH), 5.15-5.19 (m, IH), 3.89 (s, 3H), 3.68-3.70 (m, 2H), 3.38-3.40 (m, 2H), 3.29 (s, 3H), 2.95 (s, 2H), 2.09-2.16 (m, 2H) , 1.92-1.97 (m, 2H) 实验例 3 :
(3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并
[2,3-d]嘧啶 -4-基：)氨基：)六氢环戊并 [c]吡咯 -2(1Η 甲酰胺（式 IV化合物） 和其相应的柠檬酸盐、 盐酸盐、 硫酸盐和硫酸氢盐在水、 0.1N盐酸中 的溶解度比较试验， 结果表明成硫酸氢盐后， 溶解度大大提高， 同时 也远远大于其它盐。 详细结果见表 1。 表 1. 化合物 （IV) 成盐前后的溶解度比较试验
考察式（IV)化合物及其不同盐形式在恒河猴体内的药动学行为， 详细评价不同化合物形式的性质， 试验动物为 4只恒河猴， 雌雄各半，
单次给予恒河猴 50mg/kg剂量； 采用多交叉试验设计给予动物不同药 物， 每个周期恢复三天； 分别于给药前 （O h) 及给药后 0.25 h、 0.5 h、 l h、 2 h、 4 h、 6 h、 8 h和 24 h经股静脉取血 0.5 mL， 置肝素钠抗凝 化试管中， 摇匀， 3500 rpm离心 10 min， 分离血浆， 并低温保存， 采 用 LC-MS/MS分别测定血浆中及肝脏中的药物浓度并采用 WinNonlin 5.3软件分析药动学参数， 实验结果如下： 表 2. 化合物 （IV) 及柠檬酸盐、 硫酸氢盐的药代参数结果
Claims
1、 如式 ( I ) 所示的（3aR,5s,6aS)-N-(3-甲奪 ,基 -1,2,4-噻二唑 -5- 基 )-5-(甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基）氨基）: 氢环戊并 [c]吡咯 -2(1H)-甲酰胺硫酸氢盐，
α ) '
2、 根据权利要求 1所述的如式（I)所示的 (3aR,5s,6aS)-N-(3-甲氧 基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基)氨基)六氢环 戊并 [c]吡咯 -2(1H)-甲酰胺硫酸氢盐， 其中如式 （IV) 所示的化合物与 硫酸的化学配比为 1:1，
(IV) 3、 一种根据权利要求 1所述的如式（I)所示的 (3aR,5s,6aS)-N-(3- 甲氧基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,
3-d]嘧啶 -4-基)氨基)六 氢环戊并 [c]吡咯 -2(1H)-甲酰胺硫酸氢盐的制备方法， 其包括化合物 (IV) 与硫酸成盐的歩骤，
(iv) (I)
4、根据权利要求 3所述的制备方法，其中成盐反应在溶剂中进行， 所述溶剂为碳原子数小于或等于 3 的卤代垸类与醇类的混合溶剂， 优 选二氯甲垸与甲醇的混合溶液。
5、 根据权利要求 4所述的制备方法， 其中成盐反应的反应温度为 10 - 30°C , 反应时间优选为 0.5 - 4小时。
6、 一种药物组合物， 其含有根据权利要求 1所述的如式（I)所 /」、 的（3aR,5s,6aS)-N-(3-甲氧基 - 1 ,2,4-噻二唑 -5-基 )-5-(甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基)氨基)六氢环戊并 [c]吡咯 -2(1H)-甲酰胺硫酸氢盐及药 学上可接受的载体。
7、 根据权利要求 1所述的如式（I)所示的 (3aR,5s,6aS)-N-(3-甲氧 基 -1,2,4-噻二唑 -5-基) -5- (甲基 (7H-吡咯并 [2,3-d]嘧啶 -4-基)氨基)六氢环 戊并 [c]吡咯 -2(1H)-甲酰胺硫酸氢盐， 或根据权利要求 6所述的药物组 合物在制备治疗风湿及类风湿性关节炎的药物中的用途。
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| US14/895,117 US9422300B2 (en) | 2013-06-07 | 2014-05-05 | Bisulfate of janus kinase (JAK) inhibitor and preparation method therefor |
| CA2913194A CA2913194C (en) | 2013-06-07 | 2014-05-05 | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor |
| ES14807030.3T ES2655074T3 (es) | 2013-06-07 | 2014-05-05 | Bisulfato de inhibidor de quinasa Janus (JAK) y procedimiento de preparación del mismo |
| BR112015029463-4A BR112015029463B1 (pt) | 2013-06-07 | 2014-05-05 | Bissulfato de inibidor da janus quinase (jak), seu uso e seu método de preparação, e composição farmacêutica |
| MX2015016513A MX2015016513A (es) | 2013-06-07 | 2014-05-05 | Bisulfato del inhibidor de la janus quinasa (jak) y metodo de preparacion para el mismo. |
| CN201480001854.XA CN104470927B (zh) | 2013-06-07 | 2014-05-05 | 一种jak激酶抑制剂的硫酸氢盐及其制备方法 |
| KR1020157035615A KR102275326B1 (ko) | 2013-06-07 | 2014-05-05 | 야누스 키나제(jak) 억제제의 바이설페이트 및 그의 제조 방법 |
| JP2016517135A JP6323885B2 (ja) | 2013-06-07 | 2014-05-05 | ヤヌスキナーゼ（ｊａｋ）阻害剤の硫酸水素塩およびその製造方法 |
| RU2015156142A RU2665680C2 (ru) | 2013-06-07 | 2014-05-05 | Бисульфат ингибитора янус-киназы (jak) и способ его получения |
| EP14807030.3A EP3006445B1 (en) | 2013-06-07 | 2014-05-05 | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor |
| AU2014277506A AU2014277506B2 (en) | 2013-06-07 | 2014-05-05 | Bisulfate of Janus kinase (JAK) inhibitor and preparation method therefor |
| HK15106673.4A HK1206026A1 (zh) | 2013-06-07 | 2015-07-13 | 種 激酶抑制劑的硫酸氫鹽及其製備方法 |
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| CN201310227683.X | 2013-06-07 | ||
| CN201310227683 | 2013-06-07 |
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| KR (1) | KR102275326B1 (zh) |
| CN (1) | CN104470927B (zh) |
| AU (1) | AU2014277506B2 (zh) |
| BR (1) | BR112015029463B1 (zh) |
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| HK (1) | HK1206026A1 (zh) |
| HU (1) | HUE036533T2 (zh) |
| MX (1) | MX2015016513A (zh) |
| PT (1) | PT3006445T (zh) |
| RU (1) | RU2665680C2 (zh) |
| TW (1) | TWI641609B (zh) |
| WO (1) | WO2014194741A1 (zh) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016054959A1 (zh) * | 2014-10-09 | 2016-04-14 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 |
| KR20170078710A (ko) * | 2014-11-05 | 2017-07-07 | 지앙수 헨그루이 메디슨 컴퍼니 리미티드 | Jak 키나아제 억제제 바이설페이트의 결정형 및 이의 제조방법 |
| WO2018095320A1 (zh) | 2016-11-23 | 2018-05-31 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物的制备方法及中间体 |
| WO2018133823A1 (zh) * | 2017-01-20 | 2018-07-26 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法 |
| WO2019096303A1 (zh) * | 2017-11-20 | 2019-05-23 | 江苏恒瑞医药股份有限公司 | 一种局部给药的药物组合物及其制备方法 |
| CN111205290A (zh) * | 2018-11-22 | 2020-05-29 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的结晶形式及其制备方法 |
| US10786507B2 (en) | 2016-02-19 | 2020-09-29 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof |
| CN112457272A (zh) * | 2020-12-02 | 2021-03-09 | 上海再启生物技术有限公司 | (3-甲氧基-1,2,4-噻二唑-5-氨基)甲酸苯酯的制备方法 |
| CN113698404A (zh) * | 2020-05-21 | 2021-11-26 | 江苏恒瑞医药股份有限公司 | 一种低溶剂残留的六氢环戊并[c]吡咯-2(1H)-甲酰胺化合物及其制备方法 |
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| WO2020096948A1 (en) * | 2018-11-05 | 2020-05-14 | Avista Pharma Solutions, Inc. | Chemical compounds |
| CN111440127B (zh) * | 2019-01-17 | 2022-07-26 | 青岛农业大学 | 一种噻唑酰胺类化合物及其制备和应用 |
| JP2022546760A (ja) * | 2019-09-05 | 2022-11-08 | ウニベルズィテート ベルン | 三環式ヤヌスキナーゼ（ｊａｋ）阻害剤および自己免疫疾患の治療におけるそれらの使用 |
| WO2022027041A1 (en) | 2020-07-28 | 2022-02-03 | Arcutis Biotherapeutics, Inc. | Topical formulation containing jak inhibitor and laureth-4 |
| KR20230144002A (ko) | 2020-11-17 | 2023-10-13 | 아큐티스 바이오테라퓨틱스, 인크. | 심부 진피 약물 전달을 위한 조성물 및 방법 |
| WO2023114832A1 (en) | 2021-12-15 | 2023-06-22 | Arcutis Biotherapeutics, Inc. | Stable formulations of shr0302 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439010A (zh) * | 2000-06-26 | 2003-08-27 | 辉瑞产品公司 | 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂 |
| CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉－2－酮衍生物 |
| WO2012171863A1 (en) * | 2011-06-16 | 2012-12-20 | Boehringer Ingelheim International Gmbh | New selective ccr2 antagonists |
| WO2013091539A1 (zh) * | 2011-12-21 | 2013-06-27 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087142A1 (en) * | 2003-04-04 | 2004-10-14 | Novartis Ag | Quinoline-2-one-derivatives for the treatment of airways diseases |
| AU2006221065A1 (en) * | 2005-02-03 | 2006-09-14 | Vertex Pharmaceuticals Incorporated | Pyrrolopyrimidines useful as inhibitors of protein kinase |
| BR112012019511A2 (pt) * | 2010-02-05 | 2016-08-23 | Pfizer | compostos de pirrolo [2,3-d] pirimidina como inibidores de jak. |
-
2014
- 2014-05-05 WO PCT/CN2014/076794 patent/WO2014194741A1/zh active Application Filing
- 2014-05-05 RU RU2015156142A patent/RU2665680C2/ru active
- 2014-05-05 EP EP14807030.3A patent/EP3006445B1/en active Active
- 2014-05-05 CN CN201480001854.XA patent/CN104470927B/zh active Active
- 2014-05-05 HU HUE14807030A patent/HUE036533T2/hu unknown
- 2014-05-05 ES ES14807030.3T patent/ES2655074T3/es active Active
- 2014-05-05 PT PT148070303T patent/PT3006445T/pt unknown
- 2014-05-05 MX MX2015016513A patent/MX2015016513A/es active IP Right Grant
- 2014-05-05 AU AU2014277506A patent/AU2014277506B2/en active Active
- 2014-05-05 KR KR1020157035615A patent/KR102275326B1/ko active IP Right Grant
- 2014-05-05 US US14/895,117 patent/US9422300B2/en active Active
- 2014-05-05 JP JP2016517135A patent/JP6323885B2/ja active Active
- 2014-05-05 BR BR112015029463-4A patent/BR112015029463B1/pt active IP Right Grant
- 2014-05-05 CA CA2913194A patent/CA2913194C/en active Active
- 2014-05-14 TW TW103116955A patent/TWI641609B/zh active
-
2015
- 2015-07-13 HK HK15106673.4A patent/HK1206026A1/zh unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439010A (zh) * | 2000-06-26 | 2003-08-27 | 辉瑞产品公司 | 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂 |
| CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉－2－酮衍生物 |
| WO2012171863A1 (en) * | 2011-06-16 | 2012-12-20 | Boehringer Ingelheim International Gmbh | New selective ccr2 antagonists |
| WO2013091539A1 (zh) * | 2011-12-21 | 2013-06-27 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用 |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP3006445A4 * |
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| WO2016054959A1 (zh) * | 2014-10-09 | 2016-04-14 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 |
| CN105980389A (zh) * | 2014-10-09 | 2016-09-28 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 |
| RU2704795C2 (ru) * | 2014-10-09 | 2019-10-31 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Кристаллическая форма бисульфата ингибитора jak и способ ее получения |
| CN105980389B (zh) * | 2014-10-09 | 2017-12-19 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 |
| US10150770B2 (en) | 2014-10-09 | 2018-12-11 | Jiangsu Hengrui Medicine Co., Ltd. | Crystal form of bisulfate of JAK inhibitor and preparation method therefor |
| US10023577B2 (en) | 2014-11-05 | 2018-07-17 | Jiangsu Hengrui Co., Ltd. | Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof |
| RU2716260C2 (ru) * | 2014-11-05 | 2020-03-11 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Кристаллическая форма бисульфатного ингибитора jak-киназы и способ ее получения |
| KR102522895B1 (ko) | 2014-11-05 | 2023-04-17 | 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 | Jak 키나아제 억제제 바이설페이트의 결정형 및 이의 제조방법 |
| AU2015342444B2 (en) * | 2014-11-05 | 2019-12-12 | Jiangsu Hengrui Medicine Co., Ltd. | Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof |
| KR20170078710A (ko) * | 2014-11-05 | 2017-07-07 | 지앙수 헨그루이 메디슨 컴퍼니 리미티드 | Jak 키나아제 억제제 바이설페이트의 결정형 및 이의 제조방법 |
| EP3216790A4 (en) * | 2014-11-05 | 2018-04-25 | Jiangsu Hengrui Medicine Co., Ltd. | Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof |
| US10786507B2 (en) | 2016-02-19 | 2020-09-29 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof |
| CN108884100A (zh) * | 2016-11-23 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物的制备方法及中间体 |
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| CN108884100B (zh) * | 2016-11-23 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂芳环类衍生物的制备方法及中间体 |
| TWI771342B (zh) * | 2016-11-23 | 2022-07-21 | 大陸商江蘇恆瑞醫藥股份有限公司 | 吡咯并六員雜芳環類衍生物的製備方法及中間體 |
| CN108779122A (zh) * | 2017-01-20 | 2018-11-09 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法 |
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| WO2019096303A1 (zh) * | 2017-11-20 | 2019-05-23 | 江苏恒瑞医药股份有限公司 | 一种局部给药的药物组合物及其制备方法 |
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| CN111205290A (zh) * | 2018-11-22 | 2020-05-29 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的结晶形式及其制备方法 |
| CN111205290B (zh) * | 2018-11-22 | 2021-10-08 | 江苏恒瑞医药股份有限公司 | 一种jak激酶抑制剂的结晶形式及其制备方法 |
| CN113698404A (zh) * | 2020-05-21 | 2021-11-26 | 江苏恒瑞医药股份有限公司 | 一种低溶剂残留的六氢环戊并[c]吡咯-2(1H)-甲酰胺化合物及其制备方法 |
| CN112457272A (zh) * | 2020-12-02 | 2021-03-09 | 上海再启生物技术有限公司 | (3-甲氧基-1,2,4-噻二唑-5-氨基)甲酸苯酯的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104470927A (zh) | 2015-03-25 |
| MX2015016513A (es) | 2016-04-15 |
| CN104470927B (zh) | 2016-05-04 |
| CA2913194A1 (en) | 2014-12-11 |
| BR112015029463B1 (pt) | 2023-01-10 |
| HK1206026A1 (zh) | 2015-12-31 |
| CA2913194C (en) | 2021-03-02 |
| TWI641609B (zh) | 2018-11-21 |
| TW201514180A (zh) | 2015-04-16 |
| EP3006445B1 (en) | 2017-11-15 |
| AU2014277506B2 (en) | 2017-08-31 |
| US20160102098A1 (en) | 2016-04-14 |
| AU2014277506A1 (en) | 2016-01-21 |
| PT3006445T (pt) | 2018-01-09 |
| HUE036533T2 (hu) | 2018-07-30 |
| RU2015156142A (ru) | 2017-07-17 |
| JP6323885B2 (ja) | 2018-05-16 |
| KR20160032021A (ko) | 2016-03-23 |
| EP3006445A4 (en) | 2016-11-23 |
| BR112015029463A2 (pt) | 2017-07-25 |
| RU2015156142A3 (zh) | 2018-03-19 |
| KR102275326B1 (ko) | 2021-07-12 |
| JP2016520134A (ja) | 2016-07-11 |
| EP3006445A1 (en) | 2016-04-13 |
| US9422300B2 (en) | 2016-08-23 |
| ES2655074T3 (es) | 2018-02-16 |
| RU2665680C2 (ru) | 2018-09-04 |
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