CN109678775A - A kind of crystal form and preparation method thereof of COX-2 selective depressant - Google Patents
A kind of crystal form and preparation method thereof of COX-2 selective depressant Download PDFInfo
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- CN109678775A CN109678775A CN201811205923.5A CN201811205923A CN109678775A CN 109678775 A CN109678775 A CN 109678775A CN 201811205923 A CN201811205923 A CN 201811205923A CN 109678775 A CN109678775 A CN 109678775A
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- 239000013078 crystal Substances 0.000 title claims abstract description 113
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 title description 10
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 title description 10
- 230000000994 depressogenic effect Effects 0.000 title description 3
- 238000002425 crystallisation Methods 0.000 claims description 37
- 230000008025 crystallization Effects 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 229940111134 coxibs Drugs 0.000 abstract 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- -1 4- methanesulfonylphenYl Chemical class 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N 1-Pyrroline Chemical compound C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- NQWRGCGBBZZEMF-UHFFFAOYSA-N 2-methoxy-2-methylpropane;oxolane Chemical compound C1CCOC1.COC(C)(C)C NQWRGCGBBZZEMF-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- MVFGXYPEQHIKIX-UHFFFAOYSA-N acetic acid;heptane Chemical compound CC(O)=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- WGXZDYPGLJYBJW-UHFFFAOYSA-N chloroform;propan-2-ol Chemical compound CC(C)O.ClC(Cl)Cl WGXZDYPGLJYBJW-UHFFFAOYSA-N 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 description 1
- OJRIZZVWDMDVOH-UHFFFAOYSA-N dioxane heptane Chemical compound C1CCOOC1.CCCCCCC OJRIZZVWDMDVOH-UHFFFAOYSA-N 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 108010017796 epoxidase Proteins 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- PUYCICVJCRLABY-UHFFFAOYSA-N heptane;oxolane Chemical compound C1CCOC1.CCCCCCC PUYCICVJCRLABY-UHFFFAOYSA-N 0.000 description 1
- JYGYEBCBALMPDC-UHFFFAOYSA-N heptane;propan-2-one Chemical compound CC(C)=O.CCCCCCC JYGYEBCBALMPDC-UHFFFAOYSA-N 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- MKOBKYVJLNRPBV-UHFFFAOYSA-N n,n-dimethylformamide;2-methoxy-2-methylpropane Chemical compound CN(C)C=O.COC(C)(C)C MKOBKYVJLNRPBV-UHFFFAOYSA-N 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- BHIIWXJHALLFBD-UHFFFAOYSA-N oxolane;propan-2-ol Chemical compound CC(C)O.C1CCOC1 BHIIWXJHALLFBD-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
-
- 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
- A61P35/00—Antineoplastic 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of selective crystal forms of cox 2 inhibitor and preparation method thereof.Specifically, the present invention relates to II, III crystal forms of a kind of selective cox 2 inhibitor and preparation method thereof.The dynamic solubility of II crystal form and III crystal form of the invention in physiological correlations medium is better than in water.
Description
Technical field
The present invention relates to crystal forms of COX-2 selective depressant and preparation method thereof.
Background technique
Epoxidase (cyclo-oxygen-ase, COX) is enzyme necessary to prostaglandin (PGs) is synthesized and PGs synthesis
Key rate-limiting enzyme in initial step.There are two types of isodynamic enzyme COX-1 and COX-2 by COX, the former is referred to as element enzyme for structural type
Or house keeping enzyme, it is primarily present in the tissue such as blood vessel, stomach, kidney, domestic and foreign scholars generally believe that the PG that it is generated is participating in body just
Normal physiology course and defencive function such as maintain gastrointestinal mucosa integrality, adjust platelet function and renal hemodynamic；The latter is induction
Type is through stimulating the induced enzyme generated rapidly, when by inflammatory cytokine, growth factor, endotoxin and certain mitogens
When stimulation, the expression of COX-2 can be increased significantly.
US2004029951A discloses a kind of 3,4- diphenyl 2 containing sulfonyl, and 5- pyrrolin -2- ketone is derivative
Object, the analog derivative have preferable COX-2 selective inhibitory, and wherein formula (A) is a kind of non-steroidal anti-inflammatory analgesics, use
In the pain symptom of relief from osteoarthritis, structure is as follows:
The crystal form of medicinal active ingredient often influences the chemically and physically stability of the drug, crystallization condition and storage item
The difference of part is likely to result in the variation of the crystal structure of compound, sometimes can also be along with the crystal form for generating other forms.One
As for, unbodied drug products do not have well-regulated crystal structure, often have defect, for example product stability is poor, mistake
It is more difficult to filter, and easily agglomerates, poor fluidity etc..CN101774958A discloses formula (A) compound " N- n-propyl -3- (4- methylbenzene
Base) -4- (4- methanesulfonylphenYl) -2,5- pyrrolin -2- ketone " I crystal, we have found II, III crystalline substance again on this basis
Type.
Summary of the invention
The technical problem to be solved in the present invention is to provide formula (A) compound N-n-propyl -3- (4- aminomethyl phenyl) -4- (4-
MethanesulfonylphenYl) -2,5- pyrrolin -2- ketone novel crystal forms and preparation method thereof.
Technical scheme is as follows:
The present invention provides a kind of II crystal form of compound shown in formula (A), it is characterised in that: X-ray powder diffraction collection
In, it is to have feature at 6.54,10.27,11.72,13.21,14.52,15.03,16.32,17.00,18.89,19.70 in 2 θ
Peak, error range can be ± 0.3, ± 0.2 or ± 0.1,
Preferably, II crystal form 6.54,10.27,11.72,13.21,14.52,15.03,16.32,17.00,
18.89, there is characteristic peak at 19.70,20.65,21.72,22.23,23.71,24.56, error range can be ± 0.3, ± 0.2
Or ± 0.1.
It is furthermore preferred that II crystal form is 6.54,10.27,11.72,13.21,14.52,15.03,16.32,17.00,
18.89, there is spy at 19.70,20.65,21.72,22.23,23.71,24.56,25.60,29.53,31.33,36.70,43.51
Peak is levied, error range can be ± 0.3, ± 0.2 or ± 0.1.
It is furthermore preferred that II crystal form is 6.537,10.271,11.723,13.209,14.525,15.033,16.319,
16.997、18.891、19.703、20.650、21.715、22.231、23.710、24.557、25.595、29.533、31.329、
36.703, there is characteristic peak at 43.512, error range can be ± 0.3, ± 0.2 or ± 0.1.
The present invention provides a kind of III crystal form of compound shown in formula (A), it is characterised in that: X-ray powder diffraction collection
In, it is to have spy at 5.90,8.59,9.27,9.56,13.13,15.21,15.49,16.60,17.50,18.10,19.42 in 2 θ
Peak is levied, error range can be ± 0.3, ± 0.2 or ± 0.1.
Preferably, III crystal form 5.90,8.59,9.27,9.56,13.13,15.21,15.49,16.60,17.50,
18.10, there is characteristic peak at 19.42,20.29,21.31,21.50,22.30,23.45,24.24, error range can be ±
0.3, ± 0.2 or ± 0.1.
It is furthermore preferred that III crystal form is 5.90,8.59,9.27,9.56,13.13,15.21,15.49,16.60,
17.50、18.10、19.42、20.29、21.31、21.50、22.30、23.45、24.24、25.29、26.36、26.66、
27.62, there is characteristic peak at 29.27,30.49,33.56,35.39,40.94,43.72,46.67, error range can be ±
0.3, ± 0.2 or ± 0.1.
It is furthermore preferred that III crystal form is 5.895,8.594,9.273,9.556,13.133,15.207,15.491,
16.604、17.500、18.104、19.418、20.291、21.314、21.497、22.298、23.448、24.236、25.287、
26.362, there is feature at 26.661,27.622,29.274,30.488,33.565,35.387,40.940,43.717,46.666
Peak, error range can be ± 0.3, ± 0.2 or ± 0.1.
The present invention also provides a kind of methods for preparing II crystal form, it is characterised in that: compound shown in formula (A) is dissolved in two
Chloromethanes crystallization, preferably cooling crystallization, most preferably program cooling crystallization.The present invention provides a kind of method for preparing II crystal form,
It is characterized by: compound shown in formula (A) is dissolved in methylene chloride, rate of temperature fall is 1.5K/min or 0.2K/min, crystallization
Temperature is -5 DEG C；Or it is 25 DEG C that rate of temperature fall, which is 1.5K/min crystallization temperature,.
The present invention also provides a kind of methods for preparing III crystal form, it is characterised in that: compound shown in formula (A) is dissolved in three
Chloromethanes crystallization precipitates crystal or is stored at room temperature crystallization, most preferably program cooling crystallization after preferably cooling down.The present invention provides one
The method that kind prepares III crystal form, it is characterised in that: compound shown in formula (A) is dissolved in chloroform, rate of temperature fall 1.5K/
Min or 0.2K/min, crystallization temperature are -5 DEG C；Or it is 25 DEG C that rate of temperature fall, which is 0.2K/min crystallization temperature,.
Inventor has attempted suspension rotating crystal method, in EtOH, H2O, MTBE, IPA, Heptane, 10% (V/V) H2O-
EtOH, 5% (V/V) H2O-IPA, MeOH, THF, ACE, Dioxane, EA, ACN multi-solvents system, 50 DEG C and 25 DEG C of two kinds of temperature
Degree condition) under I crystal is prepared.Inventor has attempted anti-solvent method, acetic acid-H2O, acetic acid-EtOH, acetic acid-
IPAC, acetic acid-MTBE, acetic acid-hexamethylene, acetic acid-IPA, acetic acid-Heptane, CH2Cl2—EtOH、CH2Cl2—
IPAC、CH2Cl2—MTBE、CH2Cl2- hexamethylene, CH2Cl2—IPA、CH2Cl2—Heptane、CHCl3—EtOH、CHCl3—
IPAC、CHCl3—MTBE、CHCl3- hexamethylene, CHCl3—IPA、CHCl3—Heptane、DMF—H2O、DMF—EtOH、
DMF—IPAC、DMF—MTBE、DMF—IPA、THF—H2O, THF-ETOH, THF-IPAC, THF-MTBE, THF-hexamethylene
Alkane, THF-IPA, THF-Heptane, Dioxane-EtOH, Dioxane-H2O、Dioxane—IPAC、Dioxane—
MTBE, Dioxane-hexamethylene, Dioxane-IPA, Dioxane-Heptane, Acetone-EtOH, Acetone-
IPAC, Acetone-MTBE, Acetone-hexamethylene, Acetone-IPA, Acetone-H2O、Acetone—Heptane、
MIBK—H2O, MIBK-ETOH, MIBK-IPAC, MIBK-MTBE, MIBK-IPA, MIBK-hexamethylene, MIBK-
HEPTANE、EA—H2O, EA-EtOH, EA-IPAC, EA-MTBE, EA-IPA, EA-hexamethylene, EA-Heptane,
MeOH—H2O, the multi-solvents system such as MeOH-EtOH, MeOH-IPAC, MeOH-MTBE, MeOH-IPA, obtains I crystal
Or crystal form is not obtained.Inventor has attempted volatility process, DCM, CHCl3, acetic acid, THF, Acetone, Dioxane, EA, MeOH etc.
Multi-solvents system obtains crystal form I.Inventor has attempted melting rotating crystal method, DSC as the result is shown rate of temperature fall be 20K/min,
When 10K/min, 2K/min, 1K/min, turn brilliant peak without heat release in temperature-fall period, only when rate of temperature fall is 5K/min
It waits, exothermic peak occurs, 5K/min crystal belongs to brilliant I to XRD as the result is shown, and finally obtained solid is nothing to remaining rate of temperature fall
Sizing.Inventor has attempted crystallisation by cooling method, rate of temperature fall be 1.5K/min, crystallization temperature be -5 DEG C when, DMF, acetic acid,
DMSO, THF, Dioxane, Acetone, butanone, ACN, 10% (V/V) H2O-ACN, MIBK, EA, MeOH, 10% (V/V) H2O-
It in the multi-solvents system such as MeOH, obtains I crystal or cannot get crystal form, only obtained II crystal form, CHCl in DCM system3Body
III crystal form has been obtained in system.Inventor has attempted crystallisation by cooling method, is 0.2K/min in rate of temperature fall, crystallization temperature is -5 DEG C
When, DMF, THF, Acetone, butanone, ACN, 10% (V/V) H2O-ACN, MIBK, EA, MeOH, 10% (V/V) H2O-MeOH etc.
It in multi-solvents system, obtains I crystal or cannot get crystal form, only obtained II crystal form, CHCl in DCM system3In system
III crystal form is arrived.Inventor has attempted crystallisation by cooling method, when rate of temperature fall is 1.5K/min, and crystallization temperature is 25 DEG C,
CHCl3, DMF, acetic acid, THF, Dioxane, Acetone, ACN, 10% (V/V) H2The multi-solvents such as O-ACN, MIBK, EA, MeOH
It in system, obtains I crystal or cannot get crystal form, only obtained II crystal form in DCM system.Inventor has attempted crystallisation by cooling
Method, when rate of temperature fall is 0.2K/min, and crystallization temperature is 25 DEG C, DCM, DMF, THF, Dioxane, Acetone, ACN, 10%
(V/V)H2In the multi-solvents system such as O-ACN, EA, MeOH, obtains I crystal or cannot get crystal form, only CHCl3It is obtained in system
III crystal form.
The invention further relates to the pharmaceutical composition of II crystal form, described pharmaceutical composition include II crystal form with it is pharmaceutically acceptable
Carrier, diluent or excipient.
The invention further relates to the pharmaceutical composition of III crystal form, described pharmaceutical composition include III crystal form with it is pharmaceutically acceptable
Carrier, diluent or excipient.
The invention further relates to a kind of methods for preparing pharmaceutical composition, including connect II crystal form pharmaceutically can at least one
Carrier, diluent or the excipient mixing received.
The invention further relates to a kind of methods for preparing pharmaceutical composition, including connect III crystal form pharmaceutically can at least one
Carrier, diluent or the excipient mixing received.
The invention further relates to the pharmaceutical composition comprising II crystal form and/or III crystal form preparation treatment and/or prevention with
Purposes in the drug of the related disease of COX-2 or illness, the disease or illness are selected from inflammation, pain, fever, cancer.
The invention further relates to pharmaceutical compositions prepared by II crystal form of application and/or III crystal form to treat and/or prevent in preparation
Purposes in the drug of disease related with COX-2 or illness, the disease or illness are selected from inflammation, pain, fever, cancer.
By X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC) to acquired formula (A) shownization
II, III crystal form for closing object carries out structure determination, crystal form research.
Starting material used in crystal form preparation method of the present invention can be compound shown in any form of formula (A), tool
Body form includes but is not limited to: unformed, any crystal form etc..
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, science used herein and skill
Art noun has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, being provided below
The definition and explanation of part relational language.In addition, as the definition and explanation of term provided herein and those skilled in the art
When the normally understood meaning of member institute is inconsistent, with the definition of term provided herein and it is construed to quasi-.
" X-ray powder diffraction collection or XRPD " of the present invention refers to according to bragg's formula 2d sin θ=n λ
(in formula, λ is the wavelength of X-ray,The series n of diffraction is any positive integer, generally takes first-order diffraction peak, n=
1), when X-ray is incident on a certain of crystal or partial crystals sample with sweep angle θ (complementary angle of incidence angle, also known as Bragg angle)
When on the atomic plane with d lattice plane spacing, it is just able to satisfy Bragg equation, to measure this group of X-ray powder diffraction
Figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers in sample heating or thermostatic process, measures sample
Temperature difference, differential heat flow between product and reference substance are obtained with characterizing all physical changes related with fuel factor and chemical change
The transformation information of sample.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree the error model of 2 θ
Enclosing is ± 0.1~± 0.5, preferably ± 0.1~± 0.3, more preferably ± 0.2.
" SGF " of the present invention, " FESSIF ", " FASSIF " respectively refer to the simulate the gastric juice containing pepsin, simulation
Gastric juice under the postprandial fed state of the mankind under enteral intestinal juice, the simulation mankind's starvation when empty stomach.
The invention further relates to II and/or III crystal forms and optional one kind or more including formula (A) compound represented
The pharmaceutical composition of kind pharmaceutical carrier and/or diluent.Described pharmaceutical composition can be made pharmaceutically acceptable any dose
Type.For example, the pharmaceutical preparation of II and/or III crystal form of formula (A) compound represented of the invention can be formulated as tablet, capsule
Agent, pill, granule, solution, suspension, syrup, injection (including injection, injection sterile powder and injection
Concentrated solution), suppository, inhalant or spray.
In addition, pharmaceutical composition of the present invention can also with any suitable administration mode, such as oral, parenteral,
The modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When being used to be administered orally, institute
Stating pharmaceutical composition can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or mouth
Take liquid preparation, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation may be used also
Include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the pharmaceutical preparation be can be made into
Injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, described pharmaceutical composition
The conventional method in existing pharmaceutical field can be used to be produced.It, can not in the pharmaceutical preparation when preparing injection
Additives are added, suitable additives can also be added according to the property of drug.When being used for rectally, the pharmaceutical preparation can
Suppository etc. is made.When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred implementations
In scheme, II and/or III crystal form of formula of the invention (A) compound represented is to treat and/or prevention effective dose is present in medicine
In compositions or drug.In certain preferred aspects, II and/or the III of formula (A) compound represented is brilliant
Type is present in pharmaceutical composition or drug in the form of unit dose.
Formula (A) compound ii and/or III crystal form can be used for preparing treatment disease related with COX-2 or illness
Purposes in drug.Therefore, the application further relates to, and II and/or III crystal form of formula (A) compound is used to prepare drug
Purposes, the drug are used to treat the purposes in the drug of disease related with COX-2.In addition, the application further relates to, a kind of suppression
The method for making disease related with cyclooxygenase comprising apply treatment and/or prevention effective dose to subject with this need
Formula (A) compound II and/or III crystal form or pharmaceutical composition of the invention.
In certain preferred aspects, the disease is selected from inflammation, pain, fever, cancer.
Detailed description of the invention
Fig. 1 is the XRPD map of compound ii crystal form shown in formula (A).
Fig. 2 is the DSC map of compound ii crystal form shown in formula (A).
Fig. 3 is the XRPD map of compound III crystal form shown in formula (A).
Fig. 4 is the DSC map of compound III crystal form shown in formula (A).
Fig. 5 is the concentration changes with time of II, III crystal form in water.
Fig. 6 is concentration changes with time of II, III crystal form in SGF.
Fig. 7 is concentration changes with time of II, III crystal form in FESSIF.
Fig. 8 is concentration changes with time of II, III crystal form in FASSIF.
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, and non-limiting the spirit and scope of the invention.
Experiment test equipment used
1, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model: Mettler Toledo DSC 3+STARe System
Purge gass: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 25-350
2, x-ray diffraction pattern (X-ray Powder Diffraction, XRPD)
Instrument model: Bruker D8 Discover A25 X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 10-48 °
Voltage: 40KV, electric current: 40mA
The preparation of embodiment 1, II crystal form
Modus ponens (A) compound 1g is added in reaction flask, and methylene chloride (2mL) is added and is stirred to dissolve.Reaction flask is placed
In heating and cooling device, according to temperature parameter setting in table 1, stirring rate 1000rpm is being cooled to -5 with 0.2 DEG C/min
30min starts that solid is precipitated after DEG C, and product is filtered drying.The X-ray powder diffraction spectrogram (XRPD map) of the crystallized sample
See that Fig. 1, DSC spectrogram are shown in Fig. 2, has sharp melting endothermic peak at about 183.5 DEG C, this crystal form is defined as II crystal form, 2 θ features
Peak position is as shown in table 2 below:
Table 1, temperature parameter
Table 2, II crystal form characteristic peak
The preparation of embodiment 2, III crystal form
Modus ponens (A) compound (1g) is added in reaction flask, and chloroform (4ml) is added and is stirred to dissolve, is stored at room temperature,
A large amount of solids are precipitated, filter.The X-ray powder diffraction spectrogram (XRPD map) of the crystallized sample is shown in that Fig. 3, DSC spectrogram are shown in Fig. 4,
There is sharp melting endothermic peak at about 183.7 DEG C, this crystal form be defined as III crystal form, 2 θ characteristic peak positions are as shown in table 3 below:
Table 3, III crystal form characteristic peak
The preparation of embodiment 3, III crystal form
Modus ponens (A) compound (1g) is added in reaction flask, and chloroform (4ml) is added and is stirred to dissolve, is cooled to -5
After DEG C, solid is precipitated, filters, obtains III crystal form.
Embodiment 4, II/III crystal form dynamic solubility
1, it weighs 30mg sample II/III crystal form respectively to be placed in intrinsic dissolution rate metal module, in 140 pounds of pressure
Under the conditions of keep 30s, be made dissolution sample；
2, the water of 10ml, SGF, FESSIF, FASSIF is taken to be placed in dissolution bottle respectively, 37 DEG C of heat preservations；
3, each crystal form is placed in above-mentioned 4 kinds of media respectively, revolving speed 100rpm, 5,15,30,45,60,90,
The separately sampled measurement concentration of 120min.
The dynamic solubility of II crystal form and III crystal form in physiological correlations medium is better than in water.In water and
In FESSIF, crystal form II dynamic solubility behavior is better than crystal form III, and in SGF and FASSIF, crystal form III is slightly excellent.
Claims (11)
1. II crystal form of compound shown in formula (A), it is characterised in that: in X-ray powder diffraction collection, 2 θ be 6.54,
10.27, there is characteristic peak at 11.72,13.21,14.52,15.03,16.32,17.00,18.89,19.70,
2. II crystal form as described in claim 1, which is characterized in that II crystal form 6.54,10.27,11.72,13.21,
14.52, there is characteristic peak at 15.03,16.32,17.00,18.89,19.70,20.65,21.72,22.23,23.71,24.56.
3. II crystal form as described in claim 1, which is characterized in that II crystal form 6.54,10.27,11.72,13.21,
14.52、15.03、16.32、17.00、18.89、19.70、20.65、21.72、22.23、23.71、24.56、25.60、
29.53, there is characteristic peak at 31.33,36.70,43.51.
4. III crystal form of compound shown in formula (A), it is characterised in that: in X-ray powder diffraction collection, 2 θ be 5.90,
8.59, there is characteristic peak at 9.27,9.56,13.13,15.21,15.49,16.60,17.50,18.10,19.42.
5. III crystal form as claimed in claim 4, which is characterized in that III crystal form 5.90,8.59,9.27,9.56,
13.13、15.21、15.49、16.60、17.50、18.10、19.42、20.29、21.31、21.50、22.30、23.45、24.24
There is characteristic peak at place.
6. III crystal form as claimed in claim 4, which is characterized in that III crystal form 5.90,8.59,9.27,9.56,
13.13、15.21、15.49、16.60、17.50、18.10、19.42、20.29、21.31、21.50、22.30、23.45、
24.24, there is spy at 25.29,26.36,26.66,27.62,29.27,30.49,33.56,35.39,40.94,43.72,46.67
Levy peak.
7. a kind of method for preparing II crystal form as described in any one of claim 1-3, it is characterised in that: by formula (A) shownization
It closes object and is dissolved in methylene chloride crystallization, Crystallization method is selected from room temperature crystallization, cooling crystallization, solvent flashing crystallization or addition crystal seed and lures
Crystallization is led, preferably cooling crystallization, most preferably program cooling crystallization.
8. the method for II crystal form of preparation as claimed in claim 7, the detailed process of program cooling crystallization are as follows: formula (A) compound
It is added in reaction flask, methylene chloride is added and is stirred to dissolve, reaction flask is placed in heating and cooling device, and stirring rate is
1000rpm, temperature parameter setting are as follows:
By the filtering of obtained crystal, drying.
9. a kind of method for preparing III crystal form as described in any one of claim 4-6, it is characterised in that: by formula (A) shownization
It closes object and is dissolved in chloroform crystallization, Crystallization method is selected from room temperature crystallization, cooling crystallization, solvent flashing crystallization or addition crystal seed and lures
Crystallization is led, preferably cooling crystallization or is stored at room temperature crystallization, most preferably program cools down crystallization.
10. II crystal form and at least one pharmaceutically acceptable carrier, diluent or tax as described in any one of claim 1-3
The method that shape agent is mixed with pharmaceutical composition.
11. III crystal form and at least one pharmaceutically acceptable carrier, diluent or tax as described in any one of claim 4-6
The method that shape agent is mixed with pharmaceutical composition.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| CN101774958A (en) * | 2009-01-13 | 2010-07-14 | 江苏恒瑞医药股份有限公司 | I-type crystallization of N-n-propyl-3-(4-methylphenyl)-4-(4-mesylphenyl)-2,5-dihydropyrrole-2-ketone and manufacturing method thereof |
| CN102206178A (en) * | 2010-03-30 | 2011-10-05 | 上海源力生物技术有限公司 | Method for preparing imrecoxib |
| CN104193664A (en) * | 2014-08-22 | 2014-12-10 | 山东铂源药业有限公司 | Synthesis method of imrecoxib |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
| CN101774958A (en) * | 2009-01-13 | 2010-07-14 | 江苏恒瑞医药股份有限公司 | I-type crystallization of N-n-propyl-3-(4-methylphenyl)-4-(4-mesylphenyl)-2,5-dihydropyrrole-2-ketone and manufacturing method thereof |
| CN102206178A (en) * | 2010-03-30 | 2011-10-05 | 上海源力生物技术有限公司 | Method for preparing imrecoxib |
| CN104193664A (en) * | 2014-08-22 | 2014-12-10 | 山东铂源药业有限公司 | Synthesis method of imrecoxib |
Non-Patent Citations (1)
| Title |
|---|
| AI PING BAI,等: "Design, Synthesis and in vitro Evaluation of a New Class of Novel Cyclooxygenase-2 Inhibitors: 3, 4-diaryl-3-pyrrolin-2-ones", 《CHINESE CHEMICAL LETTERS》 * |
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