CN110003183A - 2-(2,4,5- replace phenylaminos) pyrimidine derivatives and its crystal form B - Google Patents
2-(2,4,5- replace phenylaminos) pyrimidine derivatives and its crystal form B Download PDFInfo
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- CN110003183A CN110003183A CN201910280191.4A CN201910280191A CN110003183A CN 110003183 A CN110003183 A CN 110003183A CN 201910280191 A CN201910280191 A CN 201910280191A CN 110003183 A CN110003183 A CN 110003183A
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- buddhist nun
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- crystal form
- pyrimidine derivatives
- replace
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- 239000013078 crystal Chemical group 0.000 title claims abstract description 35
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 title claims abstract description 12
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims abstract description 11
- 150000003230 pyrimidines Chemical group 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 24
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 12
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 11
- 201000005202 lung cancer Diseases 0.000 claims abstract description 11
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000001228 spectrum Methods 0.000 claims description 5
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- 239000003560 cancer drug Substances 0.000 claims description 2
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- 239000000470 constituent Substances 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 claims 1
- 206010044565 Tremor Diseases 0.000 abstract description 30
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 abstract description 8
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 abstract description 8
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 abstract description 8
- 231100000331 toxic Toxicity 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 6
- 230000035772 mutation Effects 0.000 abstract description 4
- 239000002547 new drug Substances 0.000 abstract description 3
- 230000000857 drug effect Effects 0.000 abstract description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 14
- 229960003278 osimertinib Drugs 0.000 description 12
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 12
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- 230000001093 anti-cancer Effects 0.000 description 7
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- -1 amino - Chemical class 0.000 description 3
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
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- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical class C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- HGKNKZDYFSNEAN-UHFFFAOYSA-N C(C)(=O)O.C(C)[P]CC Chemical compound C(C)(=O)O.C(C)[P]CC HGKNKZDYFSNEAN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical class CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
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- 238000011953 bioanalysis Methods 0.000 description 1
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- 229940125904 compound 1 Drugs 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
- 229950002205 dacomitinib Drugs 0.000 description 1
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- 238000003745 diagnosis Methods 0.000 description 1
- WSFSSNUMVMOOMR-DICFDUPASA-N dideuteriomethanone Chemical compound [2H]C([2H])=O WSFSSNUMVMOOMR-DICFDUPASA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000004989 laser desorption mass spectroscopy Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- FUKSNUHSJBTCFJ-UHFFFAOYSA-N osimertinib mesylate Chemical compound CS(O)(=O)=O.COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 FUKSNUHSJBTCFJ-UHFFFAOYSA-N 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of novel anti-lung-cancer medicaments, and in particular to 2- (2,4,5- replace phenylamino) pyrimidine derivatives I and its crystal form B belong to field of medicinal chemistry.It has the following structure:According to medicine generation and drug efficacy study as a result, compared with Austria is uncommon for Buddhist nun, the uncommon N-Me metabolite being more toxic that significantly reduces for Buddhist nun of trembling is generated, and maintain or improves drug effect.It trembles to wish and is expected to develop into the uncommon treatment non-small cell lung cancer new drug with EGFR mutation safer and more effective for Buddhist nun more difficult to understand for Buddhist nun.
Description
Technical field
The present invention relates to a kind of novel anti-lung-cancer medicaments, and in particular to 2- (2,4,5- replace phenylamino) pyrimidine derivatives and
Its crystal form B, belongs to field of medicinal chemistry.
Background technique
Lung cancer is one of highest malignant tumour of morbidity and mortality, and there are about 1,600,000 people to die of this kind of cancer every year in the whole world
Disease, China reach 800,000 in lung cancer patient in 2017.Non-small cell lung cancer (non-small cell lung cancer,
NSCLC) as " overwhelming majority " of lung cancer, account for about the 85% of cases of lung cancer；Recent years, non-small cell lung cancer (NSCLC)
Diagnosis and treatment, which have had, to be significantly changed.As non-small cell lung cancer enters the precisely medical epoch, according to the gene expression characteristics of patient's lung cancer
Selecting corresponding targeted drug treatment is current fashion trend.Especially late in the treatment of non-small cell lung cancer, medicine is targeted
Play key player.EGFR is the most common gene mutation of Patients with Non-small-cell Lung, corresponding targeted drug EGFR-TKI
Also it has listed for many years.According to some sayings sanctified by usage, EGFR-TKI is divided into three generations at present: first on behalf of Gefitinib, strategic point
Replace Buddhist nun and Conmana in Lip river；The second generation has Afatinib, Dacomitinib；The third generation is only a difficult to understand uncommon on Buddhist nun at present
City.Under normal conditions, patients with advanced NSCLC can first use first generation EGFR- after genetic test confirmation EGFR mutation
TKI treatment.But regrettably, nearly all patient for taking EGFR-TKI to the end all can drug resistance, and cause drug resistance most important
The reason of be exactly T790M mutation.Therefore, drug resistance caused by overcoming T790M to be mutated is exactly the mission of EGFR-TKI of new generation, Ao Xi
It is exactly outstanding person therein for Buddhist nun.Ao Xi is researched and developed for Buddhist nun by Astrazeneca AB, and development phase code name is AZD9291.2017 3
Month, the state food Drug Administration general bureau approval uncommon application of import for Buddhist nun difficult to understand, away from the whole world, the approval time is only separated by 1 year 04 for the first time
A month.The examination & approval link that Ao Xi lists for Buddhist nun in China only used time 7 months, embody the urgency of patient demand from side.But
Be, the uncommon indoles N- methyl for Buddhist nun of Austria be easy to be aoxidized by intracorporal P450 and slough generation demethylation-Ao Xi for Buddhist nun (AZ5104,
It is as follows).It is more uncommon for the 14.5 times strong of Buddhist nun than difficult to understand that AZ5104 inhibits the activity of wild EGFR, and anticancer activity is only 7.5 times strong.Moreover,
To the inhibiting effect of wild EGFR be considered it is related with the generation of the toxic side effects such as fash after medication (J.Med.Chem.2014,
57,8249), thus, it is found that anticancer activity is stronger, the smaller novel therapeutic lung cancer drug of toxic side effect is still very necessary.
It is a series of that Henan Mei Taibao Biology Pharmacy Co., Ltd has developed 2- (2,4,5- replace phenylamino) pyrimidine derivatives
New drug, and applied for that patent " 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, preparation method and its is preparing antineoplastic
Application in object " (2017112825988).To find the better compound of bioactivity, applicant carries out on this basis
It is further compound-modified.
Summary of the invention
It is an object of that present invention to provide a kind of novel anti-lung-cancer medicaments --- 2- (2,4,5- replace phenylamino) pyrimidine derivates
Object I and its crystal form B, compound I referred to as tremble uncommon for Buddhist nun (Dositinib).
Purpose to realize the present invention, technical solution are as follows:
It trembles uncommon for Buddhist nun's Chinese chemical name: N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl group -5-
((4- (the deuterated Methyl-1H-indole -3- of 1-) pyrimidine -2-) amino -) deuterated acetamido benzene) English language Chemical name: N- (2-
{[(2-(Dimethylamino)ethyl)](methyl) amino)-4-methoxy-5-((4-(d3-1-methyl-1H-
indol-3-yl)pyrimidin-2-yl) amino)phenyl)d2-acrylamide-mesylate.The structural formula of compound
It is as follows:
The present inventor is by preclinical animal medicine generation and pharmacodynamic study discovery, the uncommon indoles N- demethy lation for Buddhist nun of trembling
The production quantity of the product AZ5104-2D uncommon AZ5104 (see Fig. 2-5 and table 1) for Buddhist nun more difficult to understand reduce respectively 98% (male mouse) and
83% (female mice), this advantageously reduces the toxic side effect generated because inhibiting wild EGFR.
Table 1 is trembled the uncommon pharmacokinetics in rats result for Buddhist nun and AZ9291
The present inventors have additionally discovered that the uncommon advantage crystal form for Buddhist nun of trembling is crystal form B.Rapid crystallization or by solvent evaporate obtained by
Crystal form be A or A and B mixed crystal.And AZD9291 obtains the mixture (Fig. 8) of crystal form A and B under similarity condition,
Commercially available is also the mixture of crystal form A and B.It trembles uncommon more uncommon than Austria of purchase for Buddhist nun's bulk pharmaceutical chemicals (Fig. 8, crystal form A for Buddhist nun's crystal form B
With the mixture of B) it is significantly improved in the anticancer activity of HCC-827 nude mice model, the former is 2 times (Fig. 1) of the latter.The medicine of animal
For dynamics research, the result shows that, the uncommon bioavilability for replacing Buddhist nun's crystal form B of trembling improves 20% compared with the bulk pharmaceutical chemicals of AZD9291 mixed crystal
(Fig. 2-5, table 1).The uncommon raising for replacing Buddhist nun's crystal form B ratio AZD9291 mixed crystal bioavilability of trembling may be what its anticancer activity enhanced
One of reason.
The uncommon CuK α-XRD spectrum for replacing Buddhist nun's crystal form B of trembling is as shown in Fig. 7.
The invention has the advantages that 1, through medicine generation and drug efficacy study as a result, it was confirmed that compared with Austria is uncommon for Buddhist nun, tremble it is uncommon for Buddhist nun or
Its crystal form B can substantially reduce the generation for the indoles N demethy lation product being more toxic, and improve drug effect.2, it trembles uncommon brilliant for Buddhist nun
The bioavilability of type B is more preferable.Therefore, it trembles to wish and is expected to develop into the uncommon treatment safer and more effective for Buddhist nun more difficult to understand with EGFR for Buddhist nun
The non-small cell lung cancer new drug of mutation.
Detailed description of the invention
Fig. 1 is to tremble to wish to replace Buddhist nun's anticancer activity (HCC-827) comparison diagram for Buddhist nun's crystal form B and Austria are uncommon；
Fig. 2 be tremble it is uncommon for tremble in blood plasma after Buddhist nun's crystal form B 12mg/kg dosage stomach-filling male and female mouse it is uncommon for Buddhist nun's mean concentration with
Time variation diagram；
Fig. 3 is that difficult to understand wish replaces Buddhist nun's mean concentration for Ao Xi in blood plasma after Buddhist nun (AZD9291) 12mg/kg dosage stomach-filling male and female mouse
Change over time figure；
Fig. 4 be tremble it is uncommon for AZ5104-D2 mean concentration in blood plasma after Buddhist nun's crystal form B 12mg/kg dosage stomach-filling male and female mouse with
Time variation diagram；
Fig. 5 is that difficult to understand wish changes over time for AZ5104 mean concentration in blood plasma after Buddhist nun 12mg/kg dosage stomach-filling male and female mouse
Figure；
Fig. 6 is the uncommon DSC and TGA map for Buddhist nun's crystal form B of trembling.
Fig. 7 is uncommon CuK α-XRD spectrum for Buddhist nun's crystal form B of trembling.
Fig. 8 is eutectic CuK α-XRD spectrum of commercially available AZD9291.
Specific embodiment
It is as follows for embodiment for the present invention is better described:
Embodiment 1 prepares intermediate 9
Step 1:
DMF of the pre-cooling at 0-15 DEG C is added in compound 1 (2.00kg, 1.71mol) and KOH (1.44kg, 25.6mol)
In (6.0L), mixture stirs 0.5h.Compound 2 (2.47kg, 17.1 mol) is instilled into said mixture in 0-5 DEG C, 4h
In, reaction mixture continues to stir 2h at 0-10 DEG C, then 5-15 DEG C of stirring 12h.After ice water (15.0L) is added, petroleum ether is used
The extraction of (10L) and methyl tertiary butyl ether (10.0L) mixed liquor, organic phase are washed with salt, Na2SO4It dries, filters, boils off solvent and obtain
One grease (2.60kg, 82% purity, contain solvent).1H NMR(400MHz,DMSO-d6)δppm 6.41-6.48(m,1H)；
6.96-7.03(m,1H)；7.03-7.05(m,1H)；7.11-7.17 (m,1H)；7.24-7.26(m,1H)；7.55-7.57(m,
1H)。
Second step
By compound 4 (2.42kg, 16.24mol), DME (8.0L) and anhydrous FeCl3(2.64kg, 16.3mol) is added
In reactor, reaction temperature is controlled at 10 DEG C, is then heated to 60 DEG C.By the DME of compound 3 (2.18kg, 16.2mol)
(2.0L) solution is added, and is stirred to react 2h.Reaction mixture successively is added in methanol (5.0L) and water (10L) at 10-30 DEG C, is stirred
0.5h is mixed, red solid (6kg) is obtained by filtration.It is mixed, is obtained by filtration red solid with second cyanogen (12.0L) and water (24.0L)
Body (4kg).1h is mixed with second cyanogen (5.0L) again, filters, it is dry, obtain product 5 (2.14kg, 54%).1H NMR
(400MHz,DMSO-d6)δppm 7.20-7.36(m,2H)；7.58 (br d, J=7.70Hz, 1H)；7.82 (d, J=
5.38Hz,1H)；8.41 (br d, J=7.58Hz, 1H)； 8.47-8.57(m,2H).
Third step
By compound 5 (1.0kg, 3.81mol), second cyanogen (8.0L), p-methyl benzenesulfonic acid monohydrate (0.435 kg,
It 2.29mol) is mixed in reactor with compound 6 (0.852kg, 4.57mol), in 80 DEG C of stirring 12h, is cooled to 20 DEG C, mistake
Filter.Obtained solid is washed with second cyanogen (3.0L x 6), is dried to obtain a yellow solid 7 (1.2kg, 85%) in air.1H NMR
(400MHz,DMSO-d6)δppm 4.00 (s,3H)；7.09-7.17(m,1H)；7.31 (t, J=7.64Hz, 1H)；7.40-
7.52(m, 2H)；7.59 (d, J=8.19Hz, 1H)；8.09-8.40(m,2H)；8.49-8.69(m,1 H)；8.83(br d,J
=7.83Hz, 1H)
4th step
By compound 7 (3.60kg, 8.81mol), DIPEA (1.76kg, 13.6mol), DMA (14.4 L) add at 15 DEG C
Enter compound 8 (1.11kg, 10.9mol).Reaction mixture is added second cyanogen (21.6L) in 80 DEG C of stirring 12h, is cooled to 20
DEG C, red solid, filtering is precipitated, second cyanogen (12L) is washed, and solid 9 (3.45kg, 81%) is obtained.1H NMR(400MHz,DMSO-
d6) δ ppm 2.16 (s, 6H) 2.44-2.48 (m, 2H) 2.86 (s, 3H) 3.26 (t, J=6.85Hz, 2H) 3.95 (s, 3H)
6.85 (s, 1H) 7.11 (t, J=7.52Hz, 1H) 7.18-7.29 (m, 2H) 7.52 (d, J=8.07Hz, 1H) 8.09 (s, 1H)
8.27-8.42(m,3H)8.62(s,1H).
Embodiment 2, prepare compound 12
The first step
By compound 9 (2.39g, 5mmol), MeOH (200mL), ammonium formate (2.39g) and palladium carbon (200 mg, 5%) according to
Secondary addition single port bottle, compound of reaction stir 16h under hydrogen balloon, and filtering, filtrate is concentrated to dryness, and are added water (100mL), with full
It is 9 with sodium bicarbonate solution tune pH, mixture extracts (3x 100mL) with DCM, and organic phase merges, Na2SO4It dries, filters, steams
Solvent is gone to obtain white solid 10 (2.05g, 91%).1H-NMR(400MHz,DMSO-d6) δ 2.18 (s, 6H), 2.36 (t, J=
6.8Hz, 2H), 2.64 (s, 3H), 2.89 (t, J=6.8Hz, 2H), 3.75 (s, 3H), 4.58 (br s, 2H), 6.77 (s,
1H), 7.23-7.27 (m, 3H), 7.50-7.53 (m, 2H), 7.79 (s, 1H), 8.28 (d, J=5.2Hz, 1H), 8.30 (s,
1H), 8.43 (d, J=8.0Hz, 1H).LCMS[M+1]+:449.3。
Second step
By compound 10 (4.93g, 0.011mol), diethyl phosphorus acetic acid (2.35g, 0.012mol) and N, N- diisopropyl
Ethamine (1.68g, 0.013mol) is dissolved in tetrahydrofuran (25mL), is slowly added into HATU (4.94g, 0.013mol).It has been added
Bi Hou, 25 DEG C are continued stirring 5 hours.Reaction solution pours into water (50mL), and is extracted with ethyl acetate (50mL x 2), is associated with
Machine phase.Organic phase washed with water (50mL x 4) and semi-saturation saline solution (50mL x 4) washing, anhydrous Na2SO4It is dry, concentration
Faint yellow solid 11 (4.93g, yield 71.5%) is obtained, does not have to purifying, is directly used in the next step.1HNMR (400MHz,
DMSO-d6): δ 1.26 (t, J=7.2Hz, 6H), 2.20 (s, 6H), 2.31 (m, 2H), 2.70 (s, 3H), 2.94 (m, 2H),
3.12,3.17 (ss, 2H), 3.84 (s, 3H), 4.11 (q, J=7.2Hz, 4H), 7.02 (s, 1H), 7.16-7.27 (m, 3H),
7.53 (d, J=7.2Hz, 1H), 7.92 (s, 1H), 8.23 (d, J=8.0Hz, 1H), 8.31 (d, J=5.2Hz, 1H), 8.62
(s,1H),8.97 (br,1H),9.86(s,1H)。LCMS[M+1]+:627.3
Third step
By compound 11 (100mg, 0.16mmol), (CD2O)n(5mg, 0.05mmol), lithium chloride (10 mg,
0.24mmol), potassium hydroxide (27mg, 0.48mmol) is dissolved in THF/H2In O (1mL/0.5mL) solution, it is stirred overnight at room temperature
(16h).Water (5mL) is added into reaction solution, is extracted with ethyl acetate (10mL), and successively uses water (5mL x 2), saline solution
(10mL x 2) washing.Organic phase is dry with anhydrous sodium sulfate, is concentrated to get crude product (90mg), and column chromatographs (eluent: dichloromethane
Alkane: methanol=10:1) isolated faint yellow solid 12 (50mg, yield 62%).1HNMR(400MHz,DMSO-d6):δ2.24
(s, 6H),2.30(br,2H),2.72(s,3H),2.89(br,2H),3.87(s,3H),6.43(s, 1H),7.05(s,1H),
7.16 (m, 1H), 7.24 (m, 2H), 7.53 (d, J=8.4Hz, 1H), 7.89 (s, 1H), 8.24 (d, J=7.6Hz, 1H), 8.33
(d, J=5.2Hz, 1H), 8.68 (s, 1H), 9.16 (s, 1H), 10.20 (br, 1H).LCMS[M+1]+:505.3。
The preparation of 3 compound I crystal B of embodiment
Acetone (55mL) is added in compound 12 (5.04g, 10mmol), then in 50 DEG C of addition water (5 mL), to reaction solution
It is added dropwise methanesulfonic acid (0.94g, 9.8mmol), has solid precipitation, in 50 DEG C of stirring 1h.It is cooled to room temperature, filters, obtained solid is used
Acetone (5mL) is washed, and 25 DEG C of vacuum drying obtain solid product (5.5g, 91%).1HNMR(400MHz,DMSO-d6):δ2.72,
2.75 (ss, 6H), 2.90 (s, 6H), 3.29 (m, 2H), 3.50 (m, 2H), 4.03 (s, 3H), 6.56 (s, 1H), 6.99 (s,
1H), 7.21 (m, 3H), 7.46 (d, J=8.0Hz, 1H), 8.17 (s, 1H), 8.26 (d, J=5.6Hz, 1H), 8.35 (d, J=
7.6Hz, 1H), 8.67 (s, 1H).LCMS[M+1]+:505.3。
The characterize data of the monocrystalline B of compound I is as follows:
The preparation of embodiment 4, mixed crystal type
Compound 12 or AZD9291 (1mmol) are dissolved in ethyl alcohol (6mL), at 50 DEG C, by the second of methanesulfonic acid (1mmol)
Cyanogen (2mL) solution is added, and stirs 0.5h, filters after being cooled to room temperature, petroleum ether is washed, and is air-dried to obtain mixed crystal product.
Embodiment 5 is trembled and is wished for Buddhist nun's monocrystalline B and AZD9291 to Non-small cell lung carcinoma HCC827 cell Subcutaneous Xenograft
The internal pharmacodynamic study of tumour BALB/c nude mouse model
Cell culture: Non-small cell lung carcinoma HCC827 (ATCC-CRL-2868) cultured in monolayer in vitro, condition of culture are as follows:
In RPMI-1640 culture medium plus 10% fetal calf serum of mass percentage, 100U/mL penicillin and 100 μ g/mL streptomysins, 37
At DEG C, percent by volume 5%CO2Incubator culture.Biweekly conventional digestion processing passage is carried out with pancreas enzyme -EDTA.Work as cell
Saturation degree is that 80%-90% collects cell when quantity arrival requires, and is counted, inoculation.
Animal: BALB/c nude mouse, female, 6-8 week old, 18-22 grams of weight.60 (40+50%) are needed altogether only.By Shanghai
Western Poole-Bi Kai experimental animal Co., Ltd or other companies provide.
Tumor inoculation: by 0.2mL (1 × 107It is a) HCC827 cell (adding matrigel, volume ratio 1:1) inoculate in
The right back of every mouse, tumor average volume reach 150-200mm3When start grouping administration.Experimental group and dosage regimen
It see the table below.
Zoopery grouping and dosage regimen:
Note:
1.N: every group mouse number
2. volume is administered: according to 10 μ l/g of mouse weight.If weight loss is more than 15%, dosage regimen should be made accordingly
Adjustment.
Experimental index: experimental index is to investigate whether tumour growth is suppressed, delays or cures.Vernier calliper is used twice a week
Ruler measures diameter of tumor.The calculation formula of gross tumor volume are as follows: V=0.5a × b2, a and b respectively indicate the major diameter and minor axis of tumour.
The tumor suppression curative effect of compound is evaluated with TGI (%) or Relative tumor proliferation rate T/C (%).TGI (%) reflects tumour
Growth inhibition ratio.The calculating of TGI (%): TGI (%)=[(1- (mean tumor volume-processing group at the end of certain processing group is administered
Mean tumor volume when starting administration))/(when mean tumor volume-solvent control group starts treatment when solvent control group treatment end
Mean tumor volume)] × 100%.
Relative tumor proliferation rate T/C (%): calculation formula is as follows: T/C%=TRTV/CRTV× 100% (TRTV: treatment group
RTV；CRTV: negative control group RTV).Relative tumour volume (relative tumor is calculated according to the result of measurement of tumor
Volume, RTV), calculation formula RTV=Vt/V0, wherein V0(i.e. d0) measurement averaging of income gross tumor volume when being grouping administration,
VtMean tumour volume when for certain one-shot measurement, TRTVWith CRTVTake same day data.
It will test tumor weight after the end of the experiment, and calculate T/CweightPercentage, TweightAnd CweightRespectively indicate to
The knurl weight of medicine group and vehicle control group.
Data analysis: T, which is examined, is used for two comparison among groups.Three groups or more comparison among groups one-way ANOVA.If F value
There is significant difference, carries out Multiple range test again after Ying ANOVA analysis.All data analyses are carried out with SPSS 17.0.p<
0.05 thinks there is significant difference.
Pharmaceutical results are wished as shown in Figure 1, trembling for 0.5 mg/kg of Buddhist nun's monocrystalline B (code name 90-1408) in nude mice HCC-827
The anticancer activity of model is equivalent to 1 mg/kg of AZD9291.Show to tremble uncommon living in the anticancer of this model for Buddhist nun's monocrystalline B
Property improves 1 times compared with AZD9291.
Embodiment 5, the uncommon pharmacokinetic for Buddhist nun and AZD9291 of trembling
(1) test solution is prepared
(1) preparation of Bolos intravenous administration preparation:
A. suitable compound powder is weighed into suitable container.
B. D5W (5% glucose of mass percentage) aqueous solution of certain volume is added, is vortexed or stirring is straight
To obtaining clear solution (heating means hydrotropy can be taken when necessary).
C. D5W (5% glucose) aqueous solution of residual volume is added, be vortexed or stirs to obtaining clear solution.It will prepare
Good 0.22 μm of filtering with microporous membrane degerming of intravenous administration formulation, is kept in dark place in 2 DEG C to 8 DEG C.Bolos intravenous administration preparation be to
It prepares on the day of medicine, and is administered after carrying out analysis of pharmaceutical dosage forms.
(2) preparation of oral administration preparation:
A. suitable compound powder is weighed into suitable container.
B. the mass percentage 0.5%HPMC (hydroxypropyl methyl cellulose, 4000CP) that proper volume is added is water-soluble
Liquid is stirred continuously or is vortexed to obtaining uniform solution.
A) 0.5%HPMC (hydroxypropyl methyl cellulose, the 4000CP) aqueous solution of residual volume is added to final volume, no
Disconnected stirring is vortexed to obtaining uniform solution.
Gastric infusion preparation is to prepare administration the previous day, and carry out analysis of pharmaceutical dosage forms, and preparation is protected from light when not used is placed on 2 DEG C to 8
It saves in DEG C refrigerator, is used in 8 days.
Animal: rat (SD), Beijing Vital River Experimental Animals Technology Co., Ltd., 36 rats (18 males and 18
Only female), 6-10 week old, 200~300g (male)；170~280g (female) is tested first day, and the 1st group of animal is quiet by tail
Arteries and veins single injection is given to tremble and be wished for Buddhist nun's monocrystalline B (code name 90-1408) solution；2nd, 3,4 group of animal distinguish stomach-filling mode orally to
It gives trembling for various dose to wish for Buddhist nun's monocrystalline B (code name 90-1408) solution, administered volume is shown in 4.4 parts；5th group of animal, daily one
Secondary, continuous 7 days, stomach-filling was given to tremble and be wished for Buddhist nun's monocrystalline B (code name 90-1408) solution, administered volume 10mL/kg, the 6th group of animal
AZD9291 (Mesylate) solution, administered volume 10mL/kg are given by stomach-filling mode single oral.Before administration and it is administered
Afterwards 0.083,0.25,0.5,1,2,4,6,8,12, for 24 hours.
Medication: whole blood sample is acquired in the defined time by way of jugular vein (or other suitable blood sampling sites) puncture
(the 5th group of about 0.15mL, other groups of about 0.23mL), whole wet ice operation, and practical blood sampling time is recorded in experimental record.It adopts
Collecting time point acceptable error is time point ± 1 minute in administration 1 hour, and other times are theoretical time ± 5%.Blood
After sample acquisition, be immediately transferred into label contains K2In the commercialization centrifuge tube of-EDTA, subsequent centrifugal treating (3,
000g, 4 DEG C, 15 minutes) after take blood plasma.Blood plasma is transferred to centrifuge tube, it is quick-frozen in dry ice, and it is stored in -60 DEG C or lower
Ultra low temperature freezer in, until carry out LC-MS/MS analysis (1-4 group and the 6th group analysis mother medicine and its metabolin, the 5th group only
Analyze female medicine).
Plasma sample: it trembles and wishes for Buddhist nun's monocrystalline B and AZD9291 and its metabolin AZ5104-D2 and AZ5104 in blood plasma
Concentration is by bioanalysis department, Shanghai Yaoming Kangde New Medicine Development Co., Ltd using the high performance liquid chromatography-series connection matter confirmed
Spectrum (LC-MS/MS) is measured.
Compound and the integral of interior target retention time, chromatogram acquisition and chromatogram use software Analyst
(Applied Biosystems) is handled, and the statistics of data uses software Watson LIMS (Thermo Fisher
Scientific) or Analyst (Applied Biosystems) is handled.Analyte concentration unit is nM in sample, is protected
After staying 3 effective digitals, all numerical value (such as: % deviation and the % coefficient of variation) being expressed as a percentage to remain into decimal point
One.
Data analysis and report: WinNonlin is usedTMVersion 6.3(Pharsight,Mountain View, CA)
Or the non-compartment model of the pharmacokinetics software of the above version handles blood concentration, it is dynamic to calculate medicine using linear-log trapezoidal method method
Learn parameter.
By the research of preclinical animal pharmacokinetics and pharmacodynamics, it is surprisingly found by the inventors that, uncommon replace of trembling of crystal form B
The bioavilability of Buddhist nun improves 20% (being shown in Table 1) compared with the AZD9291 of mixed crystal, is conducive to improve the uncommon anti-lung cancer medicine for Buddhist nun of trembling
Effect.Meanwhile the uncommon indoles N- demethy lation product AZ5104-2D for Buddhist nun that the trembles uncommon AZ5104 for Buddhist nun more difficult to understand is (see Fig. 2-5 and table
1) production quantity reduces 98% (male mouse) and 83% (female mice) respectively, this is beneficial to reduce due to it inhibits wild EGFR
The toxic side effects such as the fash of generation.Compared with Austria is uncommon for Buddhist nun, the uncommon efficacy and saferry for replacing Buddhist nun in treatment non-small cell lung cancer of trembling
Aspect may have apparent clinical advantage.
Claims (5)
1.2- (2,4,5- replace phenylamino) pyrimidine derivatives I, which is characterized in that structural formula is as follows:
2. the crystal form B of 2- (2,4,5- replace phenylamino) pyrimidine derivatives I as described in claim 1, which is characterized in that its
CuK α -2 θ of XRD spectrum 8.55,9.47,10.31,12.65,14.47,15.17,15.61,16.29,17.07,17.31,
17.73、18.22、18.74、19.47、19.70、20.24、20.72、21.68、22.08、22.80、23.50、23.99、
24.20, there is characteristic peak at 24.83,25.65,26.15,26.99,27.69,28.30,29.57,30.74,32.58, wherein 2 θ
Being worth error range is ± 0.2.
3. 2- (2,4,5- replace phenylamino) pyrimidine derivatives I crystal B as claimed in claim 2, which is characterized in that its CuK
α-XRPD map is as shown in Fig. 7.
4. 2- (2,4,5- replace phenylamino) pyrimidine derivatives I or its crystal form B as described in one of claim 1-3 is in medicine
Application in object preparation, which is characterized in that compound I or its crystal form B is used to prepare treatment non-small cell lung as active constituent
In the drug of cancer.
5. 2- (2,4,5- replace phenylamino) pyrimidine derivatives I or its crystal form B as claimed in claim 4 is in medicine preparation
Using, which is characterized in that compound I or its crystal form B merges with other Remedies for lung cancer is used to prepare treatment non-small cell lung cancer
Drug in.
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| CN113582976A (en) * | 2021-08-24 | 2021-11-02 | 郑州大学 | Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative and preparation method and application thereof |
| US20220024897A1 (en) * | 2019-04-09 | 2022-01-27 | Henan Genuine Biotech Co., Ltd. | 2-(2,4,5-substituted phenylamino) pyrimidine derivative and crystalline form b thereof |
| WO2024183644A1 (en) * | 2023-03-03 | 2024-09-12 | 河南真实生物科技有限公司 | Anti-tumor pharmaceutical composition comprising azvudine |
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| CN108779102A (en) * | 2015-12-27 | 2018-11-09 | 纽弗姆制药有限公司 | For treating cancer and relevant disease and the deuterated compound of the patient's condition and combinations thereof and method |
| CN108047205A (en) * | 2016-12-14 | 2018-05-18 | 河南美泰宝生物制药有限公司 | 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared |
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| US20220024897A1 (en) * | 2019-04-09 | 2022-01-27 | Henan Genuine Biotech Co., Ltd. | 2-(2,4,5-substituted phenylamino) pyrimidine derivative and crystalline form b thereof |
| CN113582976A (en) * | 2021-08-24 | 2021-11-02 | 郑州大学 | Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative and preparation method and application thereof |
| WO2024183644A1 (en) * | 2023-03-03 | 2024-09-12 | 河南真实生物科技有限公司 | Anti-tumor pharmaceutical composition comprising azvudine |
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