CN101511829A - 2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成 - Google Patents
2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成 Download PDFInfo
- Publication number
- CN101511829A CN101511829A CNA2007800334161A CN200780033416A CN101511829A CN 101511829 A CN101511829 A CN 101511829A CN A2007800334161 A CNA2007800334161 A CN A2007800334161A CN 200780033416 A CN200780033416 A CN 200780033416A CN 101511829 A CN101511829 A CN 101511829A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- palladium
- alkyl
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000015572 biosynthetic process Effects 0.000 title claims description 7
- 238000003786 synthesis reaction Methods 0.000 title description 3
- DDZFNEVGSZKHPR-UHFFFAOYSA-N 2-(pyridin-2-ylamino)-6h-pyrido[2,3-d]pyrimidin-7-one Chemical class N=1C2=NC(=O)CC=C2C=NC=1NC1=CC=CC=N1 DDZFNEVGSZKHPR-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 78
- 150000001875 compounds Chemical class 0.000 claims description 117
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 68
- -1 phosphine compound Chemical class 0.000 claims description 58
- 239000003513 alkali Substances 0.000 claims description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 229910052763 palladium Inorganic materials 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 17
- 229910052723 transition metal Inorganic materials 0.000 claims description 17
- 150000003624 transition metals Chemical class 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 230000026030 halogenation Effects 0.000 claims description 15
- 238000005658 halogenation reaction Methods 0.000 claims description 15
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 10
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 10
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 claims description 9
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 9
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- AAXGWYDSLJUQLN-UHFFFAOYSA-N diphenyl(propyl)phosphane Chemical compound C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 AAXGWYDSLJUQLN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 150000002941 palladium compounds Chemical class 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- QVQGTNFYPJQJNM-UHFFFAOYSA-N dicyclohexylmethanamine Chemical compound C1CCCCC1C(N)C1CCCCC1 QVQGTNFYPJQJNM-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims 3
- 150000003839 salts Chemical class 0.000 abstract description 48
- 230000002062 proliferating effect Effects 0.000 abstract description 5
- 239000002585 base Substances 0.000 description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
- 238000011282 treatment Methods 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 206010028980 Neoplasm Diseases 0.000 description 22
- 201000011510 cancer Diseases 0.000 description 22
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 16
- 230000007812 deficiency Effects 0.000 description 16
- 208000035475 disorder Diseases 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000010586 diagram Methods 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 150000002148 esters Chemical group 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 230000000452 restraining effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 210000004907 gland Anatomy 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 101150073031 cdk2 gene Proteins 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 210000002464 muscle smooth vascular Anatomy 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 201000008006 pharynx cancer Diseases 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 206010038038 rectal cancer Diseases 0.000 description 4
- 201000001275 rectum cancer Diseases 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000009395 breeding Methods 0.000 description 3
- 230000001488 breeding effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 201000003068 rheumatic fever Diseases 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 201000008261 skin carcinoma Diseases 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- SUWKOEMQNOBJEQ-UHFFFAOYSA-N tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C([N+]([O-])=O)N=C1 SUWKOEMQNOBJEQ-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 208000003200 Adenoma Diseases 0.000 description 2
- 206010001233 Adenoma benign Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010023347 Keratoacanthoma Diseases 0.000 description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 2
- 206010062038 Lip neoplasm Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 206010054184 Small intestine carcinoma Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000219161 Theobroma Species 0.000 description 2
- 208000033781 Thyroid carcinoma Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 206010062129 Tongue neoplasm Diseases 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 208000026900 bile duct neoplasm Diseases 0.000 description 2
- 208000002352 blister Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000000220 brain stem cancer Diseases 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 201000007455 central nervous system cancer Diseases 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- DGXRZJSPDXZJFG-UHFFFAOYSA-N docosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O DGXRZJSPDXZJFG-UHFFFAOYSA-N 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 201000002313 intestinal cancer Diseases 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 201000006721 lip cancer Diseases 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 201000006512 mast cell neoplasm Diseases 0.000 description 2
- 208000006971 mastocytoma Diseases 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000002829 nitrogen Chemical class 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000002394 ovarian follicle Anatomy 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 201000010198 papillary carcinoma Diseases 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 210000004927 skin cell Anatomy 0.000 description 2
- 230000027849 smooth muscle hyperplasia Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 210000004336 spermatogonium Anatomy 0.000 description 2
- 235000013599 spices Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 201000006134 tongue cancer Diseases 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000006824 (C1-C6) dialkyl amine group Chemical group 0.000 description 1
- SRSFAZYVBGMKDG-UHFFFAOYSA-N 1-(2,2-dimethylpropylperoxy)-3-methylbutane Chemical compound C(CC(C)C)OOCC(C)(C)C SRSFAZYVBGMKDG-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- MHHOMHMNIRXARC-UHFFFAOYSA-N 1h-pyrido[2,3-d]pyrimidin-2-one Chemical compound C1=CN=C2NC(=O)N=CC2=C1 MHHOMHMNIRXARC-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 1
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 1
- AQMYQENOAWXHLL-UHFFFAOYSA-N 5-bromo-2-chloro-6-cyclopentylpyrimidin-4-amine Chemical compound NC1=NC(Cl)=NC(C2CCCC2)=C1Br AQMYQENOAWXHLL-UHFFFAOYSA-N 0.000 description 1
- ATXXLNCPVSUCNK-UHFFFAOYSA-N 5-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)C=N1 ATXXLNCPVSUCNK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical class N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- HJMPRVFVCNHHCE-UHFFFAOYSA-N BrN(C(NC(CO)=O)=O)Br Chemical compound BrN(C(NC(CO)=O)=O)Br HJMPRVFVCNHHCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 241000675108 Citrus tangerina Species 0.000 description 1
- 102000013698 Cyclin-Dependent Kinase 6 Human genes 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 239000004258 Ethoxyquin Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007696 Multicystic Dysplastic Kidney Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical group C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000012505 colouration Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- 229960003263 cyclopentamine Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DECIPOUIJURFOJ-UHFFFAOYSA-N ethoxyquin Chemical compound N1C(C)(C)C=C(C)C2=CC(OCC)=CC=C21 DECIPOUIJURFOJ-UHFFFAOYSA-N 0.000 description 1
- 229940093500 ethoxyquin Drugs 0.000 description 1
- 235000019285 ethoxyquin Nutrition 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- CXGFWBPQQXZELI-UHFFFAOYSA-N n-ethylpyridin-2-amine Chemical group CCNC1=CC=CC=N1 CXGFWBPQQXZELI-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- XDNIBIHCBXESNN-UHFFFAOYSA-N phosphane;toluene Chemical group P.CC1=CC=CC=C1 XDNIBIHCBXESNN-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84305106P | 2006-09-08 | 2006-09-08 | |
| US60/843,051 | 2006-09-08 | ||
| US94210407P | 2007-06-05 | 2007-06-05 | |
| US60/942,104 | 2007-06-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101511829A true CN101511829A (zh) | 2009-08-19 |
Family
ID=38988315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800334161A Pending CN101511829A (zh) | 2006-09-08 | 2007-08-27 | 2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US7781583B2 (https=) |
| EP (1) | EP2069344A2 (https=) |
| JP (1) | JP2008094834A (https=) |
| KR (1) | KR20090052385A (https=) |
| CN (1) | CN101511829A (https=) |
| AR (1) | AR062680A1 (https=) |
| AU (1) | AU2007297286A1 (https=) |
| BR (1) | BRPI0716880A2 (https=) |
| CA (1) | CA2662768A1 (https=) |
| IL (1) | IL197242A0 (https=) |
| MX (1) | MX2009002069A (https=) |
| RU (1) | RU2009108006A (https=) |
| TW (1) | TW200821309A (https=) |
| WO (1) | WO2008032157A2 (https=) |
| ZA (1) | ZA200901270B (https=) |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183520A1 (zh) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用 |
| CN104887641A (zh) * | 2015-04-08 | 2015-09-09 | 上海鲁源医药科技有限公司 | 帕布昔利布胃漂浮片及其制备方法 |
| CN104910149A (zh) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | 一种Palbociclib制备方法 |
| CN105418603A (zh) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | 一种高纯度帕布昔利布及其反应中间体的制备方法 |
| CN105541832A (zh) * | 2015-12-15 | 2016-05-04 | 南京艾德凯腾生物医药有限责任公司 | 一种羟乙基磺酸盐帕布昔利布的制备方法 |
| WO2016082604A1 (zh) * | 2014-11-26 | 2016-06-02 | 苏州明锐医药科技有限公司 | 帕博西尼的制备方法 |
| WO2016082605A1 (zh) * | 2014-11-26 | 2016-06-02 | 苏州明锐医药科技有限公司 | 帕博西尼的制备方法 |
| WO2016124067A1 (zh) * | 2015-02-03 | 2016-08-11 | 江苏恒瑞医药股份有限公司 | 一种周期素依赖性蛋白激酶抑制剂的羟乙基磺酸盐、其结晶形式及制备方法 |
| WO2016141881A1 (zh) * | 2015-03-11 | 2016-09-15 | 南京明德新药研发股份有限公司 | 作为抗癌药物的取代的2-氢-吡唑衍生物 |
| CN106083844A (zh) * | 2016-06-05 | 2016-11-09 | 童明琼 | 一种制备抗乳腺癌药物帕博西尼中间体的方法 |
| CN106117199A (zh) * | 2015-05-04 | 2016-11-16 | 江苏恒瑞医药股份有限公司 | 一种细胞周期蛋白依赖性激酶抑制剂的二羟乙基磺酸盐、其结晶形式及其制备方法 |
| CN106317053A (zh) * | 2015-06-29 | 2017-01-11 | 北大方正集团有限公司 | 一种帕博昔布晶型a的制备方法 |
| CN106474129A (zh) * | 2015-09-01 | 2017-03-08 | 上海方楠生物科技有限公司 | 一种帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法 |
| WO2017036390A1 (zh) * | 2015-09-01 | 2017-03-09 | 上海方楠生物科技有限公司 | 帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法 |
| CN106565707A (zh) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | 帕博西尼新合成方法 |
| CN106749259A (zh) * | 2015-11-19 | 2017-05-31 | 华东师范大学 | 一种环戊基嘧啶并吡咯类化合物的合成方法 |
| CN106967061A (zh) * | 2016-01-13 | 2017-07-21 | 常州方楠医药技术有限公司 | 帕博西林的盐、晶型及其制备方法 |
| CN107759596A (zh) * | 2017-12-05 | 2018-03-06 | 安庆奇创药业有限公司 | 一种合成帕博西尼的方法 |
| CN108117550A (zh) * | 2016-11-29 | 2018-06-05 | 上海医药工业研究院 | 吡啶并[2,3-d]嘧啶类化合物的制备方法 |
| CN108283940A (zh) * | 2018-01-22 | 2018-07-17 | 重庆华邦制药有限公司 | 帕布昔利布中间体的制备方法 |
| CN108586452A (zh) * | 2018-01-12 | 2018-09-28 | 重庆市碚圣医药科技股份有限公司 | 一种帕博西尼中间体的合成方法 |
| CN109384767A (zh) * | 2017-08-08 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | 一种吡啶并嘧啶类衍生物的制备方法及其中间体 |
| CN110143948A (zh) * | 2019-06-21 | 2019-08-20 | 上海博悦生物科技有限公司 | Cdk4/6抑制剂、其药物组合物、制备方法及应用 |
| CN112457311A (zh) * | 2020-12-04 | 2021-03-09 | 江苏豪森药业集团有限公司 | 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法 |
| CN112552297A (zh) * | 2020-12-12 | 2021-03-26 | 江西国药有限责任公司 | 一种哌柏西利的制备方法与流程 |
| CN116283969A (zh) * | 2023-02-24 | 2023-06-23 | 杭州新曦科技有限公司 | 用于制备帕博西尼及其相关中间体的方法 |
| CN118834207A (zh) * | 2024-06-26 | 2024-10-25 | 安徽大学 | 一种2-氯-8-环戊基-5-甲基-8h-吡啶并[2,3-d]嘧啶基-7-酮的合成方法 |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA04005939A (es) | 2002-01-22 | 2005-01-25 | Warner Lambert Co | 2-(piridin-2-ilamino)-pirido[2,3-d]pirimidin-7-onas. |
| EA201001030A1 (ru) * | 2007-12-19 | 2011-02-28 | Амген Инк. | Конденсированные соединения пиридина, пиримидина и триазина в качестве ингибиторов клеточного цикла |
| US8389533B2 (en) * | 2008-04-07 | 2013-03-05 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
| US8639762B2 (en) * | 2009-03-23 | 2014-01-28 | Google Inc. | Providing access to a conversation in a hosted conversation system |
| PH12012501361A1 (en) | 2009-12-31 | 2012-10-22 | Centro Nac De Investigaciones Oncologicas Cnio | Tricyclic compounds for use as kinase inhibitors |
| WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
| EP2937349B1 (en) | 2011-03-23 | 2016-12-28 | Amgen Inc. | Fused tricyclic dual inhibitors of cdk 4/6 and flt3 |
| KR102215272B1 (ko) * | 2012-09-28 | 2021-02-15 | 이그니타, 인코포레이티드 | 비정형 단백질 키나제 c의 아자퀴나졸린 억제제 |
| MX386473B (es) * | 2013-02-21 | 2025-03-18 | Pfizer | Formas solidas de un inhibidor de cdk4/6 selectivo |
| US20160024084A1 (en) * | 2013-03-15 | 2016-01-28 | Concert Pharmaceuticals, Inc. | Deuterated palbociclib |
| WO2014203129A1 (en) | 2013-06-19 | 2014-12-24 | Olema Pharmaceuticals, Inc. | Combinations of benzopyran compounds, compositions and uses thereof |
| US20170217962A1 (en) * | 2014-07-31 | 2017-08-03 | Sun Pharmaceutical Industries Limited | A process for the preparation of palbociclib |
| WO2016024249A1 (en) * | 2014-08-14 | 2016-02-18 | Sun Pharmaceutical Industries Limited | Crystalline forms of palbociclib |
| WO2016030439A1 (en) * | 2014-08-28 | 2016-03-03 | Ratiopharm Gmbh | Method of producing palbociclib and pharmaceutical compositions comprising the same |
| CN105111201B (zh) * | 2014-10-16 | 2017-01-11 | 上海页岩科技有限公司 | 5-甲基-2-(吡啶-2-基氨基)-8H-吡啶并[2,3-d]嘧啶-7-酮化合物 |
| CN104447739B (zh) * | 2014-11-07 | 2016-02-17 | 郑州泰基鸿诺药物科技有限公司 | 一种氘代Palbociclib衍生物、制备方法及应用 |
| WO2016090257A1 (en) * | 2014-12-05 | 2016-06-09 | Crystal Pharmatech Inc. | Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib) |
| CN104610254B (zh) * | 2015-01-26 | 2017-02-01 | 新发药业有限公司 | 一种帕博赛布的低成本制备方法 |
| CZ201589A3 (cs) * | 2015-02-11 | 2016-08-24 | Zentiva, K.S. | Pevné formy soli Palbociclibu |
| EP3078663A1 (en) | 2015-04-09 | 2016-10-12 | Sandoz Ag | Modified particles of palbociclib |
| WO2016156070A1 (en) | 2015-04-02 | 2016-10-06 | Sandoz Ag | Modified particles of palbociclib |
| KR102369405B1 (ko) | 2015-06-04 | 2022-03-02 | 화이자 인코포레이티드 | 팔보시클립의 고체 투여 형태 |
| SI3331881T1 (sl) | 2015-08-05 | 2019-08-30 | Ratiopharm Gmbh | Nova kristalna oblika in adukti palbocikliba in matanojske kisline |
| CN106632311B (zh) * | 2015-11-02 | 2021-05-18 | 上海科胜药物研发有限公司 | 一种帕博西尼晶型a和晶型b的制备方法 |
| CN106831759A (zh) * | 2015-12-03 | 2017-06-13 | 上海星泰医药科技有限公司 | 帕布昔利布及其中间体的制备方法 |
| CN105949189B (zh) * | 2016-06-05 | 2017-09-22 | 童明琼 | 一种用于治疗乳腺癌的帕博西尼的制备方法 |
| CN105924439B (zh) * | 2016-06-24 | 2017-11-24 | 石家庄海瑞药物科技有限公司 | 一种帕布昔利布的制备方法 |
| US10807978B2 (en) | 2016-07-04 | 2020-10-20 | Dr. Reddy's Laboratories Limited | Process for preparation of palbociclib |
| MX2019000246A (es) | 2016-07-07 | 2019-05-27 | Plantex Ltd | Formas en estado solido del dimesilato de palbociclib. |
| CN106220627A (zh) * | 2016-07-31 | 2016-12-14 | 合肥远志医药科技开发有限公司 | 一种高纯度帕布昔利布的工业化制备方法 |
| PT3497103T (pt) | 2016-08-15 | 2021-06-17 | Pfizer | Inibidores de piridopirimidinona cdk2/4/6 |
| WO2018073574A1 (en) | 2016-10-20 | 2018-04-26 | Cipla Limited | Polymorphic forms of palbociclib |
| US10849903B2 (en) | 2016-10-20 | 2020-12-01 | Pfizer Inc. | Anti-proliferative agents for treating PAH |
| US20190275049A1 (en) | 2016-11-16 | 2019-09-12 | Pfizer Inc. | Combination of an EGFR T790M Inhibitor and a CDK Inhibitor for the Treatment of Non-Small Cell Lung Cancer |
| TWI749126B (zh) | 2016-12-16 | 2021-12-11 | 大陸商基石藥業（蘇州）有限公司 | Cdk4/6抑制劑 |
| EP3573619A4 (en) | 2017-01-27 | 2020-10-28 | SignalRX Pharmaceuticals, Inc. | THIENOPYRANONES AND FURANOPYRANONES AS KINASE, BROMODOMAIN AND CHECKPOINT INHIBITORS |
| CN108794452B (zh) | 2017-05-05 | 2021-05-28 | 上海时莱生物技术有限公司 | 具有激酶抑制活性的化合物、其制备方法和用途 |
| CN111386272B (zh) | 2017-10-27 | 2023-01-06 | 费森尤斯卡比肿瘤学有限公司 | 一种改进的瑞博西尼及其盐的制备方法 |
| EP3758753A1 (en) | 2018-02-27 | 2021-01-06 | Pfizer Inc | Combination of a cyclin dependent kinase inhibitor and a bet-bromodomain inhibitor |
| CN108299422B (zh) * | 2018-02-28 | 2019-10-25 | 杭州福斯特药业有限公司 | 一种帕泊昔利布中间体的制备方法 |
| EP4309656A3 (en) | 2018-05-14 | 2024-02-28 | Pfizer Inc. | Oral solution formulation |
| MX2021000895A (es) | 2018-07-27 | 2021-08-24 | California Inst Of Techn | Inhibidores de cinasas dependientes de ciclinas (cdk) y usos de los mismos. |
| JP6952747B2 (ja) | 2018-09-18 | 2021-10-20 | ファイザー・インク | がん処置のためのＴＧＦβ阻害剤およびＣＤＫ阻害剤の組合せ |
| WO2020157709A1 (en) | 2019-02-01 | 2020-08-06 | Pfizer Inc. | Combination of a cdk inhibitor and a pim inhibitor |
| CN109721547A (zh) * | 2019-02-11 | 2019-05-07 | 陈欣 | 一种治疗乳腺癌药物帕博西尼的中间体的制备方法 |
| CA3141452A1 (en) | 2019-05-24 | 2020-12-03 | Pfizer Inc. | Combination therapies using cdk inhibitors |
| WO2020239558A1 (en) | 2019-05-24 | 2020-12-03 | Pfizer Inc. | Combination therapies using cdk inhibitors |
| KR20220054347A (ko) | 2019-08-26 | 2022-05-02 | 아비나스 오퍼레이션스, 인코포레이티드 | 에스트로겐 수용체 분해제로서의 테트라히드로나프탈렌 유도체로 유방암을 치료하는 방법 |
| CN112920182B (zh) * | 2019-12-05 | 2023-08-01 | 上海天慈国际药业有限公司 | 一种帕布昔利布的制备方法 |
| TW202146017A (zh) | 2020-03-05 | 2021-12-16 | 美商輝瑞股份有限公司 | 間變性淋巴瘤激酶抑制劑及周期蛋白依賴型激酶抑制劑之組合 |
| FI4181920T3 (fi) | 2020-07-15 | 2025-11-20 | Pfizer | Kat6-estäjämenetelmät ja yhdistelmät syövän hoitoon |
| US20230321042A1 (en) | 2020-07-20 | 2023-10-12 | Pfizer Inc. | Combination therapy |
| WO2022091001A1 (en) | 2020-10-29 | 2022-05-05 | Pfizer Ireland Pharmaceuticals | Process for preparation of palbociclib |
| WO2022123419A1 (en) | 2020-12-08 | 2022-06-16 | Pfizer Inc. | Treatment of luminal subtypes of hr-positive, her2-negative early breast cancer with palbociclib |
| CN112661753B (zh) * | 2020-12-29 | 2022-06-03 | 山东铂源药业股份有限公司 | 一种帕布昔利布中间体的制备方法 |
| CN112898299B (zh) * | 2021-01-26 | 2021-11-26 | 山东铂源药业有限公司 | 一种帕布昔利布中间体的制备方法 |
| CN113683612B (zh) * | 2021-09-07 | 2022-06-17 | 山东铂源药业股份有限公司 | 一种帕布昔利布的制备方法 |
| WO2023107525A1 (en) | 2021-12-10 | 2023-06-15 | Eli Lilly And Company | Cdk4 and 6 inhibitor in combination with fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in patients previously treated with a cdk4 and 6 inhibitor |
| US20250049802A1 (en) | 2021-12-14 | 2025-02-13 | Pfizer Inc. | Combination therapies and uses for treating cancer |
| WO2023114264A1 (en) | 2021-12-15 | 2023-06-22 | Eli Lilly And Company | Combination for treatment of high-risk metastatic hormone-sensitive prostate cancer |
| JP2025533719A (ja) | 2022-07-29 | 2025-10-09 | ファイザー・インク | がんの治療のためのｋａｔ６阻害剤を含む投与レジメン |
| CN120112291A (zh) | 2022-08-31 | 2025-06-06 | 阿尔维纳斯运营股份有限公司 | 雌激素受体降解剂的给药方案 |
| CN120456897A (zh) | 2022-11-02 | 2025-08-08 | 佩特拉制药公司 | 用于治疗疾病的磷酸肌醇3-激酶(pi3k)变构色原酮抑制剂 |
| WO2024201340A1 (en) | 2023-03-30 | 2024-10-03 | Pfizer Inc. | Kat6a as a predictive biomarker for treatment of breast cancer with a cdk4 inhibitor and an antiestrogen and methods of treatment thereof |
| CN120981721A (zh) | 2023-03-30 | 2025-11-18 | 辉瑞大药厂 | Kat6a作为用kat6a抑制剂治疗的预测性生物标志物和相关治疗方法 |
| WO2025202854A1 (en) | 2024-03-27 | 2025-10-02 | Pfizer Inc. | Cdk4 inhibitors and combinations with cdk2 inhibitors or further agents for use in the treatment of cancer |
| WO2026025013A2 (en) | 2024-07-26 | 2026-01-29 | Pfizer Inc. | Combination therapy using cdk4 inhibitors for cancer treatments |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA04005939A (es) * | 2002-01-22 | 2005-01-25 | Warner Lambert Co | 2-(piridin-2-ilamino)-pirido[2,3-d]pirimidin-7-onas. |
| AU2004255934B2 (en) * | 2003-07-11 | 2010-02-25 | Warner-Lambert Company Llc | Isethionate salt of a selective CDK4 inhibitor |
-
2007
- 2007-08-27 BR BRPI0716880-2A2A patent/BRPI0716880A2/pt not_active IP Right Cessation
- 2007-08-27 KR KR1020097007146A patent/KR20090052385A/ko not_active Ceased
- 2007-08-27 CA CA002662768A patent/CA2662768A1/en not_active Abandoned
- 2007-08-27 WO PCT/IB2007/002524 patent/WO2008032157A2/en not_active Ceased
- 2007-08-27 EP EP07804871A patent/EP2069344A2/en not_active Withdrawn
- 2007-08-27 RU RU2009108006/04A patent/RU2009108006A/ru not_active Application Discontinuation
- 2007-08-27 MX MX2009002069A patent/MX2009002069A/es not_active Application Discontinuation
- 2007-08-27 CN CNA2007800334161A patent/CN101511829A/zh active Pending
- 2007-08-27 AU AU2007297286A patent/AU2007297286A1/en not_active Abandoned
- 2007-09-06 AR ARP070103937A patent/AR062680A1/es not_active Application Discontinuation
- 2007-09-07 JP JP2007232730A patent/JP2008094834A/ja not_active Withdrawn
- 2007-09-07 TW TW096133457A patent/TW200821309A/zh unknown
- 2007-09-10 US US11/852,873 patent/US7781583B2/en not_active Expired - Fee Related
-
2009
- 2009-02-23 ZA ZA200901270A patent/ZA200901270B/xx unknown
- 2009-02-25 IL IL197242A patent/IL197242A0/en unknown
Cited By (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183520A1 (zh) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用 |
| US9850244B2 (en) | 2014-11-26 | 2017-12-26 | Suzhou Miracpharma Technology Co., Ltd. | Method for preparing Palbociclib |
| US10005778B2 (en) | 2014-11-26 | 2018-06-26 | Suzhou Miracpharma Technology Co., Ltd. | Method for preparing Palbociclib |
| WO2016082604A1 (zh) * | 2014-11-26 | 2016-06-02 | 苏州明锐医药科技有限公司 | 帕博西尼的制备方法 |
| WO2016082605A1 (zh) * | 2014-11-26 | 2016-06-02 | 苏州明锐医药科技有限公司 | 帕博西尼的制备方法 |
| US10160759B2 (en) | 2015-02-03 | 2018-12-25 | Jiangsu Hengrui Medicine Co., Ltd. | Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor |
| AU2016214897B9 (en) * | 2015-02-03 | 2020-06-04 | Jiangsu Hengrui Medicine Co., Ltd. | Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor |
| US10030018B2 (en) | 2015-02-03 | 2018-07-24 | Jiangsu Hengrui Medicine Co., Ltd. | Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor |
| WO2016124067A1 (zh) * | 2015-02-03 | 2016-08-11 | 江苏恒瑞医药股份有限公司 | 一种周期素依赖性蛋白激酶抑制剂的羟乙基磺酸盐、其结晶形式及制备方法 |
| AU2016214897B2 (en) * | 2015-02-03 | 2020-05-21 | Jiangsu Hengrui Medicine Co., Ltd. | Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor |
| US9969719B2 (en) | 2015-03-11 | 2018-05-15 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Substituted 2-hydrogen-pyrazole derivative serving as anticancer drug |
| WO2016141881A1 (zh) * | 2015-03-11 | 2016-09-15 | 南京明德新药研发股份有限公司 | 作为抗癌药物的取代的2-氢-吡唑衍生物 |
| CN104887641A (zh) * | 2015-04-08 | 2015-09-09 | 上海鲁源医药科技有限公司 | 帕布昔利布胃漂浮片及其制备方法 |
| CN104887641B (zh) * | 2015-04-08 | 2017-12-01 | 上海鲁源医药科技有限公司 | 帕布昔利布胃漂浮片及其制备方法 |
| CN104910149A (zh) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | 一种Palbociclib制备方法 |
| CN106117199A (zh) * | 2015-05-04 | 2016-11-16 | 江苏恒瑞医药股份有限公司 | 一种细胞周期蛋白依赖性激酶抑制剂的二羟乙基磺酸盐、其结晶形式及其制备方法 |
| CN106317053A (zh) * | 2015-06-29 | 2017-01-11 | 北大方正集团有限公司 | 一种帕博昔布晶型a的制备方法 |
| CN106474129A (zh) * | 2015-09-01 | 2017-03-08 | 上海方楠生物科技有限公司 | 一种帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法 |
| WO2017036390A1 (zh) * | 2015-09-01 | 2017-03-09 | 上海方楠生物科技有限公司 | 帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法 |
| CN105418603A (zh) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | 一种高纯度帕布昔利布及其反应中间体的制备方法 |
| CN106749259A (zh) * | 2015-11-19 | 2017-05-31 | 华东师范大学 | 一种环戊基嘧啶并吡咯类化合物的合成方法 |
| CN105541832A (zh) * | 2015-12-15 | 2016-05-04 | 南京艾德凯腾生物医药有限责任公司 | 一种羟乙基磺酸盐帕布昔利布的制备方法 |
| CN106967061A (zh) * | 2016-01-13 | 2017-07-21 | 常州方楠医药技术有限公司 | 帕博西林的盐、晶型及其制备方法 |
| CN106083844A (zh) * | 2016-06-05 | 2016-11-09 | 童明琼 | 一种制备抗乳腺癌药物帕博西尼中间体的方法 |
| CN106083844B (zh) * | 2016-06-05 | 2017-11-10 | 陈志明 | 一种制备抗乳腺癌药物帕博西尼中间体的方法 |
| CN106565707A (zh) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | 帕博西尼新合成方法 |
| CN106565707B (zh) * | 2016-11-03 | 2019-01-04 | 杭州科巢生物科技有限公司 | 帕博西尼新合成方法 |
| CN108117550A (zh) * | 2016-11-29 | 2018-06-05 | 上海医药工业研究院 | 吡啶并[2,3-d]嘧啶类化合物的制备方法 |
| CN108117550B (zh) * | 2016-11-29 | 2020-08-14 | 上海医药工业研究院 | 吡啶并[2,3-d]嘧啶类化合物的制备方法 |
| CN109384767A (zh) * | 2017-08-08 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | 一种吡啶并嘧啶类衍生物的制备方法及其中间体 |
| CN107759596A (zh) * | 2017-12-05 | 2018-03-06 | 安庆奇创药业有限公司 | 一种合成帕博西尼的方法 |
| CN108586452A (zh) * | 2018-01-12 | 2018-09-28 | 重庆市碚圣医药科技股份有限公司 | 一种帕博西尼中间体的合成方法 |
| CN108283940A (zh) * | 2018-01-22 | 2018-07-17 | 重庆华邦制药有限公司 | 帕布昔利布中间体的制备方法 |
| CN108283940B (zh) * | 2018-01-22 | 2021-01-29 | 重庆华邦制药有限公司 | 帕布昔利布中间体的制备方法 |
| CN110143948A (zh) * | 2019-06-21 | 2019-08-20 | 上海博悦生物科技有限公司 | Cdk4/6抑制剂、其药物组合物、制备方法及应用 |
| CN112457311A (zh) * | 2020-12-04 | 2021-03-09 | 江苏豪森药业集团有限公司 | 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法 |
| CN112457311B (zh) * | 2020-12-04 | 2022-07-12 | 江苏豪森药业集团有限公司 | 一种含有氯溴吡咯嘧啶酮结构化合物的制备方法 |
| CN112552297A (zh) * | 2020-12-12 | 2021-03-26 | 江西国药有限责任公司 | 一种哌柏西利的制备方法与流程 |
| CN116283969A (zh) * | 2023-02-24 | 2023-06-23 | 杭州新曦科技有限公司 | 用于制备帕博西尼及其相关中间体的方法 |
| CN116283969B (zh) * | 2023-02-24 | 2024-11-19 | 杭州新曦科技有限公司 | 用于制备帕博西尼及其相关中间体的方法 |
| CN118834207A (zh) * | 2024-06-26 | 2024-10-25 | 安徽大学 | 一种2-氯-8-环戊基-5-甲基-8h-吡啶并[2,3-d]嘧啶基-7-酮的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2008094834A (ja) | 2008-04-24 |
| TW200821309A (en) | 2008-05-16 |
| WO2008032157A3 (en) | 2008-10-23 |
| US20080125588A1 (en) | 2008-05-29 |
| BRPI0716880A2 (pt) | 2013-10-15 |
| KR20090052385A (ko) | 2009-05-25 |
| US7781583B2 (en) | 2010-08-24 |
| MX2009002069A (es) | 2009-03-06 |
| CA2662768A1 (en) | 2008-03-20 |
| IL197242A0 (en) | 2009-12-24 |
| AU2007297286A1 (en) | 2008-03-20 |
| EP2069344A2 (en) | 2009-06-17 |
| AR062680A1 (es) | 2008-11-26 |
| WO2008032157A2 (en) | 2008-03-20 |
| ZA200901270B (en) | 2010-05-26 |
| RU2009108006A (ru) | 2010-10-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101511829A (zh) | 2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成 | |
| CN112047948B (zh) | Kras突变体抑制剂 | |
| CA2901537C (en) | 2,3-disubstituted 1- acyl-4-amino-1 ,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors | |
| JP6131384B2 (ja) | 重水素化ジアミノピリミジン化合物およびこの化合物を含む薬物組成物 | |
| DK3057959T3 (en) | INHIBITORS FOR DNA PK | |
| WO2020259432A1 (zh) | Kras-g12c抑制剂 | |
| IL303451A (en) | Prmts inhibitors | |
| CN110078741B (zh) | 稠环嘧啶氨基衍生物﹑其制备方法、中间体、药物组合物及应用 | |
| JP2021512878A (ja) | バイアリール誘導体、その製造方法および薬学上の使用 | |
| EP2970323A1 (en) | Furopyridines as bromodomain inhibitors | |
| JP2017533266A (ja) | ピリミジン又はピリジン系化合物、それらの製造方法及び医薬使用 | |
| CN109071521A (zh) | 作为fgfr抑制剂的杂环化合物 | |
| JP2018511624A (ja) | Ｔａｍ ｒｔｋインヒビターとしてのキノリン誘導体 | |
| CA2696197A1 (en) | Pyridoneamide derivatives as focal adhesion kinase (fak) inhibitors and their use for the treatment of cancer | |
| KR20230068412A (ko) | Cbp/ep300 브로모도메인 억제제로서의 헤테로시클릭 화합물 | |
| CA3012031A1 (en) | 6-membered heteroaromatic substituted cyanoindoline derivatives as nik inhibitors | |
| CN112313207B (zh) | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 | |
| KR20250031221A (ko) | Pi3k억제제 및 그 제조방법, 용도 | |
| CA2982862A1 (en) | Preparation and use of kinase inhibitor | |
| CN117653636A (zh) | 含稠合双环类化合物的抗癌药及该化合物的制药用途 | |
| CN107573327B (zh) | 吲唑-甲酰胺-吡啶酮衍生物及其制备方法和用途 | |
| CN107793363B (zh) | 一种取代芳胺基芳杂环类化合物及其作为抗肿瘤药物的应用 | |
| JP2021527678A (ja) | Ｆｇｆｒ阻害剤、その製造方法および応用 | |
| CA3176206A1 (en) | Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors | |
| CN103601722B (zh) | 新型抗肿瘤化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1137171 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090819 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1137171 Country of ref document: HK |