TWI675028B - 做為週期素依賴型激酶(cdk)抑制劑之2-h-吲唑衍生物及其醫療用途 - Google Patents
做為週期素依賴型激酶(cdk)抑制劑之2-h-吲唑衍生物及其醫療用途 Download PDFInfo
- Publication number
- TWI675028B TWI675028B TW104124158A TW104124158A TWI675028B TW I675028 B TWI675028 B TW I675028B TW 104124158 A TW104124158 A TW 104124158A TW 104124158 A TW104124158 A TW 104124158A TW I675028 B TWI675028 B TW I675028B
- Authority
- TW
- Taiwan
- Prior art keywords
- pharmaceutically acceptable
- alkyl
- hydrogen
- compound
- acceptable salt
- Prior art date
Links
- 102000003903 Cyclin-dependent kinases Human genes 0.000 title abstract description 34
- 108090000266 Cyclin-dependent kinases Proteins 0.000 title abstract description 34
- 239000003112 inhibitor Substances 0.000 title abstract description 5
- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 201000010099 disease Diseases 0.000 claims abstract description 35
- -1 indazole compound Chemical class 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 15
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims abstract description 14
- 108091007914 CDKs Proteins 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 claims description 13
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 claims description 13
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 208000038016 acute inflammation Diseases 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 24
- 239000000651 prodrug Substances 0.000 abstract description 22
- 229940002612 prodrug Drugs 0.000 abstract description 22
- 206010028980 Neoplasm Diseases 0.000 abstract description 11
- 230000004663 cell proliferation Effects 0.000 abstract description 7
- 206010061218 Inflammation Diseases 0.000 abstract description 6
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KZSOCAIRCZPXHG-UHFFFAOYSA-N 5-(piperazin-1-ylmethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC=C1CN1CCNCC1 KZSOCAIRCZPXHG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 201000003883 Cystic fibrosis Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 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 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical group C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- AJZJKPUCLBSWRO-UHFFFAOYSA-N 2-(5-bromo-2-methylindazol-3-yl)propan-2-ol Chemical compound BrC1=CC2=C(N(N=C2C=C1)C)C(C)(C)O AJZJKPUCLBSWRO-UHFFFAOYSA-N 0.000 description 2
- AXYTVEBSJALUIG-UHFFFAOYSA-N 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-3-propan-2-ylindazole Chemical compound ClC1=NC=C(C(=N1)C1=CC2=C(N(N=C2C=C1)C)C(C)C)F AXYTVEBSJALUIG-UHFFFAOYSA-N 0.000 description 2
- BPWLZIRVIFVPOW-UHFFFAOYSA-N 5-bromo-2-methyl-3-propan-2-ylindazole Chemical compound C1=CC(Br)=CC2=C(C(C)C)N(C)N=C21 BPWLZIRVIFVPOW-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000016736 Cyclin Human genes 0.000 description 2
- 108050006400 Cyclin 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
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000010835 comparative analysis Methods 0.000 description 2
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002473 indoazoles Chemical group 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 229940001447 lactate Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000007937 lozenge Substances 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical group NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- RGHNJXZEOKUKBD-NRXMZTRTSA-N (2r,3r,4r,5s)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-NRXMZTRTSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 1
- DMNPLEDMMNWHTL-UHFFFAOYSA-N 1-[(6-bromopyridin-3-yl)methyl]-4-ethylpiperazine Chemical compound C1CN(CC)CCN1CC1=CC=C(Br)N=C1 DMNPLEDMMNWHTL-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 150000005006 2-aminopyrimidines Chemical group 0.000 description 1
- HHTDIGJBGPQTLL-UHFFFAOYSA-N 2-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole Chemical compound CN1N=C2C=CC(=CC2=C1C(C)C)B1OC(C(O1)(C)C)(C)C HHTDIGJBGPQTLL-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- NVGPCDDVDMWRHH-UHFFFAOYSA-N 4-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-6-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-amine Chemical compound C(C)N1CCN(CC1)CC=1C=CC(=NC=1)C1=C(C(=NC(=N1)N)C1=CC2=C(N(N=C2C=C1)C)C(C)C)F NVGPCDDVDMWRHH-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical group COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- STPOIQOOWDHNFI-UHFFFAOYSA-N 5-(2H-pyrimidin-1-yl)-1H-indazole Chemical compound N=1CN(C=CC=1)C=1C=C2C=NNC2=CC=1 STPOIQOOWDHNFI-UHFFFAOYSA-N 0.000 description 1
- MNJBMPQTXVZMFZ-UHFFFAOYSA-N 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine Chemical compound C1CN(CC)CCN1CC1=CC=C(N)N=C1 MNJBMPQTXVZMFZ-UHFFFAOYSA-N 0.000 description 1
- QFZOHVHNTZTZMJ-UHFFFAOYSA-N 5-bromo-2-methylindazole Chemical compound C1=C(Br)C=CC2=NN(C)C=C21 QFZOHVHNTZTZMJ-UHFFFAOYSA-N 0.000 description 1
- UFRVBZVJVRHSNR-UHFFFAOYSA-N 5-bromo-2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1C=O UFRVBZVJVRHSNR-UHFFFAOYSA-N 0.000 description 1
- PVUKGNBRJFTFNJ-UHFFFAOYSA-N 6-bromopyridine-3-carbaldehyde Chemical compound BrC1=CC=C(C=O)C=N1 PVUKGNBRJFTFNJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 0 CCC=C(C)[*@](CCC1)C1C=CC(C)=***1CC1 Chemical compound CCC=C(C)[*@](CCC1)C1C=CC(C)=***1CC1 0.000 description 1
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 102000006311 Cyclin D1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 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
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 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 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229940121742 Serine/threonine kinase inhibitor Drugs 0.000 description 1
- 229920001800 Shellac Polymers 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
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-M alpha-D-galacturonate Chemical compound O[C@H]1O[C@H](C([O-])=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-M 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical class CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000033366 cell cycle process Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 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
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001354 dialkyl silanes Chemical class 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940046257 glyceryl phosphate Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YSUHPVRJYGPMQU-UHFFFAOYSA-N hexyl-(2-phenylphenyl)phosphane Chemical group CCCCCCPC1=C(C=CC=C1)C1=CC=CC=C1 YSUHPVRJYGPMQU-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000005496 phosphonium group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical class O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 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
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 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
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本發明揭示做為週期素依賴型激酶(CDK)及細胞增殖抑制劑之式(I)之吲唑化合物及其醫療用途及製備方法。此等化合物及其醫藥學上可接受之鹽、溶劑合物、前藥及醫藥組合物適用於治療與週期素依賴型激酶,尤其CDK4/6之活性關聯之疾病及病症,該等疾病及病症包含(但不限於)各種癌症及炎症相關之疾病或病狀。
Description
本申請案按照35 U.S.C.§ 119(e)主張2014年7月24日申請之美國臨時申請案第62/028,427號之優先權。
本發明係關於用於治療或預防經由某些週期素依賴型激酶(CDK)介導之疾病、病症或醫學病狀的化合物、組合物及方法之領域。該等疾病包括各種癌症。
週期素依賴型激酶為一組調控細胞分裂與增殖的蛋白激酶。細胞週期進程受週期素及其相關聯之週期素依賴型激酶控制,諸如CDK1、CDK2、CDK3、CDK4及CDK6,同時諸如CDK7、CDK8及CDK9之其他CDK對轉錄至關重要。CDK與週期素結合形成雜二聚複合物使其在絲胺酸及蘇胺酸殘基上之受質磷酸化,其轉而引發細胞週期轉錄及進展所需之事件。由於不受控之細胞增殖為癌症之特點,且大部分癌細胞展現CDK之失調,抑制CDK已作為各種癌症之潛在療法而出現。已報導具有不同程度之針對CDK之選擇性的抑制劑;然而,選擇性CDK4/6抑制劑目前被視為有前景的一類潛在抗癌劑或消炎
劑,歸因於CDK 4/6二者在調控細胞增殖中之重要作用及與抑制CDK家族之其他成員相關聯的毒性作用。
最近,已報導若干類型之胺基嘧啶衍生物為選擇性CDK4/6抑制劑。參見,例如WO 2003/062236、WO 2007/140222及US 2010/0160340。此等類型之分子各自含有經由2-胺基與芳基或雜芳基環系統結合之2-胺基嘧啶部分。仍存在開發新的CDK 4/6抑制劑作為新穎抗癌劑及/或消炎劑之需要。
本發明係關於經2-胺基嘧啶取代之吲唑衍生物,其有效作為選擇性CDK抑制劑,且適用於治療或預防經由某些CDK(尤其CDK4及CDK6)介導之疾病、病症或醫學病狀,諸如各種類型之癌症及炎症相關之病狀。
本發明之一個態樣係針對式(I)化合物:
或其醫藥學上可接受之鹽、溶劑合物或前藥,其中:R1係選自由以下組成之群:氫、直鏈或分支鏈C1-C8烷基及C3-C7環烷基;R2及R3獨立地選自由以下組成之群:氫、直鏈或分支鏈C1-C8烷基、C3-C7環烷基及環烷基甲基;R4係選自由以下組成之群:氫、鹵素、直鏈或分支鏈C1-C8烷基及C3-C7環烷基;及R5為氫或鹵素。
本發明之另一態樣係針對醫藥組合物,其包含式(I)化合物或其醫藥學上可接受之鹽、溶劑合物或前藥,及一或多種醫藥學上可接受之賦形劑,諸如佐劑、稀釋劑及/或載劑。
本發明之另一態樣係針對治療經由週期素依賴型激酶(CDK)中的至少一者(尤其CDK4、CDK6或其組合)介導之疾病、病症或病狀之方法,其包含向有需要之個體投與治療有效量之式(I)化合物,或其醫藥學上可接受之鹽、溶劑合物或前藥。
本發明之另一態樣係針對治療經由週期素依賴型激酶(CDK)中的至少一者(尤其CDK4、CDK6或其組合)介導之疾病、病症或病狀之方法,其包含向有需要之個體投與治療有效量之醫藥組合物,該醫藥組合物包含式(I)化合物,或其醫藥學上可接受之鹽、溶劑合物或前藥,及一或多種醫藥學上可接受之賦形劑,諸如佐劑、稀釋劑及/或載劑。
在一個實施例中,與一或多種週期素依賴型激酶,尤其CDK4、CDK6或其組合相關聯之疾病、病症或病狀包含癌症,其可包括(但不限於)肺癌、尤其非小細胞肺癌(NSCLC)、乳癌、前列腺癌、結直腸癌、神經膠母細胞瘤、套細胞淋巴瘤、慢性骨髓性白血病及急性骨髓性白血病及其併發症。在另一實施例中,該等疾病、病症或病狀包含炎症相關之疾病及病狀,諸如關節炎,例如風濕性關節炎及囊腫性纖維化。
本發明之另一態樣係針對抑制細胞增殖之方法,其包含用有效量之式(I)化合物或其鹽、溶劑合物、前藥或組合物處理該等細胞。
本發明之另一態樣係針對抑制週期素依賴型激酶(CDK),尤其CDK4、CDK6或其組合之方法,其包含用有效量之式(I)化合物或其鹽、溶劑合物、前藥或組合物處理該激酶。
本發明之另一態樣係針對本發明之化合物之用途,其用於生物
學及病理學現象中CDK之研究並用於新的激酶抑制劑之比較評價。
本發明之另一態樣係針對根據本文所述之任何實施例的式(I)化合物,或其醫藥學上可接受之鹽、溶劑合物、前藥或組合物之用途,其用於製造供治療與CDK活性相關聯之疾病或病症之用的藥物。該CDK活性較佳為CDK4、CDK6或其組合之活性。
本發明之又一態樣係針對合成實質上如本文所揭示及所描述之式(I)化合物之方法。
鑒於以下實施方式及申請專利範圍結合該領域中一般已知之知識及技能,本發明之其他態樣或優點將為熟習此項技術者顯而易知。
本發明提供適用作CDK抑制劑之新穎經2-胺基嘧啶取代之2H-吲唑衍生物。
在一個態樣中,本發明提供式(I)化合物:
或其醫藥學上可接受之鹽、溶劑合物或前藥,其中:R1係選自由以下組成之群:氫、C1-C8烷基及C3-C7環烷基;R2及R3獨立地選自由以下組成之群:氫、直鏈或分支鏈C1-C8烷基、C3-C7環烷基及C3-C7環烷基甲基;R4係選自由以下組成之群:氫、鹵素、直鏈或分支鏈C1-C8烷基及C3-C7環烷基;及
R5為氫或鹵素。
在此態樣之一實施例中,R1為C1-C6烷基。
在此態樣之另一實施例中,R1為甲基、乙基、丙基或異丙基。
在此態樣之另一實施例中,R2為C1-C6烷基、C3-C6環烷基或C3-C6環烷基甲基。
在此態樣之另一實施例中,R2為甲基、乙基、丙基、異丙基、環丙基、環戊基、環丙基甲基或環戊基甲基。
在此態樣之另一實施例中,R3為C1-C6烷基或C3-C6環烷基。
在此態樣之另一實施例中,R3為甲基、乙基、丙基、異丙基或環丙基。
在某些實施例中,本發明提供式(I)化合物,其中R4取代基連接於吲唑部分之7位上,如式(Ia)中:
或其醫藥學上可接受之鹽、溶劑合物或前藥,其中:R1係選自由以下組成之群:氫、C1-C8烷基及C3-C7環烷基;R2及R3獨立地選自由以下組成之群:氫、C1-C8烷基、C3-C7環烷基及環烷基甲基;R4係選自由以下組成之群:氫、鹵素、C1-C8烷基及C3-C7環烷基;及R5為氫或鹵素。
在此態樣之另一實施例中,R4為氫或鹵素。
在此態樣之另一實施例中,R5為氫或氟。
在此態樣之另一實施例中,R1為甲基或乙基;R2為異丙基、環丙基、環丙基甲基或環戊基;R3為甲基或乙基;R4為氫或氟;且R5為氫或氟。
在此態樣之某些較佳實施例中,R4取代基連接於吲唑部分之7位上,且R5為氟,特徵為式(Ib):
其中R4較佳為氫或鹵素;且當R4為鹵素時,其較佳為氯或氟,更佳為氟。
在此態樣之某些較佳實施例中,本發明提供選自由以下組成之群的式之化合物:
或其醫藥學上可接受之鹽、溶劑合物或前藥,其中R1、R2及R3各自在本文所述之任一實施例中定義。
在此態樣之某些較佳實施例中,本發明提供表1(見下文)中所列之化合物,及其醫藥上可接受鹽、溶劑合物及前藥。
在另一態樣中,本發明提供醫藥組合物,其包含根據本文所述之任一實施例之式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的化合物,或其醫藥學上可接受之鹽、溶劑合物或前藥,及一或多種醫藥學上可接受之佐劑、稀釋劑及/或載劑。
在另一態樣中,本發明提供治療經由至少一種週期素依賴型激酶(CDK)之活性介導之疾病、病症或病狀之方法,其包含向有需要之個體投與治療有效量之根據本文所述之任一實施例的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的化合物,或其醫藥學上可接受之鹽、溶劑合物或前藥。
在此態樣之一個實施例中,本發明提供治療經由至少一種週期素依賴型激酶(CDK)之活性介導之疾病、病症或病狀之方法,其包含向有需要之個體投與醫藥組合物,其包含治療有效量之根據本文所述之任一實施例的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的化合物,或其醫藥學上可接受之鹽、溶劑合物或前藥,及一或多種醫藥學上可接受之佐劑、稀釋劑及/或載劑。
在此態樣之一個較佳實施例中,該至少一種CDK為CDK4、CDK6或其組合。
在此態樣之另一較佳實施例中,該疾病或病症為癌症或炎症相關之疾病或病狀。
在此態樣之另一較佳實施例中,該炎症相關之疾病或病狀為關節炎,諸如風濕性關節炎或囊腫性纖維化。
在此態樣之另一較佳實施例中,該癌症係選自(但不限於)結直腸癌、乳癌、肺癌、尤其非小細胞肺癌(NSCLC)、前列腺癌、神經膠母細胞瘤、套細胞淋巴瘤(MCL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)及其併發症。
在此態樣之另一實施例中,本發明之化合物可與第二治療劑之
投與組合投與有需要之個體。
在另一實施例中,該第二治療劑為不同CDK抑制劑、人類表皮生長因子受體(例如,HER2)抑制劑、絲胺酸/蘇胺酸激酶抑制劑(諸如哺乳動物雷帕黴素靶(mTOR)抑制劑)或表皮生長因子受體(EGFR)抑制劑。
在另一態樣中,本發明提供抑制細胞增殖之方法,其包含用有效量之根據所述之任一實施例的式(I)化合物或其鹽、溶劑合物、前藥或其組合物處理該等細胞。抑制細胞增殖之方法可發生在活體內(例如個體體內),或活體外(例如含有個體增殖細胞之生物樣本中)。
在此態樣之一較佳實施例中,該等增殖細胞為癌細胞,諸如(但不限於)結直腸癌、乳癌、肺癌、尤其非小細胞肺癌(NSCLC)、前列腺癌、神經膠母細胞瘤、套細胞淋巴瘤(MCL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)或其併發症之細胞。
在另一態樣中,本發明提供抑制週期素依賴型激酶(CDK)之方法,其包含用有效量之根據本文所述之任一實施例的式(I)化合物或其鹽、溶劑合物、前藥或其組合物處理該激酶。抑制CDK之方法可發生在活體內(例如個體體內),或活體外(例如含有個體增殖細胞之生物樣本中)。
在此態樣之一較佳實施例中,該週期素依賴型激酶為CDK4、CDK6或其組合。
在另一態樣中,本發明提供根據本文所述之任一實施例之式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)之化合物或其醫藥學上可接受之鹽、溶劑合物、前藥或其組合物的用途,其用於製造供治療與CDK活性相關聯之疾病或病症之用的藥物。該CDK活性較佳為CDK4、CDK6或其組合之活性。
在此態樣之一個實施例中,該疾病或病症係選自由以下組成之
群:結直腸癌、乳癌、肺癌、尤其非小細胞肺癌(NSCLC)、前列腺癌、神經膠母細胞瘤、套細胞淋巴瘤(MCL)、慢性骨髓性白血病(CML),及急性骨髓性白血病(AML)。
在此態樣之另一實施例中,該疾病或病症為炎症相關之疾病或病狀,諸如關節炎,尤其風濕性關節炎或囊腫性纖維化。
在另一態樣中,本發明提供製備式(I)化合物之方法,其包含將中間物E與中間物G進行偶合之步驟:
其中R1至R5係根據本文所述之任一實施例所定義,且X3為Cl、Br或I。
在此態樣之一個實施例中,該方法進一步包括將中間物C轉化為中間物D,且使該中間物D與嘧啶化合物H偶合以形成中間物E之步驟:
其中Rx及Ry獨立地為烷基、芳基、環烷基,或替代地一起形成伸烷基,各自視情況經獨立地選自C1-C4烷基、鹵素或苯基之一或多個取代基取代;且其中X1、X2及X3各自獨立地為Cl、Br或I,條件為化合物H與中間物D相較於X3位點選擇性地在X2位點偶合,較佳具有大於90:10選擇率,更佳具有95:5選擇率,且最佳僅在X2位點。
在此態樣之一個實施例中,該方法進一步包括將起始物質S1轉化為中間物A及將中間物A轉化為中間物C之步驟:
其中X1為Cl、Br、I或MeSO3-;且其中R2及R3如根據本文所述之任一實施例所定義。
在此態樣之另一實施例中,該方法進一步包括將中間物A轉化為中間物C,替代地,包含將中間物A轉化為醇中間物B,隨後將該醇中間物B還原以形成中間物C:
其中R2a及R2b各自獨立地為氫、烷基、環烷基或一起形成伸烷
基,使得形成於中間物C中之基團為如根據本文所述之任一實
施例所定義之R2。
在此態樣之一個實施例中,該方法進一步包括形成中間物G之步驟,其經由將吡啶醛化合物S2及哌嗪化合物S3偶合以形成中間物F,隨後將該中間物F轉化為中間物G:
其中X4係選自由以下組成之群:Cl、Br、I及-NO2;且
其中中間物F至中間物G之該轉化包含當X4為Cl、Br或I時,用NH2置換X4;或替代地,當X4為-NO2時,將硝基(-NO2)還原為胺基(-NH2)。
由本發明提供之化合物亦適用於生物學及病理學現象中激酶之研究,藉由該等激酶介導之轉導路徑之研究及新的激酶抑制劑之比較評價。
除非另外指示,否則術語「烷基」,如本文所用,意欲包括分支鏈及直鏈飽和脂族烴基兩者,其含有1至8個碳,較佳1至6個,更佳1至4個碳。該術語涵蓋(但不限於)甲基、乙基、丙基、異丙基、丁基、第三丁基、異丁基、戊基、己基或其類似基團。
除非另外指示,否則術語「伸烷基」,如本文所用,係指自烷烴藉由移除兩個氫原子而衍生之二價飽和脂族基團。實例包括(但不限於)亞甲基(-CH2-)、伸乙基(-CH2CH2-)、伸丙基(-CH2CH2CH2-)或其類似基團。
除非另外指示,否則術語「環烷基」,如本文所用,單獨的或作為另一基團之一部分,包括具有形成環之3至8個碳原子的飽和環烴基團。實例包括(但不限於)環丙基、環丁基、環戊基及環己基。
除非另外指示,否則術語「芳基」,如本文所用,單獨的或作為另一基團之一部分,係指在環部分中含有6至10個碳原子之單環或雙環芳族基(諸如苯基及萘基,包括1-萘基及2-萘基)。
「鹵基」或「鹵素」,如本文所用,係指氟(F)、氯(Cl)、溴(Br)及碘(I)。
此外,烷基、伸烷基、環烷基及環烷基甲基視情況可獨立地進一步經一或多個,較佳1至3個取代基取代,該等取代基獨立地選自由鹵素及C1-C4烷基組成之群。
本發明之化合物被普遍公認為有機鹼,其能夠與酸(特定醫藥學
上可接受之酸)反應以形成醫藥上可接受之鹽。
如本文所用之術語「醫藥學上可接受之鹽」係指在合理醫學判斷之範疇內適合與人類及較低等動物之組織接觸使用而無不當毒性、刺激、過敏反應及其類似情況且與合理益處/風險比相匹配之彼等鹽。醫藥上可接受之鹽已為此項技術中所熟知。參見,例如S.M.Berge等人,J.Pharm.Sci.,1977,66,1-19,其以引用的方式併入本文中。本發明化合物之醫藥學上可接受之鹽包括衍生自適合的無機及有機酸之彼等鹽。醫藥學上可接受之無毒酸加成鹽之實例為胺基與無機酸(諸如鹽酸、氫溴酸、磷酸、硫酸及過氯酸)或有機酸(諸如乙酸、乙二酸、順丁烯二酸、酒石酸、檸檬酸、丁二酸或丙二酸)形成之鹽,或藉由使用此項技術中所用之其他方法(諸如離子交換)形成之鹽。其他醫藥學上可接受之鹽包括己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、乙二酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、特戊酸鹽、丙酸鹽、硬脂酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及其類似物。較佳醫藥學上可接受之鹽包括氫氯酸鹽。
術語「溶劑合物」,如本文所用,意謂本發明化合物與化學計量或非化學計量之量之溶劑分子的物理性締合。舉例而言,該化合物之一個分子與一或多個,較佳1至3個溶劑分子締合。亦有可能化合物之
多個分子(例如,1.5或2個)共用一個溶劑分子。此物理性締合可包括氫鍵結。在某些情況下,溶劑合物將能夠作為結晶固體分離。溶劑合物中之溶劑分子可以有序排列及/或無序排列而存在。例示性溶劑合物包括(但不限於)水合物、乙醇合物、甲醇合物及異丙醇合物。溶合方法在此技術內通常已知。
術語「前藥」,如本文所用,係指化合物之在活體內可經轉化以產生母化合物(例如藉由在血液中水解)的衍生物。本發明中之前藥的常見實例包括(但不限於)活性胺化合物之醯胺或磷醯胺形式,例如,式(II)化合物:
其中R6為醯基(例如,乙醯基、丙醯基、甲醯基等)或磷醯基[例如-P(=O)(OH)2];或替代地,當活性化合物中之R1或R3為氫時,對應醯胺或磷醯胺化合物可充當前藥。該等醯胺或磷醯胺前藥化合物可根據此項技術中已知之習知方法製備。
當用於療法中治療有效量之本發明化合物或其醫藥學上可接受之鹽或溶劑合物可作為化學原料投與為可能時,可使活性成分作為醫藥組合物呈遞。因此,本發明進一步提供醫藥組合物,其包括任何本發明之化合物或其醫藥學上可接受之鹽或溶劑合物,及一或多種,較佳一至三種醫藥學上可接受之載劑、稀釋劑或其他賦形劑。該(等)載劑、稀釋劑或其他賦形劑必須為可接受的,即與調配物之其他成分相容,且對所治療之個體無害。
術語「醫藥學上可接受」,如本文所用,係指在合理醫學判斷範
疇內適合與患者之組織接觸使用而無過量毒性、刺激、過敏反應或其他問題或併發症且與合理益處/風險率相匹配,且有效用於其預期用途的彼等化合物、物質、組合物及/或劑型之特性。
醫藥調配物可以每單位劑量含有預定量之活性成分的單位劑型呈遞。通常,本發明之醫藥組合物將每1至5天一次至每天約1-5次或替代地作為持續輸注進行投藥。該投藥可用作慢性或急性療法。可與載劑物質組合以產生單一劑型之活性成分之量將視所治療之病狀、病狀的嚴重程度、投藥時間、投藥途徑、所用化合物之排泄率、治療持續時間及患者之年齡、性別、體重及病狀而變化。較佳單位劑量調配物為含有活性成分之如上文所述之日劑量或子劑量或其合適分劑量的彼等調配物。一般而言,治療以實質上少於化合物之最佳劑量的小劑量起始。此後,以小增量增加劑量直至達到該等情況下之最佳作用。一般而言,該化合物最宜以大體上得到有效結果而不造成實質性有害或有毒副作用之濃度水準投與。
當本發明之組合物包含本發明之化合物與一或多種,較佳一或兩種附加治療劑或預防劑之組合時,該化合物及該附加劑通常均以通常在單藥療法療程中投與之劑量的約10至150%之間,且更佳約10至80%之劑量水準存在。
醫藥調配物可適於藉由任何合適途徑投藥,例如藉由經口(包括頰內或舌下)、直腸、經鼻、局部(包括頰內、舌下或經皮)、陰道或非經腸(包括皮下、皮內、肌肉內、關節內、滑膜內、胸骨內、鞘內、病灶內、靜脈內或皮內注射或輸注)途徑投藥。該等調配物可藉由藥劑學技術中已知之任何方法(例如,藉由將活性成分與載劑或賦形劑締合)來製備。經口投與或藉由注射投與較佳。
適於經口投與之醫藥調配物可以離散單位形式呈遞,諸如膠囊或錠劑;散劑或顆粒;水性或非水性液體中之溶液或懸浮液;可食用
發泡體或起泡體;或水包油型液體乳液或油包水型乳液。
舉例來說,對於以錠劑或膠囊之形式經口投與,可將活性藥物組分與經口、無毒、醫藥學上可接受之惰性載劑(諸如乙醇、甘油、水及其類似物)組合。藉由將化合物粉碎至合適之精細大小且與同樣經粉碎之醫藥載劑(諸如可食用碳水化合物,例如澱粉或甘露糖醇)混合來製備散劑。亦可存在調味劑、防腐劑、分散劑及著色劑。
藉由製備如上所述之粉末混合物且填充成形明膠殼來製造膠囊。在填充操作之前,可將諸如膠態二氧化矽、滑石、硬脂酸鎂、硬脂酸鈣或固態聚乙二醇之助滑劑及潤滑劑添加至粉末混合物中。亦可添加諸如瓊脂、碳酸鈣或碳酸鈉之崩解劑或助溶劑以改良攝取膠囊時藥物之可用性。
此外,當需要或必要時,亦可將合適之黏合劑、潤滑劑、崩解劑及著色劑併入混合物中。適合之黏合劑包括澱粉、明膠、天然糖(諸如葡萄糖或β-乳糖)、玉米甜味劑、天然及合成膠(諸如阿拉伯膠、黃蓍膠或海藻酸鈉)、羧甲基纖維素、聚乙二醇及其類似物。用於此等劑型中之潤滑劑包括油酸鈉、氯化鈉及其類似物。崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、三仙膠及其類似物。例如藉由製備粉末混合物、粒化或乾壓、添加潤滑劑及崩解劑且壓製成錠劑來調配錠劑。藉由將適當粉碎之化合物與如上所述之稀釋劑或基質混合且視情況與黏合劑(諸如羧甲基纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、溶液阻滯劑(諸如石蠟)、再吸收加速劑(諸如四級鹽)及/或吸收劑(諸如膨潤土、高嶺土或磷酸氫鈣)混合來製備粉末混合物。可藉由以黏合劑(諸如糖漿、澱粉糊、阿卡迪亞膠漿(acadia mucilage)或纖維素或聚合物質之溶液)潤濕且迫使其穿過篩網來粒化粉末混合物。作為粒化之替代方法,可使粉末混合物穿過壓錠機且結果為不完全成形之乾壓物碎裂為顆粒。可藉助於添加硬脂酸、硬脂酸
鹽、滑石或礦物油來潤滑顆粒以防止黏住錠劑成形模。隨後,將經潤滑之混合物壓縮成錠劑。亦可將本揭示案之化合物與自由流動性惰性載劑組合且直接壓縮成錠劑而不經歷粒化或乾壓步驟。可提供由蟲膠之密封塗層、糖或聚合物質之塗層及蠟之拋光塗層組成的透明或不透明保護塗層。可將染料添加至該等塗層中以區分不同單位劑量。
可以單位劑型製備諸如溶液、糖漿及酏劑之口服液體以使得給定量含有預定量之化合物。糖漿可藉由將化合物溶解於經適當調味之水溶液中來製備,而酏劑則經由使用無毒媒劑來製備。亦可添加增溶劑及乳化劑(諸如乙氧基化異硬脂醇及聚氧乙烯山梨糖醇醚)、防腐劑、調味添加劑(諸如薄荷油或天然甜味劑,或糖精或其他人工甜味劑)及其類似物。
適當時,用於經口投與之劑量單位調配物可經微囊封。亦可製備調配物以例如藉由塗佈或包埋粒狀物於聚合物、蠟或其類似物中來延長或持續釋放。
應瞭解,除以上特定提及之成分以外,考慮到所述調配物之類型,調配物亦可包括此項技術中習知之其他藥劑,例如適於經口投與之彼等調配物可包括調味劑。
術語「個體」或「患者」包括人類及其他哺乳動物兩者,較佳為人類。
術語「治療有效量」係指當向個體投藥用於治療疾病時,足以實現針對該疾病之治療的化合物或組合物之量。「治療有效量」可尤其視化合物、疾病及其嚴重程度及所治療之個體的年齡、體重或其他因素而變化。當應用於單獨投與之個別活性成分時,該術語係指其單獨成分。當應用於組合時,該術語係指無論連續或同時以組合方式投與,產生治療作用的活性成分之組合量。
在一些實施例中,術語「治療(treating)」或「治療(treatment)」
係指:(i)抑制疾病、病症或病狀,亦即遏制其發展;(ii)緩解疾病、病症或病狀,亦即引起該疾病、病症及/或病狀之消退;或(iii)在可能易患疾病、病症及/或病狀但尚未診斷為患有其之個體體內預防該疾病、病症或病狀出現。因此,在一些實施例中,「治療(treating)」或「治療(treatment)」係指改善疾病或病症,其可包括改善一或多個身體參數,儘管其難以被所治療之個體辨別。在一些實施例中,「治療(treating)」或「治療(treatment)」包括身體上(例如,可辨別症狀的穩定)或生理上(例如,身體參數的穩定)或兩者來調節疾病或病症。在又一些實施例中,「治療(treating)」或「治療(treatment)」包括延遲疾病或病症的發作。
在本申請案中可使用以下縮寫:
B2pin2=雙(頻哪醇根基)二硼
MeOH=甲醇
LDA=二異丙胺基鋰
LiHMDS=雙(三甲基矽烷基)胺基鋰[LiN(SiMe3)2]
Pd(dppf)Cl2=[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)
Pd2(dba)3=參(二亞苄基丙酮)二鈀(0)
Xantphos=4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃
nBu3P=三-正丁基膦
DCM=二氯甲烷
THF=四氫呋喃;DIEA=DIPEA=二異丙基乙胺;sat.=飽和水溶液;aq.=水溶液
FCC=使用二氧化矽之急驟管柱層析;TFA=三氟乙酸;r.t.=室溫;DMF=N,N-二甲基甲醯胺;DMSO=二甲亞碸;DMA=N,N-二甲基乙醯胺;EtOAc=乙酸乙酯;h=小時。
式(I)化合物之合成例示於一般合成流程1-4中:
在膦(例如三丁基膦)存在的情況下使適合之5-鹵基-2-硝基苯甲醛起始物質S1(X1=Cl、Br或I)與一級胺(R3NH2)反應以形成吲唑衍生物A(Genung,N.E.等人,Org.Lett.2014 16,3114-3117),其轉而使用強鹼(例如,LDA)在3位上去質子化,接著與烷化試劑R2X(X=例如,Cl、Br、I或甲磺酸酯基)反應以形成於適當位置帶有所要R2、R3及R4之中間物C。替代地,可使去質子化化合物A與醛或酮反應以形成醇加合物,使該醇加合物還原(例如,藉由二烷基矽烷)以形成所要中間物C。
在存在催化劑(例如,鈀催化劑)的情況下使中間物C進行硼化反應以形成硼酸鹽中間物D,使其與經鹵素取代之嘧啶衍生物H偶合以形成5-(嘧啶-3-基)-吲唑中間物E。
使經6-鹵素或6-硝基取代之吡啶-3-甲醛起始物質S2及經1-R1-取代之哌嗪起始物質S3進行還原胺化反應以形成2-胺基-5-哌嗪基甲基-吡啶中間物F,其轉而經由吡啶環上鹵素之取代或硝基之還原而轉化成2-胺基-5-哌嗪基甲基-吡啶中間物G。
在存在催化劑(例如,鈀催化劑)的情況下,經嘧啶取代之吲唑中間物E與2-胺基-5-哌嗪甲基-吡啶中間物G偶合提供式(I)之化合物。
流程4
以下非限制性實例進一步說明本發明之某些態樣。此等化合物係根據上述一般合成流程製備。
作為所說明之實例,在流程5-7中分別描繪中間物E、中間物G及化合物1之合成。以下反應流程中,單獨提供一些特定試劑或反應條件以供較好理解,但該等特定試劑或條件並不意欲限制任何。如熟習此項技術者將理解,可在各種態樣中使用多種相等條件(諸如試劑、溫度、催化劑及/或溶劑等)實現該反應流程之任何特定步驟。
在以惰性氮氛圍沖洗並保持的500mL圓底燒瓶內置放5-溴-2-硝基苯甲醛(30.0g,130.4mmol,1.0當量)、甲胺(71.5mL,1.1當量)及丙-2-醇(300mL)。在80℃下攪拌所得溶液4小時。將混合物冷卻至室溫並添加三丁基膦(98mL,3.0當量)。在80℃下攪拌所得溶液12小時且隨後用500mL乙酸乙酯進行萃取。依次用300mL NH4Cl(水溶液)及300mL鹽水洗滌所得混合物。混合物經無水硫酸鈉乾燥並在真空下濃縮。將殘餘物施加於矽膠管柱上並用乙酸乙酯/石油醚(1:4)溶離。由此產生32g呈紅色油狀之(粗)5-溴-2-甲基-2H-吲唑A:MS m/z MH+=211
在以惰性氮氛圍沖洗並保持的1L三頸圓底燒瓶內置放含5-溴-2-甲基-2H-吲唑A(32.0g,128.9mmol,1.0當量,85%)之四氫呋喃(300mL)。在-78℃下向該溶液中添加LDA(97.5mL,1.5當量,2M)。在0℃至5℃下攪拌溶液10分鐘,隨後冷卻至-78℃。向溶液中添加丙-2-酮(11.3g,194.7mmol,1.5當量)。在25℃下攪拌所得溶液12小時。隨後用100mL碳酸氫鈉水溶液淬滅反應。用3×500mL乙酸乙酯萃取所
得溶液且合併有機層,經無水Na2SO4乾燥並過濾。在真空下濃縮濾液並將殘餘物施加於矽膠管柱上並用乙酸乙酯/石油醚(1:10至1:2)溶離。由此產生20g(58%)呈黃色油狀之2-(5-溴-2-甲基-2H-吲唑-3-基)丙-2-醇B:MS m/z M+=269
在500mL圓底燒瓶內置放2-(5-溴-2-甲基-2H-吲唑-3-基)丙-2-醇B(20.0g,74.3mmol,1.0當量)、三乙基矽烷(86.6g,744.4mmol,10.0當量)、三氟乙酸(85.0g,752.0mmol,10.0當量)及二氯甲烷(200mL)。在25℃下攪拌所得溶液12小時。在真空下濃縮所得混合物。用碳酸氫鈉(水溶液,2M)將溶液調整至pH 8。用3×100mL乙酸乙酯萃取所得溶液,且合併有機層並用1×100mL鹽水洗滌。混合物經無水Na2SO4乾燥、過濾並在真空下濃縮。將殘餘物施加於矽膠管柱上並用乙酸乙酯/石油醚(1:20至1:10)溶離。由此產生8g(43%)呈黃色油狀之5-溴-2-甲基-3-(丙-2-基)-2H-吲唑C:MS[M+1]+=253及255,[M+CH3CN+H]+=294及296
在以惰性氮氛圍沖洗並保持的100mL圓底燒瓶內置放5-溴-2-甲基-3-(丙-2-基)-2H-吲唑(1.9g,7.5mmol,1.0當量)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧雜硼雜環戊-2-基)-1,3,2-二氧雜硼雜環戊烷(2.3g,9.0mmol,1.2當量)、KOAc(1.47g,15.0mmol,2.0當量)、1,4-二噁烷(40mL)及水(10mL)。向該溶液中添加Pd(dppf)Cl2(612mg,0.75mmol,0.1當量)。在90℃下攪拌所得溶液12小時,並隨後冷卻至室溫,並在真空下濃縮。將殘餘物施加於矽膠管柱上並用乙酸乙酯/石油醚(1:5)溶離。由此產生2.5g呈白色固體之(粗)2-甲基-3-(丙-2-基)-5-(四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2H-吲唑D:MS m/z MH+=301
在以惰性氮氛圍沖洗並保持的100mL圓底燒瓶內置放2-甲基-3-(丙-2-基)-5-(四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2H-吲唑(2.5g,7.5mmol,1.0當量,90%)、2,4-二氯-5-氟嘧啶(1.7g,9.9mmol,1.2當量)、碳酸鉀(2.3g,16.7mmol,2.0當量)、1,4-二噁烷(40mL)及水(10mL)。向溶液中添加Pd(dppf)Cl2(680mg,0.83mmol,0.10當量)。在80℃下攪拌所得溶液2小時且隨後冷卻至室溫並在真空下濃縮。將殘餘物施加於矽膠管柱上並用乙酸乙酯/石油醚(1:2)溶離。由此產生1.2g(48%)呈灰白色固體狀之5-(2-氯-5-氟嘧啶-4-基)-2-甲基-3-(丙-2-基)-2H-吲唑E:MS m/z MH+=305;1H NMR(300MHz,CDCl3,ppm):δ 1.58(d,6H),3.48-3.57(m,1H),4.19(s,3H),7.24(d,1H),8.03-8.07(m,1H),8.47(d,1H),8.68(s,1H)。
經30分鐘向N-乙基哌嗪(7.7g,67.5mmol,1.1當量)及6-溴吡啶-3-甲醛(11.6g,62.5mmol,1.0當量)於150mL二氯甲烷中之溶液中逐份添加NaBH(OAc)3(14.4g,68.0mmol,1.1當量)。攪拌反應混合物48小時,隨後用CH2Cl2及過量2N NaOH(水溶液)稀釋。分離各層,並用CH2Cl2萃取水層。合併、乾燥(Na2SO4)並濃縮CH2Cl2萃取物以產生呈油狀之1-(6-溴-吡啶-3-基甲基)-4-乙基-哌嗪F:MS m/z MH+=285
將雙(三甲基矽烷基)胺基鋰(LiHMDS)(在THF中之1M溶液,12.7mL,12.7mmol,1.2當量)添加至中間物F(3.0g,10.6mmol,1.0當量)、二環已基膦基聯苯(0.227g,0.64mmol,0.06當量)及Pd2(dba)3(0.291g,0.32mmol,0.03當量)於15mL THF中之溶液中。在50℃下加熱混合物3小時,隨後冷卻至室溫,並經由Dicalite®過濾介質進行過濾。濃縮濾液並在CH2Cl2中溶解殘餘物,並用10% HCl(水溶液)萃取兩次。合併HCl萃取物且用EtOAc洗滌,並用1.0N NaOH鹼化水
相,並隨後用CH2Cl2萃取四次。將有機萃取物合併、經Na2SO4乾燥並濃縮以產生1.2g呈茶色固體狀之5-(4-乙基-哌嗪基-1-基甲基)-吡啶-2-基胺G:MS m/z MH+=221。
5-(2-氯-5-氟嘧啶-4-基)-2-甲基-3-(丙-2-基)-2H-吲唑(E)(700mg,2.3mmol,1.3當量)、5-((4-乙基哌嗪-1-基)甲基吡啶-2-胺(G)(389mg,1.8mmol,1.0當量)、Cs2CO3(2.3g,7.2mmol,4.0當量)、Pd2(dba)3(0.164g,0.18mmol,0.1當量)及Xantphos(0.104g,0.18mmol,0.1當量)於10mL 1,4-二噁烷中之混合物用N2脫氣,隨後加熱,同時在110℃下攪拌4小時。將混合物冷卻至室溫,隨後經由Dicalite®過濾介質過濾,並用CH2Cl2充分洗滌過濾墊。濃縮濾液並藉由矽膠管柱層析使用CH2Cl2-2% NH3/MeOH梯度純化殘餘物以得到0.475g N-(5-((4-乙基哌嗪-基)甲基)吡啶-2-基-5-氟-4-(3-異丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-胺(1)。MS m/z MH+ 489;1H NMR(300MHz,CDCl3,ppm):δ 0.97(t,3H,J=7.1Hz),1.51(d,2H,J=7.0Hz),2.27-2.51(重疊m,10H),3.33(s,3H),3.54-3.68(m,1H),4.15(s,3H),7.64-8.71(重疊m,7H),10.00(s,1H)。
本發明之化合物1及其他所選實例(化合物2-31)列於表1中,其均係或可根據上述方法製備。
式I化合物為新穎CDK4/6抑制劑,其已或可根據如下所述程序評估其活性。
將週期素D1添加至新製備之反應緩衝液[20mM Hepes(pH 7.5)、10mM MgCl2、1mM EGTA、0.02% Brij 35、0.02mg/mL BSA、0.1mM Na3VO4、2mM DTT、1% DMSO]中。將CDK4或CDK6傳遞至受質溶液並輕輕地混合。用10μM起始之3倍稀釋以10劑量IC50模式測試化合物。藉由聲學技術(Echo550;納升範圍)將在DMSO中稀釋之化合物添加至激酶反應混合物並在室溫下培育20分鐘。將33P-ATP(1μM)添加至反應混合物中以起始反應。在室溫下將激酶反應物培育2小時。將反應物點樣於P81離子交換紙上,並藉由濾紙結合方法偵測激酶活性。使用四參數邏輯方程(GraphPad Prism)將曲線與非線性回歸曲線擬合。在此等條件下,在CDK4及CDK6分析中1之IC50值經測定為<1.0nM。
MCF7人類腫瘤細胞以90微升/孔之總體積接種於透明的聚苯乙烯96孔微量細胞培養盤(Corning® Costar®96孔平底盤,目錄號3997)中。在含濕氣培育箱中在37℃下在5% CO2及95%空氣中培育24小時
後,將10μL於生長培養基中10倍連續稀釋之1一式雙份地添加至每一孔(10點劑量反應)。在含濕氣培育箱中在37℃下在5% CO2及95%空氣之氛圍中培養72小時後,使經接種細胞及Cell Titer-Glo®(Promega G7571)試劑達到室溫以平衡30分鐘。將100μL Cell Titer-Glo®試劑添加至每一孔中。震盪盤兩分鐘且隨後靜置以平衡10分鐘。在Tecan GENios微量培養盤讀取器上讀取螢光之前,將介質/Cell Titer Glo®試劑轉移至白色聚苯乙烯96孔微量細胞培養盤(Corning® Costar®96孔平底盤,目錄號3917)中。相對於未經處理之對照孔計算細胞生長之抑制百分比。所有測試在每一濃度水準下一式兩份地進行。使用Prism 6.05藉由使用以下四參數邏輯方程曲線擬合資料來估算測試藥劑之
IC50值:
其中最高值為對照吸光度之最大百分比,最低值為最高藥劑濃度下對照吸光度之最小百分比,Y為對照吸光度之百分比,X為藥劑濃度,IC 50 為相較於對照細胞抑制50%細胞生長的藥劑之濃度,且n為曲線之斜率。在此等條件下,1之IC50值經測定為<2μM。
表2概述三種已報導之CDK4/6抑制劑32、33及34的生物化學及基於MCF7細胞之資料。該等資料在本文所述之分析條件下獲得。
熟習此項技術者應理解在不偏離本發明之精神的情況下可對本發明之化合物、組合物及/或方法進行大量及各種修改。因此,本文所述的本發明之各種實施例僅為例示性的,且並不意欲以任何方式限制本發明之範疇。本文中所引用之所有參考文獻以全文引用之方式併入本文中。
Claims (16)
- 如請求項1之化合物,或其醫藥學上可接受之鹽,其中R1為C1-C6烷基。
- 如請求項1之化合物,或其醫藥學上可接受之鹽,其中R2為C1-C6烷基、C3-C6環烷基或C3-C6環烷基甲基。
- 如請求項1之化合物,或其醫藥學上可接受之鹽,其中R3為C1-C6烷基或C3-C6環烷基。
- 如請求項1之化合物,或其醫藥學上可接受之鹽,其中R4為氫或鹵素。
- 如請求項6之化合物,或其醫藥學上可接受之鹽,其中R1為甲基或乙基;R2為異丙基、環丙基、環丙基甲基或環戊基;R3為甲基或乙基;R4為氫或氟;及R5為氫或氟。
- 一種醫藥組合物,其包含如請求項1至8中任一項之化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之佐劑、稀釋劑及/或載劑。
- 一種如請求項1至8中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造供治療與CDK活性相關聯之疾病或病症之用的藥物。
- 如請求項10之用途,其中該CDK為CDK4、CDK6或其組合。
- 如請求項10之用途,其中該疾病或病症係選自由以下組成之群:結直腸癌、乳癌、肺癌、前列腺癌、神經膠母細胞瘤、套細胞淋巴瘤(MCL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)及炎症相關之疾病及病狀。
- 如請求項10之用途,其中該疾病或病症係非小細胞肺癌(NSCLC)。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462028427P | 2014-07-24 | 2014-07-24 | |
US62/028,427 | 2014-07-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201609705A TW201609705A (zh) | 2016-03-16 |
TWI675028B true TWI675028B (zh) | 2019-10-21 |
Family
ID=55163817
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW104124158A TWI675028B (zh) | 2014-07-24 | 2015-07-24 | 做為週期素依賴型激酶(cdk)抑制劑之2-h-吲唑衍生物及其醫療用途 |
Country Status (19)
Country | Link |
---|---|
US (2) | US9878994B2 (zh) |
EP (1) | EP3191469B1 (zh) |
JP (1) | JP6490215B2 (zh) |
KR (1) | KR20170031241A (zh) |
CN (2) | CN110117273B (zh) |
AP (1) | AP2017009728A0 (zh) |
AU (1) | AU2015292425B2 (zh) |
BR (1) | BR112017001058A2 (zh) |
CA (1) | CA2954298A1 (zh) |
CO (1) | CO2017000912A2 (zh) |
EA (1) | EA032693B1 (zh) |
IL (1) | IL249895B (zh) |
MX (1) | MX2017000806A (zh) |
MY (1) | MY187555A (zh) |
PH (1) | PH12017500146B1 (zh) |
SG (2) | SG10202004716RA (zh) |
TW (1) | TWI675028B (zh) |
WO (1) | WO2016014904A1 (zh) |
ZA (1) | ZA201700652B (zh) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA032693B1 (ru) * | 2014-07-24 | 2019-07-31 | Бета Фарма, Инк. | Производные 2-h-индазола в качестве ингибиторов циклинзависимых киназ (cdk) и их терапевтическое применение |
TWI696617B (zh) | 2015-04-28 | 2020-06-21 | 大陸商上海復尚慧創醫藥研究有限公司 | 特定蛋白質激酶抑制劑 |
CN106608879A (zh) * | 2015-10-27 | 2017-05-03 | 甘李药业股份有限公司 | 一种蛋白激酶抑制剂及其制备方法和医药用途 |
WO2017133701A1 (en) * | 2016-02-06 | 2017-08-10 | Shanghai Fochon Pharmaceutical Co., Ltd. | Certain protein kinase inhibitors |
WO2017160568A1 (en) * | 2016-03-16 | 2017-09-21 | Eli Lilly And Company | Combination therapy comprising the cdk4/6 inhibitor necitumumab and the egfr inhibitor abemaciclib for use in treating cancer |
WO2017161253A1 (en) | 2016-03-18 | 2017-09-21 | Tufts Medical Center | Compositions and methods for treating and preventing metabolic disorders |
CN107286134B (zh) * | 2016-04-11 | 2019-04-12 | 上海勋和医药科技有限公司 | 2,4-二取代嘧啶衍生物作为cdk抑制剂及其应用 |
US10626107B2 (en) | 2016-09-09 | 2020-04-21 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Crystal form, salt type of substituted 2-hydro-pyrazole derivative and preparation method therefor |
CN110234652B (zh) | 2016-12-22 | 2020-11-10 | 贝达药业股份有限公司 | 苯并咪唑衍生物及其制备方法和用途 |
CN109311845A (zh) * | 2017-02-06 | 2019-02-05 | 贝达药业股份有限公司 | 酪氨酸蛋白激酶调节剂、晶型及其用途 |
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 |
TW201920141A (zh) * | 2017-08-15 | 2019-06-01 | 中國大陸商北京軒義醫藥科技有限公司 | Cdk4/6抑制劑及其用途 |
CN109503573A (zh) * | 2017-09-14 | 2019-03-22 | 昆明圣加南生物科技有限公司 | 2-取代苯胺基嘧啶衍生物及其用途 |
EP3746072B1 (en) * | 2018-01-29 | 2023-04-12 | Beta Pharma, Inc. | 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof |
EP3786161A4 (en) | 2018-04-24 | 2021-05-05 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd | CDK4 / 6 INHIBITOR, PHARMACEUTICALLY ACCEPTABLE SALT, POLYMORPHIC OF THEM AND ASSOCIATED USE |
MX2020011294A (es) | 2018-04-26 | 2020-11-18 | Pfizer | Derivados de 2-amino-piridina o 2-amino-pirimidina como inhibidores de cinasa dependientes de ciclina. |
SG11202012312UA (en) * | 2018-06-18 | 2021-01-28 | UCB Biopharma SRL | Gremlin-1 antagonist for the prevention and treatment of cancer |
AU2019340436A1 (en) | 2018-09-10 | 2021-04-29 | Mirati Therapeutics, Inc. | Combination therapies |
CN113507930A (zh) * | 2019-01-29 | 2021-10-15 | 贝达医药公司 | 2h-吲唑衍生物作为脑癌和脑转移的治疗剂 |
TW202102487A (zh) * | 2019-03-20 | 2021-01-16 | 美商貝達醫藥公司 | N-(5-((4-乙基哌𠯤-1-基)甲基)吡啶-2-基)-5-氟-4-(3-異丙基-2-甲基-2h-吲唑-5-基)嘧啶-2-胺及其鹽的結晶與非晶型以及其製備方法與醫療用途 |
AU2020269469A1 (en) * | 2019-05-05 | 2021-12-09 | Regor Pharmaceuticals, Inc. | CDK inhibitors |
AU2020352528A1 (en) * | 2019-09-23 | 2022-04-21 | Beta Pharma, Inc. | Treatment of EGFR mutant-related cancers using a combination of EGFR and CDK4/6 inhibitors |
CN111100117B (zh) * | 2019-12-18 | 2021-02-19 | 上海倍而达药业有限公司 | 氨基嘧啶类化合物甲磺酸盐的晶型a及其制备方法和应用 |
CN113880816A (zh) * | 2020-07-01 | 2022-01-04 | 杭州百诚医药科技股份有限公司 | 一种含哌嗪类的氨基嘧啶衍生物及应用 |
CN114539225B (zh) * | 2020-11-11 | 2024-02-20 | 上海拓界生物医药科技有限公司 | 2-氨基-嘧啶类化合物 |
AR124154A1 (es) | 2020-11-27 | 2023-02-22 | Rhizen Pharmaceuticals Ag | Inhibidores de cdk |
WO2022149057A1 (en) | 2021-01-05 | 2022-07-14 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
WO2022162122A1 (en) | 2021-01-29 | 2022-08-04 | Biotx.Ai Gmbh | Genetically verified netosis inhibitor for use in the treatment of a sars-cov2 infection |
CN115703760B (zh) * | 2021-08-11 | 2024-05-31 | 山东大学 | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 |
CN115650968B (zh) * | 2022-12-27 | 2023-03-21 | 英矽智能科技(上海)有限公司 | 作为cdk选择性抑制剂的新型哒嗪酮化合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201031653A (en) * | 2008-12-22 | 2010-09-01 | Lilly Co Eli | Protein kinase inhibitors |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
YU54202A (sh) | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije |
KR20060111716A (ko) * | 2002-01-22 | 2006-10-27 | 워너-램버트 캄파니 엘엘씨 | 2-(피리딘-2-일아미노)-피리도[2,3-d]피리미딘-7-온 |
BR0316950A (pt) * | 2002-12-02 | 2006-01-17 | Hoffmann La Roche | Derivados de indazol como antagonistas de crf |
WO2006008874A1 (ja) * | 2004-05-21 | 2006-01-26 | Banyu Pharmaceutical Co., Ltd. | アミノチアゾール骨格を有するCdk4,6選択的阻害剤 |
US20070293491A1 (en) | 2006-04-19 | 2007-12-20 | Novartis Vaccines And Diagnostics, Inc. | Indazole compounds and methods for inhibition of cdc7 |
JO3235B1 (ar) * | 2006-05-26 | 2018-03-08 | Astex Therapeutics Ltd | مركبات بيررولوبيريميدين و استعمالاتها |
US9259399B2 (en) * | 2007-11-07 | 2016-02-16 | Cornell University | Targeting CDK4 and CDK6 in cancer therapy |
AU2009262068C1 (en) | 2008-06-27 | 2015-07-02 | Celgene Car Llc | Heteroaryl compounds and uses thereof |
KR101372104B1 (ko) * | 2008-09-25 | 2014-03-07 | 에프. 호프만-라 로슈 아게 | 이상지질혈증 및 관련 질병에 대한 fxr 조절제로서의 2,3-치환된 인다졸 또는 4,5,6,7-테트라하이드로-인다졸 |
EA032693B1 (ru) * | 2014-07-24 | 2019-07-31 | Бета Фарма, Инк. | Производные 2-h-индазола в качестве ингибиторов циклинзависимых киназ (cdk) и их терапевтическое применение |
-
2015
- 2015-07-24 EA EA201790122A patent/EA032693B1/ru unknown
- 2015-07-24 EP EP15823933.5A patent/EP3191469B1/en active Active
- 2015-07-24 JP JP2017525318A patent/JP6490215B2/ja active Active
- 2015-07-24 WO PCT/US2015/041915 patent/WO2016014904A1/en active Application Filing
- 2015-07-24 AP AP2017009728A patent/AP2017009728A0/en unknown
- 2015-07-24 SG SG10202004716RA patent/SG10202004716RA/en unknown
- 2015-07-24 MY MYPI2017700116A patent/MY187555A/en unknown
- 2015-07-24 CN CN201910409416.1A patent/CN110117273B/zh active Active
- 2015-07-24 MX MX2017000806A patent/MX2017000806A/es unknown
- 2015-07-24 CN CN201580047916.5A patent/CN106687454B8/zh active Active
- 2015-07-24 US US15/328,813 patent/US9878994B2/en active Active
- 2015-07-24 KR KR1020177004776A patent/KR20170031241A/ko not_active Application Discontinuation
- 2015-07-24 TW TW104124158A patent/TWI675028B/zh not_active IP Right Cessation
- 2015-07-24 BR BR112017001058-5A patent/BR112017001058A2/pt not_active Application Discontinuation
- 2015-07-24 CA CA2954298A patent/CA2954298A1/en not_active Abandoned
- 2015-07-24 AU AU2015292425A patent/AU2015292425B2/en active Active
- 2015-07-24 SG SG11201700037QA patent/SG11201700037QA/en unknown
-
2017
- 2017-01-02 IL IL249895A patent/IL249895B/en active IP Right Grant
- 2017-01-24 PH PH12017500146A patent/PH12017500146B1/en unknown
- 2017-01-26 ZA ZA2017/00652A patent/ZA201700652B/en unknown
- 2017-01-31 CO CONC2017/0000912A patent/CO2017000912A2/es unknown
-
2018
- 2018-01-29 US US15/882,620 patent/US10239864B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201031653A (en) * | 2008-12-22 | 2010-09-01 | Lilly Co Eli | Protein kinase inhibitors |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI675028B (zh) | 做為週期素依賴型激酶(cdk)抑制劑之2-h-吲唑衍生物及其醫療用途 | |
EP3746072B1 (en) | 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof | |
TW201704237A (zh) | 適用於治療與kit及pdfgr相關之病症的組合物 | |
EA036453B1 (ru) | Замещенные производные 2-анилинпиримидина в качестве модуляторов egfr | |
TW200846344A (en) | Chemical compounds | |
TWI710554B (zh) | 新穎苯并咪唑化合物及其醫藥用途 | |
US20200071326A1 (en) | Tam kinase inhibitors | |
CN105884695B (zh) | 杂环衍生物类酪氨酸激酶抑制剂 | |
TW202214600A (zh) | 嘧啶基衍生物、其製備方法及其用途 | |
TW201922709A (zh) | 表皮生長因子受體抑制劑 | |
WO2020156319A1 (zh) | N-甲酰胺衍生物、其制备方法及其在医药上的用途 | |
KR20210024004A (ko) | Cdk4/6의 활성을 억제하기 위한 화합물의 결정 형태 및 그것의 용도 | |
CN103936762B (zh) | 吗啉并喹啉类化合物,其制备方法和用途 | |
CN104418867B (zh) | 作为PI3K/mTOR抑制剂的化合物,其制备方法和用途 | |
CN115803325A (zh) | 一种egfr抑制剂及其制备方法和应用 | |
CN115701429B (zh) | 4-(1h-吲哚-1-基)嘧啶-2-氨基衍生物及其制备方法和应用 | |
OA19873A (en) | 2H-indazole derivatives as CDK4 and CDK6 inhibitors and therapeutic uses thereof. | |
OA18720A (en) | 2-H-indazole derivatives as cyclin-dependent kinase (CDK) inhibitors and therapeutic uses thereof. | |
CN115843296A (zh) | Cdk9抑制剂及其用途 | |
CN101346371A (zh) | 癌症治疗中用作酪氨酸激酶抑制剂的4-(3-氨基吡唑)嘧啶衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |