CN113248506A - 取代的氨基嘌呤化合物、其组合物及其治疗方法 - Google Patents
取代的氨基嘌呤化合物、其组合物及其治疗方法 Download PDFInfo
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- CN113248506A CN113248506A CN202110381676.XA CN202110381676A CN113248506A CN 113248506 A CN113248506 A CN 113248506A CN 202110381676 A CN202110381676 A CN 202110381676A CN 113248506 A CN113248506 A CN 113248506A
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- Prior art keywords
- amino
- substituted
- unsubstituted
- pyran
- compound
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- -1 aminopurine compounds Chemical class 0.000 title claims abstract description 354
- 239000000203 mixture Chemical class 0.000 title abstract description 246
- 238000000034 method Methods 0.000 title abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 160
- 201000001441 melanoma Diseases 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 24
- 239000011347 resin Substances 0.000 claims description 24
- 229920005989 resin Polymers 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical group NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 17
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 17
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 15
- 230000037396 body weight Effects 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical group 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 150000001409 amidines Chemical group 0.000 claims description 9
- 150000002081 enamines Chemical group 0.000 claims description 9
- 150000002148 esters Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 150000003949 imides Chemical group 0.000 claims description 9
- 150000002466 imines Chemical group 0.000 claims description 9
- 150000002923 oximes Chemical class 0.000 claims description 9
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 9
- 150000003457 sulfones Chemical group 0.000 claims description 9
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 9
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Chemical group CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- 125000005262 alkoxyamine group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 150000001540 azides Chemical class 0.000 claims description 8
- 239000004202 carbamide Chemical group 0.000 claims description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Chemical group CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 150000007857 hydrazones Chemical class 0.000 claims description 8
- 239000012948 isocyanate Substances 0.000 claims description 8
- 150000002513 isocyanates Chemical class 0.000 claims description 8
- 150000002540 isothiocyanates Chemical class 0.000 claims description 8
- 150000002576 ketones Chemical group 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 150000003456 sulfonamides Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 7
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- 239000004643 cyanate ester Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 2
- MLTAWPSHDKQVGA-UHFFFAOYSA-N N#C[S+]([N+]([O-])=O)S[S+](C#N)[N+]([O-])=O Chemical compound N#C[S+]([N+]([O-])=O)S[S+](C#N)[N+]([O-])=O MLTAWPSHDKQVGA-UHFFFAOYSA-N 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 4
- 125000004442 acylamino group Chemical group 0.000 claims 3
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 3
- WPCUYCLOZNOLEP-UHFFFAOYSA-N [(carboxy-cyano-nitro-lambda4-sulfanyl)sulfanyl-cyano-nitro-lambda4-sulfanyl]formic acid Chemical group C(=O)(O)S(C#N)([N+](=O)[O-])SS(C(=O)O)([N+](=O)[O-])C#N WPCUYCLOZNOLEP-UHFFFAOYSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 201000011510 cancer Diseases 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 213
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 212
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 208
- 239000000243 solution Substances 0.000 description 169
- 238000006243 chemical reaction Methods 0.000 description 153
- 238000005160 1H NMR spectroscopy Methods 0.000 description 136
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 104
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 83
- 239000007787 solid Substances 0.000 description 82
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
- 239000002904 solvent Substances 0.000 description 76
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
- 238000000746 purification Methods 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 238000010626 work up procedure Methods 0.000 description 53
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 50
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
- 229910052938 sodium sulfate Inorganic materials 0.000 description 46
- 239000007832 Na2SO4 Substances 0.000 description 42
- 239000000706 filtrate Substances 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 34
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 29
- 239000000725 suspension Substances 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 239000012043 crude product Substances 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000007821 HATU Substances 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 12
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
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- 241001465754 Metazoa Species 0.000 description 9
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- 239000002775 capsule Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000010926 purge Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- DKCLKRHHYLYVOX-UHFFFAOYSA-N 1,5-dichloro-3-fluoro-2-isocyanatobenzene Chemical compound FC1=CC(Cl)=CC(Cl)=C1N=C=O DKCLKRHHYLYVOX-UHFFFAOYSA-N 0.000 description 8
- DRNGLYHKYPNTEA-UHFFFAOYSA-N 4-azaniumylcyclohexane-1-carboxylate Chemical class NC1CCC(C(O)=O)CC1 DRNGLYHKYPNTEA-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 239000007822 coupling agent Substances 0.000 description 7
- 125000002883 imidazolyl group Chemical group 0.000 description 7
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- AJQFAPDMBFEYRX-VXGBXAGGSA-N (3S,4R)-N-benzyl-3-fluorooxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@H]1[C@@H](COCC1)F AJQFAPDMBFEYRX-VXGBXAGGSA-N 0.000 description 6
- UAIXEOIQIOOYES-DGCLKSJQSA-N (3S,4R)-N-benzyl-3-methyloxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@H]1[C@@H](COCC1)C UAIXEOIQIOOYES-DGCLKSJQSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
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- 238000010992 reflux Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- JYZWPWDEIMDHFF-JBUOLDKXSA-N (3S,4S)-3-fluorooxan-4-amine hydrochloride Chemical compound Cl.N[C@H]1CCOC[C@H]1F JYZWPWDEIMDHFF-JBUOLDKXSA-N 0.000 description 5
- JYZWPWDEIMDHFF-TYSVMGFPSA-N (3s,4r)-3-fluorooxan-4-amine;hydrochloride Chemical compound Cl.N[C@@H]1CCOC[C@H]1F JYZWPWDEIMDHFF-TYSVMGFPSA-N 0.000 description 5
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- UQOKRDJILZMZKU-UHFFFAOYSA-N 2-nitropyrimidine Chemical class [O-][N+](=O)C1=NC=CC=N1 UQOKRDJILZMZKU-UHFFFAOYSA-N 0.000 description 5
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- 125000003710 aryl alkyl group Chemical group 0.000 description 5
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 5
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- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 125000000842 isoxazolyl group Chemical group 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- KNQUEEOHOGWETD-KGZKBUQUSA-N (3S,4R)-3-methyloxan-4-amine hydrochloride Chemical compound Cl.C[C@@H]1COCC[C@H]1N KNQUEEOHOGWETD-KGZKBUQUSA-N 0.000 description 4
- VDYWXVDWKFAUKE-UHFFFAOYSA-N 1,3,5-trichloro-2-isocyanatobenzene Chemical compound ClC1=CC(Cl)=C(N=C=O)C(Cl)=C1 VDYWXVDWKFAUKE-UHFFFAOYSA-N 0.000 description 4
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- CLOXAWYNXXEWBT-UHFFFAOYSA-N tert-butyl n-(3-oxocyclopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)C1 CLOXAWYNXXEWBT-UHFFFAOYSA-N 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 229940034727 zelboraf Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462060339P | 2014-10-06 | 2014-10-06 | |
| US62/060,339 | 2014-10-06 | ||
| CN201580065272.2A CN107001372B (zh) | 2014-10-06 | 2015-10-05 | 取代的氨基嘌呤化合物、其组合物及其治疗方法 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201580065272.2A Division CN107001372B (zh) | 2014-10-06 | 2015-10-05 | 取代的氨基嘌呤化合物、其组合物及其治疗方法 |
Publications (1)
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| CN113248506A true CN113248506A (zh) | 2021-08-13 |
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| CN201580065272.2A Active CN107001372B (zh) | 2014-10-06 | 2015-10-05 | 取代的氨基嘌呤化合物、其组合物及其治疗方法 |
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| CN201580065272.2A Active CN107001372B (zh) | 2014-10-06 | 2015-10-05 | 取代的氨基嘌呤化合物、其组合物及其治疗方法 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478326A (zh) * | 2022-01-21 | 2022-05-13 | 安徽宁亿泰科技有限公司 | 一种苯嘧磺草胺关键中间体的合成方法 |
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| DK3204386T3 (da) * | 2014-10-06 | 2021-05-25 | Signal Pharm Llc | Substituerede aminopurinforbindelser, sammensætninger deraf og fremgangsmåder til behandling dermed |
| US9513297B2 (en) | 2014-12-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Methods for measurement of inhibition of c-Jun N-terminal kinase in skin |
| EP3250557B1 (en) | 2015-01-29 | 2024-11-20 | Signal Pharmaceuticals, LLC | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
| US10112944B2 (en) | 2015-03-18 | 2018-10-30 | Bristol-Myers Squibb Company | Heterocyclic compounds useful as inhibitors of TNF |
| ES2797805T3 (es) | 2015-03-18 | 2020-12-03 | Bristol Myers Squibb Co | Compuestos heterocíclicos tricíclicos sustituidos |
| ES2797685T3 (es) | 2015-03-18 | 2020-12-03 | Bristol Myers Squibb Co | Compuestos heterocíclicos tricíclicos útiles como inhibidores de TNF |
| EP3325432B1 (en) | 2015-07-24 | 2020-09-02 | Celgene Corporation | Methods of synthesis of (1r,2r,5r)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein |
| EA201890421A1 (ru) | 2015-08-03 | 2018-07-31 | Бристол-Маерс Сквибб Компани | Циклические соединения, пригодные в качестве модуляторов tnf-альфа |
| US10576085B2 (en) * | 2016-04-01 | 2020-03-03 | Signal Pharmaceuticals, Llc | Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith |
| MX379439B (es) * | 2016-04-01 | 2025-03-10 | Signal Pharm Llc | Formas sólidas de (1s,4s)-4-(2-(((3s,4r)-3-fluorotetrahidro-2h-piran-4-il)amino)-8-((2,4,6-triclorofenil)amino)-9h-purin-9-il)-1-metilciclohexano-1-carboxamida y métodos para utilizarlas. |
| US10010555B2 (en) | 2016-06-02 | 2018-07-03 | Celgene Corporation | Animal and human anti-trypanosomonal and anti-leishmania agents |
| ES2926149T3 (es) * | 2016-06-02 | 2022-10-24 | Celgene Corp | Agentes antipalúdicos animales y humanos |
| MX2020003620A (es) | 2017-10-04 | 2020-10-28 | Celgene Corp | Composiciones y métodos para usar cis-4-[2-{[(3s,4r)-3-fluorooxan- 4-il]amino}-8-(2,4,6-tricloroanilino)-9h-purin-9-il]-1-etilcicloh exano-1-carboxamida. |
| EP3692041A1 (en) * | 2017-10-04 | 2020-08-12 | Celgene Corporation | Processes for the preparation of cis-4 [2-{(3s.4r)-3-fluorooxan-4-yl]amino)-8-(2,4,6-trichloroanilino)-9h-purin-9-yl]-1-methylcyclohexane-1-carboxamide |
| CN115916747A (zh) * | 2020-07-01 | 2023-04-04 | 四川海思科制药有限公司 | 一种并环杂环衍生物及其在医药上的应用 |
| TW202329937A (zh) | 2021-12-03 | 2023-08-01 | 美商英塞特公司 | 雙環胺ｃｋ１２抑制劑 |
| US12084453B2 (en) | 2021-12-10 | 2024-09-10 | Incyte Corporation | Bicyclic amines as CDK12 inhibitors |
| CN117964497B (zh) * | 2024-01-26 | 2026-03-31 | 江西凯信生物医药有限公司 | 一种3,3-二氟环戊胺盐酸盐的合成方法 |
| CN121758295A (zh) * | 2024-09-30 | 2026-03-31 | 青岛清原化合物有限公司 | 一种亚氨基芳基类化合物及中间体的制备方法 |
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2015
- 2015-10-05 DK DK15848476.6T patent/DK3204386T3/da active
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- 2015-10-05 SG SG10202009598VA patent/SG10202009598VA/en unknown
- 2015-10-05 EA EA201790779A patent/EA201790779A1/ru unknown
- 2015-10-05 EP EP20214685.8A patent/EP3822274B1/en active Active
- 2015-10-05 EP EP15848476.6A patent/EP3204386B1/en active Active
- 2015-10-05 KR KR1020237006598A patent/KR20230035424A/ko not_active Withdrawn
- 2015-10-05 HR HRP20210656TT patent/HRP20210656T1/hr unknown
- 2015-10-05 US US14/874,513 patent/US9512124B2/en active Active
- 2015-10-05 PL PL15848476T patent/PL3204386T3/pl unknown
- 2015-10-05 CN CN202110381676.XA patent/CN113248506A/zh active Pending
- 2015-10-05 JP JP2017538172A patent/JP6884701B2/ja active Active
- 2015-10-05 SM SM20210302T patent/SMT202100302T1/it unknown
- 2015-10-05 RS RS20210632A patent/RS61884B1/sr unknown
- 2015-10-05 AR ARP150103202A patent/AR102171A1/es not_active Application Discontinuation
- 2015-10-05 HU HUE15848476A patent/HUE054694T2/hu unknown
- 2015-10-05 ES ES20214685T patent/ES2980464T3/es active Active
- 2015-10-05 SG SG11201702759XA patent/SG11201702759XA/en unknown
- 2015-10-05 WO PCT/US2015/053941 patent/WO2016057370A1/en not_active Ceased
- 2015-10-05 SI SI201531584T patent/SI3204386T1/sl unknown
- 2015-10-05 CA CA2963639A patent/CA2963639C/en active Active
- 2015-10-05 PT PT158484766T patent/PT3204386T/pt unknown
- 2015-10-05 CN CN201580065272.2A patent/CN107001372B/zh active Active
- 2015-10-05 MX MX2017004600A patent/MX388321B/es unknown
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- 2015-10-05 KR KR1020177010551A patent/KR102504849B1/ko active Active
- 2015-10-05 TW TW104132732A patent/TW201629063A/zh unknown
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2016
- 2016-10-27 US US15/335,619 patent/US9737541B2/en active Active
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2017
- 2017-04-04 CL CL2017000820A patent/CL2017000820A1/es unknown
- 2017-04-04 IL IL251566A patent/IL251566B/en active IP Right Grant
- 2017-04-06 MX MX2021014531A patent/MX2021014531A/es unknown
- 2017-04-20 CO CONC2017/0003838A patent/CO2017003838A2/es unknown
- 2017-04-27 EC ECIEPI201726210A patent/ECSP17026210A/es unknown
- 2017-07-05 US US15/641,383 patent/US10149849B2/en active Active
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2018
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2019
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- 2019-10-02 JP JP2019182133A patent/JP6987823B2/ja active Active
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2020
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2023
- 2023-01-11 US US18/095,670 patent/US20230158035A1/en not_active Abandoned
- 2023-03-09 AR ARP230100589A patent/AR128748A2/es unknown
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