BG104050A - Хидразинови производни - Google Patents
Хидразинови производни Download PDFInfo
- Publication number
- BG104050A BG104050A BG104050A BG10405099A BG104050A BG 104050 A BG104050 A BG 104050A BG 104050 A BG104050 A BG 104050A BG 10405099 A BG10405099 A BG 10405099A BG 104050 A BG104050 A BG 104050A
- Authority
- BG
- Bulgaria
- Prior art keywords
- solvent
- phenyl
- butenyl
- methanesulfonyl
- aryl
- Prior art date
Links
- 150000002429 hydrazines Chemical class 0.000 title description 19
- -1 cyano, amino, hydroxy Chemical group 0.000 claims abstract description 472
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 63
- 125000003118 aryl group Chemical group 0.000 claims abstract description 25
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 8
- 208000032843 Hemorrhage Diseases 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 206010037660 Pyrexia Diseases 0.000 claims abstract description 7
- 206010040047 Sepsis Diseases 0.000 claims abstract description 7
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 7
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- 150000003950 cyclic amides Chemical class 0.000 claims abstract description 5
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 5
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 153
- 238000000034 method Methods 0.000 claims description 138
- 239000000203 mixture Substances 0.000 claims description 108
- 150000001875 compounds Chemical class 0.000 claims description 84
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- PJBQYCIDGYKEMN-UHFFFAOYSA-N pentanehydrazide Chemical compound CCCCC(=O)NN PJBQYCIDGYKEMN-UHFFFAOYSA-N 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 125000005394 methallyl group Chemical group 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 7
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 125000000565 sulfonamide group Chemical group 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 14
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 abstract description 8
- 101800004564 Transforming growth factor alpha Proteins 0.000 abstract description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 abstract description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 abstract description 5
- 230000035755 proliferation Effects 0.000 abstract description 5
- 150000002431 hydrogen Chemical class 0.000 abstract description 3
- 102000009618 Transforming Growth Factors Human genes 0.000 abstract 1
- 108010009583 Transforming Growth Factors Proteins 0.000 abstract 1
- 102000018594 Tumour necrosis factor Human genes 0.000 abstract 1
- 108050007852 Tumour necrosis factor Proteins 0.000 abstract 1
- 208000015181 infectious disease Diseases 0.000 abstract 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 761
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 538
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 283
- 239000007787 solid Substances 0.000 description 250
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 238
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
- 239000000243 solution Substances 0.000 description 192
- 238000010828 elution Methods 0.000 description 166
- 238000004128 high performance liquid chromatography Methods 0.000 description 139
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 138
- 230000014759 maintenance of location Effects 0.000 description 137
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 131
- 239000007858 starting material Substances 0.000 description 127
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 74
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 48
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 36
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 36
- 235000017557 sodium bicarbonate Nutrition 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- 229910052717 sulfur Inorganic materials 0.000 description 25
- 239000000126 substance Substances 0.000 description 24
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 13
- 239000006071 cream Substances 0.000 description 13
- 239000006260 foam Substances 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- CSNDPGHMQACDKL-UHFFFAOYSA-N 4-methyl-2-methylsulfonylpentanehydrazide Chemical compound CC(C)CC(S(C)(=O)=O)C(=O)NN CSNDPGHMQACDKL-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000005518 carboxamido group Chemical group 0.000 description 10
- 229940098779 methanesulfonic acid Drugs 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 230000000630 rising effect Effects 0.000 description 10
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 9
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000000969 carrier Substances 0.000 description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 6
- NGSOWKPBNFOQCR-UHFFFAOYSA-N 2-methylpropylhydrazine Chemical compound CC(C)CNN NGSOWKPBNFOQCR-UHFFFAOYSA-N 0.000 description 6
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- DFLMFSOZCQWBPD-HZOVXUMNSA-N tert-butyl (2s,3r)-3-(hydrazinecarbonyl)-5-methyl-2-[(e)-3-phenylprop-2-enyl]hexanoate Chemical compound CC(C)C[C@@H](C(=O)NN)[C@@H](C(=O)OC(C)(C)C)C\C=C\C1=CC=CC=C1 DFLMFSOZCQWBPD-HZOVXUMNSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 5
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 5
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 5
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 5
- 229940067157 phenylhydrazine Drugs 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- WNMZLOWDBBFFAU-HZOVXUMNSA-N (e,2r,3s)-3-[(2-methylpropan-2-yl)oxycarbonyl]-2-(2-methylpropyl)-6-phenylhex-5-enoic acid Chemical compound CC(C)C[C@@H](C(O)=O)[C@@H](C(=O)OC(C)(C)C)C\C=C\C1=CC=CC=C1 WNMZLOWDBBFFAU-HZOVXUMNSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- FVYIOYFXCYBUEU-UHFFFAOYSA-N 2-methylpentanehydrazide Chemical compound CCCC(C)C(=O)NN FVYIOYFXCYBUEU-UHFFFAOYSA-N 0.000 description 4
- RGTLSFNPTLNPDZ-UHFFFAOYSA-N 4-(2-methylpropoxy)-4-oxobutanoic acid Chemical compound CC(C)COC(=O)CCC(O)=O RGTLSFNPTLNPDZ-UHFFFAOYSA-N 0.000 description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
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- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000011593 sulfur Chemical group 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HATVMIUBQIEHQG-BJKOFHAPSA-N tert-butyl (2s,3r)-3-(anilinocarbamoyl)-5-methyl-2-(3-phenylpropyl)hexanoate Chemical compound C([C@@H]([C@@H](CC(C)C)C(=O)NNC=1C=CC=CC=1)C(=O)OC(C)(C)C)CCC1=CC=CC=C1 HATVMIUBQIEHQG-BJKOFHAPSA-N 0.000 description 1
- YIAJOOZDZWBTDU-WCWNVHNDSA-N tert-butyl (2s,3r)-3-[(2,6-dioxopiperidin-1-yl)carbamoyl]-5-methyl-2-[(e)-3-phenylprop-2-enyl]hexanoate Chemical compound C([C@@H]([C@@H](CC(C)C)C(=O)NN1C(CCCC1=O)=O)C(=O)OC(C)(C)C)\C=C\C1=CC=CC=C1 YIAJOOZDZWBTDU-WCWNVHNDSA-N 0.000 description 1
- DTZCMLDLLCQQCV-PGRDOPGGSA-N tert-butyl (2s,3r)-5-methyl-2-(3-methylbutyl)-3-[(2-methylpropylamino)carbamoyl]-3-methylsulfonylhexanoate Chemical compound CC(C)CC[C@@H](C(=O)OC(C)(C)C)[C@@](CC(C)C)(S(C)(=O)=O)C(=O)NNCC(C)C DTZCMLDLLCQQCV-PGRDOPGGSA-N 0.000 description 1
- RLZZIIUWAXPGFO-WCWNVHNDSA-N tert-butyl (2s,3r)-5-methyl-2-[(e)-3-phenylprop-2-enyl]-3-(1,2-thiazolidin-2-ylcarbamoyl)hexanoate Chemical compound C([C@@H]([C@@H](CC(C)C)C(=O)NN1SCCC1)C(=O)OC(C)(C)C)\C=C\C1=CC=CC=C1 RLZZIIUWAXPGFO-WCWNVHNDSA-N 0.000 description 1
- OQKDESDQAVWCFC-IOWSJCHKSA-N tert-butyl (2s,3r)-5-methyl-3-[(n-phenylmethoxycarbonylanilino)carbamoyl]-2-(3-phenylpropyl)hexanoate Chemical compound C([C@@H]([C@@H](CC(C)C)C(=O)NN(C(=O)OCC=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)OC(C)(C)C)CCC1=CC=CC=C1 OQKDESDQAVWCFC-IOWSJCHKSA-N 0.000 description 1
- NMCWNAOWRKTRQX-GUYDGBRCSA-N tert-butyl (2s,3r)-5-methyl-3-[[2-methylpropanoyl(2-methylpropyl)amino]carbamoyl]-2-[(e)-3-phenylprop-2-enyl]hexanoate Chemical compound CC(C)CN(C(=O)C(C)C)NC(=O)[C@H](CC(C)C)[C@@H](C(=O)OC(C)(C)C)C\C=C\C1=CC=CC=C1 NMCWNAOWRKTRQX-GUYDGBRCSA-N 0.000 description 1
- RHYXRIDXGKSGQB-FCHUYYIVSA-N tert-butyl (2s,3r)-5-methyl-3-[[2-methylpropyl(methylsulfonyl)amino]carbamoyl]-2-(3-pyridin-3-ylpropyl)hexanoate Chemical compound CC(C)CN(S(C)(=O)=O)NC(=O)[C@H](CC(C)C)[C@@H](C(=O)OC(C)(C)C)CCCC1=CC=CN=C1 RHYXRIDXGKSGQB-FCHUYYIVSA-N 0.000 description 1
- CZHMLZHMOCLWCK-OAHLLOKOSA-N tert-butyl (3r)-5-methyl-2-methylidene-3-[[2-methylpropyl(methylsulfonyl)amino]carbamoyl]hexanoate Chemical compound CC(C)(C)OC(=O)C(=C)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O CZHMLZHMOCLWCK-OAHLLOKOSA-N 0.000 description 1
- JEMBLYHCCWYAFS-UWTGMQRYSA-N tert-butyl (3r)-5-methyl-3-[(n-methylsulfonylanilino)carbamoyl]-2-[(e)-3-pyridin-3-ylprop-2-enyl]hexanoate Chemical compound CC(C)(C)OC(=O)C([C@@H](CC(C)C)C(=O)NN(C=1C=CC=CC=1)S(C)(=O)=O)C\C=C\C1=CC=CN=C1 JEMBLYHCCWYAFS-UWTGMQRYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- AEXDSSJCKSDUEC-UHFFFAOYSA-N tert-butyl n-(thiazinan-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NN1CCCCS1 AEXDSSJCKSDUEC-UHFFFAOYSA-N 0.000 description 1
- GFVLYPGDAJSPNY-UHFFFAOYSA-N tert-butyl n-amino-n-(4-chlorobutylsulfonyl)carbamate Chemical compound CC(C)(C)OC(=O)N(N)S(=O)(=O)CCCCCl GFVLYPGDAJSPNY-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LDJBOXSVVWHBLS-UHFFFAOYSA-M triphenyl(1,3-thiazol-2-ylmethyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=NC=CS1 LDJBOXSVVWHBLS-UHFFFAOYSA-M 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- 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
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
- C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
- C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/38—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Public Health (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Paints Or Removers (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Epoxy Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Indole Compounds (AREA)
- Non-Silver Salt Photosensitive Materials And Non-Silver Salt Photography (AREA)
- Pyrane Compounds (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9713833.3A GB9713833D0 (en) | 1997-06-30 | 1997-06-30 | Novel hydrazine derivatives |
| GBGB9803335.0A GB9803335D0 (en) | 1997-06-30 | 1998-02-17 | Novel hydrazine derivatives |
| PCT/EP1998/003683 WO1999001428A1 (en) | 1997-06-30 | 1998-06-18 | Hydrazine derivatives |
Publications (1)
| Publication Number | Publication Date |
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| BG104050A true BG104050A (bg) | 2000-12-29 |
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| BG104050A BG104050A (bg) | 1997-06-30 | 1999-12-28 | Хидразинови производни |
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| AU2298399A (en) * | 1998-02-06 | 1999-08-23 | Yoshitomi Pharmaceutical Industries, Ltd. | Novel azapeptide type hydroxamic acid derivatives |
| US6239151B1 (en) * | 1998-06-26 | 2001-05-29 | Hoffmann-La Roche Inc. | Compounds as inhibitor of tumor necrosis factor alpha release |
| GB9826153D0 (en) * | 1998-11-27 | 1999-01-20 | Hoffmann La Roche | Hydrazine derivatives |
| ES2249055T3 (es) * | 1998-12-11 | 2006-03-16 | F. Hoffmann-La Roche Ag | Derivados de hidrazina. |
| US20040122011A1 (en) * | 1998-12-23 | 2004-06-24 | Pharmacia Corporation | Method of using a COX-2 inhibitor and a TACE inhibitors as a combination therapy |
| KR100465353B1 (ko) * | 1999-04-22 | 2005-01-13 | 주식회사유한양행 | 하이드라진 유도체 및 그의 제조방법 |
| US6808902B1 (en) | 1999-11-12 | 2004-10-26 | Amgen Inc. | Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules |
| PH12012502440A1 (en) | 2001-06-26 | 2013-06-17 | Amgen Inc | Antibodies to opgl |
| US6924312B2 (en) * | 2001-07-10 | 2005-08-02 | Synta Pharmaceuticals Corp. | Taxol enhancer compounds |
| TWI332943B (en) * | 2001-07-10 | 2010-11-11 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
| TWI252847B (en) * | 2001-07-10 | 2006-04-11 | Synta Pharmaceuticals Corp | Synthesis of taxol enhancers |
| TWI297335B (en) * | 2001-07-10 | 2008-06-01 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
| UY27813A1 (es) * | 2002-05-31 | 2003-12-31 | Smithkline Beecham Corp | Inhibidores de la peptido-desformilasa |
| GB0229673D0 (en) * | 2002-12-19 | 2003-01-29 | British Biotech Pharm | Antibacterial agents |
| AU2003299971A1 (en) | 2002-12-30 | 2004-07-29 | Amgen Inc. | Combination therapy with co-stimulatory factors |
| TWI330079B (en) * | 2003-01-15 | 2010-09-11 | Synta Pharmaceuticals Corp | Treatment for cancers |
| UA89035C2 (ru) | 2003-12-03 | 2009-12-25 | Лео Фарма А/С | Эфиры гидроксамовых кислот и их фармацевтическое применение |
| CN1993318B (zh) | 2004-06-23 | 2012-10-03 | Synta医药公司 | 用于治疗癌症的双(硫代-酰肼酰胺)盐 |
| JP5204489B2 (ja) * | 2004-11-19 | 2013-06-05 | シンタ ファーマスーティカルズ コーポレイション | Hsp70発現を増加するためのビス(チオ‐ヒドラジドアミド) |
| WO2006101937A1 (en) * | 2005-03-18 | 2006-09-28 | Janssen Pharmaceutica N.V. | Acylhydrazones as kinase modulators |
| WO2006113695A1 (en) * | 2005-04-15 | 2006-10-26 | Synta Pharmaceuticals Corp. | Combination cancer therapy with bis(thiohydrazide) amide compounds |
| KR20080008399A (ko) | 2005-05-16 | 2008-01-23 | 신타 파마슈티칼스 코프. | 비스(티오-히드라지드 아미드) 염의 합성 방법 |
| DE102005038344A1 (de) * | 2005-08-13 | 2007-02-15 | Tetra Laval Holdings & Finance S.A. | Vorrichtung zum Ultraschallbearbeiten von Werkstücken |
| KR20080035642A (ko) * | 2005-08-16 | 2008-04-23 | 신타 파마슈티칼스 코프. | 비스(티오-히드라지드 아미드) 제제 |
| ATE509956T1 (de) * | 2006-06-08 | 2011-06-15 | Helmholtz Zentrum Muenchen | Spezifische proteaseinhibitoren und ihre verwendung in der krebstherapie |
| TWI440632B (zh) | 2006-08-21 | 2014-06-11 | Synta Pharmaceuticals Corp | 用於治療增生性疾病的化合物 |
| JP2010502616A (ja) * | 2006-08-31 | 2010-01-28 | シンタ ファーマシューティカルズ コーポレーション | 癌を治療するためのビス(チオヒドラジドアミド)の組み合わせ |
| US7645904B2 (en) * | 2006-09-15 | 2010-01-12 | Synta Pharmaceuticals Corp. | Purification of bis(thiohydrazide amides) |
| TW200838501A (en) * | 2007-02-02 | 2008-10-01 | Theravance Inc | Dual-acting antihypertensive agents |
| CN102153490A (zh) * | 2011-02-16 | 2011-08-17 | 东营柯林维尔化工有限公司 | 肼基甲酸酯类的合成 |
| CA2880639A1 (en) | 2012-08-01 | 2014-02-06 | The Hospital For Sick Children | Inhibitors of peptidyl arginine deiminase (pad) enzymes and uses thereof |
| CN104031081B (zh) * | 2014-03-06 | 2017-03-29 | 苏州大学 | 一种多酰胺抗菌剂、制备方法及其应用 |
| MA55795A (fr) * | 2019-04-30 | 2022-03-09 | Sitryx Therapeutics Ltd | Dérivés d'acide itaconique et leurs utilisations dans le traitement d'une maladie inflammatoire ou d'une maladie associée à une réponse immunitaire indésirable |
| CN120717927B (zh) * | 2025-06-09 | 2026-03-06 | 绍兴上虞新银邦生化有限公司 | 一种联苯肼酯的合成方法 |
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| CA2058797A1 (en) | 1991-02-01 | 1992-08-02 | Michael John Broadhurst | Amino acid derivatives |
| US5399589A (en) | 1992-12-17 | 1995-03-21 | Basf Aktiengesellschaft | Oxalyl hydrazide-hydroxamic acid derivatives, their preparation and their use as fungicides |
| AU2298399A (en) | 1998-02-06 | 1999-08-23 | Yoshitomi Pharmaceutical Industries, Ltd. | Novel azapeptide type hydroxamic acid derivatives |
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- 1998-06-18 NZ NZ501455A patent/NZ501455A/en unknown
- 1998-06-18 PT PT98937498T patent/PT993442E/pt unknown
- 1998-06-18 AT AT98937498T patent/ATE238277T1/de not_active IP Right Cessation
- 1998-06-18 HU HU0002424A patent/HUP0002424A3/hu unknown
- 1998-06-18 WO PCT/EP1998/003683 patent/WO1999001428A1/en not_active Ceased
- 1998-06-18 BR BR9810952-9A patent/BR9810952A/pt not_active Application Discontinuation
- 1998-06-18 DE DE69813815T patent/DE69813815T2/de not_active Expired - Fee Related
- 1998-06-18 ID IDW991686A patent/ID24705A/id unknown
- 1998-06-18 JP JP50623099A patent/JP3801653B2/ja not_active Expired - Fee Related
- 1998-06-18 IL IL13371298A patent/IL133712A0/xx unknown
- 1998-06-18 CA CA002295062A patent/CA2295062A1/en not_active Abandoned
- 1998-06-18 ES ES98937498T patent/ES2195365T3/es not_active Expired - Lifetime
- 1998-06-18 TR TR1999/03281T patent/TR199903281T2/xx unknown
- 1998-06-18 CN CNB988075849A patent/CN1161331C/zh not_active Expired - Fee Related
- 1998-06-18 AU AU86273/98A patent/AU725039B2/en not_active Ceased
- 1998-06-18 DK DK98937498T patent/DK0993442T3/da active
- 1998-06-18 PL PL98337793A patent/PL337793A1/xx unknown
- 1998-06-18 EP EP98937498A patent/EP0993442B1/en not_active Expired - Lifetime
- 1998-06-24 IT IT1998MI001441A patent/IT1301792B1/it active IP Right Grant
- 1998-06-26 FR FR9808124A patent/FR2765219B1/fr not_active Expired - Lifetime
- 1998-06-29 ES ES009801359A patent/ES2140348B1/es not_active Expired - Lifetime
- 1998-06-29 GB GB9814027A patent/GB2326881A/en not_active Withdrawn
- 1998-06-30 MA MA25147A patent/MA26517A1/fr unknown
- 1998-06-30 DE DE19829229A patent/DE19829229A1/de not_active Withdrawn
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1999
- 1999-12-23 IS IS5322A patent/IS5322A/is unknown
- 1999-12-28 BG BG104050A patent/BG104050A/bg unknown
- 1999-12-29 NO NO996534A patent/NO996534L/no not_active Application Discontinuation
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