WO2020175851A1 - 벤조인다졸론 화합물 및 그 제조 중간체 - Google Patents
벤조인다졸론 화합물 및 그 제조 중간체 Download PDFInfo
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- WO2020175851A1 WO2020175851A1 PCT/KR2020/002459 KR2020002459W WO2020175851A1 WO 2020175851 A1 WO2020175851 A1 WO 2020175851A1 KR 2020002459 W KR2020002459 W KR 2020002459W WO 2020175851 A1 WO2020175851 A1 WO 2020175851A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzo
- indazole
- phenyl
- methoxy
- compound
- Prior art date
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- -1 Benzoindazolone compound Chemical class 0.000 title abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 229940002612 prodrug Drugs 0.000 claims abstract description 24
- 239000000651 prodrug Substances 0.000 claims abstract description 24
- 239000012453 solvate Substances 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- CGSZLTWEXJPXTG-UHFFFAOYSA-N 1H-indazole-4,5-dione Chemical compound O=C1C=Cc2[nH]ncc2C1=O CGSZLTWEXJPXTG-UHFFFAOYSA-N 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- ZYKVRFMMRAPHAZ-UHFFFAOYSA-N 7-fluoro-3 Chemical compound C1S(=O)(=O)CC(C=2)=CC(F)=CC=2CS(=O)(=O)CC2=CC=C1C=C2 ZYKVRFMMRAPHAZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- LOCAIGRSOJUCTB-UHFFFAOYSA-N indazol-3-one Chemical compound C1=CC=C2C(=O)N=NC2=C1 LOCAIGRSOJUCTB-UHFFFAOYSA-N 0.000 claims description 4
- 235000012054 meals Nutrition 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- XALDSBBQJQPYDP-UHFFFAOYSA-N 1H-indazol-5-yl acetate Chemical compound C(C)(=O)OC=1C=C2C=NNC2=CC=1 XALDSBBQJQPYDP-UHFFFAOYSA-N 0.000 claims 1
- 241000551547 Dione <red algae> Species 0.000 claims 1
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- 238000006479 redox reaction Methods 0.000 abstract description 3
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 abstract 2
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 207
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- 239000000543 intermediate Substances 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 39
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
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- VMFUMDXVTKTZQY-UHFFFAOYSA-N naphthalene-1-carbohydrazide Chemical compound C1=CC=C2C(C(=O)NN)=CC=CC2=C1 VMFUMDXVTKTZQY-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 125000005605 benzo group Chemical group 0.000 description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
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- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- YAGCIXJCAUGCGI-UHFFFAOYSA-N butoxycarbonyl butyl carbonate Chemical compound CCCCOC(=O)OC(=O)OCCCC YAGCIXJCAUGCGI-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- BHDAXLOEFWJKTL-UHFFFAOYSA-L dipotassium;carboxylatooxy carbonate Chemical compound [K+].[K+].[O-]C(=O)OOC([O-])=O BHDAXLOEFWJKTL-UHFFFAOYSA-L 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- NZEDJPAZLOUXIE-UHFFFAOYSA-N ethyl 2-amino-4-methoxynaphthalene-1-carboxylate Chemical compound NC1=C(C2=CC=CC=C2C(=C1)OC)C(=O)OCC NZEDJPAZLOUXIE-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- RDOFXDKHPHWUQW-UHFFFAOYSA-N methyl 4-methoxynaphthalene-2-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)OC)=CC(OC)=C21 RDOFXDKHPHWUQW-UHFFFAOYSA-N 0.000 description 1
- GKFXRSUWILKQJF-UHFFFAOYSA-N methyl 6-fluoro-4-hydroxynaphthalene-2-carboxylate Chemical compound C1=C(F)C=CC2=CC(C(=O)OC)=CC(O)=C21 GKFXRSUWILKQJF-UHFFFAOYSA-N 0.000 description 1
- ZKKKDKNGWIRVFK-UHFFFAOYSA-N methyl 7-fluoro-4-hydroxynaphthalene-2-carboxylate Chemical compound COC(=O)c1cc(O)c2ccc(F)cc2c1 ZKKKDKNGWIRVFK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000006705 mitochondrial oxidative phosphorylation Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ABZURHNFFCKUPB-UHFFFAOYSA-N propyl n-aminocarbamate Chemical compound CCCOC(=O)NN ABZURHNFFCKUPB-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a benzoindazolone compound and its manufacturing intermediate.
- the immune system of our body builds up various defense systems to protect the human body from the inside or outside.
- the function of this immune system is the immune response that promotes immunity and suppresses excessive increase in the immune response. It can be categorized as immune tolerance.
- immune homeostasis The proper balance of these two side effects is called immune homeostasis, which is very important for maintaining good health.
- the immune function can be unbalanced due to various causes inside and outside the human body. If the immune response is stronger than the immune tolerance, i.e. when excessive immune cells are activated, inflammatory diseases or autoimmune diseases can occur. When tolerance is stronger than the immune response, i.e. the immune system fails to function properly, it leads to diseases such as infectious diseases or cancer. Therefore, by maintaining the homeostasis of the immune system, which maintains a balance between activation and suppression of the immune response, several immunities are maintained. Attempts are being made to treat related diseases.
- ulcerative colitis is a genetic factor
- Autoimmune disease is a disease caused by an imbalance in which the immune response occurs excessively and attacks healthy cells. Representative examples include rheumatoid arthritis, type 1 diabetes, inflammatory growth disease, and atopic dermatitis. have.
- the human body In order to maintain immune homeostasis by suppressing autoimmune diseases or reducing excessive immune responses, the human body has various types of immune suppressor cells, among which macrophages are responsible for innate immunity. It is a very important immune cell and is distributed in various forms in all tissues of the human body.
- Macrophages In the normal state, macrophages invade phagocytosis or toxins. Macrophages play a role in protecting the body by secreting and destroying them. Also, macrophages play a very diverse role in immune responses such as wound healing and inflammatory reactions in our body. Macrophages are traditionally an Ml or M2 phenotype depending on pathological conditions. It is divided into. However, according to recent research trends, rather than the traditional dichotomy, it is known that macrophages have various types of phenotypes depending on the origin, place of existence, microenvironment, and pathological conditions (Nature Immunology
- LPS lipopolysaccharides
- TNFa tumor necrosis factor alpha
- M2 phenotypic macrophages the main metabolic pathway of M2 phenotypic macrophages is mitochondrial oxidative phosphorylation, which is activated by IL-4 or IL-10, and is mainly used to relieve inflammation or to heal wounds. It plays an important role (Frontiers in immunology 2017, 61).
- the purpose of the present invention is to provide new therapeutic effects for inflammatory diseases.
- the first aspect of the present invention is a compound represented by the following formula (1), its
- II 2 and II 3 do not exist independently of each other, or alkyl within 3 ⁇ 4 0, 0, substituted or
- It is selected from the group consisting of unsubstituted 6-10 aryl, and alkoxy-resistant,
- II 4 is selected from the group consisting of 0, unsubstituted 0 640 aryl and 0 alkoxy, but at least one of II 2 and II 4 is 0 or 0 alkoxy,
- II 5 and II 6 are each independently 3 ⁇ 4 0 alkyl or 0 alkylcarbonyl, or II
- [19] 4 is independently selected from (: and> ⁇ , and two of them are
- the alkyl is a linear, branched or cyclic alkyl
- the heteroaryl is a 5-membered to membered aromatic ring group having at least one heteroatom selected from 0 and 3 in the ring, and the aryl or heteroaryl disubstituted If so, the substituent is 0 1-6 alkyl, halo, or 0 !-6 alkyl substituted with 1 to 3 halo.
- the second aspect of the present invention relates to a compound represented by the following formula (2), which is an intermediate in the manufacture of the compound of formula (1):
- pharmaceutically acceptable salt means that the compound is severe in the organism to which it is administered.
- Diastereoisomer also refers to a form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
- the ⁇ pharmaceutically acceptable salt'' is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., or tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, fluoroacetic acid, glucose Conic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
- an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.
- tartaric acid formic acid, citric acid, acetic acid, trichloroacetic acid, fluoroacetic acid, glucose Conic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic
- carboxylic acid group is present in the compound of Formula 1, examples of pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., lysine, arginine, guanidine, etc. of 2020/175851 1»(:1 ⁇ 1 ⁇ 2020/002459 amino acid salt, dicyclohexylamine, methyl-: 0-glucamine,
- Organic salts formed by tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. are included.
- the compound of formula 1 according to the present invention can be converted into a salt by a conventional method.
- the solvent for the solvate may be any solvent that is volatile, non-toxic and/or suitable for administration to humans.
- prodrug is converted to a compound of formula 1 according to the present invention in vivo
- the prodrug is, in some cases, the parent drug.
- prodrugs are often used because they are easier to administer than ⁇ 13 ⁇ 4). For example, they may obtain physiological activity by oral administration, whereas the parent drug may not.
- Prodrugs may also have improved solubility in pharmaceutical formulations compared to the parent drug.
- prodrugs are esters that facilitate passage through cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, in cells where solubility in water solubility is detrimental to mobility. It may be in the form of a ("prodrug").
- Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group that is metabolized by the peptide to reveal its active site.
- keto-enol (1;0-61101), which means that the structure changes by reciprocating between both isomers.
- enantiomer refers to an isomer that does not overlap with the mirror image, such as the relationship between the right hand and the left hand, and "diastereomer” refers to a stereoisomer that does not have an enantiomer relationship. All of these isomers and Mixtures thereof are also included within the scope of the present invention.
- alkyl refers to an aliphatic hydrocarbon group, including both “saturated alkyl” and “unsaturated alkyl” having at least one double or triple bond moiety, and linear, branched and cyclic alkyl Includes.
- heterocyclyl refers to nitrogen (, oxygen (0) and sulfur (3/4) in the ring.
- Heteroaryl refers to a five to one heteroaromatic ring group having at least one hetero atom selected from nitrogen (, oxygen (0) and sulfur (3 ⁇ 4) in the ring.
- the first aspect of the present invention is a compound represented by the following formula (1), and its pharmaceutically 2020/175851 1»(:1 ⁇ 1 ⁇ 2020/002459 Acceptable salts, hydrates, solvates, enantiomers, diastereomers, tautomers or prodrugs:
- II 2 and II 3 do not exist independently of each other, or 3 ⁇ 4 0, 0 alkyl, substituted or
- 11 4 is 0, unsubstituted (: ⁇ Aryl and (: selected from the group consisting of alkoxy, but at least one of 11 2 and 11 4 is 0 or 0 alkoxy,
- Y ⁇ and II 6 may each independently be 3 ⁇ 4 0 alkyl or 0 alkylcarbonyl, or II 5 and 11 6 may be bonded to each other to form a heterocyclyl containing at least one nitrogen atom in the ring,
- [49] and 4 are each independently selected from (: and N, two of them are N, but cannot be N when X 2 and X 4 are activated, or N when X and X 4 are activated.
- the alkyl is a linear, branched or cyclic alkyl
- the heteroaryl is a 5-membered to membered heteroaromatic ring group having at least one heteroatom selected from 0 and 3 in the ring, and the aryl or heteroaryl When disubstituted, the substituent is (:alkyl, halo, or (:alkyl substituted with 1 to 3 halo).
- At least one of II 2 , II 3 and II 4 may be an alkoxy within 0, wherein the alkyl constituting the alkoxy may be a linear, branched or cyclic alkyl have.
- At least two may be double bonds.
- 2020/175851 1 (:1 ⁇ 1 ⁇ 2020/002459
- X 2 and X 3 are carbon atoms (0 and X ! And 3 is a nitrogen atom (may be non-, in this case 11 2 may be (: 6-10) substituted or unsubstituted aryl.
- the halo may be any one of fluoro, chloro, bromo, and iodo.
- the compounds of formula 1 of the present invention include compounds 1 to 25 below:
- [6 is compound 1: 1 -phenyl-1 -benzo [indazole-3, 4, 5 (2 ⁇ )-trione;
- This compound 11 2 -isopentyl-1 -phenyl-1 -benzo [indazole-3, 4, 5 (2 ⁇ )-trione;
- [8 is compound 21: 7-fluoro-2 -methyl-1 -phenyl-1 -benzo [indazole-3, 4, 5 (2 ⁇ )-trione;
- the second aspect of the present invention relates to a compound represented by the following formula (2), which is an intermediate for the manufacture of the compound of formula (1):
- II 7 is a protecting group for a conventional hydroxy group known in the art.
- the protecting group are (: ⁇ 6 alkyl; ( 6-1 ()) aryl substituted (: alkyl, eg For example, benzyl, trityl, methoxy benzyl, etc.; ( 6 alkoxy substituted (: 6 alkyl, for example, methoxymethyl, methoxyethoxymethyl, etc.; 1 hetero atom selected from among 0 and in the ring) 5- or 6-membered heterocyclyl containing more than one, for example tetrahydropyranyl, tetrahydrofuranyl, etc.; (: alkyl substituted silyl, for example trimethylsilyl, triisopropylsilyl, butyldimethylsilyl, etc.; 0 Alkylcarbonyl, for example acetyl, pivaloyl, etc. may be mentioned, but is not limited thereto.
- the third aspect of the present invention is pharmaceuticals including a compound represented by Formula 1 above as an active ingredient, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, tautomer or prodrug thereof as an active ingredient It is about red composition.
- the pharmaceutical composition may further include at least one selected from the group consisting of carriers, excipients, and diluents commonly known in the pharmaceutical composition field.
- the compound of Formula 1 according to the present invention can be used as a substrate for NQ01 to inhibit the expression and activity of inflammatory cytokines, so the pharmaceutical composition can be used for the prevention or treatment of diseases related to NQ01 activity. have.
- the residual moisture is removed from the organic layer with magnesium sulfate. After vacuum concentration, recrystallization with ethyl acetate and nucleic acid, the mother liquor is concentrated under reduced pressure and
- reaction mixture After adding 0 additionally, the reaction mixture is transferred to a separatory funnel and given three times with ethyl acetate, the organic vapor is collected, and the residual moisture is removed with anhydrous magnesium sulfate. Concentrate under reduced pressure and purify by column chromatography.
- reaction mixture was transferred to a separatory funnel, extracted three times with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and salt water. The organic layer was collected with anhydrous magnesium sulfate to remove residual moisture. Then, it is filtered under reduced pressure, the filtrate is concentrated under reduced pressure, and then purified by column chromatography.
- Phenyl- 1 -benzo [indazole- 3, 4, 5 (2 use-trione (0.2711111101, compound 1) and potassium carbonate (0.80_01) were added to a 34 round bottom flask, and anhydrous DMSO (311 small) ) To melt.
- Example 3 Compound 3 (2 -isopropyl- 1 -methyl-1 table-benzo [ ⁇ ] indazole- 3, 4, 5 (2 tables)
- Example 5 Synthesis of Compound 5 (2methyl- 1-phenyl- 1 table-benzo [yo] indazole-3, 4, 5 (2 table)-trione) 2020/175851 1»(:1 ⁇ 1 ⁇ 2020/002459
- Example 11 Compound 11 (2-isopentyl-1-phenyl-1 table-benzo [ ⁇ ] indazole-3, 4, 5 (2 tables)
- Example 1 (1) Using as a starting material, the title compound was synthesized according to the procedure described in Example 1 (1).
- Example 1 Using the 7-fluoro- 5 -methoxy- 2 -methyl- 1 -phenyl-1 -benzo[indazole-3(2 ⁇ )-one prepared above as a starting material, (1) of Example 1 The title compound was synthesized according to the procedure described in ).
- Example 22 Compound 22 (7 fluoro-3 -methoxy-1 -phenyl-1 table-benzo [ ⁇
- the title compound was synthesized.
- Example 23 Compound 23 (3 -methoxy-7 -nitro-1 -phenyl-1 table-benzo [ ⁇
- Example 25 Compound 25 (7 bromo-3 -methoxy-1 -phenyl-1 table-benzo [yo
- Tris-HC tris (hydroxymethyl) aminomethane hydrochloride (buffer)
- Equipment used Cary 100 UV-Vis spectrophotometer
- NQ01 activity (compound 5 ⁇ iM, nmol reduced cytochrome C/min/ ⁇ ig NQOl protein)
- NQ01 activity (compound 0.2 ⁇ , 1111101 reduced cytochrome (:/ ⁇ disease NQ01 protein)
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- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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US17/310,878 US20220144780A1 (en) | 2019-02-28 | 2020-02-20 | Benzoindazolone compound and intermediate thereof |
CN202080015831.XA CN113454068A (zh) | 2019-02-28 | 2020-02-20 | 苯并吲唑酮化合物及其中间体 |
JP2021550095A JP7359463B2 (ja) | 2019-02-28 | 2020-02-20 | ベンゾインダゾロン化合物およびその製造中間体 |
EP20762099.8A EP3932909A4 (en) | 2019-02-28 | 2020-02-20 | BENZOINDAZOLON COMPOUND AND INTERMEDIATE THEREOF |
AU2020229601A AU2020229601B2 (en) | 2019-02-28 | 2020-02-20 | Benzoindazolone compound, and intermediate thereof |
CA3129943A CA3129943A1 (en) | 2019-02-28 | 2020-02-20 | Benzoindazolone compound, and intermediate thereof |
BR112021016912A BR112021016912A2 (pt) | 2019-02-28 | 2020-02-20 | Composto de benzoindazolona e intermediário do mesmo |
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KR1020190023942A KR102201768B1 (ko) | 2019-02-28 | 2019-02-28 | 벤조인다졸론 화합물 및 그 용도 |
KR10-2019-0023942 | 2019-02-28 |
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EP (1) | EP3932909A4 (ko) |
JP (1) | JP7359463B2 (ko) |
KR (1) | KR102201768B1 (ko) |
CN (1) | CN113454068A (ko) |
AU (1) | AU2020229601B2 (ko) |
BR (1) | BR112021016912A2 (ko) |
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JP2001509509A (ja) * | 1997-07-09 | 2001-07-24 | アストラ・フアーマシユウテイカルズ・リミテツド | 新規な化合物 |
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KR20080099174A (ko) * | 2007-05-07 | 2008-11-12 | 주식회사 머젠스 | 비만, 당뇨, 대사성 질환, 퇴행성 질환 및 미토콘드리아이상 질환의 치료 또는 예방을 위한 나프토퀴논계 약제조성물 |
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JP2022522701A (ja) | 2022-04-20 |
EP3932909A1 (en) | 2022-01-05 |
AU2020229601B2 (en) | 2022-09-15 |
KR102201768B1 (ko) | 2021-01-12 |
CA3129943A1 (en) | 2020-09-03 |
CN113454068A (zh) | 2021-09-28 |
KR20200105165A (ko) | 2020-09-07 |
BR112021016912A2 (pt) | 2021-11-03 |
EP3932909A4 (en) | 2022-12-14 |
AU2020229601A1 (en) | 2021-09-16 |
US20220144780A1 (en) | 2022-05-12 |
JP7359463B2 (ja) | 2023-10-11 |
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