CN1350536A - 氨基甲酰基四氢吡啶衍生物 - Google Patents
氨基甲酰基四氢吡啶衍生物 Download PDFInfo
- Publication number
- CN1350536A CN1350536A CN00807454A CN00807454A CN1350536A CN 1350536 A CN1350536 A CN 1350536A CN 00807454 A CN00807454 A CN 00807454A CN 00807454 A CN00807454 A CN 00807454A CN 1350536 A CN1350536 A CN 1350536A
- Authority
- CN
- China
- Prior art keywords
- nco
- alkyl
- hydrogen atom
- bromo
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- KTXSODKVFJNBQU-UHFFFAOYSA-N 3,4-dihydro-2h-pyridine-1-carboxamide Chemical class NC(=O)N1CCCC=C1 KTXSODKVFJNBQU-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 150
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 56
- -1 trifluoromethoxy, amino Chemical group 0.000 claims description 40
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 150000007980 azole derivatives Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 150000004944 pyrrolopyrimidines Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- 239000011734 sodium Substances 0.000 description 48
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 33
- 150000001875 compounds Chemical group 0.000 description 32
- 239000002585 base Substances 0.000 description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 23
- 150000003233 pyrroles Chemical class 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 238000001035 drying Methods 0.000 description 22
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 21
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 20
- 229940093499 ethyl acetate Drugs 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000000376 reactant Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 208000019901 Anxiety disease Diseases 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 206010019196 Head injury Diseases 0.000 description 4
- 208000023105 Huntington disease Diseases 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 208000026106 cerebrovascular disease Diseases 0.000 description 4
- 230000002596 correlated effect Effects 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 235000012631 food intake Nutrition 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 238000010931 ester hydrolysis Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 3
- WKYGMSYBNGFBEX-UHFFFAOYSA-N 1,2,3,6-tetrahydropyridine-4-carboxylic acid;hydrobromide Chemical class Br.OC(=O)C1=CCNCC1 WKYGMSYBNGFBEX-UHFFFAOYSA-N 0.000 description 2
- ABBVAMUCDQETDO-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl 4-oxopiperidine-1,3-dicarboxylate Chemical class CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O ABBVAMUCDQETDO-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical class CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ROWKJAVDOGWPAT-UHFFFAOYSA-N Acetoin Chemical compound CC(O)C(C)=O ROWKJAVDOGWPAT-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical class COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 210000002442 prefrontal cortex Anatomy 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- XFGOZIGBENRIKG-UHFFFAOYSA-N 1,2,3,6-tetrahydropyridin-5-amine hydrochloride Chemical class C1CNCC(=C1)N.Cl XFGOZIGBENRIKG-UHFFFAOYSA-N 0.000 description 1
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Abstract
提供下式表示的氨基甲酰基四氢吡啶衍生物或其可药用盐,及其制备中间体。[式中,R1和R2相同或不同,表示氢原子、C1-5烷基等,Y1-Y2表示(R4)C=C(R5)、(R6)C=N、N=N、(R7)N-CO或N=C(R8),X1、X2和X3相同或不同,表示氢原子、卤素原子等,R3、R4、R5和R6相同或不同,表示氢原子或烷基,R7表示氢原子、C1-5烷基等,R8表示氢原子或氨基甲酰基]。上述衍生物对于与CRF有关的疾病有效。
Description
技术领域
本发明涉及抑郁症、焦虑症、阿耳茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、摄食障碍、高血压、消化器官疾病、药物依赖、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关疾病等与促肾上腺皮质激素释放因子(CRF)有关的疾病的治疗剂。
背景技术
CRF是由41个氨基酸构成的激素(Science,213,1394-1397,1981;J.Neurosci.,7,88-100,1987),提示它在对于应激的机体反应中发挥核心作用(Cell.Mol.Neurobiol.,14,579-588,1994;Endocrinol.,132,723-728,1994;Neuroendocrinol.61,445-452,1995)。CRF具有通过下丘脑-垂体-肾上腺***作用于末梢的免疫***、交感神经***的途径以及在中枢神经***中作为神经传导物质发挥功能的2种途径(in Corticotropin ReleasingFactor:Basic and Clinical Studies of a Neuropeptide,pp29-52,1990)。如果将CRF投至除去垂体的大鼠以及正常大鼠的脑室内,这两种大鼠均会产生焦虑样症状(Pharmacol.Rev.,43,425-473,1991;Brain Res.Rev.,15,71-100,1990)。也就是说,认为CRF干预下丘脑-垂体-肾上腺***并且在中枢神经***中作为神经传导物质发挥功能。
与CRF有关的疾病在1991年归纳于Owens和Nemeroff综述(Pharmacol.rev.,43,425-474,1991)中。也就是说,CRF与抑郁症、焦虑症、阿耳茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、摄食障碍、高血压、消化器官疾病、药物依赖、炎症、免疫相关疾病等有关。最近有报道指出CRF还与癫痫、脑梗塞、脑缺血、脑水肿、头部外伤有关(Brain Res.545,339-342,1991;Ann.Neurol.31,48-498,1992;Dev.Brain Res.91,245-251,1996;Brain Res.744,166-170,1997),因此CRF受体拮抗剂作为这些疾病的治疗剂是有用的。
本发明的目的在于提供一种作为抑郁症、焦虑症、阿耳茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、摄食障碍、高血压、消化器官疾病、药物依赖、癫痫、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关疾病等与CRF有关的疾病的治疗剂或预防剂有效的CRF拮抗剂。
发明公开
本发明人对于氨基甲酰基四氢吡啶衍生物进行了悉心地研究,结果发现了对CRF受体显示高亲和性的新型氨基甲酰基四氢吡啶衍生物,进一步发现了合成这种新型氨基甲酰基四氢吡啶衍生物所必要的合成中间体——吡咯并嘧啶衍生物、吡咯衍生物以及氨基甲酰基-1,2,3,6-四氢吡啶,完成了本发明。
以下,说明本发明。
本发明是下式〔1〕表示的氨基甲酰基四氢吡啶衍生物或其可药用盐。〔式中,R1和R2相同或不同,表示氢原子、C1-5烷基或苯基,或R1与R2连成一体,与相邻的氮原子一同表示下式所示的5~8元饱和杂环基团,(式中,A为CH2、NH、N-C1-5烷基、O或S),R3表示氢原子或C1-5烷基,Y1-Y2表示(R4)C=C(R5)、(R6)C=N、N=N、(R7)N-CO或N=C(R8),X1、X2和X3相同或不同,表示氢原子、卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基、三氟甲氧基、氨基或C1-5烷基氨基。其中,R4和R5相同或不同,表示氢原子或C1-5烷基,R6表示氢原子或C1-5烷基,R7表示氢原子、C1-5烷基、C1-5烷氧基羰基甲基、羧甲基或式CH2CONR11(R12)表示的基团(式中,R11和R12相同或不同,表示氢原子或C1-5烷基,或R11和R12连成一体,与相邻的氮原子一同表示下式所示的5~8元饱和杂环基团,(式中,B为CH2、NH、N-C1-5烷基、O或S)),R8表示氢原子或氨基甲酰基〕。其中,优选R1和R2为氢原子的化合物组,其中更优选R3为甲基,Y1-Y2为(R4)C=C(R5),R4和R5相同或不同,为氢或甲基的化合物组。
另外,本发明是下式〔2〕表示的吡咯并嘧啶衍生物。(式中,R3表示氢原子或C1-5烷基,R4和R5相同或不同,表示氢原子或C1-5烷基,X4表示羟基、氯原子、溴原子或碘原子,X5表示卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基或三氟甲氧基。)
另外,本发明是下式〔3〕表示的吡咯衍生物。(式中,R4和R5相同或不同,表示氢原子或C1-5烷基,X5表示卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基或三氟甲氧基。)
另外,本发明是下式〔4〕表示的4-或5-氨基甲酰基-1,2,3,6-四氢吡啶或其可药用盐。
本发明式〔1〕中(R2)R1NCO基的取代位置为4位或5位。
另外,本发明中使用的术语定义如下。
C1-5烷基是指直链状或支链状的碳原子数1~5个的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基甲基、戊基、异戊基等。
饱和杂环基团如果能够提供下述反应式中表示的式(10)的化合物,由于任何饱和杂环基团均可以合成,没有特别的限定,是指可以具有氮原子、氧原子、硫原子作为成环原子的5~8元饱和杂环基团。这些基团例如吡咯烷基、哌啶子基、吗啉代基、硫代吗啉代基、哌嗪基、4-甲基哌嗪基等。
卤素原子是指氟原子、氯原子、溴原子或碘原子。
C1-5烷氧基是指直链状或支链状的碳原子数1~5个的烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基、异戊氧基等。
C1-5烷硫基是指直链状或支链状的碳原子数1~5个的烷硫基,例如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、戊硫基、异戊硫基等。
C1-5烷基氨基是指被1个或2个直链状或支链状的碳原子数1~5个的烷基取代的氨基,例如甲基氨基、二甲基氨基、乙基氨基、二乙基氨基、丙基氨基、二丙基氨基、异丙基氨基等。
C1-5烷氧基羰基甲基是指被直链状或支链状的碳原子数1~5个的烷氧基取代的羰基甲基,例如甲氧基羰基甲基、乙氧基羰基甲基、丙氧基羰基甲基、异丙氧基羰基甲基、丁氧基羰基甲基、异丁氧基羰基甲基、戊氧基羰基甲基、异戊氧基羰基甲基等。
式CH2CONR11(R12)表示的基团例如氨基甲酰基甲基、N-甲基氨基甲酰基甲基、N,N-二甲基氨基甲酰基甲基、N-乙基氨基甲酰基甲基、N,N-二乙基氨基甲酰基甲基、N-丙基氨基甲酰基甲基、N,N-二丙基氨基甲酰基甲基、N-异丙基氨基甲酰基甲基、吡咯烷基羰基甲基、哌啶子基羰基甲基、吗啉代基羰基甲基、哌嗪基羰基甲基等。
另外,本发明中的可药用盐例如与硫酸、盐酸、磷酸等无机酸形成的盐,与醋酸、草酸、乳酸、酒石酸、富马酸、马来酸、枸橼酸、苯磺酸、甲磺酸等有机酸形成的盐。
式〔1〕、〔2〕、〔3〕和〔4〕的化合物可以按照下述制备。(以下的反应式中,R1、R2、R3、R4、R5、R6、R7、R8、Y1-Y2、X1、X2、X3、X4和X5与上述定义相同,R9和R10相同或不同,表示C1-5烷基或苯甲基,R13表示C1-5烷基,Boc表示叔丁氧基羰基,X6表示氯原子、溴原子、碘原子、甲磺酰氧基、苯磺酰氧基、甲苯磺酰氧基或三氟甲磺酰氧基。)
本发明化合物氨基甲酰基四氢吡啶衍生物(3)通过在碱存在或不存在的条件下,使4-或5-氨基甲酰基-1,2,3,6-四氢吡啶衍生物(1)与化合物(2)在惰性溶剂中反应得到。
其中,碱例如是三乙胺、二异丙基乙胺、吡啶等有机碱,碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢化钠等无机碱,甲醇钠、乙醇钠、叔丁醇钾等醇化物,氨基化钠、二异丙基氨基化锂等金属氨基化物,溴化甲基镁等格氏试剂。惰性溶剂例如是甲醇、乙醇、异丙醇、乙二醇等醇类,***、四氢呋喃、二氧六环、1,2-二甲氧基乙烷等醚类,苯、甲苯等烃类,N,N-二甲基甲酰胺等酰胺类,乙腈、水或选自这些溶剂的混合溶剂等。
4-氨基甲酰基-1,2,3,6-四氢吡啶衍生物(4)可以通过下述一系列的操作得到。通过N-甲基-4-烷氧基羰基-1,2,3,6-四氢吡啶(5)的甲基变换以及接着的水解合成1,2,3,6-四氢吡啶-4-甲酸(7),对其进行N-保护、酰胺化、脱N-Boc这一系列的操作。
其中,甲基的变换表示用烷氧基羰基取代N-甲基,例如在二异丙基乙胺等有机碱或碳酸钾等无机碱存在或不存在的条件下,与氯甲酸乙酯、氯甲酸苯甲酯等卤甲酸酯类在苯、甲苯、氯仿等惰性溶剂中反应。水解表示化合物(6)的N-取代基的除去以及酯基的水解,例如在氢溴酸等酸性条件下或氢氧化钡等碱性条件下反应。N-保护是指用叔丁氧基羰基(Boc)保护化合物(7)的NH基,例如按照使用(Boc)2O等的常规方法可以进行N-Boc化。酰胺化表示例如经由酰氯或酰溴等酰卤的酰胺化,使用氯甲酸乙酯、氯甲酸异丁酯等卤甲酸酯类经由混合酸酐的酰胺化,或使用1-(3,3-二甲氨基丙基)-3-乙基碳化二亚胺、1,3-二环己基碳化二亚胺、二苯基磷酰基叠氮化物、氰基磷酸二乙酯或羰基二咪唑等缩合剂的一般酰胺化。脱N-Boc表示一般的除去Boc基团的反应,在例如乙酸乙酯、二氯甲烷、氯仿、二氧六环、水等惰性溶剂中,使例如三氟醋酸、氯化氢或甲酸等反应。酯的水解、N-保护和脱N-Boc可以采用PROTE CTIVEGROUPS IN ORGANIC SYNTHESIS,THEODORA W.GREENE and PETER G.M.WU TS著中记载的方法。
5-氨基甲酰基-1,2,3,6-四氢吡啶衍生物(12)可以由通过N-Boc-4-哌啶酮(13)与碳酸二烷基酯的缩合反应、还原、羟基的脱离以及水解衍生出的N-Boc-1,2,3,6-四氢吡啶-5-甲酸(18),与上述由N-Boc-1,2,3,6-四氢吡啶-4-甲酸(9)合成4-氨基甲酰基-1,2,3,6-四氢吡啶衍生物(4)的方法同样得到。
其中,与碳酸二烷基酯的缩合表示在例如氢化钠、氢化钾等无机碱,甲醇钠、乙醇钠、叔丁醇钾等醇化物,氨基化钠、二异丙基氨基化锂等金属氨基化物等碱的存在下,在例如甲醇、乙醇、异丙醇、乙二醇等醇类,***、四氢呋喃、二氧六环、1,2-二甲氧基乙烷等醚类,苯、甲苯等烃类,N,N-二甲基甲酰胺等酰胺类等惰性溶剂中,与例如碳酸二甲酯、碳酸二乙酯等碳酸二烷基酯类反应。还原表示一般的由酮到醇的还原,例如采用硼氢化钠等无机还原剂的还原,或使用钯/碳、氧化铂等进行加氢的还原等。羟基的脱离表示将化合物(16)的羟基变换成离去基团的反应,在采用例如亚硫酰氯、三苯基膦-四溴化碳等的卤化,采用例如乙酰氯等的酰化或采用例如甲磺酰氯、苯磺酰氯、甲苯磺酰氯或三氟甲磺酸酐等的磺酰化之后,通过例如1,8-二氮杂二环〔5.4.0〕-7-十一碳烯或吡啶等的碱处理进行离去反应。水解表示通常的酯的水解,例如使用氢氧化钠或氢氧化钾等碱,在例如醇、水等惰性溶剂中反应。酯的水解可以采用PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,THEODORA W.GREENE andPETER G.M.WU TS著中记载的方法。
本发明化合物吡咯衍生物(23)可以通过使苯胺衍生物(19)与化合物(20),在例如对甲苯磺酸、氯化氢或氯化锌等有机酸、无机酸或路易斯酸的存在下,在例如甲苯等烃类溶剂中,在共沸脱水条件下反应,向该反应混合物中加入丙二腈(21),在共沸脱水条件下,或加热至150~250℃蒸馏除去溶剂的同时进行反应得到。另外,吡咯衍生物(23)也可以通过使苯胺衍生物(19)与亚乙基丙二腈衍生物(22)在惰性溶剂中或无溶剂的条件下,在碱存在或不存在的条件下,在室温至250℃的温度范围内进行反应得到。其中惰性溶剂例如是乙醇、异丙醇等醇类,甲苯、苯等烃类,四氢呋喃、1,2-二甲氧基乙烷等醚类,碱例如是氢氧化钠、碳酸钾等无机碱,吡啶、N-甲基吗啉、三乙胺等有机碱。
另外,吡咯衍生物(23)与醋酸酐等酸酐等在醋酸等惰性溶剂中,在冰冷条件下~150℃的温度下反应后,用磷酸等无机酸在冰冷条件下~150℃的温度下处理,可以得到本发明化合物吡咯并嘧啶衍生物(24)。
而且,吡咯并嘧啶衍生物(24)与***等卤化剂在室温至150℃的温度下反应,可以衍生得到本发明化合物——衍生物(25)。
本发明的化合物作为与CRF有关的疾病的治疗剂或预防剂是有用的。为了实现这一目的,本发明的化合物可以添加常用的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等,按照常用的制剂技术制成片剂、丸剂、胶囊剂、颗粒剂、粉剂、溶液剂、乳剂、悬浊剂、注射剂等。
本发明的化合物对于成人患者,可以给药0.1~500mg/日,1日1次或分数次口服或非口服给药。这种给药量可以根据疾病的种类、患者的年龄、体重、症状适当增减。
发明的最佳实施方式
以下,结合实施例和试验例,具体说明本发明。
实施例1
4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2,5-二甲基-7-(4-异丙基-2-甲硫基苯基)-7H-吡咯并〔2,3-d〕嘧啶的合成
1)将1-甲基-1,2,3,6-四氢吡啶-4-甲酸乙酯108.9g与二异丙基乙胺41.6g溶解于苯640ml,用70分钟滴加氯甲酸乙酯279.1g。加热回流30分钟后,将反应溶液冷却至室温,注入饱和碳酸氢钠水溶液。用乙酸乙酯萃取该反应混合物,用饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=7∶1)精制残渣,得到油状1-乙氧基羰基-1,2,3,6-四氢吡啶-4-甲酸乙酯104.4g。
2)在1-乙氧基羰基-1,2,3,6-四氢吡啶-4-甲酸乙酯104.4g中加入47%氢溴酸1500g,加热回流100小时。减压浓缩反应溶液,得到粗1,2,3,6-四氢吡啶-4-甲酸氢溴酸盐。将得到的粗1,2,3,6-四氢吡啶-4-甲酸氢溴酸盐溶解于二氧六环0.481和2M氢氧化钠水溶液0.481的混合溶液中,加入二碳酸叔丁酯105.2g,在室温下搅拌过夜。减压浓缩反应溶液后,注入1M的硫酸氢钾水溶液1.41,过滤收集析出的1-叔丁氧基羰基-1,2,3,6-四氢吡啶-4-甲酸的晶体100.5g。
3)将1-叔丁氧基羰基-1,2,3,6-四氢吡啶-4-甲酸20.0g溶解于氯仿400ml和二甲基甲酰胺100ml的混合溶液中,加入1-羟基苯并***水合物14.2g和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐17.7g,在室温下搅拌40分钟。用冰冷却反应溶液,加入28%氨水溶液5.6ml,搅拌6小时。将反应溶液升高至室温后,减压浓缩,注入5%硫酸氢钾水溶液。用乙酸乙酯萃取反应混合物,用饱和碳酸氢钠水溶液和饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=1∶2)精制残渣,得到1-叔丁氧基羰基-4-氨基甲酰基-1,2,3,6-四氢吡啶5.1g的晶体。
4)将1-叔丁氧基羰基-4-氨基甲酰基-1,2,3,6-四氢吡啶3.7g溶解于氯仿20ml,加入三氟醋酸13ml,室温下搅拌1小时。减压浓缩反应溶液,得到粗4-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐4.1g的晶体。
将粗4-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐溶解于乙酸乙酯,通入氯化氢后,减压浓缩,得到4-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐的晶体。
m.p.243-245℃
将4-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐溶解于饱和碳酸氢钠,用氯仿萃取后,用无水硫酸钠干燥有机层,过滤除去干燥剂后,减压浓缩滤液,得到游离型4-氨基甲酰基-1,2,3,6-四氢吡啶的晶体。
m.p.104-106℃
5)将4-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐0.25g和4-氯-2,5-二甲基-7-(异丙基-2-甲硫基苯基)-7H-吡咯并〔2,3-d〕嘧啶0.35g溶解于乙醇4ml中,加入二异丙基乙胺0.39g,加热回流7.5小时后,向反应溶液中注入饱和碳酸氢钠水溶液。用乙酸乙酯萃取反应混合物,用饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶氯仿-甲醇=60∶1)精制残渣,在醋酸乙酯-***混合溶剂中结晶,得到4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2,5-二甲基-7-(4-异丙基-2-甲硫基苯基)-7H-吡咯并〔2,3-d〕嘧啶0.17g。
本化合物以及同样得到的化合物的结构与物理参数记载于表1中。
实施例2
4-(5-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-7-(4-异丙基-2-甲硫基苯基)-2,5,6-三甲基-7H-吡咯并〔2,3-d〕嘧啶的合成
1)将油性的氢化钠6.2g用己烷洗涤2次后,悬浊于四氢呋喃30ml,加入少量油性的氢化钾和碳酸二乙酯14.8g,加热回流的同时用10分钟滴加1-叔丁氧基羰基-4-哌啶酮10.0g的四氢呋喃溶液。再加热回流5.5小时后,用冰冷却反应溶液,注入0.8M的硫酸氢钾水溶液200ml。用乙酸乙酯萃取反应混合物,用饱和食盐水洗涤萃取液后用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=15∶1~4∶1)精制残渣,得到1-叔丁氧基羰基-3-乙氧基羰基-4-哌啶酮11.9g的晶体。
2)将1-叔丁氧基羰基-3-乙氧基羰基-4-哌啶酮6.1g溶解于乙醇60ml中,加入氧化铂100mg,在氢气环境中,室温下搅拌2小时。用硅藻土过滤除去氧化铂后,减压浓缩滤液,得到粗1-叔丁氧基羰基-3-乙氧基羰基-4-羟基哌啶。将这里得到的粗1-叔丁氧基羰基-3-乙氧基羰基-4-羟基哌啶溶解于氯仿100ml,加入三乙胺11.4g和4-二甲氨基吡啶0.55g后,在冰冷条件下滴加甲磺酰氯6.2g,室温下搅拌5.5小时。依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤反应溶液,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,得到粗1-叔丁氧基羰基-3-乙氧基羰基哌啶-4-基甲磺酸酯。将这里得到的粗1-叔丁氧基羰基-3-乙氧基羰基哌啶-4-基甲磺酸酯溶解于苯50ml,加入1,8-二氮杂二环〔5.4.0〕-7-十一碳烯3.4g,加热回流30分钟。冷却至室温后,用5%硫酸氢钾水溶液和饱和食盐水洗涤反应溶液,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=10∶1~6∶1)精制残渣,得到油状1-叔丁氧基羰基-5-乙氧基羰基-1,2,3,6-四氢吡啶5.3g。
3)将N-Boc-5-乙氧基羰基-1,2,3,6-四氢吡啶2.5g溶解于乙醇5ml,加入1M氢氧化钠水溶液10ml,室温下搅拌4小时后,在反应溶液中加入5%硫酸氢钾水溶液,将溶液调节为酸性。用乙酸乙酯萃取反应液,用饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,得到粗1-叔丁氧基羰基-1,2,3,6-四氢吡啶-5-甲酸的晶体。将这里得到的1-叔丁氧基羰基-1,2,3,6-四氢吡啶-5-甲酸溶解于氯仿15ml和二甲基甲酰胺2ml的混合溶液中,加入1-羟基苯并***水合物1.6g和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐2.0g,室温下搅拌30分钟后,用冰冷却反应溶液,加入28%氨水溶液0.64ml,搅拌1小时。将反应溶液升高至室温后,减压浓缩,注入5%硫酸氢钾水溶液。用乙酸乙酯萃取反应混合物,依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=1∶2)精制残渣,得到1-叔丁氧基羰基-5-氨基甲酰基-1,2,3,6-四氢吡啶1.4g的晶体。
4)将1-叔丁氧基羰基-5-氨基甲酰基-1,2,3,6-四氢吡啶1.1g溶解于氯仿4.0ml,加入三氟醋酸4.0ml,室温下搅拌30分钟。减压浓缩反应溶液,得到无定形的粗5-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐1.4g。
将粗5-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐溶解于乙酸乙酯,通入氯化氢后,减压浓缩,得到5-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐的晶体。
m.p.270-272℃
将5-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐溶解于饱和碳酸氢钠中,用氯仿萃取后,用无水硫酸钠干燥有机层,过滤除去干燥剂后,减压浓缩滤液,得到游离型的5-氨基甲酰基-1,2,3,6-四氢吡啶的晶体。
m.p.122-124℃
5)将5-氨基甲酰基-1,2,3,6-四氢吡啶三氟醋酸盐0.27g和4-氯-7-(4-异丙基-2-甲硫基苯基)-2,5,6-三甲基-7H-吡咯并〔2,3-d〕嘧啶0.36g溶解于乙醇4ml中,加入二异丙基乙胺0.39g,加热回流8.5小时后,向反应溶液中注入饱和碳酸氢钠水溶液。用乙酸乙酯萃取反应混合物,用饱和食盐水洗涤萃取液后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶氯仿-甲醇=60∶1)精制残渣,在醋酸乙酯-***混合溶剂中结晶,得到4-(5-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-7-(4-异丙基-2-甲硫基苯基)-2,5,6-三甲基-7H-吡咯并〔2,3-d〕嘧啶0.12g。
本化合物以及同样得到的化合物的结构与物理参数记载于表1中。
实施例3
2-〔6-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕-乙酰胺的合成
1)将6-氯-9-(4-异丙基-2-甲硫基苯基)-2-甲基-8,9-二氢嘌呤-8-酮0.70g溶解于二甲基甲酰胺5ml中,冰冷条件下加入油性的氢化钠80mg,搅拌40分钟后,加入溴代乙酸乙酯0.39g,升高至室温后,再搅拌20分钟,注入水。用乙酸乙酯萃取反应混合物后,用饱和食盐水洗涤萃取液,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=4∶1)精制残渣,得到油状的2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕乙酸乙酯0.85g。
2)将2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕乙酸乙酯0.83g溶解于甲醇3ml和水1ml的混合溶液后,加入氢氧化钠80mg,室温下搅拌30分钟。向反应溶液中注入水,用氯仿萃取反应混合物后,用无水硫酸钠干燥萃取液。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶氯仿-甲醇=8∶1)精制残渣,得到油状的2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕醋酸0.47g。
3)将2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕醋酸0.47g溶解于四氢呋喃4ml,冷却至-15℃后,加入N-甲基吗啉0.14g和氯甲酸异丁酯0.19g,搅拌5分钟后,加入28%氨水溶液0.085ml,升高至室温后搅拌过夜,注入水。用乙酸乙酯萃取反应混合物后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶氯仿-甲醇=50∶1)精制残渣,得到油状的2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕乙酰胺0.41g。
4)将5-氨基-1,2,3,6-四氢吡啶盐酸盐0.16g、2-〔6-氯-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕乙酰胺0.40g和二异丙基乙胺0.38g溶解于乙醇4ml,加入水数滴后,加热回流17小时。减压浓缩反应溶液,用硅胶柱色谱法(展开溶剂∶氯仿-甲醇=7∶1)精制残渣后,用乙酸乙酯结晶,得到2-〔6-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基-8-氧代-9-(4-异丙基-2-甲硫基苯基)-8,9-二氢嘌呤-7-基〕乙酰胺0.22g。
本化合物以及同样得到的化合物的结构与物理参数记载于表1中。表1*1 Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)01 1 4-H2NCO (Me)C=C(Me) Me 2-SMe 4-i-Pr H 211-213(AcOEt-Et2O)02 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-i-Pr H 224-226(己烷-AcOEt)03 1 4-H2NCO (Me)C=C(Me) Me 2-Me 4-Me 6-Me 212-213(己烷-AcOEt)04 2 5-H2NCO (Me)C=C(Me) Me 2-SMe 4-i-Pr H 147-149(Et2O)05 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-i-Pr H 130-132(Et2O)06*22 5-H2NCO (Me)C=C(Me) Me 2-Me 4-Me 6-Me 189-192(AcOEt)07 1 4-H2NCO (Me)C=C(H) Me 2-SMe 4-1-Pr H 194-195(AcOEt-Et2O)08 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-i-Pr H 145-147(己烷-AcOEt)09 1 4-H2NCO (Me)C=C(H) Me 2-Me 4-Me 6-Me 208-209(己烷-AcOEt)10 2 5-H2NCO (Me)C=C(H) Me 2-SMe 4-i-Pr H 212-214(Et2O)11 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-i-Pr H 190-192(己烷-AcOEt)12 2 5-H2NCO (Me)C=C(H) Me 2-Me 4-Me 6-Me 183-184(己烷-AcOEt)13 1 4-H2NCO (Et)C=C(Et) Me 2-Me 4-Me 6-Me 157-159(己烷-AcOEt)14 2 5-H2NCO (Et)C=C(Et) Me 2-Me 4-Me 6-Me 180-181(己烷-AcOEt)15 1 4-H2NCO (Et)C=N Me 2-Cl 4-Cl 6-Cl 231-232 (己烷-AcOEt)16 2 5-H2NCO (Et)C=N Me 2-Cl 4-Cl 6-Cl 189-190(己烷-AcOEt)17 1 4-H2NCO (H)N-C(O) Me 2-SMe 4-i-Pr H 202-204(Et2O)18 1 4-H2NCO (H)N-C(O) Me 2-Br 4-i-Pr H 283-285(Et2O)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)19 1 4-H2NCO (H)N-C(O) Me 2-Me 4-Me 4-Me 300-302(Et2O)20 2 5-H2NCO (H)N-C(O) Me 2-SMe 4-i-Pr H 253-255(Et2O)21 2 5-H2NCO (H)N-C(O) Me 2-Br 4-i-Pr H 205-207(Et2O)22 2 5-H2NCO (H)N-C(O) Me 2-Me 4-Me 4-Me 257-259(Et2O)23 3 4-H2NCO (Me)N-C(O) Me 2-SMe 4-i-pr H 146-148(己烷-AcOEt)24 3 4-H2NCO (Me)N-C(O) Me 2-Br 4-i-pr H 211-213(己烷-AcOEt)25 3 4-H2NCO (Me)N-C(O) Me 2-Me 4-Me 4-Me 224-226(己烷-AcOEt)26 3 5-H2NCO (Me)N-C(O) Me 2-SMe 4-i-Pr H 179-181(Et2O)27 3 5-H2NCO (Me)N-C(O) Me 2-Br 4-i-Pr H 210-211(Et2O)28 3 5-H2NCO (Me)N-C(O) Me 2-Me 4-Me 4-Me 220-221(Et2O)29 3 4-H2NCO (Et)N-C(O) Me 2-SMe 4-i-Pr H 209-211(己烷-AcOEt)30 3 4-H2NCO (Et)N-C(O) Me 2-Br 4-i-Pr H 173-175(己烷-AcOEt)31 3 4-H2NCO (Et)N-C(O) Me 2-Me 4-Me 4-Me 244-246(己烷-AcOEt)32 3 5-H2NCO (Et)N-C(O) Me 2-SMe 4-i-pr H 124-126(Et2O)33 3 5-H2NCO (Et)N-C(O) Me 2-Br 4-i-Pr H 186-187(Et2O)34 3 5-H2NCO (Et)N-C(O) Me 2-Me 4-Me 4-Me 207-209(Et2O)35 3 4-H2NCO (H2NOCCH2)N-C(O) Me 2-SMe 4-i-Pr H 249-251(AcOEt)36 1 4-H2NCO N=C(H) Me 2-SMe 4-i-Pr H 145-147(Et2O)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)37 1 4-H2NCO N=C(CONH2) Me 2-SMe 4-i-Pr H 232-234(己烷-AcOEt)38 1 4-H2NCO N=N Me 2-SMe 4-i-Pr H 198-199(AcOEt-Et2O)39 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Cl 152-154(Et2O)40 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-Me 158-160(Et2O)41 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Me 157-159(Et2O)42 1 4-H2NCO (Me)C=C(Me) Me 2-Me 4-Br 6-Me 166-168(Et2O)43 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-Cl 6-Cl 226-228(Et2O)44 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Br 153-155(Et2O)45 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-OMe 6-OMe 143-145(Et2O)46 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-Cl 146-148(己烷-AcOEt)47 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-H 245-247(己烷-AcOEt)48 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-H 227-229(Et2O)49 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Cl 6-H 224-226(Et2O)50 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-iPr 6-Br 156-158(己烷-AcOEt)51 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-SMe 161-163(己烷-AcOEt)52 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-F 145-147(己烷-AcOEt)53 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 229-231(己烷-AcOEt)54 1 4-MeHNCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*3表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)55 1 4-PrHNCO (Me)C=C(Me) Me 2-Br 4-CF2 6-Br 无定形*456 1 4-PhHNCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*557 1 4-Me2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*658 1 4-吡咯烷基CO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*759 1 4-吗啉代基CO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*860 1 4-H2NCO (Me)C=C(Me) Me 2-Me 4-OMe 6-Me 217-219(IPE)61 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-Cl 6-Me 141-143(IPE)62 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-CF2 6-Cl 150-152(IPE)63 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-OMe 176-178(Et2O)64 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Cl 150-152(Et2O)65 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-Me 143-145(Et2O)66 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Me 144-146(Et2O)67 2 5-H2NCO (Me)C=C(Me) Me 2-Me 4-Br 6-Me 138-140(Et2O)68 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-Cl 6-Cl 148-150(Et2O)69 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-Br 150-152(Et2O)70 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-OMe 6-OMe 145-147(Et2O)71 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-Cl 148-150(己烷-AcOEt)72 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-H 194-196(己烷-AcOEt)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X3 m.p.(℃)No. No. (结晶溶剂)73 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-Br 6-H 165-167(Et2O)74 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Cl 6-H 187-189(Et2O)75 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-iPr 6-Br 264-266(己烷-AcOEt)76 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-SMe 214-216(己烷-AcOEt)77 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-F 142-144(己烷-AcOEt)78 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 215-217(己烷-AcOEt)79 2 5-MeHNCO (Me)C=C(Me) Me 2-Br 4-CF2 6-Br 无定形*980 2 5-PrHNCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*1081 2 5-PhHNCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*1182 2 5-Me2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*1283 2 5-吡咯烷基CO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*1384 2 5-吗啉代基CO (Me)C=C(Me) Me 2-Br 4-CF3 6-Br 无定形*1485 2 5-H2NCO (Me)C=C(Me) Me 2-Me 4-OMe 6-Me 无定形*1586 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-Cl 6-Me 无定形*1687 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-CF3 6-Cl 216-218(Et2O)88 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-OMe 230-232(Et2O)89 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Cl 218-220(AcOEt)90 1 4-H2NCO (Me)C=C(H) Me 2-Cl 4-Br 6-Me 204-206(AcOEt)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X3 m.p.(℃)No. No. (结晶溶剂)91 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Br 248-250(AcOEt)92 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-CF3 6-Br 235-237(Et2O)93 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Cl 282-284(AcOEt)94 2 5-H2NCO (Me)C=C(H) Me 2-Cl 4-Br 6-Me 255-257(AcOEt/MeOH)95 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Br 287-289(AcOEt)96 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-CF3 6-Br 253-255(AcOEt)97 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-H 242-243(AcOEt)98 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-NMe2 6-H 299-301(AcOEt)99 1 4-H2NCO (Me)C=C(Me) Me 2-Cl 4-CF3 6-H 232-234(AcOEt)100 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-CF3 6-H 239-240(AcOEt)101 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-NMe2 6-H 242-244(AcOEt)102 2 5-H2NCO (Me)C=C(Me) Me 2-Cl 4-CF3 6-H 233-235(AcOEt)103 1 4-H2NCO (Me)C=C(H) Me 2-Me 4-Br 6-Me 221-223(AcOEt)104 1 4-H2NCO (Me)C=C(H) Me 2-SMe 4-Br 6-Br 251-253(Et2O)105 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-CF3 6-H 230-231(Et2O)106 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Me 220-222(AcOEt)107 1 4-H2NCO (Me)C=C(H) Me 2-OMe 4-Br 6-Br 257-259(Et2O)108 1 4-H2NCO (Me)C=C(H) Me 2-Me 4-Cl 6-Cl 180-182(Et2O)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R2 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)109 1 4-H2NCO (Me)C=C(H) Me 2-C1 4-Br 6-Cl 229-230(Et2O)110 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-H 239-241(Et2O)111 1 4-H2NCO (Me)C=C(H) Me 2-Cl 4-CF2 6-H 240-242(Et2O)112 1 4-H2NCO (Me)C=C(H) Me 2-C1 4-Br 6-H 237-239(Et2O)113 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Cl 6-H 250-252(Et2O)114 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-NMe2 6-H 255-257(Et2O)115 2 5-H2NCO (Me)C=C(H) Me 2-Me 4-Br 6-Me 232-234(AcOEt)116 2 5-H2NCO (Me)C=C(H) Me 2-SMe 4-Br 6-Br 168-170(AcOEt)117 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-CF3 6-H 183-185(Et2O)118 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-Me 260-262(AcOEt)119 2 5-H2NCO (Me)C=C(H) Me 2-OMe 4-Br 6-Br 233-235(Et2O)120 2 5-H2NCO (Me)C=C(H) Me 2-Me 4-Cl 6-Cl 241-243(Et2O)121 2 5-H2NCO (Me)C=C(H) Me 2-Cl 4-Br 6-Cl 284-285(Et2O)122 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-H 227-228(Et2O)123 2 5-H2NCO (Me)C=C(H) Me 2-Cl 4-CF3 6-H 200-202(Et2O)124 2 5-H2NCO (Me)C=C(H) Me 2-Cl 4-Br 6-H 193-195(Et2O)125 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Cl 6-H 223-225(Et2O)126 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-NMe2 6-H 197-199(Et2O)表1*1(续)Com. Exp. R1R2NCO Y1-Y2 R3 X1 X2 X2 m.p.(℃)No. No. (结晶溶剂)127 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-OCF3 142-144(IPE)128 1 4-H2NCO (Me)C=C(Me) Me 2-Br 4-OCF3 6-Br 212-214(IPE)129 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-OCF3 229-231(AcOEt)130 1 4-H2NCO (Me)C=C(H) Me 2-Br 4-OCF3 6-Br 233-235(AcOEt)131 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-Br 6-OCF3 128-130(IPE)132 2 5-H2NCO (Me)C=C(Me) Me 2-Br 4-OCF2 6-Br 231-233(IPE)133 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-Br 6-OCF2 221-223(AcOEt)134 2 5-H2NCO (Me)C=C(H) Me 2-Br 4-OCF2 6-Br 254-256(AcOEt)*1:(表1中的标记)Com.No.=化合物序号.Exp.No.=合成时采用的实施例序号.IPE=异丙基醚*2:HCl盐*3:NMR(CDCl2)δ(ppm);2.05(3H,s),2.40(3H,s),2.49(3H,s),2.56-2.72(2H,
m),2.91(3H,d,J=6.0Hz),3.70(2H,t,J=5.2Hz),4.13-4.26(2H,m),5.70-5.
88(1H,m),6.62-6.73(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;622(M+Na)+,624(M+2+Na)+,626(M+4+Na)+*4:NMR(CDCl2)δ(ppm);0.97(3H,t,J=7.5Hz),1.50-1.64(2H,m),2.05(3H,s),
2.40(3H,s),2.49(3H,s),2.56-2.73(2H,m),3.32(2H,dd,J=13.6,6.6Hz),
3.71(2H,t,J=5.5Hz),4.12-4.27(2H,m),5.70-5.83(1H,m),.6.60-6.72(1H,
m),7.95(2H,s).
ESIMS(Pos)m/z;650(M+Na)+,652(M+2+Na)+,654(M+4+Na)+*5:NMR(CDCl2)δ(ppm);2.06(3H,s),2.43(3H,s),2.51(3H,s),2.68-2.87(2H,
m).3.76(2H,t,J=5.4Hz),4.20-4.35(2H,m),6.72-6.88(1H,m),7.06-7.63
(5H,m),7.40-7.58(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;684(M+Na)+,686(M+2+Na)+,688(M+4+Na)+*6:NMR(CDCl2)δ(ppm);2.05(3H,s),2.41(3H,s),2.49(3H,s),2.52-2.70(2H,
m),2.90-3.19(6H,m),3.74(2H,t,J=5.5Hz),4.06-4.20(2H,m),5.91-6.02
(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;636(M+Na)+,638(M+2+Na)+,640(M+4+Na)+*7:NMR(CDCl2)δ(ppm);1.80-2.00(4H,m),2.05(3H,s),2.41(3H,s),2.49(3H,
s),2.58-2.73(2H,m),3.43-3.62(4H,m),3.72(2H,t,J=5.4Hz),4.09-4.20
(2H,m),6.07-6.17(1H,m),7.96(2H,s).
ESIMS(Pos)m/z;662(M+Na)+,664(M+2+Na)+,666(M+4+Na)+*8:NMR(CDCl2)δ(ppm);2.05(3H,s),2.41(3H,s),2.48(3H,s),2.52-2.67(2H,
m),3.53-3.80(10H,m),4.06-4.20(2H,m),5.92-6.02(1H,m),7.96(2H,s).
ESIMS(Pos)m/z;678(M+Na)+,680(M+2+Na)+,682(M+4+Na)+*9:NMR(CDCl2)δ(ppm);2.04(3H,s),2.41(3H,s),2.49(3H,s),2.45-2.60(2H,
m),2.91(3H,d,J=4.8Hz),3.68(2H,t,J=5.6Hz),4.25-4.35(2H,m),5.78-5.
92(1H,m),6.60-6.70(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;622(M+Na)+,624(M+2+Na)+,626(M+4+Na)+*10:NMR(CDCl2)δ(ppm);0.96(3H,t,J=7.5Hz),1.50-1.66(2H,m),2.03(3H,s),
2.41(3H,s),2.49(3H,s),2.4 2-2.60(2H,m),3.31(2H,dd,J=13.9,6.5Hz),
3.68(2H,t,J=5.6Hz),4.25-4.35(2H,m),5.72-5.87(1H,m),6.58-6.68(1
H,m),7.95(2H,s).
ESIMS(Pos)m/z;650(M+Na)+,652(M+2+Na)+,654(M+4+Na)+*11:NMR(CDCl2)δ(ppm);2.04(3H,s),2.43(3H,s),2.50(3H,s),2.54-2.67(2H,
m),3.75(2H,t,J=5.0Hz),4.36-4.47(2H,m),6.72-6.81(1H,m),7.08-7.1
9(1H,m),7.28-7.40(2H,m),7.46-7.60(3H,m),7.95(2H,s).
ESIMS(Pos)m/z;684(M+Na)+,686(M+2+Na)+,688(M+4+Na)+*12:NMR(CDCl2)δ(ppm);2.04(3H,s),2.41(3H,s),2.47(3H,s),2.28-2.52(2H,
m),2.83-3.20(6H,m),3.72(2H,t,J=5.7Hz),4.18-4.32(2H,m),5.92-6.0
7(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;636(M+Na)+,638(M+2+Na)+,640(M+4+Na)+*13:NMR(CDCl2)δ(ppm);1.75-2.02(4H,m),2.03(3H,s),2.41(3H,s),2.47(3H,
s),2.35-2.55(2H,m),3.45-3.65(4H,m),3.72(2H,t,J=5.6Hz),4.23-4.3
3(2H,m),6.10-6.20(1H,m),7.95(2H,s).
ESIMS(Pos)m/z;662(M+Na)+,664(M+2+Na)+,666(M+4+Na)+*14:NMR(CDCl2)δ(ppm);2.05(3H,s),2.41(3H,s),2.46(3H,s),2.31-2.50(2H,
m),3.69(8H,s),3.62-3.77(2H,m),4.20-4.30(2H,m),5.96-6.07(1H,m),
7.96(2H,s).
ESIMS(Pos)m/z;678(M+Na)+,680(M+2+Na)+,682(M+4+Na)**15:NMR(CDCl2)δ(ppm);1.83(6H,s),1.95(3H,s),2.40(3H,s),2.50(3H,s)
,2.50-2.65(2H,m),3.65(2H,t,J=6.0Hz),3.83(3H,s),4.25-4.32(2H,
m),5.63(2H,br s),6.70(2H,s),6.71-6.83(1H,m).
ESIMS(Pos)m/z;420(M+H)+*16:NMR(CDCl2)δ(ppm);1.90(3H,s),2.00(3H,s),2.39(3H,s),2.48(3H,s),
2.50-2.65(2H,m),3.53-3.78(2H,m),4.24-4.33(2H,m),5.56(2H,br s)
,6.72-6.82(1H,m),7.26(1H,m),7.42(1H,m).
ESIMS(Pos)m/z;444(M+H)+实施例4
2-氨基-4,5-二甲基-1-(2,6-二溴-4-三氟甲基苯基)吡咯-3-甲腈的合成
将4-氨基-3,5-二溴三氟甲苯5.5g、乙偶姻1.9g以及甲苯磺酸34mg溶解于甲苯15ml中,共沸脱水的同时加热回流2.5小时。向反应溶液中加入丙二腈1.42g,在180℃下浓缩的同时加热4小时。向反应溶液中加入水,用氯仿萃取后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=5∶1)精制残渣,放置后结晶,得到2-氨基-4,5-二甲基-1-(2,6-二溴-4-三氟甲基苯基)吡咯-3-甲腈1.2g。
m.p.158-161℃
同样操作得到以下化合物。2-氨基-4,5-二甲基-1-(2,6-二溴-4-异丙基苯基)吡咯-3-甲腈
m.p.205-207℃2-氨基-4,5-二甲基-1-(2,4,6-三溴苯基)吡咯-3-甲腈
m.p.214-216℃2-氨基-4,5-二甲基-1-(2,4-二溴-6-氯苯基)吡咯-3-甲腈
m.p.206-208℃2-氨基-4,5-二甲基-1-(2,4-二溴-6-甲基苯基)吡咯-3-甲腈
m.p.186-189℃2-氨基-4,5-二甲基-1-(2,4-二溴-6-甲硫基苯基)吡咯-3-甲腈
m.p.136-138℃2-氨基-4,5-二甲基-1-(2,4-二溴-6-氟苯基)吡咯-3-甲腈
m.p.155-157℃2-氨基-4,5-二甲基-1-(2,4-二溴-6-甲氧基苯基)吡咯-3-甲腈
NMR(CDCl3)δ(ppm);
1.72(3H,s),2.07(3H,s),3.64(2H,br s),3.82(3H,s),7.15(1H,d,J=2.0Hz),
7.51(1H,d,J=2.0Hz)
ESIMS(Neg)m/z;
396(M-H)-,398(M+2-H)-,400(M+4-H)-2-氨基-4,5-二甲基-1-(2,4-二溴-6-三氟甲氧基苯基)吡咯-3-甲腈5
NMR(CDCl3)δ(ppm);
1.75(3H,s),2.06(3H,s),3.33(2H,br s),7.56-7.63(1H,m),7.83-7.91(1H,m)
ESIMS(Pos)m/z;
474(M+Na)+,476(M+2+Na)+,478(M+4+Na)+2-氨基-4,5-二甲基-1-(2,6-二溴-4-三氟甲氧基苯基)吡咯-3-甲腈
NMR(CDCl3)δ(ppm);
1.79(3H,s),2.19(3H,s),3.65(2H,br s),7.61(2H,s)
ESIMS(Pos)m/z;
474(M+Na)+,476(M+2+Na)+,478(M+4+Na)+2-氨基-4,5-二甲基-1-(2,4-二溴-6-三氟甲基苯基)吡咯-3-甲腈
NMR(CDCl3)δ(ppm);
1.74(3H,s),2.08(3H,s),3.55(2H,br s),7.95(1H,d,J=2.0Hz),
8.12(1H,d,J=2.0Hz)
ESIMS(Pos)m/z;
458(M+Na)+,460(M+2+Na)+,462(M+4+Na)+
实施例5
4-氯-2,5,6-三甲基-7-(2,6-二溴-4-三氟甲基苯基)-7H-吡咯并〔2,3-d〕嘧啶的合成
1)将2-氨基-4,5-二甲基-1-(2,6-二溴-4-三氟甲基)吡咯-3-甲腈1.2g和醋酸酐0.82g溶解于醋酸3ml,加热回流30分钟。向反应溶液中加入水,用乙酸乙酯萃取后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,得到粗N-〔3-氰基-4,5-二甲基-1-(2,6-二溴-4-三氟甲基苯基)-1H-吡咯-2-基〕乙酰胺。在这里得到的粗N-〔3-氰基-4,5-二甲基-1-(2,6-二溴-4-三氟甲基苯基)-1H-吡咯-2-基〕乙酰胺中加入85%磷酸3ml,在130℃下加热0.5小时。向反应溶液中加入水,用氯仿萃取后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=1∶1)精制残渣,放置后结晶,得到2,5,6-三甲基-7-(2,6-二溴-4-三氟甲基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮0.67g。NMR(CDCl3)δ(ppm);
1.99(3H,s),2.43(3H,s),2.44(3H,s),7.96(2H,d,J=0.7Hz),11.56(1H,br s)ESIMS(Neg)m/z;-476(M-H)-,478(M+2-H)-,480(M+4-H)-
同样操作得到以下化合物。2,5,6-三甲基-7-(2,4-二溴-6-氯苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);1.91(3H,s),2.20(3H,s),2.28(3H,s),8.10(1H,d,J=2.2Hz),8.18(1H,d,J=2.2Hz),11.80(1H,br s)ESIMS(Neg)m/z;442(M-H)-,444(M+2-H)-,446(M+4-H)-2,5,6-三甲基-7-(2,4-二溴-6-甲基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮 NMR(DMSO-d6)δ(ppm);
1.88(3H,s),1.90(3H,s),2.19(3H,s),2.29(3H,s),7.74(1H,d,J=2.2Hz),
7.95(1H,d,J=2.2Hz),11.79(1H,br s)ESIMS(Neg)m/z;
422(M-H)-,424(M+2-H)-,426(M+4-H)-2,5,6-三甲基-7-(2,4,6-三溴苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);1.91(3H,s),2.20(3H,s),2.28(3H,s),8.20(2H,s),11.84(1H,br s)ESIMS(Neg)m/z;486(M-H)-,488(M+2-H)-,490(M+4-H)-,492(M+6-H)-2,5,6-三甲基-7-(2,6-二溴-4-异丙基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(CDCl3)δ(ppm);
1.31(6H,d,J=7.0Hz),1.98(3H,s),2.45(6H,s),2.95(1H,sept,J=7.0Hz),
7.54(2H,s),12.18(1H,br s)ESIMS(Neg)m/z;
450(M-H)-,452(M+2-H)-,454(M+4-H)-2,5,6-三甲基-7-(2,4-二溴-6-甲硫基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);1.88(3H,s),2.22(3H,s),2.28(3H,s),2.42(3H,s),7.51(1H,d,J=2.0Hz),7.86(1H,d,J=2.0Hz),11.79(1H,br s)ESIMS(Neg)m/z;454(M-H)-,456(M+2-H)-,458(M+4-H)-2,5,6-三甲基-7-(2,4-二溴-6-氟苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);
1.94(3H,s),2.20(3H,s),2.28(3H,s),7.97(1H,dd,J=8.8,1.9Hz),
8.06(1H,dd,J=3.5,1.9Hz),11.86(1H,br s)ESIMS(Neg)m/z;
426(M-H)-,428(M+2-H)-,430(M+4-H)-2,5,6-三甲基-7-(2,4-二溴-6-甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);
1.85(3H,s),2.18(3H,s),2.27(3H,s),3.76(3H,s),7.57(1H,d,J=2.0Hz),
7.66(1H,d,J=2.0Hz),11.72(1H,br s)ESIMS(Neg)m/z;
438(M-H)-,440(M+2-H)-,442(M+4-H)-2,5,6-三甲基-7-(2,4-二溴-6-三氟甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);1.92(3H,s),2.19(3H,s),2.28(3H,s),7.95-8.02(1H,m),8.23-8.30(1H,m),11.86(1H,br s)ESIMS(Neg)m/z;492(M-H)-,494(M+2-H)-,496(M+4-H)-2,5,6-三甲基-7-(2,6-二溴-4-三氟甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮 NMR(DMSO-d6)δ(ppm);
1.90(3H,s),2.19(3H,s),2.28(3H,s),8.06(2H,s),11.85(1H,br s)ESIMS(Neg)m/z;
492(M-H)-,494(M+2-H)-,496(M+4-H)-
2)向2,5,6-三甲基-7-(2,6-二溴-4-三氟甲基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮0.67g中加入***1.3ml,在100℃下加热0.5小时,冷却。将反应混合物注入到冰水中,用乙酸乙酯萃取后,用饱和碳酸氢钠水溶液洗涤有机层,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,放置后结晶,得到4-氯-2,5,6-三甲基-7-(2,6-二溴-4-三氟甲基苯基)-7H-吡咯并〔2,3-d〕嘧啶0.66g。
m.p.202-204℃
同样操作得到以下化合物。4-氯-2,5,6-三甲基-7-(2,6-二溴-4-异丙基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.173-175℃4-氯-2,5,6-三甲基-7-(2,4,6-三溴苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.216-218℃4-氯-2,5,6-三甲基-7-(2,4-二溴-6-氯苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.206-208℃4-氯-2,5,6-三甲基-7-(2,4-二溴-6-甲基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.215-217℃4-氯-2,5,6-三甲基-7-(2,4-二溴-6-甲硫基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.249-251℃4-氯-2,5,6-三甲基-7-(2,4-二溴-6-氟苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.170-172℃4-氯-2,5,6-三甲基-7-(2,4-二溴-6-甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶
NMR(CDCl3)δ(ppm);
2.02(3H,s),2.41(3H,s),3.75(3H,s),7.57(1H,d,J=2.0Hz),
7.74(1H,d,J=2.0Hz)
ESIMS(Pos)m/z;
458(M+H)+,460(M+2+H)+,462(M+4+H)+4-氯-2,5,6-三甲基-7-(2,4-二溴-6-三氟甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.148-150℃4-氯-2,5,6-三甲基-7-(2,6-二溴-4-三氟甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.141-143℃
实施例6
2-氨基-4-甲基-1-(2,4-二溴-6-氯苯基)吡咯-3-甲腈的合成
将6-氯-2,4-二溴苯胺5.3g和2-(2-溴-1-甲基亚乙基)丙二腈3.5g的混合物溶解于异丙醇10ml和四氢呋喃10ml的混合溶液中后,在120℃下浓缩,同时加热2小时。在反应溶液中注入水,用氯仿萃取后,用饱和碳酸氢钠水溶液洗涤有机层,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,放置后结晶,得到2-氨基-4-甲基-1-(2,4-二溴-6-氯苯基)吡咯-3-甲腈1.9g。
m.p.197-199℃
同样操作得到以下化合物。2-氨基-4-甲基-1-(2,4,6-三溴苯基)吡咯-3-甲腈
m.p.208-210℃2-氨基-4-甲基-1-(2,4-二溴-6-甲硫基苯基)吡咯-3-甲腈
m.p.127-130℃2-氨基-4-甲基-1-(2,4-二溴-6-甲氧基苯基)吡咯-3-甲腈
m.p.122-125℃2-氨基-4-甲基-1-(2,6-二溴-4-三氟甲基苯基)吡咯-3-甲腈
m.p.178-180℃2-氨基-4-甲基-1-(2,4-二溴-6-甲基苯基)吡咯-3-甲腈
m.p.169-171℃2-氨基-4-甲基-1-(2,4-二溴-6-三氟甲氧基苯基)吡咯-3-甲腈
m.p.158-160℃2-氨基-4-甲基-1-(2,6-二溴-4-三氟甲氧基苯基)吡咯-3-甲腈NMR(CDCl3)δ(ppm);2.16(3H,d,J=1.1Hz),3.76(2H,br s),5.87(1H,d,J=1.1Hz),7.58(2H, d,J=0.8Hz)ESIMS(Neg)m/z;436(M-H)-,438(M+2-H)-,440(M+4-H)-2-氨基-4-甲基-1-(2,4-二溴-6-三氟甲基苯基)吡咯-3-甲腈NMR(CDCl3)δ(ppm);
2.12(3H,s).3.66(2H,br s),5.87(1H,s),7.92(1H,d,J=2.0Hz),
8.10(1H,d,J=2.0Hz)ESIMS(Pos)m/z;
444(M+Na)+,446(M+2+Na)+,448(M+4+Na)+
实施例7
4-氯-2,5-二甲基-7-(2,4-二溴-6-氯苯基)-7H-吡咯并〔2,3-d〕嘧啶的合成
1)将2-氨基-4-甲基-1-(2,4-二溴-6-氯苯基)吡咯-3-甲腈1.9g和醋酸酐1.48g溶解于醋酸5ml中,加热回流30分钟。向反应溶液中加入水,用乙酸乙酯萃取后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,得到粗N-〔3-氰基-4-甲基-1-(2,4-二溴-6-氯苯基)-1H-吡咯-2-基〕乙酰胺。在这里得到的粗N-〔3-氰基-4-甲基-1-(2,4-二溴-6-氯苯基)-1H-吡咯-2-基〕乙酰胺中加入85%磷酸8ml,在130℃下加热0.5小时。向反应溶液中加入水,用氯仿萃取后,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,用硅胶柱色谱法(展开溶剂∶己烷-乙酸乙酯=1∶1)精制残渣,放置后用乙酸乙酯洗涤析出的晶体,得到2,5-二甲基-7-(2,4-二溴-6-氯苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮1.1g。NMR(CDCl3)δ(ppm);
2.22(3H,s),2.31(3H,d,J=1.1Hz),6.80(1H,d,J=1.1Hz),8.06(1H,d,J=2.1Hz),
8.14(1H,d,J=2.1Hz),11.91(1H,br s)ESIMS(Neg)m/z;
428(M-H)-,430(M+2-H)-,432(M+4-H)-
同样操作得到以下化合物。2,5-二甲基-7-(2,4-二溴-6-甲基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMS0-d6)δ(ppm);
1.96(3H,s),2.21(3H,s),2.32(3H,d,J=1.1Hz),6.75(1H,d,J=1.1Hz),
7.70(1H,d,J=2.1Hz),7.91(1H,d,J=2.1Hz),11.86(1H,br s)ESIMS(Neg)m/z;
408(M-H)-,410(M+2-H)-,412(M+4-H)-2,5-二甲基-7-(2,4,6-三溴苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮 NMR(DMSO-d6)δ(ppm);
2.23(3H,s),2.31(3H,J=1.1Hz),6.78(1H,d,J=1.1Hz),8.16(2H,s),
11.90(1H,br s)ESIMS(Neg)m/z;
472(M-H)-,474(M+2-H)-,476(M+4-H)-,478(M+6-H)-2,5-二甲基-7-(2,4-二溴-6-甲硫基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);
2.21(3H,s),2.31(3H,d,J=1.1Hz),2.41(3H,s),6.67(1H,d,J=1.1Hz),
7.50(1H,d,J=2.1Hz),7.83(1H,d,J=2.1Hz),11.86(1H,br s)ESIMS(Neg)m/z;
440(M-H)-,442(M+2-H)-,444(M+4-H)-2,5-二甲基-7-(2,6-二溴-4-三氟甲基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(DMSO-d6)δ(ppm);
2.22(3H,s),2.33(3H,d,J=1.2Hz),6.84(1H,d,J=1.2Hz),8.31(2H,d,J=0.6Hz),
11.94(1H,br s)ESIMS(Neg)m/z;
462(M-H)-,464(M+2-H)-,466(M+4-H)-2,5-二甲基-7-(2,4-二溴-6-甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮 NMR(DMSO-d6)δ(ppm);
2.20(3H,s),2.29(3H,d,J=1.1Hz),3.74(3H,s),6.66(1H,d,J=1.1Hz),
7.47(1H,d,J=2.0Hz),7.62(1H,d,J=2.0Hz),11.79(1H,br s)ESIMS(Neg)m/z;
424(M-H)-,426(M+2-H)-,428(M+4-H)-2,5-二甲基-7-(2,4-二溴-6-三氟甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(CDCl3)δ(ppm);
2.41(3H,s),2.47(3H,s),6.48(1H,s),7.51-7.58(1H,m),7.82-7.87(1H,m),
10.64(1H,br s)ESIMS(Neg)m/z;
478(M-H)-,480(M+2-H)-,482(M+4-H)-2,5-二甲基-7-(2,6-二溴-4-三氟甲氧基苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮NMR(CDCl3)δ(ppm);
2.43(3H,s),2.48(3H,s),6.47(1H,s),7.57(2H,s),10.62(1H,br s)ESIMS(Neg)m/z;
478(M-H)-,480(M+2-H)-,482(M+4-H)-
2)向2,5-二甲基-7-(2,4-二溴-6-氯苯基)-3,7-二氢吡咯并〔2,3-d〕嘧啶-4-酮1.0g中加入***3.2ml,在100℃下加热0.5小时,冷却。将反应混合物注入到冰水中,用乙酸乙酯萃取后,用饱和碳酸氢钠水溶液洗涤有机层,用无水硫酸钠干燥。过滤除去干燥剂后,减压浓缩滤液,放置后用己烷-***洗涤析出的晶体,得到4-氯-2,5-二甲基-7-(2,4-二溴-6-氯苯基)-7H-吡咯并〔2,3-d〕嘧啶0.76g。
m.p.157-159℃
同样操作得到以下化合物。4-氯-2,5-二甲基-7-(2,4,6-三溴苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.162-164℃4-氯-2,5-二甲基-7-(2,4-二溴-6-甲硫基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.203-205℃4-氯-2,5-二甲基-7-(2,4-二溴-6-甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.175-177℃4-氯-2,5-二甲基-7-(2,6-二溴-4-三氟甲基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.153-155℃4-氯-2,5-二甲基-7-(2,4-二溴-6-甲基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.159-161℃4-氯-2,5-二甲基-7-(2,4-二溴-6-三氟甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶
m.p.157-159℃4-氯-2,5-二甲基-7-(2,6-二溴-4-三氟甲氧基苯基)-7H-吡咯并〔2,3-d〕嘧啶NMR(CDCl3)δ(ppm);
2.54(3H,d,J=1.1Hz),2.68(3H,s),6.82(1H,d,J=1.1Hz),7.60(2H,d,J=0.9Hz)ESIMS(Pos)m/z;
498(M+H)+,500(M+2+H)+,502(M+4+H)+,504(M+6+H)+试验例〔CRF受体结合实验〕
使用大鼠前额皮质膜作为受体标准品。
使用125I-CRF作为125I标识配体。
使用125I标识配体的结合反应按照The Journal ofNeuroscience,7,88(1987年)记载的下述方法进行。
受体膜标准品的制备:将大鼠前额皮质用含有10mM MgCl2和2mMEDTA的50mM Tris盐酸缓冲液(pH7.0)匀化,以48000×g离心分离,将沉渣用Tris盐酸缓冲液洗涤1次。将沉渣悬浊于含有10mMMgCl2、2mM EDTA、0.1%牛血清白蛋白以及100激肽释放酶单位/ml抑肽酶的50mM Tris盐酸缓冲液(pH0.7)中,制成膜标准品。
CRF受体结合实验:使膜标准品(0.3mg蛋白质/ml)、125I-CRF(0.2nM)以及被测药物在25℃下反应2小时。反应结束后,用0.3%聚乙烯亚胺处理后的玻璃滤器(GF/C)抽滤。将玻璃滤器用含有0.01%TritonX-100的磷酸缓冲化生理盐水洗涤3次。洗涤后,用γ计数器测定滤纸的放射能。
以1μM CRF存在下进行反应时的结合量作为125I-CRF的非特应性结合,以总结合和非特应性结合的差作为特异结合。使一定浓度(0.2nM)的125I-CRF和浓度改变的被测药物在上述条件下反应,得到抑制曲线,由该抑制曲线求出抑制125I-CRF结合50%的被测药物浓度(IC50)。
结果,显示100nM以下的IC50值的代表性化合物是表1中下述Com.No.的化合物。
Com.No.:01,02,07,12,39,44,46,47,51,53,61,63,66,69,72,78,79,87,88,89,93,97,104,107,116,118
工业实用性
按照本发明,可以提供对CRF受体显示高亲和性的化合物。这些化合物对于与CRF有关的疾病,例如抑郁症、焦虑症、阿耳茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、摄食障碍、高血压、消化器官疾病、药物依赖、癫痫、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关疾病等是有效的。
Claims (7)
1、下式表示的氨基甲酰基四氢吡啶衍生物或其可药用盐,式中,R1和R2相同或不同,表示氢原子、C1-5烷基或苯基,或R1与R2连成一体,与相邻的氮原子一同表示下式所示的5~8元饱和杂环基团,式中,A为CH2、NH、N-C1-5烷基、O或S,R3表示氢原子或C1-5烷基,Y1-Y2表示(R4)C=C(R5)、(R6)C=N、N=N、(R7)N-CO或N=C(R8),X1、X2和X3相同或不同,表示氢原子、卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基、三氟甲氧基、氨基或C1-5烷基氨基,其中,R4和R5相同或不同,表示氢原子或C1-5烷基,R6表示氢原子或C1-5烷基,R7表示氢原子、C1-5烷基、C1-5烷氧基羰基甲基、羧甲基或式CH2CONR11(R12)表示的基团(式中,R11和R12相同或不同,表示氢原子或C1-5烷基,或R11和R12连成一体,与相邻的氮原子一同表示下式所示的5~8元饱和杂环基团,式中,B为CH2、NH、N-C1-5烷基、O或S,R8表示氢原子或氨基甲酰基。
2、如权利要求1所述的氨基甲酰基四氢吡啶衍生物或其可药用盐,其中饱和杂环基团是吡咯烷基、哌啶子基、吗啉代基、硫代吗啉代基、哌嗪基或4-甲基哌嗪基。
3、如权利要求1所述的氨基甲酰基四氢吡啶衍生物或其可药用盐,其中R1和R2为氢原子。
4、如权利要求3所述的氨基甲酰基四氢吡啶衍生物或其可药用盐,其中R3为甲基,Y1-Y2为(R4)C=C(R5),R4和R5相同或不同,为氢或甲基。
5、下式表示的吡咯并嘧啶衍生物,式中,R3表示氢原子或C1-5烷基,R4和R5相同或不同,表示氢原子或C1-5烷基,X4表示羟基、氯原子、溴原子或碘原子,X5表示卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基或三氟甲氧基。
6、下式表示的吡咯衍生物,式中,R4和R5相同或不同,表示氢原子或C1-5烷基,X5表示卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基或三氟甲氧基。
7、下式表示的4-或5-氨基甲酰基-1,2,3,6-四氢吡啶或其可药用盐,
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JP65004/99 | 1999-03-11 | ||
JP65004/1999 | 1999-03-11 | ||
JP6500499 | 1999-03-11 | ||
JP18562899 | 1999-06-30 | ||
JP185628/99 | 1999-06-30 | ||
JP185628/1999 | 1999-06-30 | ||
JP258353/1999 | 1999-09-13 | ||
JP258353/99 | 1999-09-13 | ||
JP25835399 | 1999-09-13 |
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US (2) | US6600038B1 (zh) |
EP (2) | EP1449843A1 (zh) |
KR (1) | KR20010102544A (zh) |
CN (1) | CN1174984C (zh) |
AT (1) | ATE297393T1 (zh) |
AU (1) | AU756702B2 (zh) |
CA (1) | CA2366642A1 (zh) |
DE (1) | DE60020692T2 (zh) |
ES (1) | ES2239592T3 (zh) |
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CN100376573C (zh) * | 2002-12-04 | 2008-03-26 | 卫材R&D管理有限公司 | 稠合的1,3-二氢-咪唑环化合物 |
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AR028782A1 (es) | 2000-07-05 | 2003-05-21 | Taisho Pharmaceutical Co Ltd | Derivados heterociclicos tetrahidropiridino o piperidino |
AR042667A1 (es) * | 2002-12-26 | 2005-06-29 | Taisho Pharmaceutical Co Ltd | Derivados de pirrolopirimidina y pirrolopiridina sustituidos con un grupo amino ciclico |
US7112585B2 (en) | 2003-04-18 | 2006-09-26 | Bristol-Myers Squibb Company | Pyrimidine derivatives as corticotropin releasing factor inhibitors |
US7030145B2 (en) | 2003-04-18 | 2006-04-18 | Bristol-Myers Squibb Company | Pyridinyl derivatives for the treatment of depression |
RU2006128580A (ru) * | 2004-01-06 | 2008-02-20 | Тайсо Фармасьютикал Ко., Лтд. (Jp) | Производные тиенопиримидина и тиенопиридина, замещенные циклической аминогруппой |
ATE356129T1 (de) | 2004-01-06 | 2007-03-15 | Taisho Pharmaceutical Co Ltd | Triazacyclopenta(cd)indenderivate |
CA2552503C (en) * | 2004-01-06 | 2011-09-13 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolotriazine derivatives |
JP2007526906A (ja) * | 2004-03-05 | 2007-09-20 | 大正製薬株式会社 | ピロロピリミジン誘導体 |
MXPA06015002A (es) * | 2004-06-25 | 2007-02-08 | Taisho Pharma Co Ltd | Derivados de pirrolopirimidina y pirrolopiridina sustituidos con tetrahidropiridina como antagonistas de crf. |
JP2007161585A (ja) | 2004-06-25 | 2007-06-28 | Taisho Pharmaceut Co Ltd | 環状アミノ基で置換されているピロロピリミジン及びピロロピリジン誘導体 |
WO2006073610A2 (en) * | 2004-11-23 | 2006-07-13 | Reddy Us Therapeutics, Inc. | Novel bicyclic heterocyclic compounds, process for their preparation and compositions containing them |
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DE2818676A1 (de) * | 1978-04-27 | 1979-11-08 | Troponwerke Gmbh & Co Kg | Substituierte 5,6-dimethylpyrrolo 2,3-d pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO1994013676A1 (en) | 1992-12-17 | 1994-06-23 | Pfizer Inc. | Pyrrolopyrimidines as crf antagonists |
US6187781B1 (en) * | 1997-03-26 | 2001-02-13 | Taisho Pharmaceutical Co., Ltd. | 4-Tetrahydropyridylpyrimidine derivatives |
JPH11335376A (ja) | 1998-05-25 | 1999-12-07 | Taisho Pharmaceut Co Ltd | アリールテトラヒドロピリジン誘導体 |
JP2000086663A (ja) * | 1998-09-09 | 2000-03-28 | Taisho Pharmaceut Co Ltd | アリールテトラヒドロピリジン誘導体 |
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- 2000-03-10 KR KR1020017011455A patent/KR20010102544A/ko not_active Application Discontinuation
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CN100376573C (zh) * | 2002-12-04 | 2008-03-26 | 卫材R&D管理有限公司 | 稠合的1,3-二氢-咪唑环化合物 |
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EP1176146A1 (en) | 2002-01-30 |
ES2239592T3 (es) | 2005-10-01 |
CN1174984C (zh) | 2004-11-10 |
CA2366642A1 (en) | 2000-09-14 |
US20030191122A1 (en) | 2003-10-09 |
KR20010102544A (ko) | 2001-11-15 |
ATE297393T1 (de) | 2005-06-15 |
DE60020692D1 (de) | 2005-07-14 |
US6600038B1 (en) | 2003-07-29 |
AU2941400A (en) | 2000-09-28 |
EP1449843A1 (en) | 2004-08-25 |
EP1176146A4 (en) | 2003-07-09 |
WO2000053604A1 (fr) | 2000-09-14 |
DE60020692T2 (de) | 2006-03-23 |
HK1046683A1 (en) | 2003-01-24 |
US6894168B2 (en) | 2005-05-17 |
EP1176146B1 (en) | 2005-06-08 |
AU756702B2 (en) | 2003-01-23 |
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