JPS60204788A - 7-deazapurine derivative - Google Patents
7-deazapurine derivativeInfo
- Publication number
- JPS60204788A JPS60204788A JP59061995A JP6199584A JPS60204788A JP S60204788 A JPS60204788 A JP S60204788A JP 59061995 A JP59061995 A JP 59061995A JP 6199584 A JP6199584 A JP 6199584A JP S60204788 A JPS60204788 A JP S60204788A
- Authority
- JP
- Japan
- Prior art keywords
- group
- amino
- reaction
- compound
- pyrimidin
- 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
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 125000006239 protecting group Chemical group 0.000 abstract description 17
- JJJQHTCJNMSSJV-UHFFFAOYSA-N pyrrolo[2,3-d]pyrimidin-4-one Chemical compound O=C1N=CN=C2N=CC=C12 JJJQHTCJNMSSJV-UHFFFAOYSA-N 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 abstract description 5
- 238000010511 deprotection reaction Methods 0.000 abstract description 4
- 238000006969 Curtius rearrangement reaction Methods 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- 239000000645 desinfectant Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- -1 2-substituted aminoethyl group Chemical group 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 108020004566 Transfer RNA Proteins 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- WYROLENTHWJFLR-ACLDMZEESA-N queuine Chemical compound C1=2C(=O)NC(N)=NC=2NC=C1CN[C@H]1C=C[C@H](O)[C@@H]1O WYROLENTHWJFLR-ACLDMZEESA-N 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JDUMICHRQFXDJN-UHFFFAOYSA-N 1H-pyrimidin-6-one dihydrochloride Chemical compound Cl.Cl.O=C1C=CN=CN1 JDUMICHRQFXDJN-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 108020005098 Anticodon Proteins 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
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- 238000010348 incorporation Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical group CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000006606 n-butoxy group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- ZGPUVZXQCFMRCI-UHFFFAOYSA-N 1,2-dimethoxyethane;ethoxyethane Chemical compound CCOCC.COCCOC ZGPUVZXQCFMRCI-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- CAFAOQIVXSSFSY-UHFFFAOYSA-N 1-ethoxyethanol Chemical compound CCOC(C)O CAFAOQIVXSSFSY-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- PBVZQAXFSQKDKK-UHFFFAOYSA-N 3-Methoxy-3-oxopropanoic acid Chemical compound COC(=O)CC(O)=O PBVZQAXFSQKDKK-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- USWINTIHFQKJTR-UHFFFAOYSA-N 3-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C=C(S(O)(=O)=O)C(O)=CC2=C1 USWINTIHFQKJTR-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
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- 241000894006 Bacteria Species 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
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- 229920000742 Cotton Polymers 0.000 description 1
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- 239000005977 Ethylene Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
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- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000017524 noni Nutrition 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- CPGRMGOILBSUQC-UHFFFAOYSA-N phosphoryl azide Chemical compound [N-]=[N+]=NP(=O)(N=[N+]=[N-])N=[N+]=[N-] CPGRMGOILBSUQC-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 108091029536 tRNA precursor Proteins 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 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
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 技術分野 本発明は、新規な7−デアザプリン誘導体に関する。[Detailed description of the invention] Technical field The present invention relates to novel 7-deazapurine derivatives.
背景技術
本発明と同一の骨格を有する天然のQ塩基類(例、Q塩
基、 PreQ1塩基)は、特定のtRNA(tRNA
Tyr、 tRNAH18,tRNAA8P オ!ヒt
RNAA8n)の構成成分として、広く生物界に分布し
ておシ、上記tRNAのアンチコドンの第−字目に位置
し、直接mRNAからの遺伝情報を認識し蛋白質合成に
関与する重要な生物学的意義を有している。特に最近の
生化学的基艇研究の進展にともない、種々のtRN A
の構造解析や生命現象における役割の解明が急速に進み
、癌細胞と正常細胞との間におけるtRNAの差異が明
らかになってきた。その差異の1つは、癌細胞では、Q
塩基のtRNA前駆体への取シ込みが完全ではなく、常
にQ欠損tRMAが存在することである。又、外部よJ
)Q塩基を与えることによシ、Q欠損tRNAはQ塩基
を所定の位置(アンチコドンの第−字目)に取シ込み正
常なtRNAになること、さらにQ塩基の取シ込みは一
般の正常−細胞には認められず癌細胞に特異的であるこ
とが観察されている〔西村迷、代WM * voL 1
71臨時増刊号[癌80Jp127〜136 (198
0))。BACKGROUND ART Natural Q bases (e.g., Q base, PreQ1 base) having the same skeleton as the present invention can be used for specific tRNA (tRNA
Tyr, tRNAH18, tRNAA8P Oh! Hit
As a component of RNAA8n), it is widely distributed in the living world, and is located at the first position of the anticodon of the above tRNA, and has important biological significance as it directly recognizes genetic information from mRNA and is involved in protein synthesis. have. In particular, with the recent progress in biochemical substrate research, various tRNA
Structural analysis of tRNA and elucidation of its role in biological phenomena have progressed rapidly, and the differences in tRNA between cancer cells and normal cells have become clear. One of the differences is that in cancer cells, Q
The incorporation of the base into the tRNA precursor is not complete, and Q-deficient tRMA always exists. Also, outside J
) By providing a Q base, a Q-deficient tRNA will incorporate a Q base at a predetermined position (the -th position of the anticodon) and become a normal tRNA, and the incorporation of a Q base will be normal. - It has been observed that it is not observed in cells but is specific to cancer cells [Mei Nishimura, WM * voL 1
71 special issue [Cancer 80Jp127-136 (198
0)).
発明の開示
本発明者らは、q塩基類と同一の骨格を有する7−デア
ザプリン誘導体について種々検索したところ、C−,7
位にQ塩基μよシも炭素数が1つ伸びた2−アミノエチ
ル基または2−置換アミノエチル基を持つ7−ジアザグ
アニン類が新規化合物であ〕、かつtRNA前駆体へ効
率よく取シ込まれ優れた抗腫瘍作用を示すことを見い出
し、さらに研究を重ねた結果、本発明を完成した。DISCLOSURE OF THE INVENTION The present inventors conducted various searches for 7-deazapurine derivatives having the same skeleton as q bases, and found that C-,7
7-diazaguanines having a 2-aminoethyl group or a 2-substituted aminoethyl group with one more carbon number than the Q base μ are new compounds, and can be efficiently incorporated into tRNA precursors. It was discovered that it rarely exhibits excellent antitumor effects, and as a result of further research, the present invention was completed.
本発明は、一般式
〔式中 R1およびR2は同−又は異って水素原子また
は置換基を有していてもよい炭化水素残基を示し、R1
とR2が隣接する窒素原子とともに環を形成していても
よく、R3は保護されていてもよいアミノ基を示す。〕
で表わされる7−デアザプリン誘導体またはその塩であ
る。The present invention is based on the general formula [wherein R1 and R2 are the same or different and represent a hydrocarbon residue which may have a hydrogen atom or a substituent, and R1
and R2 may form a ring together with the adjacent nitrogen atom, and R3 represents an optionally protected amino group. ]
It is a 7-deazapurine derivative represented by or a salt thereof.
上記式中、R1およびR2で示される置換基を有してい
てもよい炭化水素残基としては、基としての分子量が約
400以下のものが好ましい。In the above formula, the optionally substituted hydrocarbon residues represented by R1 and R2 preferably have a molecular weight of about 400 or less as a group.
上記式中 R1およびR2で示される置換基を有しても
よい炭化水素残基における炭化水素残基としては、アル
キル基、アμケニμ基、シクロアμキμ基、シクロアμ
グニ/L/基、アフルキμ基。In the above formula, hydrocarbon residues in the hydrocarbon residues which may have substituents represented by R1 and R2 include alkyl groups, aμ groups, cycloaμ groups, and cycloaμ groups.
Guni/L/ group, Afuruki μ group.
アリ−/L/’(aryl ) 話などが挙げられる。Examples include stories such as aryl/L/' (aryl).
アルキル基としては、たとえば炭素数1ないし18のア
ルキル基(例、メチμ、エチル、プロピμ、イソプロピ
μ、ブチμ、イソブチμ、 5ea−ブチル。Examples of the alkyl group include alkyl groups having 1 to 18 carbon atoms (eg, methiμ, ethyl, propyμ, isopropyμ, butyμ, isobutyμ, 5ea-butyl).
tert−ブチル、ベンチμ、イソベンチμ、ヘキシp
、イソヘキシμ、へ7zチμ、オクチル、ノニ〜、デシ
ル、ウンデニル、ドデシ/l/、テトラデシμ、ヘキサ
デシμ、オクタデシル、1,2−ジメチμプロピ/l/
、1−エチルグロビμ、1.2.2−トリメチ〃プロピ
/l/、1−プロピμブチμ、2−ブチ)Vヘキシμ基
)があげられる。アpケ二μ基としては、たとえば炭素
数2ないし12のγμケ二二基基例、ビニル、アリ/I
/(allyl) 、 1−メチルビニ〃、2−メチμ
ビニ/l/、1−オクテニμ、1−デセニル基〕があげ
られる。シクロアルキル基としては、たとえ#′i次素
数3ないし12のシクロアルキル基(例、シクロプロピ
μ、シクロブチル、Vクロベンチ!、シクロヘキシμ、
シクロヘプチ!、シクロオクチμ、アダマンチμ基)が
あげられる。シクロアρヶ二μ基としては、たとえば炭
素数3ないし8のシクロアルケニル基(例、シクロベン
テニμ、シクロヘキセニ!、シクロヘプテニ!、シクロ
オクテニμ、シクロペンタジェニ/L/、シクロヘキサ
ジェニル、シクロヘプタジェニル、シクロオクタジエニ
μ基)があげられる。tert-butyl, bench μ, isobenchi μ, hexy p
, isohexyμ, he7ztiμ, octyl, noni~, decyl, undenyl, dodecyl/l/, tetradecylμ, hexadecylμ, octadecyl, 1,2-dimethyμpropyl/l/
, 1-ethylglobiμ, 1.2.2-trimethy〃propy/l/, 1-propyμbutyμ, 2-buty)Vhexyμ group). Examples of the apkey group include a γμ group having 2 to 12 carbon atoms, vinyl, ali/I
/(allyl), 1-methylviny〃, 2-methyμ
vinyl/l/, 1-octenyl μ, 1-decenyl group]. Examples of the cycloalkyl group include cycloalkyl groups of #'i order prime number 3 to 12 (e.g., cyclopropyμ, cyclobutyl, V-crobench!, cyclohexyμ,
Cyclohepti! , cyclooctyl μ, and adamantyl μ groups). Examples of the cycloa2μ group include cycloalkenyl groups having 3 to 8 carbon atoms (e.g., cyclobenteniμ, cyclohexeni!, cyclohepteni!, cycloocteniμ, cyclopentageni/L/, cyclohexagenyl, cycloheptagenyl) , cyclooctadiene μ group).
アラルキル基としては、たとえば炭素数7ないし13の
アラルキル基(例、ベンジル、α−メチμベンジ/L/
、フエネチ/L/、ジフェニルメチμ基)があげられる
。アリーμ基としては、たとえば炭素数6ないし10程
度のアリーμ基(例、フェニp、a−ナフチμ、β−ナ
フチμ基)があげられる。Examples of aralkyl groups include aralkyl groups having 7 to 13 carbon atoms (e.g., benzyl, α-methylμbenzi/L/
, fenethi/L/, diphenylmethymu group). Examples of the ary .mu. group include ary .mu. groups having about 6 to 10 carbon atoms (eg, phenyl p, a-naphthi .mu., and .beta.-naphthi .mu. groups).
R1とR2とは隣接する窒素原子とともに環を形成して
もよい。かかる環としては、4ないしl。R1 and R2 may form a ring together with adjacent nitrogen atoms. Such a ring includes 4 to 1.
員環が好ましく、たとえばアゼチジニμ、ビロリジニl
vIピロリニル、ピロリル、イミダゾリμ。Member rings are preferred, such as azetidini μ, virolidini l
vI pyrrolinyl, pyrrolyl, imidazolyμ.
ピヲゾリ〃、イミダゾリニ〜、ピペリジノ、七μホリノ
、ジヒドロピリジμ、テトラハイドロピリジμ1M−メ
チルピペラジニル、N−エチμピペラジニμ、アザシク
ロへブチル、アザシクロオクチμ、イソインドリμ、イ
ンドリμ、インドリニμ、2−イソインドリニル、アザ
シクロノ=lv。Piwozoli, imidazolini, piperidino, 7μholino, dihydropyridiμ, tetrahydropyridiμ, 1M-methylpiperazinyl, N-ethylpiperazinyl, azacyclohebutyl, azacyclooctyμ, isoindriμ, indriμ, indoliniμ, 2 -isoindolinyl, azacyclono=lv.
アザシクロデシ/I/などが挙げられる。Examples include azacyclodecyl/I/.
これらのR1,R2とで示される炭化水素残基、あるい
はR1とR2が隣接する窒素原子とともに形成した環は
、工ないし3個の置換基を有していてもよい。かかる置
換基としては、たとえば炭素数1ないし4程度のアルキ
ル基(例、メチμ、エチル、プロピμ、イソプロピμ、
イソグチ!、8e〇−ブチμ、 tert−ブチA/)
、水酸基を置換基として有していてもよい炭素数1ない
し4程度のアルコキシ基(例、メトキシ、エトキシ、プ
ロポキン、 1so−プロポキシ、n−ブトキシ、1a
O−ブトキシ、 5ea−グトキV 、 tert−ブ
トキシ基)、*素数1ないし4程度のアμカノイμ基(
例、ホ〃ミμ、アセチμ、プロピオニμ、n−ブチリμ
。The hydrocarbon residue represented by R1 and R2, or the ring formed by R1 and R2 together with the adjacent nitrogen atom, may have 1 to 3 substituents. Such substituents include, for example, alkyl groups having about 1 to 4 carbon atoms (e.g., methiμ, ethyl, propyμ, isopropyμ,
Isocroft! , 8e〇-buti μ, tert-buti A/)
, an alkoxy group having 1 to 4 carbon atoms which may have a hydroxyl group as a substituent (e.g., methoxy, ethoxy, propoquine, 1so-propoxy, n-butoxy, 1a
O-butoxy, 5ea-gutokiV, tert-butoxy group), *Aμ group with a prime number of about 1 to 4 (
Examples: homi μ, aceti μ, propioni μ, n-butyri μ
.
1so−ブチリμ基)、炭素数1ないし4程度のアμカ
ッイルオキシ基(例、ホルミμオキシ、アセチルオキシ
、プロピオニμオキシ、n−ブチリルオキシ、18o−
グチリμオキシ基)、力μボキシ基、灰素?!12ない
し4程度のアルコキシカμポニμ基(例、メトキシカμ
ボニ1vlエトキシカpボニμ、n−プロボキシカルポ
ニ/L/、1ao−プロポキシカμポニ!基、n−プト
キシカにボニル、イソブトキシカルボニル、t−ブトキ
シカルポニμ)、ハロゲン原子(例、フッ素、塩素、臭
素、沃素)、水酸基、ニトロ基、シアノ基、トリフμオ
ロメチμ基、アミノ基、モノ置換アミノ基(例、メチμ
アミノ、エチルアミノ、プロピルアミノ。1so-butyryl group), a-kalyloxy group having about 1 to 4 carbon atoms (e.g., formyloxy, acetyloxy, propionyloxy, n-butyryloxy, 18o-
Glycy μ oxy group), force μ boxy group, gray? ! 12 to 4 alkoxycarbonyl groups (e.g., methoxycarbonyl
Boni 1vl Ethoxycarp Boniμ, n-Proboxycarponi/L/, 1ao-Propoxycarponi! group, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl), halogen atom (e.g., fluorine, chlorine, bromine, iodine), hydroxyl group, nitro group, cyano group, trifluoromethiμ group, amino group , a monosubstituted amino group (e.g., methyμ
Amino, ethylamino, propylamino.
イソプロピμアミノ、ブチルアミノ、力pポキシメチμ
アミノ基)、シアルキルアミノ基(例、ジメチルアミノ
、ジエチルアミノ、ジプロピルアミノ、ジイソプロピル
アミノ、ジグチルアミノ、シカμボキシメチルアミノ基
)、アルカノイルアミド基(例、ホμムアミド、アセタ
ミド、プロピオニルアミド、ブチリルアミド、イソブチ
リルアミド基)などがあげられる。R3で示される保護
基を有しているアミノ基における保護基としては、たと
えば、アシル基、アpコキシカμボニル基。Isopropylamino, butylamino, poxymethymu
amino group), sialkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino, digtylamino, cicaμboxymethylamino group), alkanoylamide group (e.g., homamide, acetamide, propionylamide, butyrylamide) , isobutyrylamide group), etc. Examples of the protecting group for the amino group having a protecting group represented by R3 include an acyl group and an ap-koxy carbonyl group.
アリーμオキシカμボニμ基、N−置換力μバモイμ基
、チオアルコキシカμボニ/l’基、チオアリ−μオキ
シカルボニル基、アリーμメチμ基、N、N−ジアルキ
pアミノメチレン基、ホスホリμ基、スルホニ/l/i
、)リアルキルシリル基などが挙げられる。aryμoxycarbonyμ group, N-substituted μbamoyμ group, thioalkoxycarbony/l′ group, thioary-μoxycarbonyl group, aryμmethyμ group, N,N-dialkylp aminomethylene group, Phosphory μ group, sulfony/l/i
, ) realkylsilyl group, etc.
該保護基としてのアシル基としては、基としての分子量
が約400以下のものが好゛ましく、その具体例として
はたとえばアルカノイル基、アロイル基などが挙げられ
る。上記アμカノイμ基としては、炭素数1ないし18
のものが好ましく、その例としては、ホルミμ、ア七千
p、プロピオニμ、ブチリル、イソブチリμ、サクシニ
ル、バレリμ、イソパレリμ、ピパロイμ、ヘキサノイ
μ、ヘプタノイ/L/、オクタノイル、2−エチルヘキ
サノイμ、ノナノイル、デカノイμ、ウンデカノイμ、
トリデカノイ!、テトフデカノイμ、ペンタデカノイμ
、ヘキサデカノイ!、ヘプタデカノイμ、オクタデカノ
イμなどが挙げられ、なかでも、炭素数1ないし10の
ものが好都合に用いられる。上記アロイμ基としては炭
素数7ないし12のものが好ましく、その例としてはベ
ンシイA’、p−アニソイル、0−シアノベンシイ!、
O−ニトロベンゾイμ、トルオイル、フタロイμ。The acyl group used as the protecting group preferably has a molecular weight of about 400 or less, and specific examples include an alkanoyl group and an aroyl group. The above Akanoi μ group has 1 to 18 carbon atoms.
Preferred examples include formiμ, a7000p, propioniμ, butyryl, isobutyrylμ, succinyl, valeriμ, isoparelliμ, pipaloyμ, hexanoylμ, heptanoyl/L/, octanoyl, 2-ethyl hexanoyl μ, nonanoyl, decanoy μ, undecanoyl μ,
Tridekanoi! , tetofdecanoi μ, pentadecanoi μ
, Hexadecanoi! , heptadecanoy μ, octadecanoy μ, etc. Among them, those having 1 to 10 carbon atoms are preferably used. The above alloy μ group preferably has 7 to 12 carbon atoms, examples of which include benzyA', p-anisoyl, 0-cyanobensy! ,
O-nitrobenzoi μ, toluoyl, phthaloy μ.
ナフトイルなどがあげられ、なかでもベンシイμ基など
が好都合に用いられる。Examples include naphthoyl, among which a benzyi μ group is advantageously used.
アルコキシカルボニμ基としては炭素数1ないし15の
ものが好ましく、その例としては、メトキシカルボニル
、エトキシカルボニル
シカμボニル、イソプロポキシカルボニルキシカルボニ
μ, sea−エトキシカルボニル。The alkoxycarbonyl μ group is preferably one having 1 to 15 carbon atoms, and examples thereof include methoxycarbonyl, ethoxycarbonylcabonyl, isopropoxycarbonyloxycarbonyl μ, and sea-ethoxycarbonyl.
tert−ブトキシカルボニル、ベンジルオキシカルボ
ニル、p−メトキシベンジμオキシカルボニμ、2−(
p−ゼニ/L/)イソプロポキシカルボニルロピリ
ニμ,ベンジμオキシカルボニμ基などが好都合に用い
られる。アリーμオキシカμポニμ基トシては、炭素数
6ないし12のものが好ましく、その例としては、フェ
ノキシカルボニル、p−メトキシフエノキシカルボニμ
,a−ナフトキシカルボニμ,βーナフトキシカμボニ
μなどがあげられる。N−置換カルパモイル基としては
ピペリジツカμパモイ/L’, N 、 N−ジフェニ
ル力μバモイμ基などが用いられる。チオアμコキシカ
μボニμ基としては炭素数1ないし7のものが好゛まし
く、その例としては、チオメトキシカルボニル、チオエ
トキシカルボニμ,チオプロポキンカルボニμ、チオグ
トキシカpボニμ,チオベンジμオキシカpボニμなど
があげられ、なかでもチオベンジμオキシカルポニμ基
などが好都合に用いられる。tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybendiμoxycarbonylμ, 2-(
p-zeny/L/) isopropoxycarbonyllopiriniμ, benzyμoxycarbonyμ groups, etc. are conveniently used. The aryl oxycarbonyl group preferably has 6 to 12 carbon atoms, examples of which include phenoxycarbonyl, p-methoxyphenoxycarbonyl, and p-methoxyphenoxycarbonyl.
, a-naphthoxycarboniμ, β-naphthoxycarboniμ, etc. As the N-substituted carpamoyl group, a piperidzka/L', N, N-diphenyl group is used. The thioamyl carbonyl group preferably has 1 to 7 carbon atoms, examples of which include thiomethoxycarbonyl, thioethoxycarbonyl, thiopropoquine carbonyl, thiogutoxycarbonyl, and thiobendicarbonyl. Examples thereof include .mu.oxycarboni.mu., among which thiobendi.mu.oxycarpony.mu. group is conveniently used.
チオアリールオキVカμボニル基としては、チオフェノ
キシカルボニル、チオα−ナフトキシカルボニル、チオ
−β−ナフトキシカルボニルが用いられる。アリールメ
チμ基としては、ベンジμ,p−メトキシベンジμ.3
.4.5−トリメトキシベンジμ,ジ(p−メトキシベ
ンジ/l/)メチμ、トリチル、モノメトキシトリチI
VM、などが用いられる。N、N−ジアルキルアミノメ
チレニルアミノメチレン
リル基トしては、p−ニトロベンジルホスホリル、p−
ブロモベンジルホスホリル
スホリ/L/,ジ(p−ニトロベンジル)ホスホリル、
ジ(p−7’ロモペンジlV)ホスホリμ.s’(p−
ヨードベンジル)ホスホリμ基などが用いられる。ヌル
ホニ/l/基としてはスμホニルオキシ,ベンジルスル
ホニル
ゼンスルホニ/l/,)ルエンヌμホニル基なトカアげ
られる。トリアルキルシリル
メチルシリμ, tert−プチルジメチμシリル基な
どがあげられる。As the thioaryloki V carbonyl group, thiophenoxycarbonyl, thio α-naphthoxycarbonyl, and thio-β-naphthoxycarbonyl are used. Examples of the arylmethy[mu] group include bendi[mu], p-methoxybendi[mu]. 3
.. 4.5-trimethoxybendiμ, di(p-methoxybendi/l/)methyμ, trityl, monomethoxytrithi I
VM, etc. are used. N,N-dialkylaminomethylenylaminomethylenelyl group includes p-nitrobenzylphosphoryl, p-
Bromobenzylphosphorylphosphoryl/L/, di(p-nitrobenzyl)phosphoryl,
di(p-7'romopendiIV) phosphoryμ. s'(p-
(iodobenzyl) phosphoryμ group, etc. are used. Examples of the nulfony/l/ group include sulfonyloxy, benzylsulfonylzenesulfony/l/, )ruene μhonyl group. Examples include trialkylsilylmethylsilyl silyl group, tert-butyldimethylsilyl group, and the like.
化合物(I)の塩としては、たとえば塩酸,@酸,硝酸
,リン酸,ホウ酸などとの鉱酸塩、シュウ酸,酒石酸,
酢酸.トリフルオロ酢酸,メタンスルホン酸,ベンゼン
スルホン酸,p−)/I/エンスルホン酸,カンフアー
スpホン酸などとの有機酸塩、臭化メチル、ヨウ化メチ
μ,メタンスμホン酸メチルエステル、ベンゼンスルホ
ン酸メチμエステル、p−)μエンスルホン酸エステl
’lどとの四級塩があげられる。Examples of the salt of compound (I) include mineral acid salts with hydrochloric acid, @acid, nitric acid, phosphoric acid, boric acid, etc., oxalic acid, tartaric acid,
Acetic acid. Organic acid salts with trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-)/I/enesulfonic acid, camphor p-phonic acid, etc., methyl bromide, methi-μ iodide, methanes-μ fonic acid methyl ester, benzene Methyμ sulfonic acid ester, p-)μene sulfonic acid ester
'ldo and quaternary salts are mentioned.
本発明化合物(I)は、たとえば次に示す各合成法によ
って製造し得る。Compound (I) of the present invention can be produced, for example, by the following synthetic methods.
A)
一般式
〔式中、R3は前記と同意義を有する。〕で表わされる
化合物をCurtius転位反応に付し必要ならばR3
中の保護基を脱保護反応に付して除去することによシ
式(工, R1 = R2 =水素原子)で表わされる
7−デアザプリン誘導体を得ることができる。A) General formula [In the formula, R3 has the same meaning as above. ] is subjected to Curtius rearrangement reaction, and if necessary, R3
A 7-deazapurine derivative represented by the formula (R1 = R2 = hydrogen atom) can be obtained by removing the protecting group therein by subjecting it to a deprotection reaction.
上記Curtius転位反応は文献公知の方法”1)を
適用することによシ容易に行うことが出来る。The above-mentioned Curtius rearrangement reaction can be easily carried out by applying method 1) known in the literature.
ml) P. A. S. Smith, Organ
ic Reacfiona 3 。ml) P. A. S. Smith, Organ
ic Reacfiona 3.
337(1946) ; K. Ninomiya,
’I’. Shioiri 。337 (1946); K. Ninomiya,
'I'. Shioiri.
and S. Yamada, Chem.Pharm
. Bull 、 22 。and S. Yamada, Chem. Pharm
.. Bull, 22.
1398(1974)。1398 (1974).
R3 中の保護基がアシル基の場合、脱アシル化反応は
自体公知の方法*2)によシ加水分解(例、酸加水分解
,アルカリ加水分解,アンモニア分解)することによシ
行うことが出来る。When the protecting group in R3 is an acyl group, the deacylation reaction can be carried out by hydrolysis (e.g., acid hydrolysis, alkaline hydrolysis, ammonialysis) by a method known per se *2). I can do it.
*2)ヘントリック・クラム・ハモノド。有機化学(第
3版)〔工〕および〔■〕,広川書用(1973) 。*2) Hentric Crum Hamonod. Organic Chemistry (3rd edition) [Eng.] and [■], Hirokawa Shoyo (1973).
その他の保護基に関しても、自体公知の方法*3)によ
シ容易に脱保護することが出来る。Other protecting groups can also be easily deprotected by a method known per se *3).
*3) 、T. F’. W. McOmie, Pr
otective Groups inOrganic
Chemistry, Plenum Press。*3), T. F'. W. McOmie, Pr.
otective Groups inOrganic
Chemistry, Plenum Press.
London and New York (19 7
3 )一本法で使用される原料化合物(II)はたと
えば次の工程に示す方法によって製造し得る。London and New York (19 7
3) The raw material compound (II) used in the single method can be produced, for example, by the method shown in the following step.
上記式中、R3は前記と同意義を有する。R4およびR
5 は同一まだは異なって、アシル基.アシコキシカμ
ポニp基.Hに置換基を有してもよい力μパモイル基,
シアノ基を示す。In the above formula, R3 has the same meaning as above. R4 and R
5 are the same or different, and are acyl groups. Ashikoxicaμ
Pony p group. a μ-pamoyl group which may have a substituent on H;
Indicates a cyano group.
上記R4 およびR5 で表わされるアシル基としては
、灰素数2ないし8のものが好ましく、その例としては
、アセチル、プロピオニμ,ブチリμ、イソブチリル、
バレリル、イソバレリμ,ピバロイμ,ヘキサノイ1v
.ベンゾイル、トμオイμ基があげられ、なかでもアセ
チル基が好都合に用いられる。アμコキシカルポニμ基
としては、次素数2ないし9のものが好ましく、その例
としては、メトキシカμボニμ,エトキシカμポニp。The acyl group represented by R4 and R5 above is preferably one having an ash number of 2 to 8, and examples thereof include acetyl, propionyl μ, butyryl μ, isobutyryl,
Valeryl, Isovaleri μ, Pivaloy μ, Hexanoi 1v
.. Mention may be made of the benzoyl, toy, and mu groups, among which the acetyl group is advantageously used. The a[mu]koxycarboni[mu] group is preferably a prime number of order 2 to 9, such as methoxycarboni[mu], ethoxycarboni[mu], and ethoxycarboni[mu].
プロポキシカルボニル、イソプロポキシカルポニp、グ
トキシカルポニμ、 5ea−ブトキシカμポニμ、
tert−グトキシカルボニμ、ペンジルオキシカルボ
ニμ、p−メトキシペンジルオキシカルボニル基などが
あげられ、なかでもメトキシカμポニμ、エトキシカ〃
ボニ/L/ 、 tert−プトキシカルボニμ、ベン
ジμオキシカルボニμ基が好都合に用いられる。Nに置
換基を有してもよいカルバモイル基の置換基としては、
炭素数1ないし4程度のものが好ましく、例えばメチル
、エチル、プロピμ、イソプロピ!、ブチル、 5ea
−ブチμ。Propoxycarbonyl, isopropoxycarbonyl, gutoxycarpony, 5ea-butoxycarpony,
Examples include tert-gutoxycarbonyl, penzyloxycarbonyl, p-methoxypenzyloxycarbonyl, and among them, methoxycarbonyl, ethoxycarbonyl, etc.
The groups Boni/L/, tert-poxycarboniμ, benzyμoxycarboniμ are conveniently used. As the substituent of the carbamoyl group which may have a substituent on N,
Those having about 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propymu, isopropy! , butyl, 5ea
- Spot μ.
tert−ブチル基などがあげられる。Examples include tert-butyl group.
R6,R7は、α位がメチレン基であるアμキル基、ア
ルケニiv基またはアフルキ/L/基をそれぞれ示し、
R6とR7とが隣接する窒素原子とともに環状アミノ基
を形成していてもよい。R6 and R7 each represent an aμkyl group, an alkeni IV group, or an afurkyl/L/ group in which the α-position is a methylene group,
R6 and R7 may form a cyclic amino group together with adjacent nitrogen atoms.
R6およびR7で示される各基は同一もしくは異なって
いてもよく、0位がメチレン基であるアルキp基として
は、炭素数1ないし10程度の、たとえばメチル、エチ
μ、n−プロピ7tz、H−ブチμ、イソブチμ、ペン
チル、イソベンチμ、ヘキシμ、イソヘキシp、ヘプチ
ル、オクチル、ノニル、デシル基などがあげられ、なか
でも炭素数1ないし6程度のアルキル
る。0位がメチレン基であるアルケニル基としては、炭
素数3ないし13程度の、たとえばアリル(2−プロベ
ニ/l/) 、 2−グチニル、2−ベンテニμ.2−
へキセニル,4ープロピyv−2−ペンテニル、シンナ
ミ/l/,2−ノニ1v−2−ブチ二p基などがあげら
れ、なかでも炭素数3ないし9程度のγμケ二ル基が好
都合に用いられる。これらのアルキル基およびアルケニ
ル基はα位以外の任意の位置に1ないし3個の置換基を
有していてもよく、かかる置換基としては、炭素g11
1ないし4程度のアルキル基(例、メチル、エチル、プ
ロピμ,イソプロピル、ブチμ,イソブチl 、 se
C−ブチル、 tert−ブチIv)、炭素数1ないし
4程度のアμコキシ基(例、メトキシ、エトキシ、プロ
ポキシ、180−プロポキシ、n−ブトキシ、18〇−
ブトキシ、 sec−ブトキシ、 tert−ブトキシ
基)J2素数1ないし4程度のアルカノイμ基(例、ホ
ルミル、アセチル、プロピオニμ,n−ブチリμ,18
o−ブチリμ基)、水酸基,ニトロ基.ハロゲン原子(
例、フッ素,塩素,臭素,沃素)。Each group represented by R6 and R7 may be the same or different, and the alkyl p group having a methylene group at the 0-position is an alkyl p group having about 1 to 10 carbon atoms, such as methyl, ethylμ, n-propyl 7tz, H Examples include -buty μ, isobuty μ, pentyl, isobenchi μ, hexy μ, isohexy p, heptyl, octyl, nonyl, decyl groups, and among them, alkyl groups having about 1 to 6 carbon atoms. Examples of the alkenyl group having a methylene group at the 0-position include those having about 3 to 13 carbon atoms, such as allyl (2-probeni/l/), 2-guthynyl, 2-bentenyl μ. 2-
Examples include hexenyl, 4-propyyv-2-pentenyl, cinnamyl/l/, 2-nony1v-2-butydip group, among which γμkenyl group having about 3 to 9 carbon atoms is conveniently used. It will be done. These alkyl groups and alkenyl groups may have 1 to 3 substituents at any position other than the α position, and such substituents include carbon g11
1 to 4 alkyl groups (e.g., methyl, ethyl, propylμ, isopropyl, butyμ, isobutyl, se
C-butyl, tert-butyl IV), aμkoxy group having about 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, 180-propoxy, n-butoxy, 180-
(butoxy, sec-butoxy, tert-butoxy group)
o-butyl μ group), hydroxyl group, nitro group. Halogen atom (
e.g., fluorine, chlorine, bromine, iodine).
カルボキシ基,シアノ基,トリフルオロメチル基、シア
μキルアミノ基(例、ジメチルアミノ、ジエチルアミノ
、ジグロピルアミノ,ジイソプロピμアミノ、ジプチル
アミノ基)、アルカッイルアミド基(例、ホルムアミド
、アセタミド、プロピオニルアミド、ブチリルアミド、
イソブチリルアミド基)などがあげられる。Carboxy group, cyano group, trifluoromethyl group, cyamino group (e.g., dimethylamino, diethylamino, diglopylamino, diisopropylamino, diptylamino group), alkylamide group (e.g., formamide, acetamide, propionylamide, butyrylamide,
isobutyrylamide group), etc.
R6およびR7で示されるα位がメチレン基であるアラ
ルキル基としては、たとえば炭素数7ないし12程度の
ベンジlv,フエネチμ,3−フェニルプロピル
基などがあげられ、なかでもベンジル基が好都合に用い
られる。これらのアラルキル基も0位以外のアルキレン
鎖部分および/またはアリール(フエニ/L/)環部分
に置換基を有していてもよく、かかる置換基としては、
上記アルキル基およびアルケニル基について例示した各
基があげられる。Examples of the aralkyl group in which the α-position represented by R6 and R7 is a methylene group include benzylv, fenethyl, and 3-phenylpropyl groups having about 7 to 12 carbon atoms, among which a benzyl group is conveniently used. It will be done. These aralkyl groups may also have a substituent on the alkylene chain portion other than the 0-position and/or the aryl (feni/L/) ring portion, and such substituents include:
Examples of the above-mentioned alkyl groups and alkenyl groups include the groups listed above.
R6とR7 とが隣接する窒素原子とともに形成する環
状アミノ基としては、たとえば5ないし6員程度の環状
アミノ基があげられ、上記窒素原子以外に2個目の環へ
テロ原子(例、N,0)を有していてもよい。かかる環
状アミノ基としては、たとえば1−ピロリジニル、1−
ピロリニμ,1−イミダゾリジニル、1−イミダゾリニ
ル、1−ピラゾリジニル,1−ピラゾリニル、モルホリ
ノ、ピペリジノ、1−ピペラジニμ基などがあげられ、
これらの環状アミノ基は窒素原子に隣接する位置(α位
)を除いて置換基を有していてもよく、かかる置換基と
しては、前記アルキル基およびアルケニル基について例
示した各基があげられる。The cyclic amino group formed by R6 and R7 together with the adjacent nitrogen atom includes, for example, a 5- to 6-membered cyclic amino group, in which a second ring heteroatom (e.g., N, 0). Such cyclic amino groups include, for example, 1-pyrrolidinyl, 1-
pyrrolini μ, 1-imidazolidinyl, 1-imidazolinyl, 1-pyrazolidinyl, 1-pyrazolinyl, morpholino, piperidino, 1-piperazini μ group, etc.
These cyclic amino groups may have a substituent other than the position adjacent to the nitrogen atom (α-position), and such substituents include the groups exemplified above for the alkyl group and alkenyl group.
上記工程工の反応においては、化合物(IV)と化合物
(I[)とを(IV)/(N)=1ないし50(モル比
)程度でそれら自体又は適当な反応溶媒を用いて約O℃
からその反応溶媒の沸点、好ましくは約20ないし10
0℃の範囲の反応温度で約10分間から48時間程度反
応させ化合物(V)を得ることができる。なお、反応溶
媒としては、水、メタノ−IL/、エタノ−μ、プロパ
ノーρ、ゲタノーμ、ペンタノ−μ、テトラヒドロフヲ
ン。In the reaction of the above step, compound (IV) and compound (I[) are mixed by themselves or in an appropriate reaction solvent at a ratio of about (IV)/(N)=1 to 50 (molar ratio) at about 0°C.
to the boiling point of the reaction solvent, preferably about 20 to 10
Compound (V) can be obtained by reacting at a reaction temperature in the range of 0° C. for about 10 minutes to about 48 hours. In addition, as a reaction solvent, water, methano-IL/, ethanol-μ, propano-ρ, getano-μ, pentano-μ, and tetrahydrofone.
ジオキサン、アセトニトリ!、ピリジン、ジメチルホμ
ムアミド、ジメチμス!ホキシト、スμホヲン又はそれ
らの適宜の混合物が使用される。反応溶液に塩基(例、
水酸化ナトリウム、水酸化カリウム、水酸化リチウム、
水酸化バリウム、ピリジン、N、N−ジメチルアニリン
、トリエチルアミン)を添加することによシ反応速度並
びに収率を向上させることが出来る。Dioxane, acetonitrile! , pyridine, dimethylphoμ
Muamido, dimethi μs! Phoxylate, fluorine or suitable mixtures thereof are used. Add a base to the reaction solution (e.g.
Sodium hydroxide, potassium hydroxide, lithium hydroxide,
By adding barium hydroxide, pyridine, N,N-dimethylaniline, triethylamine), the reaction rate and yield can be improved.
上記方法によって製造される化合物(V)は、反応混合
物から通常の分離精製手段、たとえば濃縮、溶媒抽出、
再結晶、クロマトグラフィーなどを適宜利用して単離す
る事ができる。Compound (V) produced by the above method can be obtained from the reaction mixture by conventional separation and purification means such as concentration, solvent extraction,
It can be isolated using recrystallization, chromatography, etc. as appropriate.
工程πにおいては、化合物(V)を自体公知の方法で加
水分解(例、酸加水分解、アルカリ加水分解)すると脱
灰酸反応又は脱アシル反応が同時におこシ目的とする原
料化合物(I[)が−挙に生成する。必要ならば、この
加水分解反応の工程で、R3中の保護基を除去すること
も出来る。本原料化合物(II)は前述の通常の分難精
製手段によシ容易に単離することができる。In step π, when compound (V) is hydrolyzed by a method known per se (e.g., acid hydrolysis, alkali hydrolysis), a deashing acid reaction or a deacyl reaction occurs simultaneously, and the desired raw material compound (I[) are generated all at once. If necessary, the protecting group in R3 can be removed during this hydrolysis reaction step. The starting material compound (II) can be easily isolated by the conventional separation purification method described above.
B)
合成法人)で製造される式
〔式中、R3は前記と同意義を有する。〕で表わされる
化合物と式
〔式中、R1およびR2は前記と同意義を有する。B) Formula manufactured by a synthetic corporation (wherein, R3 has the same meaning as above). ] and the compound represented by the formula [wherein R1 and R2 have the same meanings as above.
〕で表わされるアルデヒドまたはケトン類とを脱水縮合
させ、いわゆるシップ塩基を形成させた後還元反応で還
元して、さらに必要ならばR3中における保護基を脱保
護反応に付して除去することによシ式(1)で表わされ
る7−デアザプリン誘導体を得ることが出来る。式(V
I)と式(■)の脱水縮合反応によシシッフ塩基を形成
する際、それら自体又は適当な反応溶媒を用いて、約O
ないし100℃、約10分間ないし2日間反応すること
によシシツフ塩基に導くことが出来る。] is dehydrated and condensed with an aldehyde or ketone represented by the formula to form a so-called ship base, which is then reduced by a reduction reaction, and if necessary, the protecting group in R3 is removed by a deprotection reaction. A 7-deazapurine derivative represented by formula (1) can be obtained. Formula (V
When forming a Schissiff base by the dehydration condensation reaction of I) and formula (■), approximately O
By reacting at 100°C to 100°C for about 10 minutes to 2 days, a schistoph base can be obtained.
反応溶媒としては、ア〃コー/l/類(例、メタノ−μ
、エタノーμ、プロパノー!、ブタノール。As a reaction solvent, alcohol/l/type (e.g., methanol-μ
, ethanolμ, propano! , butanol.
5ec−ブタノール、t−ブタノ−1vlエチレングリ
コ−μ、メトキシエタノール、エトキシエタノ−/L/
)、エーテ/L/類(ジエチルエーテル、ジエチルエー
テル
モノグライム、ジグライム)、ハロゲン化仄化水素(例
、ジクロロメタン、クロロホμム,四塩化R1is )
+ベンゼン、トルエン、キシレン、アセトニトリ〃,
ジメチルホルムアミド、又はそれ等の適宜の混合溶媒が
使用される。5ec-butanol, t-butano-1vl ethylene glyco-μ, methoxyethanol, ethoxyethanol-/L/
), ether/L/s (diethyl ether, diethyl ether monoglyme, diglyme), halogenated hydrogen peroxide (e.g. dichloromethane, chloroform, R1is tetrachloride)
+ Benzene, toluene, xylene, acetonitrile〃,
Dimethylformamide or an appropriate mixed solvent thereof is used.
本縮合反応に際しては、脱水剤(例、モレギュラーシー
ブス,塩化カルシウム、硫酸マグネシウム)等を添加す
ることによシ緩和な条件で速やかに反応を進行させるこ
とが出来る。この様にして生成したシップ塩基は、単離
してもよくまたは単離せず直接次の還元反応に付しても
よい。還元は通常用いられる試薬(例、水素化ホウ素ナ
トリウム、シアノ水素化ホウ素ナトリウム、リチウムア
ルミニウムヒドリド)によシ行うかまたは接触還元(触
媒例、パラジウム、白金,ロジウム、ニッケ/L/)に
よシ水素添加することによシ容易にかつ高収率でアミン
誘導体に導くことができる。In this condensation reaction, the reaction can be rapidly progressed under mild conditions by adding a dehydrating agent (eg, molecular sieves, calcium chloride, magnesium sulfate), etc. The ship base thus produced may be isolated or may be directly subjected to the next reduction reaction without being isolated. Reduction can be carried out using commonly used reagents (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride) or by catalytic reduction (e.g. catalysts such as palladium, platinum, rhodium, nickel/L/). By hydrogenation, amine derivatives can be easily obtained in high yield.
さらに必要とあれば、R3中の保護基を自体公知の方法
によシ脱保護することによシ行うことができる。Further, if necessary, the protecting group in R3 can be deprotected by a method known per se.
C)
式(VI)で表わされる化合物と式
x − R1 (■)
〔式中、Xはハロゲン原子 R1は前記と同意義を有す
る。〕で表わされる化合物とを反応させ、必要によJ)
R3中の保護基を脱保護反応で除去することによシ式(
1)で表わされる7−デアザプリン誘導体を得ることが
出来る。Xで示されるハロゲン原子としてはヨウ素,臭
素.塩素,フッ素があげられる。式(VI)と式(■)
との反応において、(■)に対して(■)を2倍当量−
I:lv以上用いると式(VI)のアミノ基に対して一
挙に2個以上の炭化水素残基を導入することが出来る。C) Compound represented by formula (VI) and formula x-R1 (■) [In the formula, X is a halogen atom and R1 has the same meaning as above. ] and, if necessary, J)
By removing the protecting group in R3 by deprotection reaction, the formula (
A 7-deazapurine derivative represented by 1) can be obtained. The halogen atoms represented by X include iodine and bromine. Examples include chlorine and fluorine. Formula (VI) and formula (■)
In the reaction with (■), 2 times equivalent amount of (■) to (■) -
When I:lv or more is used, two or more hydrocarbon residues can be introduced at once to the amino group of formula (VI).
又、最初に1つの炭化水素残基を導入し次いでこれと異
る他の炭化水素残基を導入することも出来る。It is also possible to first introduce one hydrocarbon residue and then introduce another different hydrocarbon residue.
更に式(■)において、置換基としてX以外にもハロゲ
ン原子を有する場合、式(VI)の2−アミノエチル基
の窒素原子とともに新しい環を形成することも可能であ
る。式(VI)と式(■)を反応させる際、それら自体
又は適当な反応溶媒を用いて、約0ないし100℃で、
約1o分間ないし2日間反応する仁とによ)実施し得る
が、特に脱酸剤(例、水酸化カリウム、水酸化ナトリウ
ム、水M化すチウム、水酸化バリウム、炭酸カリウム。Furthermore, when formula (■) has a halogen atom in addition to X as a substituent, it is also possible to form a new ring together with the nitrogen atom of the 2-aminoethyl group of formula (VI). When reacting formula (VI) and formula (■), using themselves or a suitable reaction solvent at about 0 to 100 °C,
Oxidizing agents (eg, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate) can be used.
炭酸ナトリウム、R酸バリウム、炭酸力バリウム、炭酸
水素ナトリウム、酸化マグネシウム、トリエチルアミン
、ピリジン、ピコリン、N、N−ジメチμアニリン)を
添加すると反応をよシ緩和な条件で有利に進めることが
出来る。By adding sodium carbonate, barium R acid, barium carbonate, sodium bicarbonate, magnesium oxide, triethylamine, pyridine, picoline, N,N-dimethymu aniline, the reaction can be advantageously proceeded under milder conditions.
反応溶媒としては、水、アμコー/1/類(例、メタノ
−μ、エタノー/L/、プロパノーμ、ゲタノーμ、
sea 7プタノー!、t−ブタノール、エチレングリ
コ−、/L’、メトキシエタノール、エトキシエタノ−
/l/)、エーテル類(ジメチルエーテル、ジエチルエ
ーテμ、テトラヒドロフラン、ジオキサン、モノグライ
ム、ジグライム)、ハロゲン化度化tklA (例、ジ
クロロメタン、クロロホルム、四m(lJ素)、ベンゼ
ン、トルエン、キシレン、アセトニトリル、ジメチルホ
μムアミド、又はそれ等の適宜の混合溶媒が使用される
。さらに必要とあれば、R3中の保護基を自体公知の方
法により脱保護することによシ行うことが出来る。As a reaction solvent, water, alcohol/1/s (e.g., methanol-μ, ethanol/L/, propano-μ, getano-μ,
sea 7 petano! , t-butanol, ethylene glycol, /L', methoxyethanol, ethoxyethanol
/l/), ethers (dimethyl ether, diethyl ether μ, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated tklA (e.g. dichloromethane, chloroform, 4m (lJ), benzene, toluene, xylene, acetonitrile, Dimethylformamide or an appropriate mixed solvent thereof is used.If necessary, the protecting group in R3 can be deprotected by a method known per se.
なお、化合物(III)は、日本特開昭58−8588
9号公報あるいは日本特開昭58−157790号公報
に記載の方法あるhはそれらと同様の方法で製造するこ
とができる。In addition, compound (III) is disclosed in Japanese Patent Publication No. 58-8588.
9 or Japanese Unexamined Patent Publication No. 157790/1988 can be produced by a method similar to those described.
R1,R2で示される炭化水素残基が有するこれら置換
基のうち、例えば、カルボキシ基、水酸基、アミノ基あ
るいはアルキルアミノ基のような場合、必要とあれば、
自体公知の方法(X、 r、 w。Among these substituents possessed by the hydrocarbon residues represented by R1 and R2, for example, in the case of a carboxy group, hydroxyl group, amino group or alkylamino group, if necessary,
Methods known per se (X, r, w.
McOmie、Protective Groups
in OrganicCbemistry、Plenu
m Press、London and NewYor
k (1973)−)によシ保護された、または、既に
保護されている置換基(例、アpカノイμオキシ基、ア
ルコキシカμボニル基、アルカノイルアミド基)を有す
る原料化合物(■)および(■)を用いて化合物(1)
としたのちに保護基の脱離反応を行ってもよい。McOmie, Protective Groups
in OrganicCbemistry, Plenu
m Press, London and NewYor
(1973)-) or having a substituent already protected (e.g., apkanoyl μoxy group, alkoxycarbonyl group, alkanoylamide group) (■) and Compound (1) using (■)
After that, a protective group elimination reaction may be performed.
該保護基の脱離反応は通常行なわれる自体公知の保護基
脱離反応に付すことによシ行なわれる。The protecting group elimination reaction is carried out by subjecting the protective group to a conventionally known protecting group elimination reaction.
上記各方法によシ製造された7−デアザプリン誘導体(
I)は、通常の分離精製手段、たとえば濃縮、溶媒抽出
、クロマトグラフィー、再結晶などによシ、反応混合物
から単離することが出来る。7-deazapurine derivatives produced by each of the above methods (
I) can be isolated from the reaction mixture by conventional separation and purification means, such as concentration, solvent extraction, chromatography, recrystallization, etc.
また、化合物(I)が遊離形で得られたときは、常法に
よシ、薬学的に許容される塩の形に変換してもよい。Furthermore, when compound (I) is obtained in free form, it may be converted into a pharmaceutically acceptable salt form by a conventional method.
産業上の利用可能性
このようにして得られた化合物(1)またはその塩は、
in vitroにおけるL5178Y#!を養細胞の
増殖およびin vivoにおけるMeth A 。Industrial applicability The compound (1) thus obtained or its salt is
L5178Y# in vitro! Meth A in cell growth and in vivo.
Sarcoma、l g Qなどの増殖をそれぞれ抑制
するので1、抗腫瘍作用を有する。また、化合物(I)
またはその塩は、マウスに2001Mf!/に9となる
量を腹腔内投与しても、死亡例を認めない。したがって
、化合物(I)またはその塩は、温血動物とシわけ哺乳
動物(例、マウス、ラット、ネコ、犬、ウサギなど)の
腫瘍の治療を目的として、抗腫瘍剤として用いることが
できる。It inhibits the proliferation of Sarcoma, lgQ, etc. 1, and has an antitumor effect. Also, compound (I)
Or the salt is 2001Mf for mice! No deaths were observed even when a dose of 9 was administered intraperitoneally. Therefore, compound (I) or a salt thereof can be used as an antitumor agent for the purpose of treating tumors in warm-blooded animals and mammals (eg, mice, rats, cats, dogs, rabbits, etc.).
抗腫瘍剤として用いる場合には、そのもの、あるいは通
常用いられる方法によシ薬理的に許容されうる担体、賦
形剤、稀釈剤などを使用して、たとえば、粉末、顆粒1
錠剤、カプセル剤、坐剤。When used as an anti-tumor agent, it can be prepared as such or in a commonly used manner using a pharmacologically acceptable carrier, excipient, diluent, etc., for example, as a powder or granule.
Tablets, capsules, suppositories.
注射剤などの形態で経口的まだは非経口的に投与し得る
。投与量は、対象動物、疾患、症状、化合物の種類、投
与経路などによシ異なるが、経口投与の場合は化合物(
1)として1日当シ約10ないし200111/k1体
重であシ、非経口投与の場合は1日当ル約10ないし1
00η/ky体重である。It can be administered orally or parenterally in the form of injections and the like. The dosage varies depending on the target animal, disease, symptoms, type of compound, administration route, etc., but in the case of oral administration,
1) is about 10 to 200111/k1 body weight per day, and in the case of parenteral administration, about 10 to 1 kg per day.
00η/ky body weight.
さらに、化合物(I)またはその塩は種々のつイルレス
および微生物に対して抗つイ〃ス作用および抗菌作用を
有し、上述のように毒性が低いので、温血動物とシわけ
哺乳動物(例、マウス、ラット、ネコ、犬、ウサギ、人
)のウィルスおよび細菌感染症の予防、治療を目的とす
る抗ウィルス剤。Furthermore, compound (I) or a salt thereof has anti-inflammatory and antibacterial effects against various types of bacteria and microorganisms, and has low toxicity as mentioned above, so it can be used in warm-blooded animals and mammals ( Antiviral agents for the prevention and treatment of viral and bacterial infections in mice, rats, cats, dogs, rabbits, and humans.
抗菌剤、消毎剤として用いることができる。It can be used as an antibacterial agent and a deodorant.
化合物(I)またはその塩を殺菌剤、消毒剤として使用
する場合には、たとえば化合物(I)tたはその塩を約
0.5ないし500啼/ゴの濃度で水9等張のブドウ糖
溶液、リンゲル液の様な水溶液又は植物性(例、木綿種
子、ビーナツツ、コーン、ごま)脂肪油の様な非水溶液
中に含有する液剤とし、これを哺乳動物の手9足、耳な
どに塗布することによシ、投与部位の殺菌、消毒に用い
ることができる。When compound (I) or a salt thereof is used as a bactericidal agent or disinfectant, for example, compound (I) or a salt thereof is added to an isotonic glucose solution in water at a concentration of about 0.5 to 500 μg/g. , in an aqueous solution such as Ringer's solution or in a non-aqueous solution such as a vegetable (e.g., cotton seed, peanut, corn, sesame) fatty oil, and applied to the hands, feet, ears, etc. of a mammal. It can be used for disinfection, sterilization, and disinfection of the administration site.
また、化合物(1)またはその塩を約0.5ないし50
011gを乳糖、澱粉、タルク等の賦形剤を含む錠剤と
して経口的に該哺乳動物のウィルス感染症、細菌感染症
の予防、治療に用いることができる。この場合の投与量
は、化合物(I)として−旧約10ないし200q/1
9体重となる量である。Further, compound (1) or a salt thereof may be added to about 0.5 to 50
011g can be used orally in the form of tablets containing excipients such as lactose, starch, and talc for the prevention and treatment of viral infections and bacterial infections in mammals. In this case, the dosage as compound (I) is approximately 10 to 200q/1
This is the amount that will give you a weight of 9.
本発明の化合物(IF)および(V)は、たとえば化合
物(I)を製造する際の合成中間体として有用である。Compounds (IF) and (V) of the present invention are useful, for example, as synthetic intermediates in producing compound (I).
発明を実施するだめの最良の形態
以下に、実験例、参考例および実施例を挙げて本発明を
さらに具体的に説明する。BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in more detail below with reference to experimental examples, reference examples, and examples.
参考例1 2−アミノ−5−(2,2−ジェトキシカル
ボニルエチル
リミジン−4−オンの製造:
5−ジベンジルアミノメチ/L’−2−オクタノイルア
ミノピロロ〔2,3−a)ピリミジン−4−オン(29
,2g)、マロン酸エチルエステル3 8、 4 ’I
)および決酸カリウム(49.7g)をエタノール(
750d)に溶解,′懸濁し、70℃で)、5時間攪拌
下に反応−レh0不溶物をp去後、炉液を減圧乾固して
得られた残渣に水(300g/)を加えて析出する結晶
をp取しRoこのものをエタノ−lv/テトラヒトtf
f7ラン( 1 : 1 、 1.2jl)に溶解し、
少量の不溶物を沖去した後、ろ液を濃縮すると目的物(
xo.zg)が得られた。Reference Example 1 Production of 2-amino-5-(2,2-jethoxycarbonylethylrimidin-4-one: 5-dibenzylaminomethy/L'-2-octanoylaminopyrrolo[2,3-a) Pyrimidin-4-one (29
, 2g), malonic acid ethyl ester 3 8, 4 'I
) and potassium sulfate (49.7g) in ethanol (
750d), 'suspended at 70°C), and reacted with stirring for 5 hours. After removing the insoluble matter, the furnace solution was dried under reduced pressure. Water (300g/) was added to the resulting residue. Collect the precipitated crystals and convert them into ethanol-lv/tetrahydrogen tf.
Dissolved in f7 run (1:1, 1.2jl),
After removing a small amount of insoluble material, the filtrate is concentrated to obtain the target product (
xo. zg) was obtained.
N M R (MSO−d6/D20/CDCI3)δ
:t.o7(t。NMR (MSO-d6/D20/CDCI3)δ
:t. o7(t.
6H)、2.97(d,2H)、3.97(q,4H)
、4.00(t、IH)、6.17(a,IH)0
工R (KBr): y 3380. 1740. 1
720. 1670。6H), 2.97 (d, 2H), 3.97 (q, 4H)
, 4.00 (t, IH), 6.17 (a, IH) 0 Engineering R (KBr): y 3380. 1740. 1
720. 1670.
1625、 1235CI11 。1625, 1235CI11.
参考例2 2−アミノ−5−(2−カルポキシエチ/L
/)ピロロC2.3−d)ピリミジン−4−オンの製造
:
参考例1で得られた2−アミノ−5−(2.2−ジェト
キシカルボニルエチル)ピロロ(2.3−d)ピリミジ
ン−4−オン(13.OV)を2規定塩酸(150m/
)と酢酸(250譚t)の混液に溶解し、130℃で1
5時間反応し″r−o冷後析出する結晶を沖取し、次い
でエタノールおよびエチルエーテルで洗滌後、乾燥する
と目的物(8.8g)が得られた。Reference example 2 2-amino-5-(2-carpoxyethyl/L
/) PyrroloC2.3-d) Production of pyrimidin-4-one: 2-amino-5-(2.2-jethoxycarbonylethyl)pyrrolo(2.3-d)pyrimidine- obtained in Reference Example 1 4-one (13.OV) in 2N hydrochloric acid (150m/
) and acetic acid (250 tons) and heated at 130℃ for 1
After reacting for 5 hours and cooling the reaction mixture, the precipitated crystals were collected, washed with ethanol and ethyl ether, and dried to obtain the desired product (8.8 g).
N M R (DMSO−d5/D20/CDC13)
δ: 3.53(8。NMR (DMSO-d5/D20/CDC13)
δ: 3.53 (8.
2)1)、6.37(8,IH)。2) 1), 6.37 (8, IH).
I R (KBr)ニジ3470, −3350. 3
245. 1710。I R (KBr) Niji 3470, -3350. 3
245. 1710.
1630、1590a 0
参考例3 5−N,N−ジベンジルアミノメチ!−2−
N,N−ジメチルアミノメチリデンアミノピロロ(2.
3−d)ピリミジン−4−オンの製造:
2−アミノ−5−ジベンジμアミノメチμピロロ(2.
3−d)ピリミジン−4−オン(540jl!’)全乾
燥したジメチルホμムアミド(101+1t)に溶解し
、これにジメチpホμムアミドジメチμアセター/’(
1.0jl)を加えた後、室温で24時間攪拌反応した
。溶媒を減圧で留去し、残渣をエチルエーテルで洗滌す
ると目的物(SSOHy)が得られた。1630, 1590a 0 Reference Example 3 5-N,N-dibenzylaminomethy! -2-
N,N-dimethylaminomethylidene aminopyrrolo (2.
3-d) Preparation of pyrimidin-4-one: 2-amino-5-dibendiμ aminomethyμ pyrrolo (2.
3-d) Pyrimidin-4-one (540jl!') was dissolved in completely dried dimethylformamide (101+1t) and dimethypformamide dimethyμ acetate/'(
After adding 1.0 jl), the reaction was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl ether to obtain the desired product (SSOHy).
N M R (DMSO−a6)δ: 2.9B(a,
3H)、3.10(s,3H)、3、57(8,41,
3.75(8,2H)。NMR (DMSO-a6)δ: 2.9B(a,
3H), 3.10 (s, 3H), 3, 57 (8, 41,
3.75 (8,2H).
6、67(d,IH)、7.10〜7.50(m,IO
H)、8.47(8.1H)。6, 67 (d, IH), 7.10-7.50 (m, IO
H), 8.47 (8.1H).
工R (KBr):y 1645. 1625. 15
50CtR−1。Engineering R (KBr):y 1645. 1625. 15
50CtR-1.
参考例4 5−(2−力μポキシエチlv)−2−N
、 N−ジメチμアミノメチリデンアミノビロロC2,
3−d)ピリミジン−4−オンの製造:参考例3で得ら
れた5−N、N−ジベンジルアミノメチル−2−N、N
−ジメチルアミノメチリデンアミノピロロ(2,3−d
)ピリミジン−4−オン(4,1g)、マロン酸メチル
エステル(5,3g)および炭酸カリウム(8,39)
をtert−ブタノ−*(3oog/)に懸澗)溶解し
、85℃で6時間攪拌反応した。溶媒を減圧で留去し、
残渣に水(i5o*/)を加えて、生ずる沈澱をp取す
る、!:、2−N、N−ジメチルアミノメチリデンアミ
ノ−5−(2,2−ジメトキシカルボニルエチル)ピロ
ロ〔2.3−a)ピリミジン−4〜オン(2.5g)が
得られた。このもの全量を酢酸(200*/)と2規定
塩酸(10耐)の混液に溶解し、120℃で13時間攪
拌下に反応した。冷後、溶媒を減圧で留去し、残渣にア
ンモニア水を加えて、不溶物を枦去し、p液を塩酸で中
和すると目的物(0.65g)が得られた。Reference example 4 5-(2-poxyethylv)-2-N
, N-dimethyμ aminomethylidene aminovirolo C2,
3-d) Production of pyrimidin-4-one: 5-N,N-dibenzylaminomethyl-2-N,N obtained in Reference Example 3
-dimethylaminomethylideneaminopyrrolo(2,3-d
) Pyrimidin-4-one (4,1 g), malonic acid methyl ester (5,3 g) and potassium carbonate (8,39)
was dissolved in tert-butano-* (3 oog/suspended) and stirred and reacted at 85°C for 6 hours. The solvent was distilled off under reduced pressure,
Add water (i5o*/) to the residue and collect the resulting precipitate! :,2-N,N-dimethylaminomethylideneamino-5-(2,2-dimethoxycarbonylethyl)pyrrolo[2.3-a)pyrimidin-4-one (2.5 g) was obtained. The entire amount of this product was dissolved in a mixed solution of acetic acid (200*/) and 2N hydrochloric acid (10 proof) and reacted at 120° C. for 13 hours with stirring. After cooling, the solvent was distilled off under reduced pressure, aqueous ammonia was added to the residue to remove insoluble matter, and the p solution was neutralized with hydrochloric acid to obtain the desired product (0.65 g).
N M R (DMSO−d6/D20)δ: 2.3
3 〜2.9o(m。NMR (DMSO-d6/D20)δ: 2.3
3~2.9o(m.
41、6.23(8.11)、8.97(s.IH)。41, 6.23 (8.11), 8.97 (s.IH).
工R (KBr)ニジ1685. 1645. 159
5a−1。Engineering R (KBr) Niji 1685. 1645. 159
5a-1.
参考例5 2−ベンゾイルアミノ−5−(2−カルポキ
シエチ)V)ピロロC2 、3−d)ピリミジン−4−
オンの製造:
参考例4と同様にして、2−ベンゾイルアミノ−5−N
,N−ジベンジμアミノメチルピロロ〔2、3−d)ビ
リーミジン−4−オン(4.6g)から2−ベンゾイル
アミノ−5−(2.2−ジメトキシカルボニルエチ/L
/)ピロロ(2.3−a)ピリミジン−4−オン( 2
. 7 g)が得られた。氷晶全量を一考例4と同様に
して、加水分解,脱灰酸反応に付すと目的物(0、(1
)が得られた。Reference example 5 2-benzoylamino-5-(2-carpoxyethyl)V) pyrroloC2, 3-d) pyrimidine-4-
Production of 2-benzoylamino-5-N in the same manner as in Reference Example 4
, N-dibendiμ aminomethylpyrrolo[2,3-d) birymidin-4-one (4.6 g) to 2-benzoylamino-5-(2,2-dimethoxycarbonylethyl/L
/) pyrrolo(2.3-a)pyrimidin-4-one (2
.. 7 g) was obtained. When the total amount of ice crystals is subjected to hydrolysis and deashing acid reaction in the same manner as in Example 4, the target product (0, (1
)was gotten.
N M R (DMSO−d6/D20)δ: 2.4
7〜3.1 3 ( m 。NMR (DMSO-d6/D20)δ: 2.4
7-3.13 (m.
4H)、6.27(s.1)1)、7.17 〜7.4
3tm.3H) 。4H), 6.27 (s.1) 1), 7.17 to 7.4
3tm. 3H).
7、6 7〜7.9 3 ( m 、 2H )。7, 6 7-7.9 3 (m, 2H).
工R (KBr)ニジ1700, 1675. 159
0Cffl 1。Engineering R (KBr) Niji 1700, 1675. 159
0Cffl 1.
実施例1 2−アミノ−5−(2−アミノエチル)ピロ
ロ〔2,3−d〕ピリミジン−4−オン(2塩酸塩)の
製造:
参考例2で得られた2−アミノ−5−(2−カルポキシ
エチ/l/)ピロロ(2,3−d,lピリミジン−4−
オン(6.6(1)をジメチルホルムアミド(300s
g/)に溶解し、氷水浴で冷却後、攪拌下にジフエニ!
ホスホリルアジド(xx.og)およびトリエチルアミ
ン(4.6f)を加え3時間反応した。反応液を氷水(
31)に性用し、沈澱を枦取、次いで水およびエチルエ
ーテμで洗滌し、乾燥すると中間体として2−アミノ−
5−(2−アジドカルポニμエチル)ピロロC2,3−
a)ピリミジン−4−オンの粗結晶(s.2og)が得
られた。工R (Nujol)ニジ2140. 171
5. 16701M111。Example 1 Production of 2-amino-5-(2-aminoethyl)pyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride): 2-amino-5-(2-amino-5-(2-aminoethyl)pyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride)) 2-carpoxyethyl/l/)pyrrolo(2,3-d,lpyrimidine-4-
(6.6(1)) in dimethylformamide (300s
g/), cooled in an ice-water bath, and added dipheni! with stirring.
Phosphoryl azide (xx.og) and triethylamine (4.6f) were added and reacted for 3 hours. Pour the reaction solution into ice water (
31), the precipitate was collected, washed with water and ethyl ether, and dried to give 2-amino-
5-(2-azidocarponiμethyl)pyrroloC2,3-
a) Crude crystals (s.2 og) of pyrimidin-4-one were obtained. Engineering R (Nujol) Niji 2140. 171
5. 16701M111.
とのもの全量を酢酸(4O阿/)に溶解しこれを70℃
に加温した2規定塩酸/酢酸(1:1)の混液(80だ
/)に攪拌下滴下した。滴下終了後更に10分間同温度
に放置した後、溶媒を減圧で濃縮乾固した。残渣に水(
2OS/)を加え、不溶物を沖去し、炉液を約半量にな
るまで濃縮した後、エチルアルコ−μを加えて析出させ
ると目的物(3.49)が得られた。Dissolve the entire amount in acetic acid (4O/) and heat it at 70°C.
The mixture was added dropwise to a mixture of 2N hydrochloric acid/acetic acid (1:1) (80°C) heated to 20°C while stirring. After the dropwise addition was completed, the mixture was left at the same temperature for another 10 minutes, and then the solvent was concentrated to dryness under reduced pressure. Add water to the residue (
2OS/) was added, insoluble matters were removed, and the furnace solution was concentrated to about half its volume. Ethyl alcohol-μ was added to precipitate the mixture to obtain the desired product (3.49).
N M R (D20) :δ3.03〜3.73(m
.4H)、7.OO(s,IH)。NMR (D20): δ3.03 to 3.73 (m
.. 4H), 7. OO(s, IH).
IR(KBr): v 3390,3270,3170
,2920。IR (KBr): v 3390, 3270, 3170
, 2920.
2710、2630. 1690. 1675備 。2710, 2630. 1690. 1675 equipment.
実m例2 2−アミノ−5−(2−シクロヘキシルアミ
ノエチル)ピロロ(2.3−d)t”Jミジン−4−オ
ン(2塩酸塩)の製造:
実施例1で得られた2−アミノ−5−(2−アミノエチ
ル)ピロロ〔2.3−d〕ピリミジン−4−オン(2塩
酸塩)(53211y)、酢酸ナトリウム(328#)
およびシクロヘキサノン(78 4り)を80%含水メ
タノ−/’(10*?)に溶解し、室温攪拌下、シアノ
水素化ホウ累ナトリウム(126q)を加えた。次いで
酢酸(206q)を添加し、反応液を室温で15時間攪
拌放置した後、2規定塩酸(15屑J)を加えて液量が
約半分になるまで濃縮すると目的物(566fP)が白
色沈み物として得られた。Practical Example 2 Preparation of 2-amino-5-(2-cyclohexylaminoethyl)pyrrolo(2.3-d)t”J midin-4-one (dihydrochloride): 2-obtained in Example 1 Amino-5-(2-aminoethyl)pyrrolo[2.3-d]pyrimidin-4-one (dihydrochloride) (53211y), sodium acetate (328#)
and cyclohexanone (784 ml) were dissolved in 80% aqueous methanol/' (10*?), and sodium cyanoborohydride (126 q) was added under stirring at room temperature. Next, acetic acid (206q) was added, and the reaction solution was left to stir at room temperature for 15 hours, and then 2N hydrochloric acid (15 scraps J) was added and concentrated until the liquid volume was reduced to about half, resulting in a white precipitate of the target product (566fP). Obtained as a thing.
N M R (DMSO−d6/D20) :δ1.
1 3〜2.4 3 ( bm 。NMR (DMSO-d6/D20): δ1.
13~2.43 (bm.
xou)ez.s3(bm*IH)t:3.oo 〜3
.63(m,4H)、7.03(s、IH)。xou)ez. s3(bm*IH)t:3. oo~3
.. 63 (m, 4H), 7.03 (s, IH).
工R(KBr)ニジ 3420,3170.2930.
2720゜1695、 1675国 。Engineering R (KBr) Niji 3420, 3170.2930.
2720°1695, 1675 country.
実施例3 2−アミノ−5−(2−(1−(4−クロロ
フエニlv)エチμアミノ〕エチル〕ピロロ(2,3−
d)ピリミジン−4−オン(2塩酸塩)の製造:
実施例2と同様にして、実施例1で得られた2−アミノ
−5−(2−アミノエチ1v)ピロロ〔2、a−a)ピ
リミジン−4−オン(2塩酸塩)(532ダ)と4−ク
ロロアセトフェノン(1,54g)とから目的物(47
oq)が得られた。Example 3 2-Amino-5-(2-(1-(4-chlorophenylv)ethyμamino]ethyl]pyrrolo(2,3-
d) Production of pyrimidin-4-one (dihydrochloride): 2-amino-5-(2-aminoethylv)pyrrolo[2, aa) obtained in Example 1 in the same manner as in Example 2 From pyrimidin-4-one (dihydrochloride) (532 da) and 4-chloroacetophenone (1,54 g), the desired product (47
oq) was obtained.
N M R(DMSO−a6/p2o)δ: 1.67
(cl、3H)。NMR(DMSO-a6/p2o)δ: 1.67
(cl, 3H).
3.07(bm、4H)、4.47(q、IH)、6.
73(8,IH)、7.60(13,4H)。3.07 (bm, 4H), 4.47 (q, IH), 6.
73 (8, IH), 7.60 (13, 4H).
工R(KBr):l’ 3350.3130. 295
0. 2770゜16801:Im 。Engineering R (KBr): l' 3350.3130. 295
0. 2770°16801: Im.
実施例4 2−アミノ−5−(2−(4−シアノベンジ
ルアミノ)エチル〕ピロロ(2,3−d〕ピリミジン−
4−オンの製造:
実施例1で得られた2−アミノ−5−(2−アミノエチ
lv)ピロロ(2,3−d)ピリミジン−4−オン(2
塩酸塩)(x、o6g)、酢酸ナトリウム(656q)
およびシアノ水素化ホウ素ナトリウム(756q)を8
0%含水メタノ−/l/(40ml)に溶解し、これに
4−クロロベンツアμデヒド(624#)oメタz−/
1/(15*/)溶液を約1時間で攪拌下に滴下した。Example 4 2-amino-5-(2-(4-cyanobenzylamino)ethyl]pyrrolo(2,3-d]pyrimidine-
Preparation of 4-one: 2-amino-5-(2-aminoethylv)pyrrolo(2,3-d)pyrimidin-4-one (2
hydrochloride) (x, o6g), sodium acetate (656q)
and sodium cyanoborohydride (756q) at 8
Dissolve in 0% aqueous methanol/l/(40 ml) and add 4-chlorobenza μdehyde (624#) o metaz-/
A 1/(15*/) solution was added dropwise over about 1 hour while stirring.
さらに酢酸(’x、og)を添加し、室温に100時間
放置した後、生じた沈載を枦取、次いで水およびメタノ
−μで洗滌すると目的物(576q)が得られた。Further, acetic acid ('x, og) was added and the mixture was allowed to stand at room temperature for 100 hours, and the resulting precipitate was collected and washed with water and methanol-μ to obtain the desired product (576q).
N M R(DMSO−d6/D20)δ: 2.90
〜a、5o(m。NMR(DMSO-d6/D20)δ: 2.90
~a, 5o (m.
4H)、4.30(8,2H)、6.60(R,IH)
、’1.7’1(d、2H)、7.87(d、2H)。4H), 4.30 (8, 2H), 6.60 (R, IH)
, '1.7'1 (d, 2H), 7.87 (d, 2H).
I R(KBr) :y 3410.2770.222
5.1670c’l+! 。I R (KBr) :y 3410.2770.222
5.1670c'l+! .
実施例5 2−アミノ−5−(2−ピペリジノエチ/L
/)ピロロ(2,3−d)ピリミジン−4−オン(2塩
酸塩)の製造:
実施例1で得られた2−アミノ−5−(2−アミノエチ
/L/)ピロロC2,3−d〕ピリミジン−a−#:i
c 2塩酸塩)(798rIv)、炭酸水素ナトリウム
(1,z3g)、ペンタメチレンジプロミド(7601
17”)およびミラ化カリウム(24■)を60%含水
エタノ−/I/(100胃l)に溶解し、85℃で攪拌
下45時間反応した。冷後、減圧下に大部分のエタノ−
〃を留去すると淡黄色の析出物が生じた。このものを戸
数し、再び水(10にl)に懸濁し2規定塩酸(3,0
*/)を加えて溶解後、活性度(x、oe)処理した。Example 5 2-amino-5-(2-piperidinoethyl/L
/) Production of pyrrolo(2,3-d)pyrimidin-4-one (dihydrochloride): 2-amino-5-(2-aminoethyl/L/)pyrroloC2,3-d obtained in Example 1 ]Pyrimidine-a-#:i
c dihydrochloride) (798rIv), sodium bicarbonate (1,z3g), pentamethylene dipromide (7601
17") and potassium milate (24") were dissolved in 60% aqueous ethanol/I/(100 stomach liters) and reacted at 85°C with stirring for 45 hours. After cooling, most of the ethanol was dissolved under reduced pressure.
When 〃 was distilled off, a pale yellow precipitate was formed. This material was mixed, suspended in water (10 l) again, and 2N hydrochloric acid (3.0 l)
*/) was added and dissolved, and then processed for activity (x, oe).
炉液を濃縮乾固し、残渣をエタノ−μで洗滌すると目的
物(156q)が得られた。The filtrate was concentrated to dryness, and the residue was washed with ethanol μ to obtain the desired product (156q).
n M R(D20)δ: 1.70〜2.30(bm
、6H)。n M R (D20) δ: 1.70 to 2.30 (bm
, 6H).
3.03〜3.90(m、8H)、6.90(8,1H
)。3.03-3.90 (m, 8H), 6.90 (8,1H
).
工R(KBr):y 3420.3210.2700.
1675trl
実施例6 2−アミノ−5−C2−(2,4−ジニトロ
フェニル)アミノエチル〕ピロロ〔2゜3−d)ピリミ
ジン−4−オンの製造:実施例1で得られた2−アミノ
−5−(2−アミノエチル)ピロロ(2,3−cl)ピ
リミジン−4−オン(2塩酸塩)(27り)をナトリウ
ムメトキシドのメタノール溶液(Q、 4 mmol/
l/ ; 0.5m1)に溶解し室温で30分間攪拌放
置した。これに炭酸水素ナトリウム(8ダ)と2.4−
シニ)ロフ!オロベンゼン(21s)とを加え、ジメチ
μホμムアミドで稀釈した後、室温で2時間反応した。Engineering R (KBr):y 3420.3210.2700.
1675 trl Example 6 Preparation of 2-amino-5-C2-(2,4-dinitrophenyl)aminoethyl]pyrrolo[2°3-d)pyrimidin-4-one: 2-amino- obtained in Example 1 5-(2-aminoethyl)pyrrolo(2,3-cl)pyrimidin-4-one (dihydrochloride) (27) was added to a methanol solution of sodium methoxide (Q, 4 mmol/
l/; 0.5ml) and left stirring at room temperature for 30 minutes. Add sodium hydrogen carbonate (8 da) to this and 2.4-
Shini) Roff! After adding Olobenzene (21s) and diluting with dimethyl μformamide, the mixture was reacted at room temperature for 2 hours.
減圧下に溶媒を留去し、残渣に水を加えて不溶物を枦取
、次いで水および少量のエタノ−μで洗滌後乾燥すると
目的物(284)が得られた。The solvent was distilled off under reduced pressure, water was added to the residue to remove insoluble materials, and the residue was washed with water and a small amount of ethanol and dried to obtain the desired product (284).
N M R(DMSO−a6)δ: 2.77〜3.0
7(bm、2H)、3.57〜4.00(bm、2H)
、6.53(bs、IH)。NMR(DMSO-a6)δ: 2.77-3.0
7 (bm, 2H), 3.57-4.00 (bm, 2H)
, 6.53 (bs, IH).
7.53(d、IH)、8.17(d4.LH)、8.
80(d、IH)。7.53 (d, IH), 8.17 (d4.LH), 8.
80 (d, IH).
IR(KBr)ニジ3350.1670. 1615.
1585゜1335Cr。IR (KBr) Niji 3350.1670. 1615.
1585°1335Cr.
実施例7 2−アミノ−5−(2−アリμアミノエチ/
L/)ピロロC2,3−d)ピリミジン−4−オンの製
造:
実施例1で得られた2−アミノ−5−(2−アミノエチ
/I/)ピロロ(2,3−d)ピリミジン一4−オン(
2塩酸塩)(266#)、アリルプロミド(1339)
および炭酸水素ナトリウム(a 3 oq)をエタノ−
/’ (5ttl )に懸濁、溶解し、封管中80℃で
15時間攪拌反応した。反応終了後、溶媒を減圧で留去
し、残渣をシリカゲルカラムクロマトグラフィーで分離
精製すると目的物(65wv)が得られた。Example 7 2-amino-5-(2-aryμaminoethyl/
L/)pyrroloC2,3-d) Production of pyrimidin-4-one: 2-amino-5-(2-aminoethyl/I/)pyrrolo(2,3-d)pyrimidine-4-one obtained in Example 1 −On (
dihydrochloride) (266#), allylpromide (1339)
and sodium bicarbonate (a 3 oq) in ethanol
/' (5ttl) and stirred and reacted in a sealed tube at 80°C for 15 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the desired product (65 wv).
N M R(DMSO−d6/D20)δ: 2.70
〜3.23(m。NMR(DMSO-d6/D20)δ: 2.70
~3.23 (m.
6H)、4.93〜5.27(m、2H)、5.63〜
6.07(m。6H), 4.93-5.27 (m, 2H), 5.63-
6.07 (m.
xa)、6.68(a、IH)。xa), 6.68(a, IH).
工R(KBr)ニジ1680.1645.1600cf
fi 1゜実施例8 2−アミノ−5−(2−(4,5
−ジヒドロキシシクロベント−1−エン−3−イルアミ
ノ)二チル)ピロロ(2,3−a)ピリミジン−4−オ
ン(2塩酸塩)の製造:
実施例1で得られた2−アミノ−5−(2−アミノエチ
/I/)ピロロ(2,3−d)ピリミジン−4−オン(
2塩酸塩)(1,xg)を、メタノール(100m/)
中、28%のナトリウムメトキシド−メタノール溶液(
tsg)で中和し、溶媒を減圧で留去した。この残渣に
、3.4−)ランス;4.5−シス−3−ブロモシクロ
ベント−1−エン−4,5−ジオールジベンゾエート(
1,559)および炭酸水素ナトリウム(36oW)を
加、tて、ジメチμホμムアミド(50y/)に懸局、
溶解した後、40℃で24時間攪拌反応した。反応終了
後、溶媒を減圧で留去し、残渣をシリカゲルカラムクロ
マトグラフィーで分hTe精製すると2−アミノ−5−
(2−(4,5−ジベンゾイルオキシシクロベント−1
−エン−3−イルアミノ)エチμ)ピロロC2,3−d
)ピリミジン−4−オン(16!l’)が得られた。こ
のもの全量をメタノ−、u(20y/)に溶解し、水冷
攪拌下4規定力性ソーダ液(1ml)を加えて、2時間
反応した。反応液をイオン交換樹脂(CG−50,H+
型)で精製し、流出液に1規定塩酸(Ir!t/)を加
えた後、濃縮乾固し、残渣をエタノ−μで洗滌すると目
的物(85〜)が得られた。Engineering R (KBr) Niji 1680.1645.1600cf
fi 1゜Example 8 2-amino-5-(2-(4,5
-Dihydroxycyclobent-1-en-3-ylamino)dityl)pyrrolo(2,3-a)pyrimidin-4-one (dihydrochloride) Production: 2-amino-5- obtained in Example 1 (2-aminoethyl/I/)pyrrolo(2,3-d)pyrimidin-4-one (
dihydrochloride) (1,xg), methanol (100m/)
28% sodium methoxide-methanol solution (
tsg) and the solvent was distilled off under reduced pressure. To this residue, 3.4-) lance; 4.5-cis-3-bromocyclobent-1-ene-4,5-diol dibenzoate (
1,559) and sodium bicarbonate (36oW) to dimethyl μformamide (50y/),
After dissolving, the mixture was stirred and reacted at 40° C. for 24 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-amino-5-
(2-(4,5-dibenzoyloxycyclobent-1
-en-3-ylamino)ethylμ)pyrroloC2,3-d
) Pyrimidin-4-one (16!l') was obtained. The entire amount of this product was dissolved in methanol, u (20y/), and 4N soda solution (1 ml) was added while stirring under water cooling, and the mixture was reacted for 2 hours. The reaction solution was mixed with an ion exchange resin (CG-50, H+
After adding 1N hydrochloric acid (Ir!t/) to the effluent, it was concentrated to dryness and the residue was washed with ethanol-μ to obtain the desired product (85~).
N M R(D20)δ:3.00〜3.70(m、4
H)、4.10〜4.80(m、3H)、5.90〜6
.30(m、2H)、7.00(s、IH)。NMR (D20) δ: 3.00 to 3.70 (m, 4
H), 4.10-4.80 (m, 3H), 5.90-6
.. 30 (m, 2H), 7.00 (s, IH).
工R(KBr)ニジ 1690.1680.1615C
11。Engineering R (KBr) Niji 1690.1680.1615C
11.
実施例9 2−アミノ−5−(2−n−オクチμアミノ
エチ/l/)ピロロC2,3−d、lピリミジン−4−
オンの製造:
実施例7と同様にして、実施例1で得られた2−アミノ
−5−(2−アミノエチル)ピロロ〔2,3−d)ピリ
ミジン−4−オン(2塩酸塩)(266#)、n−オク
チルプロミド(205r4)、炭酸水素ナトリウム(3
30q)およびヨウ化カリウム(5q)よシ目的物(3
1q)が得られた。Example 9 2-amino-5-(2-n-octyμaminoethyl/l/)pyrroloC2,3-d,lpyrimidine-4-
Production of 2-amino-5-(2-aminoethyl)pyrrolo[2,3-d)pyrimidin-4-one (dihydrochloride) obtained in Example 1 in the same manner as in Example 7. 266#), n-octyl bromide (205r4), sodium bicarbonate (3
30q) and potassium iodide (5q) and the desired product (3
1q) was obtained.
N M R(DMSO−d6/D20)δ: 0.90
(bt、3H)。NMR(DMSO-d6/D20)δ: 0.90
(bt, 3H).
1.33(bs、12H)、2.70〜3.23(m、
6H)、6.33(8,IIH)。1.33 (bs, 12H), 2.70-3.23 (m,
6H), 6.33 (8, IIH).
工R(KBr)ニジ1680,1645− 1600”
。Engineering R (KBr) Niji 1680, 1645- 1600”
.
実施例10 2−アミノ−5−(N、N−ジーn−プチ
ルアミノエチ/l/)ピロロ[2,3−d)ピリミジン
−4−オンの製造:
実施例7と同様にして、実施例1で得られた2−アミノ
−5−(2−アミノエチlv)ピロロ〔2,3−d)ピ
リミジン−4−オン(2塩酸塩)(5321F)、n−
ブチルプロミド(60aW)、伏醜水素ナトリウム(8
4(1’)およびヨウ化カリウム(1011’)よシ目
的物C’12q>が得られた。Example 10 Preparation of 2-amino-5-(N,N-di-n-butylaminoethyl/l/)pyrrolo[2,3-d)pyrimidin-4-one: In the same manner as in Example 7, in Example 1 The obtained 2-amino-5-(2-aminoethylv)pyrrolo[2,3-d)pyrimidin-4-one (dihydrochloride) (5321F), n-
Butylbromide (60aW), Fubo Sodium Hydrogen (8
4(1') and potassium iodide (1011'), the desired product C'12q> was obtained.
N M R(DMSO−d6/D20)δ: o、9o
(bt、6a)。NMR(DMSO-d6/D20)δ: o, 9o
(bt, 6a).
1.37(bs、8H)、2.73〜3.30(m、8
H)、6.30(S、 la)。1.37 (bs, 8H), 2.73-3.30 (m, 8
H), 6.30 (S, la).
IR(KBr)ニジ1675.1650.15951’
f1゜実施例11 5−(2−アミノエチ/l/) −
2−N、N−ジメチルアミノメチリデンアミノピロロ〔
2,3−d)ピリミジン−4−オン(2塩酸塩)の製造
:
実施例1と同様にして、参考例4で得られた5−(2−
力μボキシエチ/l/)−2−N 、 N−ジメチルア
ミノメチリデンアミノピロロC2,3−d〕ピリミジン
−4−オン(263q)よシ目的物(8111fI)が
得られた。IR (KBr) Niji 1675.1650.15951'
f1゜Example 11 5-(2-aminoethyl/l/) -
2-N,N-dimethylaminomethylidene aminopyrrolo [
2,3-d) Production of pyrimidin-4-one (dihydrochloride): In the same manner as in Example 1, 5-(2-
The desired product (8111fI) was obtained from N-dimethylaminomethylideneaminopyrroloC2,3-d]pyrimidin-4-one (263q).
N M R(DMSO(16/D20)δ: 3.37
(s、3H)。NMR(DMSO(16/D20)δ: 3.37
(s, 3H).
3.47(a、3H)、3.03〜3.73(m、4H
)、6.87(s、IH)、9.03(a、IH) 。3.47 (a, 3H), 3.03-3.73 (m, 4H
), 6.87 (s, IH), 9.03 (a, IH).
工R(KBr)ニジ 1685,1665備 。Engineering R (KBr) Niji 1685, 1665 equipped.
実施例12 5−(2〜アミノエチμ)−2−ベンゾイ
ルアミノピロロ(2,3−d)ピリミジン−4−オン(
塩酸塩)の製造:
実施例1と同様にして、参考例5で得られた2−ベンゾ
イルアミノ−5−(2−カルボキシエチル)ピロロ(2
,3−d)ピリミジン−4−オン(326′q)よシ目
的物(xo5#)が得られた。Example 12 5-(2~aminoethyl)-2-benzoylaminopyrrolo(2,3-d)pyrimidin-4-one (
Production of 2-benzoylamino-5-(2-carboxyethyl)pyrrolo(2-hydrochloride) obtained in Reference Example 5 in the same manner as in Example 1.
, 3-d) Pyrimidin-4-one (326'q) and the desired product (xo5#) were obtained.
N M R(DMSOd6/D20)δ:3.OO〜3
.63(m。NMR(DMSOd6/D20)δ:3. OO~3
.. 63 (m.
4H)、6.90(s、IH)、7.20〜7.47(
m、3H)。4H), 6.90 (s, IH), 7.20-7.47 (
m, 3H).
7.70〜7.97(m、2H)。7.70-7.97 (m, 2H).
Claims (1)
は置換基を有していてもよい次イE水素残基を示し、R
1とR2が隣接する窒素原子とともに環を形成していて
もよく、R3は保護されていてもよいアミノ基を示す。 〕で表わされる7−デアザプリン誘導体またはその塩。[Scope of Claims] General formula [wherein R1 and R2 are the same or different hydrogen atoms or the following hydrogen residues which may have substituents, and R
1 and R2 may form a ring together with the adjacent nitrogen atom, and R3 represents an optionally protected amino group. ] A 7-deazapurine derivative or a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59061995A JPS60204788A (en) | 1984-03-28 | 1984-03-28 | 7-deazapurine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59061995A JPS60204788A (en) | 1984-03-28 | 1984-03-28 | 7-deazapurine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS60204788A true JPS60204788A (en) | 1985-10-16 |
JPH0417196B2 JPH0417196B2 (en) | 1992-03-25 |
Family
ID=13187290
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP59061995A Granted JPS60204788A (en) | 1984-03-28 | 1984-03-28 | 7-deazapurine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS60204788A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62228019A (en) * | 1985-11-29 | 1987-10-06 | Takeda Chem Ind Ltd | Antitumor agent |
-
1984
- 1984-03-28 JP JP59061995A patent/JPS60204788A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62228019A (en) * | 1985-11-29 | 1987-10-06 | Takeda Chem Ind Ltd | Antitumor agent |
Also Published As
Publication number | Publication date |
---|---|
JPH0417196B2 (en) | 1992-03-25 |
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