CS231959B2 - Manufacturing process of new heterocyclic compounds - Google Patents
Manufacturing process of new heterocyclic compounds Download PDFInfo
- Publication number
- CS231959B2 CS231959B2 CS775984A CS598477A CS231959B2 CS 231959 B2 CS231959 B2 CS 231959B2 CS 775984 A CS775984 A CS 775984A CS 598477 A CS598477 A CS 598477A CS 231959 B2 CS231959 B2 CS 231959B2
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- CS
- Czechoslovakia
- Prior art keywords
- chloro
- naphthyridin
- carbonyloxy
- piperazinyl
- formula
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims 2
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 2-quinolyl Chemical group 0.000 claims description 46
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 7
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- USDIRSJFHPHMAS-UHFFFAOYSA-N ClC1=NC=C(C=2C1=NC=CN=2)F Chemical compound ClC1=NC=C(C=2C1=NC=CN=2)F USDIRSJFHPHMAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 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
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HHXLDBGLGUQHNO-UHFFFAOYSA-N 4-acetylpiperazine-1-carbonyl chloride Chemical compound CC(=O)N1CCN(C(Cl)=O)CC1 HHXLDBGLGUQHNO-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DELDSEMAUXQLSY-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1H-isoindol-1-yl] 4-formylpiperazine-1-carboxylate Chemical compound N=1C2=NC(Cl)=CC=C2C=CC=1N(C(C1=CC=CC=C11)=O)C1OC(=O)N1CCN(C=O)CC1 DELDSEMAUXQLSY-UHFFFAOYSA-N 0.000 description 2
- VGPGDRBZBDONLK-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1h-isoindol-1-yl] 4-(2-methylprop-2-enoyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)C(=C)C)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 VGPGDRBZBDONLK-UHFFFAOYSA-N 0.000 description 2
- LAWZKSCHNNJKKD-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1h-isoindol-1-yl] 4-(3-methylbut-2-enoyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)C=C(C)C)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 LAWZKSCHNNJKKD-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 1
- MXSSHXZXAAXCOW-UHFFFAOYSA-N 2,3-dihydro-[1,4]dithiino[2,3-c]furan-5,7-dione Chemical compound S1CCSC2=C1C(=O)OC2=O MXSSHXZXAAXCOW-UHFFFAOYSA-N 0.000 description 1
- SAIRAKVVYHJGMH-UHFFFAOYSA-N 2,3-dihydrofuro[3,4-b][1,4]oxathiine-5,7-dione Chemical compound O1CCSC2=C1C(=O)OC2=O SAIRAKVVYHJGMH-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical group C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- UGXNXDWCEXJGHH-UHFFFAOYSA-N 4-O-tert-butyl 1-O-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1H-isoindol-1-yl] piperazine-1,4-dicarboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 UGXNXDWCEXJGHH-UHFFFAOYSA-N 0.000 description 1
- MQOQTPZMPMFLSB-UHFFFAOYSA-N 4-o-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1h-isoindol-1-yl] 1-o-ethyl piperazine-1,4-dicarboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 MQOQTPZMPMFLSB-UHFFFAOYSA-N 0.000 description 1
- GSIQLKOFXMCKNK-UHFFFAOYSA-N 6,7-dihydro-5h-pyrrolo[3,4-b]pyrazine Chemical compound C1=CN=C2CNCC2=N1 GSIQLKOFXMCKNK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- ZTPGVIPRTRFMKZ-GORDUTHDSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1H-isoindol-1-yl] 4-[(E)-but-2-enoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)/C=C/C)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 ZTPGVIPRTRFMKZ-GORDUTHDSA-N 0.000 description 1
- QGFXKQIACHMJLC-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1H-isoindol-1-yl] 4-methanethioylpiperazine-1-carboxylate Chemical compound N=1C2=NC(Cl)=CC=C2C=CC=1N(C(C1=CC=CC=C11)=O)C1OC(=O)N1CCN(C=S)CC1 QGFXKQIACHMJLC-UHFFFAOYSA-N 0.000 description 1
- GFDGOSHUZXJKSP-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1h-isoindol-1-yl] 4-propanoylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)CC)CCN1C(=O)OC1C2=CC=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 GFDGOSHUZXJKSP-UHFFFAOYSA-N 0.000 description 1
- VGOUHXJDKPQCFN-UHFFFAOYSA-N [5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1h-isoindol-1-yl] 4-(2-methylprop-2-enoyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)C(=C)C)CCN1C(=O)OC1C2=CC=C(Cl)C=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 VGOUHXJDKPQCFN-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011197 physicochemical method Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003236 pyrrolines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 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 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Ri, Rz a Het mají svrchu uvedený význam.R1, R2 and Het are as defined above.
S výhodou se uvede v reakci sloučenina obecného vzorce II s alkalickou solí sloučeniny obecného vzorce III, popřípadě vyrobenou přímo v reakční směsi, a to v bezvodém organickém rozpouštědle, jako dimethylformamidu nebo tetrahydrofuranu při teplotě nižší než 60 °C.Preferably, the compound of formula II is reacted with an alkali salt of the compound of formula III, optionally prepared directly in the reaction mixture, in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60 ° C.
Sloučeniny vzorce III je možno získat částečnou redukcí imidu obecného vzorce IVCompounds of formula III may be obtained by partial reduction of the imide of formula IV
kdewhere
Ri, Rž a Het mají svrchu uvedený význam.R1, R2 and Het are as defined above.
Reakce se obvykle provádí v prostředí borohydridu alkalického kovu v organickém rozpouštědle nebo ve směsi vody a organického rozpouštědla, například ve směsi dioxamu a vody, dioxanu a methanolu, methanolu a vody, ethanolu a vody nebo tetrahydrofuranu a methanolu.The reaction is usually carried out in an alkali metal borohydride medium in an organic solvent or in a mixture of water and an organic solvent, for example, a mixture of dioxam and water, dioxane and methanol, methanol and water, ethanol and water or tetrahydrofuran and methanol.
Částečná redukce sloučenin obecného vzorce IV, v nichž Ři a R2 tvoří spolu s pyrrolinovým jádrem jádro isoindolinové, substituované svrchu uvedeným způsobem, může vést k tvorbě isomerních produktů, které je možno od sebe oddělit fyzikálně-chemickými způsoby, jako trakční krystalizací nebo chromatografií.Partial reduction of compounds of formula IV wherein R 1 and R 2 together with the pyrroline nucleus form an isoindoline core substituted as described above may result in the formation of isomeric products which may be separated by physicochemical methods such as traction crystallization or chromatography.
Imid obecného vzorce IV je možno vyrobit působením aminu obecného vzorce VThe imide of formula (IV) may be prepared by treatment with an amine of formula (V)
H2N—het (V) kde : Het má svrchu uvedený význam na anhydrid obecného vzorce VI kdeH2N-het (V) wherein: Het is as defined above for the anhydride of formula VI wherein
Ri, R2 a Het mají svrchu uvedený význam.R1, R2 and Het are as defined above.
Obvykle se reakce aminu obecného vzorce V s amhydridem kyseliny obecného vzorce VI provádí zahřátím v organickém rozpouštědle jako ethanolu, kyselině octové, dimethylformamidu, acetonitrilu, fenyloxidu nebo dimethylformamidu s příměsi dicyklohexylkarbodiimidu nebo N-hydroxysukcinimidu.Typically, the reaction of an amine of formula V with an acid amide of formula VI is carried out by heating in an organic solvent such as ethanol, acetic acid, dimethylformamide, acetonitrile, phenyloxide or dimethylformamide admixed with dicyclohexylcarbodiimide or N-hydroxysuccinimide.
Cyklizace sloučeniny obecného vzorce VII na sloučeninu obecného vzorce IV se obvykle provádí zahřátím s anhydridem kyseliny octové nebo s acetylchloridem v kyselině octové nebo v anhydridu kyseliny octové nebo působením kondenzačního činidla jako dicyklohexylkarbodiimidu v dimethylformamidu při teplotě 20 °C nebo působením thionylchloridu a zahřátím.The cyclization of a compound of formula VII to a compound of formula IV is usually carried out by heating with acetic anhydride or acetyl chloride in acetic acid or acetic anhydride or by treating with a condensing agent such as dicyclohexylcarbodiimide in dimethylformamide at 20 ° C or with thionyl chloride and heating.
Anhydrid kyseliny 2,3-pyrazindikarboxylové je možno-vyrobit způsobem, popsaným v publikaci S. Gabriel a A. Sornn, Chem. Ber., 40, 4850 (1907), anhydrid kyseliny 5,6-dihydro-l,4-oxathiin-2,3-dikarboxylcvé je možno vyrobit podle publikace P. Haken, J. Het. Chem., 7, 1211 (1970) a anhydrid kyseliny 5,6-dihydro-l,4-dithiin-2,3-dikarboxylové je možno vyrobit podle publikace H. R. Schweizer, Helv. Chim. Acta, 52, 2229 (1969 j.2,3-Pyrazinedicarboxylic acid anhydride can be prepared as described by S. Gabriel and A. Sornn, Chem. Ber., 40, 4850 (1907), 5,6-dihydro-1,4-oxathiine-2,3-dicarboxylic acid anhydride can be prepared according to P. Haken, J. Het. Chem., 7, 1211 (1970) and 5,6-dihydro-1,4-dithiine-2,3-dicarboxylic acid anhydride can be prepared according to H. R. Schweizer, Helv. Chim. Acta, 52, 2229 (1969).
Sloučeniny obecného vzorce VI, v nichž substituenty Ri a R2 tvoří s jádrem pyrrolinovým jádro isoindolinové, substituované atomem halogenu je možno také získat některým z následujících způsobů:Compounds of formula VI wherein R 1 and R 2 form a halogen-substituted isoindoline nucleus with a pyrroline nucleus can also be obtained by any of the following methods:
a) působením aminu obecného vzorce VIII na halogenid kyseliny o-toluylové, substituované atomem halogenu za vzniku výsledného produktu obecného vzorce XIa) treatment of an o-toluylic acid halide substituted by a halogen atom with an amine of formula VIII to give the final product of formula XI
kdewhere
Ri a R2 mají svrchu uvedený význam, přes meziprodukt obecného vzorce VIIR 1 and R 2 are as defined above, via an intermediate of formula (VII)
COOHCOOH
X ivn) kdeX ivn) where
Het má svrchu uvedený význam, a fenylový zbytek je substituován atomem halogenu, načež se tento produkt cyklizuje N-bromsukcinimidem za přítomnosti azodiizob.utyronitrilu, působením gem-diesteru v prostředí vody a organického rozpouštědla nebo dichlormethylderivátem, neboHet is as defined above, and the phenyl moiety is substituted with a halogen atom, after which the product is cyclized with N-bromosuccinimide in the presence of azodiisobutyronitrile, treatment with a gem-diester in water and an organic solvent or dichloromethyl derivative, or
b) nahradí se nitroskupina na isoindolinovém kruhu produktu obecného vzorce VI atomem halogenu působením diazoniové soli. .b) replacing the nitro group on the isoindoline ring of the product of formula VI with a halogen atom with the action of a diazonium salt. .
Nové sloučeniny obecného vzorce I je popřípadě možno čistit fyzikálním způsobem, například krystalizací nebo chromatografií.The novel compounds of formula (I) may optionally be purified by physical means, for example by crystallization or chromatography.
Nové sloučeniny podle vynálezu mají zajímavé farmakologické vlastnosti, jsou účinné zejména jako uklidňující látky, látky pro231959 tikřečové, uspávadla a látky, snižující vznik kontraktu!·.The novel compounds of the present invention possess interesting pharmacological properties, in particular as calming agents, chickens, tranquilizers and contract-reducing agents.
U krys jsou tyto látky účinné v dávkáchIn rats, these compounds are effective in doses
0,1 až 100 mg/kg při perorálním podání například v následujících pokusech:0.1 to 100 mg / kg when administered orally in, for example, the following experiments:
— elektrický šok, prováděný způsobem podle publikace Tedeschi a další, J. Pharmacol., 125, 28 (1959), — pentatetrazolové křeče podle publikace Everett a Richards, J. Pharmacol., 81, 40 (1944), — supramaximální elektrošok způsobem podle publikace Wwinyard a další, J. Pharmacol., 106, 319 (1952) a — lokomoční aktivita podle publikace Courvoisler (Congrěs des Médecins Aliénistes et Neurologistes-Tours — 8.—12. juin 1959) a Julou (Buletin de la Société de Pharmacie de Lilie, č. 2, leden 1957, str. 7).Electric shock performed by the method of Tedeschi et al., J. Pharmacol., 125, 28 (1959), pentatetrazole seizures according to Everett and Richards, J. Pharmacol., 81, 40 (1944), supramaximal electroshock according to the method of Wwinyard et al., J. Pharmacol., 106, 319 (1952) and - locomotion activity according to Courvoisler (Congrès des Médecins Alienistes et Neurologistes-Tours - 8-12 June 1959) and Julou (Buletin de la Societe de Pharmacie de Lilie, No. 2, January 1957, p. 7).
Mimoto mají tyto látky jen velmi malou toxicitu a jejich letálmí dávka DLso je obvykle u krys vyšší než 300 mg/kg per os.In addition, these substances have very little toxicity and their lethal dose of D 50 is usually greater than 300 mg / kg orally in rats.
Zvláštní význam mají sloučeniny obecného vzorce I, v nichž Rt a Ra tvoří spolu s pyrrolinovým jádrem jádro isoindolinové, 6,7-dihydro-5H-pyrrolO'[ 3,4-b ] pyrazin, 2,3,6,7-tetrahydr o-5H-oxathiin [ 1,4]<[ 2,3-c ] pyrrol nebo 2,3,6,7-tetrahydro-5H-dithiin[l,4]í[2,3-c] pyrrol, Het znamená zbytek jako 2-pyridyl, 2-chinolyl nebo l,8-maftyridin-2-yl, substituovaný atomem halogenu, Z znamená atom kyslíku nebo síry a R znamená atom vodíku nebo alkyl o 1 až 4 atomech uhlíku s přímým nebo rozvětveným řetězcem, popřípadě substituovaný 3 atomy halogenu, alkenyl o 2 až 4 atomech uhlíku, alkinyl o 2 až 4 atomech uhlíku nebo alkoxyl o 1 až 4 atomech uhlíku.Of particular interest are compounds of formula I wherein Rt and Ra together with the pyrroline ring form an isoindoline, 6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine, 2,3,6,7-tetrahydrofuran nucleus. -5H-oxathiine [1,4] <[2,3-c] pyrrole or 2,3,6,7-tetrahydro-5H-dithiine [1,4] f [2,3-c] pyrrole, Het means a residue such as 2-pyridyl, 2-quinolyl or 1,8-maphthyridin-2-yl, substituted with a halogen atom, Z represents an oxygen or sulfur atom and R represents a hydrogen atom or a straight or branched chain alkyl of 1 to 4 carbon atoms optionally substituted 3 halogen atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
Zvláštní význam mají sloučeniny obecného vzorce I, v nichž Ri a R2 tvoří s pyrrolinovým jádrem jádro isoindolinové, Het znamená l,8-naftyridin-2-yl, substituovaný atomem chloru, Z znamená atom kyslíku nebo síry a R znamená atom vodíku nebo alkyl o 1 až 4 atomech uhlíku, alkoxyl o 1 až 4 atomech uhlíku, alkenyl o 2 až 4 atomech uhlíku nebo trifluormethyl.Of particular interest are compounds of formula I wherein R 1 and R 2 form an isoindoline nucleus with the pyrroline ring, Het is 1,8-naphthyridin-2-yl substituted with chlorine, Z is oxygen or sulfur, and R is hydrogen or alkyl; C 1 -C 4, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl or trifluoromethyl.
Z výhodných sloučenin podle vynálezu je možno uvést zejména tyto látky:Preferred compounds of the present invention include:
(4-akryloyl-l-piperazinyl) -3-karbonyloxy-2-(7-chlor-l,8-naftyridin-2-yl)-1-isoindolinon,(4-Acryloyl-1-piperazinyl) -3-carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone,
2- (7-chlor-l,8-naftyridin-2-yl) - (4-methakryloyl-l-piperazinyl j -3-karbonyloxy-l-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-methacryloyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone,
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-pr opionyl-l-piperazinyl)-3-karbonyloxy-l-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-propionyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone,
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-trif luoracetyl-l-piperazinyl) -3-karbonyloxy-l-isoinaolinon, (4-butyryl-l-piperazinyl) -3-karbonyloxy-2- (7-chlor-l,8-naf tyridin-2-yl) -1-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-trifluoroacetyl-1-piperazinyl) -3-carbonyloxy-1-isoinaolinone, (4-butyryl-1-piperazinyl) -3- carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone,
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-f ormyl-l-piperazinylj-3-karbonyloxy-l-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-formyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone,
2- (7-chlor-l,8-naftyridin-2-yl) - (4-thiof ormyl-l-piperazinyl) -3-karbonyloxy-1-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-thiophenyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone,
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-ethoxykarbonyl-l-piperazinyl) -3-karbonyloxy-l-isoindolinon,2- (7-chloro-1,8-naphthyridin-2-yl) - (4-ethoxycarbonyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone,
2- (7-chlor-1,8-naf tyridin-2-yl) - [ 4- (3-methyl-2-butenoyl j -1-piperazinyl ] -3-karbonyloxy-l-isoindolinon.2- (7-chloro-1,8-naphthyridin-2-yl) - [4- (3-methyl-2-butenoyl) -1-piperazinyl] -3-carbonyloxy-1-isoindolinone.
Vynález bude osvětlen následujícími příklady.The invention will be illustrated by the following examples.
Příklad 1Example 1
K suspenzi 0,20 g hydridu sodíku v 10 ml bezvodého dimethylformamidu se přidá při teplotě 0 °C 2,5 g 6-(7-chlor-l,8-naftyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-dithiin[l,4] [ 2,3-c jpyrrolu. Reakční směs se hodinu míchá při teplotě 2°C, načež se přidá 2,85 g l-acetyl-4-chlorfcrmylpiperazinu v roztoku ve 20 ml bezvodého dimethylformamidu. Po 18 hodinách stání při teplotě 2 CC se reakční směs zředí 100 ml destilované vody. Vyloučená sraženina se oddělí filtrací, promyje se 10 ml destilované vody a usuší se na vzduchu. 3,6 g takto získaného produktu se rozpustí v 50 ml chloroformu, roztok se zfiltruje přes 50,0 g silikagelu ve sloupci o průměru 4,1 cm. Roztok se promývá směsí 400 ml chloroformu a methanolu v objemovém poměru 98 : 2 a eluát se odloží. Pak se sloupec dále vymývá 400 ml téže směsi. Tento eluát se odpaří dosucha za sníženého tlaku 2660 Pa. Chromatografovaný produkt se čistí překrystalováním z 20 ml směsi dimethylformamidu a ethanolu v objemovém poměru 50:50. Tímto způsobem se získá 1,40 g (4-acetyl-1-piperazinyl) -5-karbcmyloxy-6- (7-chlor-l,8-naftyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-dithiin[l,4][2,3-cjpyrrolu o bodu tání 271 °C.To a suspension of 0.20 g of sodium hydride in 10 ml of anhydrous dimethylformamide is added at 0 ° C 2.5 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo- 2,3,6,7-tetrahydro-5H-dithiine [1,4] [2,3-c] pyrrole. The reaction mixture was stirred at 2 ° C for 1 hour, then 2.85 g of 1-acetyl-4-chloroformylpiperazine in solution in 20 ml of anhydrous dimethylformamide was added. After standing at 2 ° C for 18 hours, the reaction mixture was diluted with 100 mL of distilled water. The precipitate formed is collected by filtration, washed with 10 ml of distilled water and air-dried. 3.6 g of the product thus obtained are dissolved in 50 ml of chloroform, and the solution is filtered over 50.0 g of silica gel in a 4.1 cm diameter column. The solution is washed with a mixture of 400 ml of chloroform and methanol (98/2 by volume) and the eluate is discarded. Then the column is further eluted with 400 ml of the same mixture. This eluate was evaporated to dryness under reduced pressure (100 mm Hg). The chromatographed product is purified by recrystallization from 20 ml of a 50:50 by volume mixture of dimethylformamide and ethanol. 1.40 g of (4-acetyl-1-piperazinyl) -5-carbamyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-2,3,6 are obtained; 7-tetrahydro-5H-dithiine [1,4] [2,3-c] pyrrole, m.p. 271 ° C.
l-acetyl-á-chlorformylpiperazin je možno vyrobit působením 9,9 g fosgenu na 26,5 g 1-acetylpiperazinu v 75 ml bezvodého· toluenu v průběhu 1 hodiny při teplotě 2 °C. 1-acetylplperazinhydrochlorid, vytvořený v průběhu reakce se oddělí filtrací, promyje se 50 ml bezvodého toluenu, toluenový filtrát se odpaří dcsucha při tlaku 20 torr, a získá se 15,0 g l-acetyl-4-chlorformylpiperazinu jako olejovltá kapalina.1-Acetyl-.alpha.-chloroformylpiperazine can be prepared by treating 9.9 g of phosgene with 26.5 g of 1-acetylpiperazine in 75 ml of anhydrous toluene for 1 hour at 2 ° C. The 1-acetylplperazine hydrochloride formed during the reaction was collected by filtration, washed with 50 ml of anhydrous toluene, the toluene filtrate was evaporated to dryness at 20 torr, to give 15.0 g of 1-acetyl-4-chloroformylpiperazine as an oily liquid.
Postupuje-li se obdobným způsobem zaIf a similar procedure is followed for
231939 použití příslušných výchozích látek, získají se produkty z příkladů 2 až 39.231939 using the appropriate starting materials, the products of Examples 2 to 39 are obtained.
P ř í k 1 a d 2 (4-akryloyl-l-piperazinyl) -3-karbonyloxy-2- (7-chlor-l,8-naftyridin-2-yl) -1-isoindollnon o bodu tání 188 °C.EXAMPLE 2 2- (4-Acryloyl-1-piperazinyl) -3-carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolone, m.p. 188 ° C.
P ř í k 1 a d 3 (4-acetyl-l-piperazinyl j-3-karbouyloxy-2- (7-chlor-l,8-naftyridín-2-yl j -1-isoindolinon o bodu tání 224 °C.EXAMPLE 3 3- (4-Acetyl-1-piperazinyl) -3-carbouyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone, m.p. 224 ° C.
Příklad 4 (4-benzoyl-lipíperazjjnyl ] -3-karbonyloxy-2-(7-chlor-l,8-naftyridin-2-yl)-l-isoIndolinon o bodu tání 216 °C.EXAMPLE 4 (4-Benzoyl-lipiperazinyl) -3-carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone, m.p. 216 [deg.] C.
Příklad 5Example 5
2- (7-chlor-l,8-naf tyridln-2-yl) - (4-cyklopropylkarbonyl-l-plperazinyl) -3-karbonyloxy-l-iscindolinon o bodu tání 252 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-cyclopropylcarbonyl-1-plperazinyl) -3-carbonyloxy-1-iscindolinone, m.p. 252 ° C.
Příklad 6Example 6
2- (7-chlor-l,8-naf tyridin-2-yl ] - (4-ethoxykarbomyl-l-plperazinyl j -3-karbonyloxy-l-isoindolinon o bodu tání 211 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-ethoxycarbomyl-1-plperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 211 ° C.
Příklad 7 (4-acetyl-l-piperazinyl) -5-karbonyloxy-6-(7-chlor-l,8-naftyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyr rolo [3,4-b ] pyrazln o bodu tání 270 °C.Example 7 (4-Acetyl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3] 4-b] pyrazine, m.p. 270 ° C.
Příklad 8 (4-akryloyl-l-piperazinyl )-5-karbonyloxy-6- (7-chlor-l,8-naf tyridin-2-yl j -7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b ] pyrazin hydratovaný o bodu tání 224 °C.Example 8 (4-Acryloyl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3] 4-b] pyrazine hydrated with a melting point of 224 ° C.
P ř í k 1 a d 9 (4-akryloyl-l-piperazinyl) -5-karbonyl'Oxy-6-(5-chlor-2-pyridyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-g]pyrazin, hydratovaný o bodu tání 202 až 204 °C.Example 9 (4-acryloyl-1-piperazinyl) -5-carbonyl-oxy-6- (5-chloro-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo [3] 4-g] pyrazine, hydrated, m.p. 202-204 ° C.
Příklad 10 (4-akryloyl-l-piperazlnyl j -5-karbonyloxy-6-(7-chlor-2-chinolyl)-6,7-dihydro-5H-ipyrrolo[ 3,4-b] pyrazin o bodu tání 226 °C po přeměně při 150 °C.Example 10 (4-Acryloyl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-2-quinolyl) -6,7-dihydro-5H-ipyrrolo [3,4-b] pyrazine, m.p. 226 ° C after conversion at 150 ° C.
Příklad 11 [ 4-acetyl-l-piperazinyl) -5-karbonyl-6- (5-methyl-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b] pyrazin o bodu tání 200 °C.Example 11 [4-Acetyl-1-piperazinyl) -5-carbonyl-6- (5-methyl-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine mp 200 ° C.
P ř í k 1 á d 12 (4-benzoyl-l-piperazinyl) -5-karbonyloxy-6- (5-methyl-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b] pyrazin o bodu tání 194 °C.Example 12 (4-benzoyl-1-piperazinyl) -5-carbonyloxy-6- (5-methyl-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo [3, 4-b] pyrazine, m.p. 194 ° C.
Příklad 13 (4-akryloyl-l-piperazinyl) -5-karbonyloxy-6- [ 5-methyl-2-pyridyl) -7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b] pyrazin o bodu tání 221 °C.Example 13 (4-Acryloyl-1-piperazinyl) -5-carbonyloxy-6- [5-methyl-2-pyridyl] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine mp 221 ° C.
Příklad 14 (4-acetyl-l-piperazinyl)-5-karbonyloxy-6-[7-chlor-2-chinolyl]-7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b] pyrazln o bodu tání 270 °C.Example 14 (4-Acetyl-1-piperazinyl) -5-carbonyloxy-6- [7-chloro-2-quinolyl] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine mp 270 ° C.
Příklad 15Example 15
2- (7-chl0‘r-l,8-n.aftyridin-2-yl) - (4-f ormyl-l-ipiperazínyl) -3-karbonyloxy-l-isoindolinon o bodu tání 260 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-formyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 260 ° C.
Příklad 16Example 16
2- (7-chlor-l,8-naftyridin-2-yl j - (4-propionyl-l-piperazinyl ] -3-karbonyloxy-l-isoindolimon o bodu tání 221 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-propionyl-1-piperazinyl) -3-carbonyloxy-1-isoindolimide, m.p. 221 ° C.
Příklad 17 (4-butyryl-l-piperazinyl ] -3-karbonyloxy-2- [ 7-chlor-l,8-naftyridln-2-yl) -1-isoindolinon o bodu tání 202 °C.Example 17 (4-Butyryl-1-piperazinyl) -3-carbonyloxy-2- [7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone, m.p. 202 ° C.
Příklad 18 [4-isobutyryl-l-piperazinyl)-3-karbonyloxy-2- (7-chíor-l,8-naf tyridin-2-yl ]-l-isoindolinon o bodu tání 254 °C.Example 18 [4-Isobutyryl-1-piperazinyl) -3-carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone, m.p. 254 ° C.
Příklad 19Example 19
2- (7-chlor-l,8-naftyridim-2-yl ] - (4-cyklohexylkarbonyl-l-piperazínyl j-3-karbonyloxy-l-isoindolimon o bodu tání 240 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-cyclohexylcarbonyl-1-piperazinyl) -3-carbonyloxy-1-isoindolimide, m.p. 240 ° C.
P ř í k 1 a d 20 (4-chloracetyl-l-piperazinyl ] -3-karbonyloxy-2- (7-chlor-l,8-naftyridtn-2-yl) -1-isoindolinon o bodu tání 222 až 224 °C.Example 20 (4-chloroacetyl-1-piperazinyl) -3-carbonyloxy-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindolinone, m.p. 222-224 ° C .
Příklad 21Example 21
2- (7-chl-or-l,8-naf tyr idin-2-yl ] - [4-trif luor acetyl-l-piperaziinyl)-3-karbonyloxy-l-isoindolinon o bodu tání 218 °C.2- (7-chloro-or-1,8-naphthyridin-2-yl) - [4-trifluoroacetyl-1-piperazinyl] -3-carbonyloxy-1-isoindolinone, m.p. 218 ° C.
Příklad 22Example 22
2- (7-chlor-l,8-naftyridin-2-yl) - (4-isoni9 kctinoyl-l-piperazinyl)-3-karbonyloxy-l-isoindolinon o bodu tání 185 ®C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-isonocinoyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p.
Příklad 23Example 23
2- (7-chlor-l,8-naftyridin-2-yl) - (4-krotonoyl-l-piperazinyl) -3-karbonyloxy-l-isoindolinon © bodu tání 220 až 222 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-crotonoyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 220-222 ° C.
Příklad 24Example 24
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-methakryloyl-l-piper azinyl) -3-karbonyloxy-l-isoindolinon o bodu tání 165 až 200 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-methacryloyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 165-200 ° C.
Příklad 25Example 25
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-terc.butoxykarbonyl-l-piperazinyl)-3-karbonyloxy-l-isoíndolinon o bodu tání 195 °C. Příklad 262- (7-chloro-1,8-naphthyridin-2-yl) - (4-tert-butoxycarbonyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 195 ° C. Example 26
2- (7-chlor-l,8-naf tyridin-2-yl) - (4-propioloyl-l-piperazimyl)-3-karbonyloxy-l-isoindolinon o bodu tání 265 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-propioloyl-1-piperazimyl) -3-carbonyloxy-1-isoindolinone, m.p. 265 ° C.
Příklad 27Example 27
2- (7-chlor-l,8-naf tyridin-2-yl )-(4-( 3-methyl-2-butenoyl)-1-piperazinyl ]-3-karbonyloxy-l-isoindolinon o bodu tání 205 °C.2- (7-chloro-1,8-naphthyridin-2-yl) - (4- (3-methyl-2-butenoyl) -1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 205 ° C .
Příklad 28 (4-akryloyl-l-piperazinyl) -3-karbonyloxy-6-chlor-2- (7-chlor-l,8-naftyridin-2-yl)-l-isoindoliinoin o bodu tání 272 °C.Example 28 (4-Acryloyl-1-piperazinyl) -3-carbonyloxy-6-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) -1-isoindoliinoin, m.p. 272 ° C.
Příklad 29Example 29
6-chlor-2-(7-chlor-l,8-naftyridin-2-yl)- (4-methakryloyl-l-'piperazinyl) -3-karbonyloxy-l-isoindolinon o bodu tání 211 °C.6-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) - (4-methacryloyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 211 ° C.
Příklad 30Example 30
2- (7-chlor-l,8-naftyridin-2-yl) - (4-thioformyl-l-piperazinyl)-3-karbonyloxy-l-isoindolinon o bodu tání 295 CC za rozkladu.2- (7-chloro-1,8-naphthyridin-2-yl) - (4-thioformyl-1-piperazinyl) -3-carbonyloxy-1-isoindolinone, m.p. 295 DEG C. with decomposition.
Příklad 31Example 31
2- (5-chlor-2-pyridyl) - (4-ethoxykarbonyl-l-piperazimyl)-3-karbo«yloxy-l-isoindolincn o bodu tání 160 °C.2- (5-chloro-2-pyridyl) - (4-ethoxycarbonyl-1-piperazimyl) -3-carbonyloxy-1-isoindoline, m.p. 160 ° C.
IQIQ
Příklad 32Example 32
6- (7-chlor-l,8-naftyridiin-2-yl) -7-oxo- (4-proipionyl-l-piperazinyl)-5-karbonyloxy-2,3,6,7-tetrahydro-5H-oxathiino[ 1,4] [2,3-c] pyrrol o bodu tání 240 °C.6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo- (4-proipionyl-1-piperazinyl) -5-carbonyloxy-2,3,6,7-tetrahydro-5H-oxathiino [ 1,4] [2,3-c] pyrrole, m.p. 240 ° C.
Příklad 33Example 33
6- (7-chIcr-l,8-naf tyridin-2-yl) -7-oxo- (4-propioloyl-l-piperazinyl) -5-karbonyloxy-2,3,6,7-tetrahydro-5H-oxathiin[1,4] [2,3-c]pyrrol o bodu tání 203 °C za rozkladu.6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo- (4-propioloyl-1-piperazinyl) -5-carbonyloxy-2,3,6,7-tetrahydro-5H-oxathiin [1,4] [2,3-c] pyrrole, m.p. 203 DEG C. with decomposition.
P ř í k 1 a d 34 (4-akryloyl-l-piperazinyl)-5-karbonyloxy-6- (7-chlcr-l,8-naf tyridin-2-yl) -7-oxo-2,3,6,7-tetrahydro-5H-oxathiin[l,4] [ 2,3-c]pyrrol o bodu tání 287 °C za rozkladu.Example 34 (4-acryloyl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-2,3,6, 7-Tetrahydro-5H-oxathiine [1,4] [2,3-c] pyrrole, m.p. 287 DEG C. with decomposition.
Příklad 35Example 35
6- (7-chlor-l,8-naf tyridin-2-yl) - (4-formyl-l-pirazinyl)-5-karbonyloxy-7-oxo-2,3,6,7-tetrahydro-5H-oxanthiin[ 1,4] [ 2,3-c Jpyrrol o bodu tání 305 °C.6- (7-Chloro-1,8-naphthyridin-2-yl) - (4-formyl-1-pirazinyl) -5-carbonyloxy-7-oxo-2,3,6,7-tetrahydro-5H-oxanthiine [1,4] [2,3-c] pyrrole, m.p. 305 ° C.
Příklad 36Example 36
6- (7-chlor-l,8-naf tyr idin-2-yl) - (4-ethoxykarbonyl-l-piperazinyl) -5-karbonyloxy-7-oxo-2,3,6,7-tetrahydro-5H-oxathiin[l,4][2,3-c]pyrrol o bodu tání 275 °C.6- (7-chloro-1,8-naphthyridin-2-yl) - (4-ethoxycarbonyl-1-piperazinyl) -5-carbonyloxy-7-oxo-2,3,6,7-tetrahydro-5H- oxathiine [1,4] [2,3-c] pyrrole, m.p. 275 ° C.
P ř í k 1 a d 37 (4-butyryl-l-piperazinyl) -5-karbonyloxy-6- (7-chlor-l,8-naf tyridin-2-yl) -7-oxo-2,3,6,7 -tetrahydr o-5H-dithiin [ 1,4 ];[ 2,3-c ] pyrrol o bodu tání 248 °C.EXAMPLE 37 (4-Butyryl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-2,3,6, 7-tetrahydro-5H-dithiine [1,4], [2,3-c] pyrrole, m.p. 248 ° C.
Příklad 38Example 38
6- (7-chlar-l,8-mia|fty,ridm-2-yl) - (4-methiakryloyl-l-piperazinyl) -5-karbonyloxy-7-oxo-2,3,6,7-tetrahydro-5H-dithiin[l,4][ 2,3-c] pyrrol o bodu tání 240 CC.6- (7-chloro-1,8-methyl-pyridin-2-yl) - (4-methacryloyl-1-piperazinyl) -5-carbonyloxy-7-oxo-2,3,6,7-tetrahydro- 5H-Dithiine [1,4] [2,3-c] pyrrole, m.p. 240 DEG C.
Příklad 39 (4-akryloyl-l-piperazinyl) -5-karbonyloxy-6- (7-chlor-l,8-naf tyridin-2-yl) -7-oxo-2,3,6,7-tetrahydro-5H-dithiin [ 1,4 ], [ 2,3-c ] pyrrol o bodu tání 250 °C.Example 39 (4-Acryloyl-1-piperazinyl) -5-carbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-2,3,6,7-tetrahydro-5H -dithiine [1,4], [2,3-c] pyrrole, m.p. 250 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS775984A CS231959B2 (en) | 1975-11-07 | 1977-09-14 | Manufacturing process of new heterocyclic compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS757510A CS231957B2 (en) | 1974-11-07 | 1975-11-07 | Manufacturing process of heterocyclic compounds |
| CS775984A CS231959B2 (en) | 1975-11-07 | 1977-09-14 | Manufacturing process of new heterocyclic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS231959B2 true CS231959B2 (en) | 1985-01-16 |
Family
ID=5424366
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS775984A CS231959B2 (en) | 1975-11-07 | 1977-09-14 | Manufacturing process of new heterocyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS231959B2 (en) |
-
1977
- 1977-09-14 CS CS775984A patent/CS231959B2/en unknown
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