CS244131B2 - Method of substituted pyrido-(1,2-a) pyrimidines production - Google Patents
Method of substituted pyrido-(1,2-a) pyrimidines production Download PDFInfo
- Publication number
- CS244131B2 CS244131B2 CS835287A CS528783A CS244131B2 CS 244131 B2 CS244131 B2 CS 244131B2 CS 835287 A CS835287 A CS 835287A CS 528783 A CS528783 A CS 528783A CS 244131 B2 CS244131 B2 CS 244131B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- pyrido
- pyrimidine
- oxo
- methylene
- carboxylic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- VFMCUTPRJLZEEW-UHFFFAOYSA-N 4h-pyrido[1,2-a]pyrimidine Chemical class C1=CC=CN2CC=CN=C21 VFMCUTPRJLZEEW-UHFFFAOYSA-N 0.000 title claims description 3
- -1 ethenyl-3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine Chemical compound 0.000 claims description 83
- 150000001875 compounds Chemical class 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims 3
- 229920002261 Corn starch Polymers 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000008120 corn starch Substances 0.000 claims 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 claims 1
- 229940099364 dichlorofluoromethane Drugs 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 31
- 238000000354 decomposition reaction Methods 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
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- 230000003266 anti-allergic effect Effects 0.000 description 8
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- 238000003756 stirring Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical compound C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 description 2
- NNJFRARRNSPGFB-PKNBQFBNSA-N 2-[(e)-2-(2-methylphenyl)ethenyl]-4-oxo-3-propylpyrido[1,2-a]pyrimidine-7-carboxylic acid Chemical compound N1=C2C=CC(C(O)=O)=CN2C(=O)C(CCC)=C1\C=C\C1=CC=CC=C1C NNJFRARRNSPGFB-PKNBQFBNSA-N 0.000 description 2
- YMDNODNLFSHHCV-UHFFFAOYSA-N 2-chloro-n,n-diethylethanamine Chemical compound CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- GSYNZJYYKAXPCD-BQYQJAHWSA-N 6-ethyl-5-[(e)-2-(3-methylphenyl)ethenyl]-7-oxo-1,8a-dihydrocyclopropa[1,2]pyrido[3,6-c]pyrimidine-1a-carboxylic acid Chemical compound N1=C2C=CC3(C(O)=O)CC3N2C(=O)C(CC)=C1\C=C\C1=CC=CC(C)=C1 GSYNZJYYKAXPCD-BQYQJAHWSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
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- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 2
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- 238000007796 conventional method Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
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- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 2
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- 230000007062 hydrolysis Effects 0.000 description 2
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- QQXDJRGWSOUAHV-MDZDMXLPSA-N methyl 10-ethyl-11-oxo-9-[(E)-2-phenylethenyl]-1,8-diazatricyclo[5.4.0.02,4]undeca-5,7,9-triene-4-carboxylate Chemical compound COC(=O)C12C=CC=3N(C(C(=C(N=3)\C=C\C3=CC=CC=C3)CC)=O)C1C2 QQXDJRGWSOUAHV-MDZDMXLPSA-N 0.000 description 2
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- 159000000000 sodium salts Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- KFUSEUYYWQURPO-UHFFFAOYSA-N 1,2-dichloroethene Chemical compound ClC=CCl KFUSEUYYWQURPO-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
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- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical compound O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 description 1
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- YCSSWAXUTPJCNB-MDZDMXLPSA-N 5-[(e)-2-(3-ethoxyphenyl)ethenyl]-7-oxo-6-propyl-1,8a-dihydrocyclopropa[1,2]pyrido[3,6-c]pyrimidine-1a-carboxylic acid Chemical compound N1=C2C=CC3(C(O)=O)CC3N2C(=O)C(CCC)=C1\C=C\C1=CC=CC(OCC)=C1 YCSSWAXUTPJCNB-MDZDMXLPSA-N 0.000 description 1
- FJFNWYPSOAMGGJ-CMDGGOBGSA-N 5-[(e)-2-(3-methoxyphenyl)ethenyl]-7-oxo-6-propyl-1,8a-dihydrocyclopropa[1,2]pyrido[3,6-c]pyrimidine-1a-carboxylic acid Chemical compound N1=C2C=CC3(C(O)=O)CC3N2C(=O)C(CCC)=C1\C=C\C1=CC=CC(OC)=C1 FJFNWYPSOAMGGJ-CMDGGOBGSA-N 0.000 description 1
- GDWSVLIEUXZPCW-CMDGGOBGSA-N 5-[(e)-2-(3-methylphenyl)ethenyl]-7-oxo-6-propyl-1,8a-dihydrocyclopropa[1,2]pyrido[3,6-c]pyrimidine-1a-carboxylic acid Chemical compound N1=C2C=CC3(C(O)=O)CC3N2C(=O)C(CCC)=C1\C=C\C1=CC=CC(C)=C1 GDWSVLIEUXZPCW-CMDGGOBGSA-N 0.000 description 1
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Landscapes
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
244131 2244131 2
Tento vynález se týká způsobů výroby substituovaných pyrido/1,2-a/pyrimidinů (I),The present invention relates to methods for producing substituted pyrido [1,2-a] pyrimidines (I),
Vynález se týká slouSenin obecného vzorce IThe present invention relates to compounds of formula I
CuCu
OO
RjOOCRjOOC
CH-CH-Re α β 3 v němž zněměná atom vodíku, metylovou, etylovou nebo dietylamlnoetylovou skupinu,znamená atom vodíku nebo alkylovou skupinu s 1 až 4 atomy uhlíku,znamená tienylovou skupinu nebo fenylovou skupinu, která může být popřípaděsubstituována chlorem, 1 nebo 2 metylovými skupinami nebo 1 až 3 alkoxyekupi-nami s 1 až 2 atomy uhlíku, a jejich farmaceuticky přijatelných solí.CH-CH-Re α β 3 in which the hydrogen atom, methyl, ethyl or diethylaminoethyl group means a hydrogen atom or a C 1 -C 4 alkyl group means a thienyl group or a phenyl group which may optionally be substituted with chlorine, 1 or 2 methyl groups or 1-3 alkoxy groups having from 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof.
Mezi slouSeniny podle vynálezu patří taká farmaceuticky přijatelná soli slouSeninobecného vzorce I, věechny možné isomery <např. cis- nebo trans-isomeky) a jejich smlsl.Skupina -CH=CH-Rj má s výhodou trans-konfiguracl.Compounds of the invention include such pharmaceutically acceptable salts of Formula I, all possible isomers < the cis- or trans-isomers) and their mixtures -CH = CH-Rj preferably have a trans-configuration.
SlouSeniny jsou zde oznaSovány jako 6,7-metylenové slouSeniny, aby bylo možno přij-mout jednotný nomenklaturní systém, který je založený na kondenzovaném pyridopyrimldOno-vém systému. Tyto slouSeniny mohou být alternativně oznaSovány jako deriváty 1,5-diaza--4-oxo-tricyklo/5,4,0,0/undeka-2,9,11 -trienu. Číslování, které se používá k oznaSování poloh substltuentů ve skupině Rj je kon-venSní, jek ukazují následující příklady:a) jestliže Rj zněměná fenylovou skupinu: 2 3 b) jestliže Rj znamená tienylovou skupinu:The compounds are referred to herein as 6,7-methylene compounds in order to adopt a uniform nomenclature system which is based on a condensed pyridopyrimidine system. Alternatively, these compounds may be referred to as 1,5-diaza-4-oxo-tricyclo [5.4.0.0] undeca-2,9,11-triene derivatives. The numbering used to indicate the positions of the substituents in the Rj group is conventional, as shown in the following examples: a) when Rj is a phenyl group: 2 b) when Rj is a thienyl group:
1 Výraz "zvláště", pokud ae zde používá, znamená výhodnost nebo dolil výhodnost dotyěněho předmětu. Renl zamýělen jako omesení dotySného předmětu svláětnín způsobem.The term "particularly" when used herein means convenience or convenience of the object in question. Renl intended as a delicacy of the subject in question in a way that is light.
Alkylový a elkoxylová skupina nohou mít pMsý nebo rozvětvený řetěsec.The alkyl and alkoxy groups may have a long or branched chain.
Rj znosená a výhodou alkylovou skupinu s 1 až 4 atomy uhlíku, výhodou metylovou,propylovou nebo butylovou skupinu.R 1 is preferably a C 1 -C 4 alkyl group, preferably a methyl, propyl or butyl group.
Jestliže Rj snsmená tienylovou skupinu, pak a výhodou znamená 2-tiemylovou skupinu. 5 24413, Příklady farmaceuticky přijatelných solí jsou soli anorganických bází, např. soli sodná, draselná, vápenatá a hlinitá, nebo soli organických bází, např. lysinu, trietyl-eminu, dibenzylaminu, metylbenzylaminu, di-(2-etylhexyl)aminu, piperidinu, K-etylpiperi-dinu, Ν,Ν-dietyleminoetylaminu, N-etylmorfolinu, beta-fenetylaminu, N-benzyl-beta-fenetyl-aminu, N-benzyl-beta-fenetylaminu, N-benzyl-N,N-dimetylamlnu a jihých přijatelných organichkých aminů, a také soli s anorganickými kyselinami, např. kyselinou chlorovodíkovou, bromo-vodíkovou a sírovou, a s organickými kyselinami, např. kyselinou citrónovou, vinnou,maleinovou, jáblečnou, fumarovou, metansulfonovou a etanaulfonovou. Výhodnými solemi jsousodná nebo draselná soli a taká hydrochloridy bázických esterů, např. dietylaminoetyl-a dimetyleminoetyl-estery.When R1 is a straight-chain thienyl group, it is preferably a 2-thiyl group. Examples of pharmaceutically acceptable salts are salts of inorganic bases such as sodium, potassium, calcium and aluminum salts, or salts of organic bases such as lysine, triethyl-emine, dibenzylamine, methylbenzylamine, di- (2-ethylhexyl) amine, piperidine , K-ethylpiperidine, Ν, Ν-diethyleminoethylamine, N-ethylmorpholine, beta-phenethylamine, N-benzyl-beta-phenethylamine, N-benzyl-beta-phenethylamine, N-benzyl-N, N-dimethylamine and south acceptable organic amines, as well as salts with inorganic acids such as hydrochloric, hydrobromic and sulfuric acids, and organic acids such as citric acid, tartaric acid, maleic acid, amidic acid, fumaric acid, methanesulfonic acid, and ethanesulfonic acid. Preferred salts are the sodium or potassium salts and such basic ester hydrochlorides, e.g., diethylaminoethyl and dimethyleminoethyl esters.
ZvláStS výhodnými slouSeninami podle vynálezu jsou sloufieniny obecnáho vzorce I,v námi R, znamenáa'') atom vodíku, b'í) metyl, etyl nebo dietylaminoetyl, K2 znamená alkylovou skupinu s , až 4 atomy uhlíku a R-j znamená s ·) fenylovou skupinu, která je buS neaebatituovaná nebo substituovaná atomem chloru,metylovou skupinou, nebo alkoxylovou skupinou s 1 až 2 atomy uhlíku, nebo b'") 2-tienylovou a taká jejich farmaceuticky přijatelná soli.Particularly preferred compounds of the invention are compounds of formula I wherein R 1 is hydrogen, b 1 is methyl, ethyl or diethylaminoethyl, K 2 is C 1 -C 4 alkyl and R 1 is phenyl. which is either unsaturated or substituted with a chlorine atom, a methyl group, or a C 1 -C 2 alkoxy group, or b '"2-thienyl, and the pharmaceutically acceptable salts thereof.
Ve výhodných sloučeninách podle vynálezu skupina GOORj znamená skupinu karboxylovákyseliny. TSmito sloučeninami jsou pak volná, kyseliny nebo soli karboxylových kyselin. Příklady zvláátá výhodných sloučenin podle vynálezu jsou: 2-trans-(2-fenyletylen)-3-propyl-6,7-raetylen-4-oxo-4H-pyrido/1,2-a/pyrimidln-7-karboxylovákyselina, 2-trans-(2-fenyletphyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylovákyselina, 2-trans-/2-(2-metylfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7--karboxylová kypeline, 2-trans-/2-(3-metylfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyriďo/1,2-a/pyrimidin-7--karboxylová kyselina, 2-trans-/2-(4-metylfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7--karboxylová kyselina, 2-trans-/2-(2-metoxyfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-ejípyrimidin-7--karboxylová kyselina, 2-trans-/2-(3-metoxyfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-·-karboxylová kyselina, * 2-trans-/2-(2,3-dimetoxyfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin--7-karboxylová kyselina, 2-trans-/2-(2-metylfenyl)etenyl/-3-propyl-6,7-metylen-4-oxo-4H-pyrldo/1,2-a/pyrimidin--7-karboxylová kyselina, 2-trana-/2-í2,3-dimetoxyfenyl)etenyl/-3-propyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimi-din-7-karboxylová kyselina, 244131 4 2-trans-/2-(2-Betoxy-3-etoxyfenyl)etenyl/-3-propyl-6,7-metylen-4-oxo-4H-pyrido/1 ,2-a/pyri-midin-7-kařboxylové kyselina, 2-trans-/2-i2*metoxy-3-etoxyřenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyri-midin-7-karbOxylová kyselina a také jejich farmaceuticky přijatelné soli, zvláítí sodné soli, bázické estery (napříkladestery, 2-dietylaminoetanolu)i a jejich alkylestery s alkylovou skupinou β 1 až 2 atomyuhlíku.In preferred compounds of the invention, the group GOOR 1 is a carboxylic acid group. These compounds are then free, acids or salts of carboxylic acids. Examples of particular preferred compounds of the invention are: 2-trans- (2-phenylethylene) -3-propyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid; trans- (2-Phenylethyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2-methylphenyl)] ethenyl / 3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (3-methylphenyl) ethenyl] - 3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-trans- [2- (4-methylphenyl) ethenyl] -3-ethyl -6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2-methoxyphenyl) ethenyl] -3-ethyl-6, 7-methylene-4-oxo-4H-pyrido [1,2-i] pyrimidine-7-carboxylic acid 2-trans- [2- (3-methoxyphenyl) ethenyl] -3-ethyl-6,7-methylene-4 -oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid; 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-ethyl-6,7-methylene- 4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-trans- [2- (2-methylphenyl) ethenyl] -3-propyl-6,7-methylene-4-ox o-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-propyl-6,7-methylene-4-oxo- 4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 244131 4 2-trans- [2- (2-Betoxy-3-ethoxyphenyl) ethenyl] -3-propyl-6,7-methylene- 4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2) methoxy-3-ethoxyphenyl) ethenyl] -3-ethyl-6,7-methylene -4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carbonic acid as well as pharmaceutically acceptable salts thereof, especially sodium salts, basic esters (for example esters, 2-diethylaminoethanol) and their alkyl esters with the alkyl group β 1 to 2 carbon atoms.
Sloučeniny podle vynálezu se aohou vyrábít způsobem vyznačujícím se tím, ie secyklopropanuje sloučenina obecného vzorce IVThe compounds of the invention may be prepared by a process characterized in that the compound of formula (IV) is cyclic
O (IV) CH=CH—R3 v nimž R,, Rj a B3 znamenají, jek shora uvedeno, nebo její sůl a je-li to žádoucí, získanásloučenina obecného vzorce I se převede na jinou sloučeninu obecného vzorce I a/nebo,je-li to Žádoucí, sloučenina obecného vzorce I se převede na farmaceuticky přijatelnousůl, a/nebo, je-li to žádoucí, sůl se převede na volnou kyselinu, a/nebo, je-li to žádoucísmis isomerů se rozdílí na jednotlivé isomery.O (IV) CH = CH-R 3 wherein R 1, R 1 and B 3 are as defined above, or a salt thereof and, if desired, the compound of formula I obtained is converted to another compound of formula I and / or is If desired, the compound of formula (I) is converted into a pharmaceutically acceptable salt, and / or, if desired, the salt is converted to the free acid, and / or, if desired, the individual isomers are different.
Cyklopropanace sloučeniny obecného vzorce IV se Bůže provádít například tak, Že sezpracuje s dimetylsulfoxoniummetylidem (který se vyrábí např. metodou popsanou v J. Chsm.Soc. 1967, 2 495). Zpracování,se provádí v inertním organickém rozpouitídle, které je vy-bráno ze skupiny sestávající z dimetylformamidu, dimetylsulfoxidu v rozmezí od asi 0 doasi 50 °C. Reakční doba je obvykle menlí než.5 hodin, a výhodou aeníí než 2 hodiny. Najeden nol sloučeniny obecného vzorce I se s výhodou používá 1 až 3 moly reakčního činidla,zvláltí 1 až 1,5 molu činidla.The cyclopropanation of a compound of formula IV can be carried out, for example, by treatment with dimethylsulfoxonium methylide (which is produced, for example, by the method described in J. Chsm. Soc. 1967, 2,495). The treatment is carried out in an inert organic solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide in the range of about 0 ° C to 50 ° C. The reaction time is usually less than 5 hours, and preferably less than 2 hours. Preferably, 1 to 3 moles of reagent is used per nole of the compound of the formula I, in particular 1 to 1.5 mol of the reagent.
Jak je shora uvedeno, sloučenina obecného vzorce I se Bůže převádít na jinou slouče-ninu obecného vzorce I známými způsoby. Například sloučenina obecného vzorce I, v nímž-COOR, znamená esterifikovanou karboxylovou skupinu, se může převést na sloučeninu obec-ného vzorce I, v nímž -GOORj znamená kerboxylovou skupinu, hydrolýzou, například bázickouhydrolýzou, při básické hydrolýae sa používá např. hydroxid sodný nebo hydroxid draselnýv rozpoultldle, jako ja např. voda nebo nižlí alifatický alkohol, sa teploty v rozneslod teploty aíatnoati do aal 150 °C. Stojná roakeo se nůža provést např. také zpracováníma bromidem litnýn v dlnetylforswnidu při toplotl vyžil než 50 °C. *As noted above, a compound of formula I can be converted to another compound of formula I by known methods. For example, a compound of formula (I) wherein -COOR is an esterified carboxyl group can be converted to a compound of formula (I) wherein -GOOR1 is a carboxyl group by hydrolysis, for example, by basic hydrolysis, e.g. potassium hydroxide in a solvent such as, for example, water or a lower aliphatic alcohol, the temperature is raised to about 150 ° C. The standing roakeo is cut with the knife, for example, by treatment with lithium bromide in dimethylformamide at a temperature of 50 ° C. *
Sloučenina obecného vsorce Z, v nínž -OOOR, znamená karboxylovou skupinu, se můžepřevézt na sloučeninu obecného vzorce Z, v nínž -GOQa, znamená eateriflkovsnou kerboxy-lovou skupinu, např. alkoxykařboaylovou skupinu, obvyklými způsoby. Například ae alkalickásůl kyseliny zpracovává a vhodní substituovaným alkylhelogeniden v inertnía rozpoultldle,jako např. v acetonu, dioxanu, dimetylformanidu nebo hexametylfoafortrlamidu, při teplotlv rozmezí od aal 0 do aal 100 °C.The compound of general formula Z, in which -OOOR, represents a carboxyl group, can be converted to a compound of formula Z, in which -GOQa, is an erythiocarboxylic group, for example an alkoxy group, by conventional means. For example, and the alkali metal salt is treated and suitably substituted with an alkyl halide in an inert solvent such as acetone, dioxane, dimethylformanide or hexamethylfoafortrlamide, at a temperature ranging from aal to 0 ° to 100 ° C.
Sloučeninu obecného vzorce Z lze také eaterlfikovat a ) převedením sloučeniny obecného vzorce Z, v nimi -COOR, znamená karboxylovou skupinu,na odpovídající halogenkarbonylový, a výhodou chlorkarbonylový derivát zpracováním např.z příalulným halogenidem kysSllay, například chloridem kyseliny oxelové, tionylohloriden, 5 244131 chloridem fosforitým, chloridem fosforečným nebo oxychloridem fosforečným. loto zpracováníse provádí bu3 bez rozpouštědle nebo v inertním organickém rozpouětědle, jako napříkladv benzenu, toluenu, xylenu, dioxenu, dichloretenu, dlchlormetanu nebo tetrahydrofuranu,při teploti v rozmezí e výhodou od asi 0 do asi 120 °C, a pak b') se zpracovává získaný helogenkerbonylový derivát s vhodným alkoholem obecnéhovzorce R^-OH, v nímž R, znamená,jak shora uvedeno. Toto zpracování se provádí v inertnímrozpouětědle, jako například v benzenu, toluenu, xylenu, dioxenu, dichloretanu, dichloř-me tanu, nebo v tetrahydrofuranu, při teplotč v rozmezí od asi 0 do asi 120 °C. Zpracováníse provádí s výhodou za přítomnosti báze, jako je například trietylaminu nebo dietylaminu. Běžnými způsoby lze sloučeninu obecného vzorce 1 také převést na její sdl, převésttuto sdl na volnou kyselinu a dělit směsi isomerů na jednotlivé isomery. Dělení smési optických Isomerů na jednotlivé isomery lze provést tak, že se vyrobísůl s opticky aktivní bází a produkt se frakčné krystaluje.The compound of formula Z can also be purified by a) converting a compound of formula Z, in which -COOR, is a carboxyl group to the corresponding halocarbonyl, and preferably chlorocarbonyl derivative, by treatment with, for example, an oxalic acid halide, for example oxelic chloride, thionyl chloride, 5,241,131 chloride phosphorous, phosphorus pentachloride or phosphorus oxychloride. This treatment is carried out either without solvent or in an inert organic solvent such as benzene, toluene, xylene, dioxene, dichloroethene, dichloromethane or tetrahydrofuran, at a temperature in the range of preferably from 0 to about 120 ° C, and then b ') is processed. the resulting helogen carbonyl derivative with a suitable alcohol of the general formula R 1 -OH, in which R 1 is as defined above. This treatment is carried out in an inert solvent such as benzene, toluene, xylene, dioxene, dichloroethane, dichloromethane, or tetrahydrofuran at a temperature in the range of about 0 to about 120 ° C. The treatment is preferably carried out in the presence of a base such as triethylamine or diethylamine. Conventional methods can also be used to convert the compound of Formula 1 into its sd1, convert it into the free acid, and divide the isomer mixtures into individual isomers. The separation of the mixture of optical isomers into individual isomers can be accomplished by making a salt with an optically active base and fractionating the product.
Smés geometrických isomerů se může rozdělit například frakční krystalizací.The mixture of geometric isomers can be separated, for example, by fractional crystallization.
Sloučeniny obecného vzorce IV se mohou vyrábět například tak, že se sloučeninaobecného vzorce IICompounds of formula IV may be prepared, for example, by the compound of formula II
OO
kdewhere
R, a Rg znamenají jak shora uvedeno, zpracuje s aldehydem obecného vzorce III OHC-Rj (III), v němžR 1 and R 8 are as defined above, treated with an aldehyde of formula III OHC-R 1 (III) in which
Rj znamená jak shora uvedeno, za shora uvedených experimentálních podmínek.R 1 is as defined above under the above experimental conditions.
Sloučeniny obecného vzorce II, se mohou vyrábět například cyklizacl sloučeniny’ obecného vzorce VI kdeThe compounds of formula (II) can be prepared, for example, by the cyclization compounds of formula (VI) wherein:
(VI), R, a Rj znamenají jak shora uvedeno a fi10 znamená atom vodíku nebo nižěí alkylovouskupinu, s výhodou metylovou nebo etylovou skupinu. 244131 6(VI), R 1 and R 1 are as defined above, and f 10 is a hydrogen atom or a lower alkyl group, preferably a methyl or ethyl group. 244131 6
Cyklizece sloučeniny obecného vzorce VI se může provádět například za přítomnostikyselého katalyzátoru, Jako Je například pólyfosforečná kyselina (kyselinou polyfosforečnouse rozumí smés stejných hmotnostních podílů 99% kyseliny fosforečné a kysličníku fosforeč-ného), kyselina chlorovodíková, bromovodíková, jodovodíkové, sírová a p-toluensulfonová,za tpploty v rozmezí s výhodou od 90 do 290 °C. Cyklizece se může provádět v inertnímorganickém rozpouštědle, které je vybráno například ze skupiny sestávající z alifatickéhoalkoholu s 1 až 6 atomy uhlíku, dimetylformamidu, dioxanu, tetrahydrofuranu, benzenu,toluenu, xylenu, kyseliny octové, monome tyle*teru etylenglykolu a jejich směsí. Cyklizecese vSak s výhodou provádí bez rozpouštědel.The cyclization of the compound of formula (VI) may be carried out, for example, in the presence of an acid catalyst, such as, for example, polyphosphoric acid (polyphosphoric acid means a mixture of equal parts by weight of 99% phosphoric acid and phosphorus pentoxide), hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and p-toluenesulfonic acid, at temperatures in the range of preferably 90 to 290 ° C. The cyclization may be carried out in an inert organic solvent selected, for example, from the group consisting of an aliphatic alcohol of 1 to 6 carbon atoms, dimethylformamide, dioxane, tetrahydrofuran, benzene, toluene, xylene, acetic acid, ethylene glycol and mixtures thereof. However, the cyclisecession is preferably carried out without solvents.
Sloučeniny obecného vzorce VI se mohou vyrábět tak, že se sloučenina obecnéhovzorce IXCompounds of formula (VI) may be prepared by forming a compound of formula (IX)
RtOOCRtOOC
nh2 (ix), v němžnh2 (ix) in which
znamená jak shora uvedeno, zpracuje se sloučeninou obecného vzorce X COOR, Λ10 CHR„means as above, treated with a compound of formula X COOR, Λ10 CHR „
CO (X), v němž a R)o znamenají jak shora uvedeno.CO (X) wherein a R 1 is as defined above.
Zpracování sloučeniny obecného vzorce IX se sloučeninou obecného vzorce X se mdžeprovádět například za stejných experimentálních podmínek, jaké byly shora uvedeny procyklizaci sloučenin obecného vzorce VI.The treatment of a compound of formula IX with a compound of formula X can be carried out, for example, under the same experimental conditions as the aforementioned procyclization of compounds of formula VI.
Sloučenina obecného vzorce III je známé sloučenina. Lze ji vyrábět konvenčnímizpůsoby a jde o komerčně dostupný produkt.The compound of formula III is a known compound. It can be produced by conventional methods and is a commercially available product.
Sloučeniny podle vynálezu mají antialergickou účinnost. Jsou tedy užitečné připrevenci a léčení všech onemocnění alergického původu, např. bronchiálnl astma, alergickárinitida (zánět nosní sliznice), senná rýma, urtikarle(kopřivka) a dermetitida (zánětkůže). /The compounds of the invention have antiallergic activity. They are therefore useful in the treatment and treatment of all diseases of allergic origin, such as bronchial asthma, allergic rhinitis (inflammation of the nasal mucosa), hay fever, urticarle (urticaria) and dermetitis (inflammation). /
Antialergickou účinnost sloučenin podle vynálezu ukazuje fakt, že tyto sloučeninyjsou účinné při testu pasivní kožní anafylaxie (PCA test) ne krysách podle J. Goosehoa A. U. J. N. Blaira /Immunology 16. 749 (1969)/. Důležitou zvláštností těchto sloučeninpodle vynálezu je to, že vykazují vysokou antialergickou účinnost také při orálním po-dávání . V následující tabulce jsou uvedeny účinnosti při PCA testu u krys po orálním podá-váni několika sloučenin podle vynálezu, které jsou*identifikovány kódy: K 13 608, PCE 20 909, X 13 830, FCE 20 099, PCE 20 183, PCX 20 461, resp. FCE 20 188, ve srovnánís velmi dobře známou antialergickou sloučeninou DSCG (dinatriumkromoglykát). 7 24*131 Účinnost je vyjádřena v hodnotčKg, která je definována jako taková dávka účinná látky,která je schopna snížit účinnost sára, použitého pro senzitizaci, na jadnu polovinu:The anti-allergic activity of the compounds of the present invention is demonstrated by the fact that these compounds are effective in the passive skin anaphylaxis (PCA test) test in rats according to J. Goose A. U. J. N. Blair (Immunology 16,749 (1969)). An important feature of these compounds according to the invention is that they also exhibit high antiallergic activity in oral administration. The following table shows the efficacy in the PCA test in rats following the oral administration of several compounds of the invention, which are identified by codes: K 13 608, PCE 20 909, X 13 830, FCE 20 099, PCE 20 183, PCX 20 461 , respectively. FCE 20 188, as compared to the well-known antiallergic compound DSCG (disodium necromoglycate). 7 24 * 131 The potency is expressed as Kg, which is defined as the dose of the active ingredient that is capable of reducing the effectiveness of the sera used for sensitization by half:
B DH- 1 kde B znamená dávku antagonistické sloučeniny v mg/kg a DB znamená pomér dávek: antilogaritmus rozdílu funkcí log účinku dávky séra s a bas antagonistické sloučeniny (J. H. Gaddum a spol: fixp. Physlol. 40. *9 /1955/.).B DH-1 where B is the antagonist compound dose in mg / kg and DB is the dose ratio: antilogarithm of the difference in the function of the log dose of the serum and the bas antagonist compound (JH Gaddum et al., Fixp. Physlol. 40: 9/1955). .
Hodnota Kg se zde používá proto, že tato hodnota je nezávislá jek na dávce drogy, taki na koncentraci činidla použitého pr.o senzitizaci. Cím nižčí je hodnota Κβ, tím vySSí je antialergická účinnost. V následující tabulce jsou sloučeniny identifikované tčmito kódy: K 13 808: 2-trans-(2-fenyletenyl)-3-propyl-4-oxo-4H-pyrido/1 ,2-a/pyrimidin-7-karboxylovákyselina, K 13 830: 2-trans-(2-fenyletenylJ-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidinu-7--karboxylová kyselina, FCE 20 099: 2-trans-/2-(2-metylfenyl)etenyl/-3-propyl-4-oxo-4H-pyrido/1,2-a/pyrimidin--7-karboxylové kyselina, PCE 20 183: 2-trans-/2-(3-metoxyfenyl)etenyl/-3-propyl-4-oxo-4H-pyrido/1,2-a/pyrimidin--7-tarboxylová kyselina, PCE 20 188: 2-trans-(2-fenyletenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrlmidin-—7-karboxylová kyselina, PCE 20 509: 2-trsns-/2-(3-metoxyfenyl)etenyl/-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/py-rimidin-7-karboxylová kyselina, PCE 20 461: 2-trans-/2-(2,3-dimetoxyfenyl)etenyl/-3-propyl-6,7-metylen-4-oxo-*H-pyrido/1,-2-a/pyrimidin-7-karboxylové kyselina,The Kg value is used here because this value is independent of the drug dose and the concentration of reagent used for sensitization. The lower the Κβ value, the higher the anti-allergic activity. The following table identifies the compounds identified by the following codes: K 13 808: 2-trans- (2-phenylethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, K 13 830 : 2-trans- (2-phenylethenyl-3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, FCE 2099: 2-trans- [2- (2-Methylphenyl) ethenyl] -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE20 183: 2-trans- / 2- (3 -methoxyphenyl) ethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-tarboxylic acid, PCE 20 188: 2-trans- (2-phenylethenyl) -3-propyl- 6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE 20 509: 2-tris- [2- (3-methoxyphenyl) ethenyl] -3-ethyl -6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE 20 461: 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-Propyl-6,7-methylene-4-oxo- H -pyrido [1,2-a] pyrimidine-7-carboxylic acid
TabulkaTable
Sloučenina Doba před podáním antigenu Antialergická účinnost KB (mg/kg) - p.o. FCE 15' 2,34 K 13 830 15' 1,15 FCE 20 183 15' 1,48 FCE 20 009 15' 2,02 K 13 808 15' 2,16 FCE 20 509 15' 0,61 FCE 20 461 15' 1,22 DSCG 15' více než 200Compound Time before antigen administration Antiallergic activity KB (mg / kg) - p.o. FCE 15 '2.34 K 13 830 15' 1.15 FCE 20 183 15 '1.48 FCE 20 009 15' 2.02 K 13 808 15 '2.16 FCE 20 509 15' 0.61 FCE 20 461 15 '1.22 DSCG 15' over 200
244131244131
Antielergická účinnost byle stenovováne např. inhibicí IgE-zprostředkovené PCA podleJ. Qooseho a A. M. J. N, Blaira (Immunology 16. 749 /1969/.) pomocí homocytotropickýchprotilátek z krys způsoben podle I. Mot?: Immunology £, 681 (1964).The anti-allergic efficacy has been refined, e.g., by inhibiting IgE-mediated PCA. Qoose and A.M. J. N, Blair (Immunology 16,749 (1969)) using homocytotropic rat antibodies caused by I. Mot ?: Immunology, 681 (1964).
Testované sloučeniny byly podávány per os (p.o.) 18 minut před podáním entlgenu.Pro každou dávku bylo použito alespoň 6 krys.Test compounds were administered per os (p.o.) 18 minutes before entlgen administration. At least 6 rats were used for each dose.
Sloučeniny podle tohoto vynálezu vykazují táž protivředovou účinnost, což bylo demonstro-váno např. tak, že se prokázala účinnost při inhibici vředů vyvolaných stresem ú krys,které jsou drženy 40 minut ve vodní lázni o teplotě 25 °C podle modifikace popsané Taka-gim K. a Okabem S. /Jep. J. of Pharmacology 12, 9 (1968)./.The compounds of the present invention exhibit the same anti-ulcer activity as demonstrated, for example, by demonstrating efficacy in the inhibition of stress-induced ulcers in rats that are kept in a 25 ° C water bath according to the modification of the described Taka-gim K for 40 minutes. and Okabem S. / Jep. J. of Pharmacology 12, 9 (1968).
Vedle antialergické účinnosti jsou sloučeniny podle tohoto vynálezu, zvláětě slouče-nina obecného vzorce I, v němž Rg znamená atom vodíku nebo metylovou skupinu, užitečnéjako antidiabetická Činidle. To bylo ukázáno například tak, že tyto sloučeniny jsouúčinné při snižování hyperglycemického účinku glukosaminu u myěí.In addition to antiallergic activity, the compounds of the present invention, in particular the compound of formula I wherein R8 is hydrogen or methyl, are useful as antidiabetic agents. This has been shown, for example, by such compounds being effective in reducing the hyperglycemic effect of glucosamine in mice.
Vzhledem ke svému vysokému terapeutickému indexu mohou být sloučeniny podle vynálezubezpečně používány v lékařství. Například přibližná akutní toxicita (LD50) sloučeniny2-trana-(2-fenyletenyl)-3-propyl-4-oxo-4H-pyrido/,,2-a/pyrimidin-7-kerboxylové kyselinyu myěí je vyiií než 800 mg/kg (stanoveno jednotlivým podáváním zvyěujících se dávek;měřeno sedmý den po perorálním podání). Analogická toxicita byle nalezena u jiných slouče-nin podle vynálezu.Because of their high therapeutic index, the compounds of the invention can be safely used in medicine. For example, the approximate acute toxicity (LD50) of 2-trana- (2-phenylethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid is higher than 800 mg / kg ( determined by single administration of increasing doses, measured on day 7 after oral administration. Analogous toxicity was found with other compounds of the invention.
Sloučeniny podle vynálezu se mohou podávat obvyklým způsobem. Například při léčeníalérgií, například bronchiálního astmatu, orálně a parenterálně v denních dávkách s vý-hodou 0,5 až 1)5 mg/kg, inhalací v denních dávkách 0,5 až 100 mg výhodněji 0,5 až 25 mg,nebo povrchovou aplikací (například při léčení zánětu- sliznice nosní nebo kožních onemocně-ní), například jako krém, který obsahuje 0,5 až 5 mg, s výhodou 1 až 2 mg účinné složkyve 100 mg krému. Při léčení cukrovky se sloučeniny podle vynálezu mohou podávat orálně, v denníchdávkách s výhodou od 500 do 1 00Ó mg.The compounds of the invention may be administered in conventional manner. For example, in the treatment of allergies, for example bronchial asthma, orally and parenterally at daily doses of preferably 0.5 to 1) 5 mg / kg, by inhalation at daily doses of 0.5 to 100 mg, more preferably 0.5 to 25 mg, or topical application (e.g., in the treatment of nasal or skin inflammation), for example, as a cream containing 0.5 to 5 mg, preferably 1 to 2 mg, of the active ingredient in 100 mg of cream. In the treatment of diabetes, the compounds of the invention may be administered orally, preferably in daily doses of from 500 to 10000 mg.
Charakter farmaceutických prostředků, které obsahují sloučeniny podle vynálezu spoluβ farmaceuticky vhodnými nosiči nebo ředidly, závisí ověem na terapeutickém použití ana způsobu podávání. ' Prostředky mohou být fármulovány běžným způsobem za použití obvyklých přísad.The nature of the pharmaceutical compositions which contain the compounds of the invention together with pharmaceutically acceptable carriers or diluents is dependent on the therapeutic use and mode of administration. The compositions may be formulated in conventional manner using conventional additives.
Sloučeniny podle vynálezu se mohou podávat ve formě vodných nebo olejových roztoků/ nebo suspenzi, aerosolů a také prážky, tabletka, pilulky, želatinové tobolky, sirupy, kapky, čípky nebo jako krémy ne^o lotiony (omývadla) pro povrchové použití.The compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, aerosols as well as powders, tablets, pills, gelatin capsules, syrups, drops, suppositories or lotions (lotions) for topical use.
Pro orální podávání jsou tedy farmaceutické prostředky, které obsahují sloučeninypodle vynálezu, s výhodou ve formě tablet, pilulek nebo želatinových tobolek. Spolue účinnou složkou obsahují ředidla-, jeko je například laktóza, dextroze, sacherose,manitol, sorbitol a celulóza, mazadla, například kysličník křemičitý, talek, kyselinastesrová, stearát hořečnatý nebo vápenatý a/nebo polyetylenglykoly. Nohou obsahovattaké pojidla, jako jsou například ikroby, želatina, metylcelulóza, karboxymetylcelulóza,arabská guma, tragant a polyvinylpyrrolidon, desintegrační činidla, jako jsou napříkladikroby, alginová kyselina, algináty a sodná sůl glykolátu žkrobu, efervescenční (žúmící)Směsi, barviva, sladidla, amáčacl činidla, jako například leclthin, polysorbáty a lauryl-sulfáty a obecni řečeno netoxické a farmakologicky neúčinné sloučeniny, které se používají(Viř farmaceutických prostředcích. 9 244131Thus, for oral administration, the pharmaceutical compositions containing the compounds of the invention are preferably in the form of tablets, pills or gelatin capsules. The active ingredient comprises diluents such as lactose, dextrose, sacherose, mannitol, sorbitol and cellulose, lubricants, for example silica, talc, esters, magnesium or calcium stearate and / or polyethylene glycols. They also contain binders, such as, for example, starches, gelatin, methylcellulose, carboxymethylcellulose, acacia, tragacanth and polyvinylpyrrolidone, disintegrating agents such as microbes, alginic acid, alginates and sodium starch glycolate, effervescent mixtures, dyes, sweeteners, amaccharides. agents such as leclthin, polysorbates and lauryl sulfates and, in general, non-toxic and pharmacologically inactive compounds to be used (See Pharmaceutical Compositions.
Uvedené farmaceutické prostředky se mohou vyrábět známým způsobem, například smíšením,granulecí, tabletováním, potahováním cukrem nebo potahováním filmovými povlaky. Při léčení alergického astmatu se sloučeniny podle vynálezu podávají také jakoinhalace. Vhodnými prostředky pro toto použití mohou být suspenze nebo roztoky účinnésložky, e výhodou ve formě soli, jako například sodné soli, ve-vodě, při podávání běžnýmrozprašovačem. Prostředky mohou být také suspenze nebo roztoky účinné složky v konvenčníkapalné hnací látce, jako je dichlordifluormetan nebo dichlortetrafluoretan, ty jsoupak podávány z tlakové nádoby, například aerosolového rozprašovače. Jestliže medikamentnení rozpustný v hnací látce, může být nutné přidat k prostředku rozpouštědlo, jako jeetanol, dipropylenglykol, isopropylmyristan, a/nebo povrchově aktivní prostředek, aby semedikament suspendoval v hnacím prostředí. Těmito povrchově aktivními prostředky mohoubýt kterékoliv povrchově aktivní prostředky, které se obvykle používají pro tyto účely,jako jsou neionogenní povrchově aktivní prostředky, např. lecithin.Said pharmaceutical compositions may be prepared in a manner known per se, for example by mixing, granulating, tabletting, sugar-coating or film-coating. In the treatment of allergic asthma, the compounds of the invention are also administered as inhalations. Suitable formulations for this use may be suspensions or solutions of the active ingredient, preferably in the form of a salt, such as a sodium salt, in water, when administered by conventional spray. The compositions may also be suspensions or solutions of the active ingredient in a conventional liquid propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane, which are then administered from a pressurized container, for example, an aerosol dispenser. If the drug is soluble in the propellant, it may be necessary to add a solvent, such as ethanol, dipropylene glycol, isopropyl myristate, and / or a surfactant to the composition to suspend the semedicament in the propellant. These surfactants may be any of the surfactants conventionally used for such purposes, such as nonionic surfactants, e.g., lecithin.
Sloučeniny podle vynálezu mohou být podávány také ve formě prášků vhodným zařízením. V tomto případě se jemný prášek účinné složky může smísit s ředidlem, jako je laktdza.The compounds of the invention may also be administered in the form of powders by suitable devices. In this case, the fine powder of the active ingredient may be mixed with a diluent such as lactose.
Sloučeniny podle vynálezu mohou být podávány také obvyklým způsobem intradermálnl(podkožní) nebo intravenosní injekcí.The compounds of the invention may also be administered by the usual route of intradermal (subcutaneous) or intravenous injection.
Vedle vnitřního podávání se sloučeniny podle tohoto vynálezu mohou používati v prostředcích určených pro povrchové aplikace, např. jako krémy, lotiony (omývadla)nebo pasty, při léčení dermatitid. Při výrobě těchto prostředků se účinná složka můžesmíchat s konvenčními olejovitými nebo emulgačními/éxcipienty. Následující příklady ilustrují, ale neomezují tento vynález. Přiklad lIn addition to internal administration, the compounds of this invention may be used in topical applications, e.g., creams, lotions or pastes, for the treatment of dermatitis. In the preparation of these compositions, the active ingredient may be mixed with conventional oily or emulsifying agents. The following examples illustrate, but do not limit, the invention. Example 1
Trimetylsulfoxoniumjodid (0,7 g) se zpracovává 1 hodinu s 50% hydridem sodným (0,15 g)v dimetylformamidu (30 ml) za míchání při teplotě místnosti. Potom se přidá roztok metyl-esteru 2-trans-(2-fenyletenyl)-3-etyl-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylové ky-seliny (0,S2 g, t.t. 214 až 216 °C) v dimetylformamidu (20 ml).Trimethylsulfoxonium iodide (0.7 g) was treated with 50% sodium hydride (0.15 g) in dimethylformamide (30 ml) for 1 hour with stirring at room temperature. Then a solution of 2-trans- (2-phenylethenyl) -3-ethyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid methyl ester (0.5 g, tt) is added. 214-216 ° C) in dimethylformamide (20 mL).
Směs se nechá reagovat 3 hodiny za teploty místnosti při míchání. Potom se směszředí ledovou vodou a filtruje. Krystalizací z acetonu se získá metylester 2-trans-(2--fenyletenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido/l,2-a/pyrimidin-7-karboxylové kyseliny(0,53 g, t.t. 194 až 195 °C). Tento ester se zpracovává 15 minut s 1% hydroxidem drasel-ným v 95% etanolu (11 ml) při teplotě varu reakčnl směsi. Po ochlazení se reakčnl směsokyselí kyselinou octovou, odpaří ve vakuu a zředí ledovou vodou. Sraženina se odfiltrujea promyje vodou do neutrální reakce. Krystalizací z acetonu se vyrobí 0,34 g 2-trans-(2--fenyletenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido/l,2-a/pyrimidin-7-karboxylové kyseliny,t.t. 215 až 216 °C. NMB spektrum (CFjCOOD) :<S: 1,22 (m) a 2,93 (m) (6,7-CH2 protony), 1,36 (t, CH^CHj). 2,93 (m, CH--GHj). 5,51 (dd, C^6 proton), 7,01 (d, C-9 proton), 7,31 (d, H vinylovýproton), 7,63 (br a, fenylové protony), 7,76 (d, vinylový proton).The mixture is reacted for 3 hours at room temperature with stirring. Then the mixture is diluted with ice water and filtered. Crystallization from acetone yields 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid methyl ester (0, 53 g, mp 194-195 ° C). This ester was treated with 1% potassium hydroxide in 95% ethanol (11 mL) for 15 minutes at the boiling point of the reaction mixture. After cooling, the reaction mixture was acidified with acetic acid, evaporated in vacuo and diluted with ice water. The precipitate is filtered off and washed with water until neutral. Crystallization from acetone yields 0.34 g of 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid , tt Mp 215-216 ° C. NMB spectrum (CF 3 COOD): δ: 1.22 (m) and 2.93 (m) (6,7-CH 2 protons), 1.36 (t, CH 2 CH 3). 2.93 (m, CH-GH3). 5.51 (dd, C ^ 6 proton), 7.01 (d, C-9 proton), 7.31 (d, H vinylprotone), 7.63 (br and, phenyl protons), 7.76 (d , vinyl proton).
Analogickým způsobem se vyrábějí následující sloučeniny: 2-trane-(2-fenyletenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylovákyselina, t.t. 222 až 224 °C, MIH spektrum (CPjCOOD):6: 1,18 (t) a 2,84 (dd) (6,7-metylenové'protony), 5,44 (dd, C-6 proton), 6,95 (d, C-9 proton), 8,18 (d, C-8 proton), 244131 10 2-tr8ns(2-f6nyletenyl)-3-propyl-6,7-metylen-4-oxo-4Hipyrido/1,2-e/pyrimidin-7-*arboxylovákyselina, t.t. 160 °C (rozklad), NMR spektrum (CFjC00D):6: 1,13 (t, 6,7-metylenový protona -CHgClUgBj). 1,60 až 2,00 (m, ). 2,76 až 3,02 (m, -CH-C^GH-^) 5,47 (dd, C-6 proton), 6,97 (d, C-9 proton), 7,26 (d, Hp vinylový proton), 7,38 až 7,80 (m, Ha viny-lový proton a fenylová protony), 8,20 (d, C-8 proton), 2-trana-(2-fenyletenyl)-6,7-metylen-4-oxo-4H-pyriúo/1,2-e/pyrimidln-7-karboxylová kyselme,t.t. 205 až 210 °C (rozklad) a 2-trans-(2-fenyletenyl)-3-buty1-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylovákyselina, t.t. 135 °C (rozklad), NUR spektrum (CF^COOB)^: 1,00 (m, 6,7-metylenový proton),2,90 (m, 6,7-metylenový proton a -CH^-GtU-GHo-GHj). 5,66 (dd, C-6 proton), 6,95 (d, C-9proton), 8,19 (d, (d, C-8 proton). Příklad 2 lThe following compounds were prepared analogously: 2-trans- (2-Phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 222-224 ° C, MIH spectrum (CP 2 COOD): 6: 1.18 (t) and 2.84 (dd) (6,7-methyleneprotones), 5.44 (dd, C-6 proton), 6 , 95 (d, C-9 proton), 8.18 (d, C-8 proton), 244131 10 2-tris (2-phenylethenyl) -3-propyl-6,7-methylene-4-oxo-4Hipyridone 1,2-e / pyrimidine-7- * arboxylic acid, m.p. 160 ° C (decomposition), NMR spectrum (CF 3 CO 2 D): 6: 1.13 (t, 6,7-methylene proton -CHgClUgBj). 1.60 to 2.00 (m,). 2.76 to 3.02 (m, -CH-C 6 H 4 H), 5.47 (dd, C-6 proton), 6.97 (d, C-9 proton), 7.26 (d, Hp) vinyl proton), 7.38 to 7.80 (m, Ha vinyl proton and phenyl protons), 8.20 (d, C-8 proton), 2-trans- (2-phenylethenyl) -6,7- methylene-4-oxo-4H-pyrrolo [1,2-e] pyrimidine-7-carboxylic acid, m.p. 205 DEG-210 DEG C. (decomposition); and 2-trans- (2-phenylethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 135 ° C (decomposition), NUR spectrum (CF 3 COOB) δ: 1.00 (m, 6,7-methylene proton), 2.90 (m, 6,7-methylene proton and -CH 2 -GtU-GHo -GHj). 5.66 (dd, C-6 proton), 6.95 (d, C-9protone), 8.19 (d, (d, C-8 proton).
Trimetylsulfoxoniumjodid (1 g) se zpracovává 30 minut za mícháni za teploty místnosti;s 509 hydridem sodným (0,22 g) v dimetylformamidu (30 ml). Potom se přidá roztok.metylests»ru 2-trBns-(2-/3-metoxyfenyl/etenyl)-3-etyl-4-oxo-4H-pyrido/1,2-a/-pyrimidin-7-karboxylovákyseliny (t.t. 177 až 179 °C, 1,27 g) v dimetylformamidu (20 ml). Smás se nechá reagovat2 hodiny za míchání při teplotá místnosti,poté se zředí ledovou vodou a sraženina se od-'filtruje. Vyrobí se tak 1,19 g metylesteru 2-trans-(2-/3-metoxyfenyl/-etenyl)-3-etyl--6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylová kyseliny (t.t. 184 až 188 °C).Trimethylsulfoxonium iodide (1 g) was treated with stirring at room temperature for 30 minutes, with 509 sodium hydride (0.22 g) in dimethylformamide (30 ml). A solution of the methyl ester of 2-tris (2- (3-methoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid (tt 177) is then added. to 179 ° C, 1.27 g) in dimethylformamide (20 mL). The mixture was reacted with stirring at room temperature for 2 hours, then diluted with ice water and the precipitate was filtered off. 1.19 g of 2-trans- (2- (3-methoxyphenyl) -ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine methyl ester is obtained. -7-carboxylic acid (mp 184-188 ° C).
Ten se zpracovává 15 minut s 0,59 hydroxidem draselným v 959 etanolickám roztoku(40 ml). Po ochlazení se reakční smás zředí vodou, okyselí se.kyselinou octovou a sraže-nina Se odfiltruje. Krystalizecl ze smási dlchlormetan-metanol se vyrobí 2-trens(2-/3--metoxyfenyl/-etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido/1,2-a/pyrimidin-7-karboxylovákyselina (0,65 g), t.t. 184 až 188 °C. NMR spektrum (CFjCOOD):6: 1,22 (dd, jeden ze 6,7-metylenových protonů), 1,36 (t,-OH^-CHj). 3,96 (m, -CH-CHj a 6,7-metylenový proton), 4,12 (s, OCH^), 5,50 (dd, C-6 pro-ton), 7,03 (d, C-9 proton), 7,36 (d, Hp vinylový proton), 7,68 (d, Ha vinylový proton), 7,18 až 7,70 (m, 4 fenylová protony), 8,26 (d, C-8 proton), JHo,Hp “ H··This was treated with 0.59 potassium hydroxide for 15 minutes in 959 ethanolic solution (40 ml). After cooling, the reaction mixture was diluted with water, acidified with acetic acid, and the precipitate was filtered off. Crystallization from a mixture of dichloromethane-methanol produces 2-trens (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine. 7-carboxylic acid (0.65 g), m.p. Mp 184-188 ° C. NMR Spectrum (CF 3 COOD): 6: 1.22 (dd, one of the 6,7-methylene protons), 1.36 (t, -OH 2 -CH 3). 3.96 (m, -CH-CH3 and 6,7-methylene proton), 4.12 (s, OCH3), 5.50 (dd, C-6-ton), 7.03 (d, C -9 proton), 7.36 (d, Hp vinyl proton), 7.68 (d, Ha vinyl proton), 7.18 to 7.70 (m, 4 phenyl protons), 8.26 (d, C- 8 proton), JHo, Hp “H ··
Podobným způsobem se vyrábájl tyto sloučeniny: 2-trans-(2-/2-metylfenyl/etenyl)-1-ety1-6,7-metylen-4-oxo-4H-pyrido(1,2-a) pyrlmidin-7--karboxylová kyselina, t.t. 225 až 227 °C, 2-trans-(2-/3-metylfe«yl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyselina, t.t. 165 °C (rozklad), ’ 2-tran8(2-/3-metylfenyl/etenyl)-3-propy1-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyseliny, t.t. 140 °C (rozklad), 2-trans-(2-/4-metylfenyl/etenyl)-3-etyl-6,7-netylen-4-oxo-4H-pyrido(1,2-e)pyrlmldln-7--karboxylová kyselina, t.t. 225 až 239 °C (rozklad), 2-trans(2-/4-metylfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrldo(1,2-a)pyrlmldln-7--karboxylová kyselina, t.t. 140 až 150 °C (rozklad), 2-trans-(2-/2-metoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrlmldin-7--karboxylová kyselino, t.t. 208 až 210 °C, 11 244131 2-trens-(2-/2-metoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrldo(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 130 °C (rozkled), 2-trens-(2-/2-metylfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 140 °C (rozklad), NMK spektrum (GFjCOOD):»: 1,12 (m, 6,7--metylenový proton a -CH^CH^CHj), 1,73 (m, -CH^CH^CHj). 2,47 (s, -CH^), 2,87>{m, 6,7-metyle-nový proton a -CH^CH^CHO. 5,46 (dd, C-6 proton), 6,94 (d, C-9 proton), 7,16 (d, d, Ηβ viny-lový proton), 7,96 (d, Ha vinylový proton), 8,19 Cd, C-8 proton), JH H 16 Hz, 2-trans-(2-/3-metoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyselina, t.t. 130 °C (rozklad), NMR spektrum (GF^COOD)^: 1,13 (m, 6,7--metylenový proton a -CH^CH^CH^). 2,88 (m, 6,7-metylenový proton a -GH^CH^CHj). 5,46 (dd, C-6 proton), 6,97 (d, C-9 proton), 7,18 (d, Ηβ vlnylový proton), 7,64 (d, Ha vinylovýproton), 8,21 (d, C-8 proton), g = .,6 Hz, 2-trans-(2-/3-etoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyselina, t.t. 188 až 190 °C, 2-trans-(2-/3-etoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyselina, t.t. 97 až 102 °C (rozklad), 2-trans-(2-/2,3-dimetoxyíenyl/etenyl):‘3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimid,in--7-karboxylová kyselina, t.t. 188 až 190 °C, 2-trans-(2-/2,3-dimetoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t,t. 100 až 110 °C (rozklad), 2-trans-(2-/2,5-dimetoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 170 až 173 °C, NMK spektrum (CF^COODbs: 1,20 (m, 6,7-mety-lenový proton), 2,89 (m, 6,7-metylenový proton a -CH^CH^CH^). 5,48 (dd, C-6 proton), 7,00(d, C-9 proton), 7,45 (d, Ηβ vinylový proton), 7,98 (d, H„ vinylový proton), 8,22 (d, C-8 proton), JH = 16 Hz, 2-trana-(2-/2,5-dimetoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. ,92 až 195 °C, 2-trans-(2-/2-metoxy-3-etoxyfenyl/etenyí)-3-etyl-6,7-metylen-4-oxo-3H-pyrido(1,2-a)pyrimidln--7-karboxylová kyselina, t.t. 180 až 185 °C (rozklad), 2-trans-(2-/2-metoxy-3-etoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyri-midin-7-karboxylová kyselina, t.t. 141 až 143 °C, 2-trane-(2-/2-metoxy-3-metoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(, ,2-e)pyrl-tmidin-7-karboxylová kyselina, t.t. 181 až 183 °C, 2-trans-(2-/2,4,5-trimetoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrf-midin-7-karboxylová kyselina, t.t. 224 až 226 °Č, 2-trens-(2-/2,4-dimetylfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidiB-7--kprboxylová kyselina, t.t. ,84 až ,86 °C, 2-trans-(2-/3,4-dimetoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-<H-pyrido(1,2-a)pyrimi-din-7-karboxylová kyselina, t.t. 208 až 209 °C, 2-trans-(2-/4-metoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 180 až 190 °C, 244131 12 2-traaa-(2-/4-aetoxyfenyl/etenyl)-3-etyl-ó,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-kerboxylová kyselině, t.t. 235 až 237 °C, 2-traas-(2-/2-etoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1,2-e)pyrimidin-7--karboxylová kyselina, t.t. 178 až 180 °C, 2-trana-(2-/3,5-dÍBetoxyfenyl/etenyl)-3-propyl-6,7-metylan-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxyiová kyselina, t.t. 170 až 180 °C, (rozklad), 2-trane-(2-/2,5-dlBetylfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrldo(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 150 °C (rozklad), 2-trane-(2-/2,5-dÍBetylfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimldin--7-kerboxylová kyselina, t.t. 205 až 207 °C, 2-trans-(2-/2-aetylCenyl/etenyl)-3-butyl-6,7-aetylen-4-oxo-4H-pyrido(1,2-a)pyrinidin-7--karboxylová kyselina, t.t. 240 °C (rozklad), 2-tvens-(2-/3-netoxyfenyl/etenyl)-3-butyl-6,7-metylen-4-oxo-4H-pyridO(1,2-a)pyrimidin-7--kerboxylová kyselina, t.t. 156 až 158 °C, 8^traas-(2-/2,3-diaetoxyfenyl/etenyl)-3-butyl-6,7-metylen-4-oxo-4H-pyrido(1 ,2-a)pyriBidin--7-karboxylová kyselina, t.t. 197 až 198 °C, 2-trane-(2-/2-aetoxy-3-etoxyfenyl/eteayl)-3-butyl-6,7-aetylen-4-oxo-4H-pyrido(1,2-a)pyrimi4din-7-karboxylová kyselina, t«t.155 až 157 °C,“ 2-trane-(2-/2,3-dietoxyfenyl/etenyl)-3-propyl-6,7-aetylen-4-oxo-4H-pyrido(1 ,2-a)pyrimidin--7-karboxylová kyselina, t.t. 177 až 179 °C, Příklad 3The following compounds were prepared in a similar manner: 2-trans- (2- (2-methylphenyl) ethenyl) -1-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrlmidine-7- carboxylic acid, m.p. 225-227 ° C, 2-trans- (2- (3-methylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 165 ° C (decomposition), 2-trans (2- (3-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140 ° C (decomposition), 2-trans- (2- (4-methylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyridine-7- carboxylic acid, m.p. 225-239 ° C (decomposition), 2-trans (2- (4-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140-150 ° C (decomposition), 2-trans- (2- (2-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine- 7-carboxylic acid, m.p. 208-210 ° C, 11 244131 2-Trens- (2- (2-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 130 ° C (decomposed), 2-trens- (2- (2-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140 ° C (decomposition), NMK spectrum (GF 2 COOD): 1.12 (m, 6.7-methylene proton and -CH 2 CH 2 CH 3), 1.73 (m, -CH 2 CH 2 CH 3) . 2.47 (s, -CH2), 2.87 (m, 6,7-methyl-new proton and -CH2CH2CHO). 5.46 (dd, C-6 proton), 6.94 (d, C-9 proton), 7.16 (d, d, Ηβ vinyl proton), 7.96 (d, Ha vinyl proton), 8.19 Cd, C-8 proton), 1H H 16 Hz, 2-trans- (2- (3-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1 , 2-a) pyrimidine-7-carboxylic acid, m.p. 130 ° C (decomposition), NMR spectrum (GF 4 COOD) δ: 1.13 (m, 6,7-methylene proton and -CH 2 CH 2 CH 3). 2.88 (m, 6,7-methylene proton and -GH 2 CH 2 CH 3). 5.46 (dd, C-6 proton), 6.97 (d, C-9 proton), 7.18 (d, lovýβ wave proton), 7.64 (d, Ha vinylproton), 8.21 (d , C-8 proton, g = 1.6 Hz, 2-trans- (2- (3-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2 -a) pyrimidine-7-carboxylic acid, m.p. 188-190 ° C, 2-trans- (2- (3-ethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, m.p. 97-102 ° C (decomposition), 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl): 3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine, 7-carboxylic acid, m.p. 188-190 ° C, 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, t. 100-110 ° C (decomposition), 2-trans- (2- (2,5-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 170-173 ° C, NMK spectrum (CF 3 COODbs: 1.20 (m, 6,7-methylene proton), 2.89 (m, 6,7-methylene proton and -CH 2 CH 2 CH 2 CH 2) 5.48 (dd, C-6 proton), 7.00 (d, C-9 proton), 7.45 (d, Ηβ vinyl proton), 7.98 (d, H "vinyl proton), 8, 22 (d, C-8 proton), JH = 16 Hz, 2-trans- (2- / 2,5-dimethoxyphenyl / ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido ( 1,2-a) pyrimidine-7-carboxylic acid, mp 92-195 ° C 2-trans- (2- (2-methoxy-3-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene -4-oxo-3H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 180-185 ° C (decomposition), 2-trans- (2- / 2-methoxy-3-ethoxyphenyl / ethenyl) ) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 141-143 ° C, 2-trans- (2- 2-methoxy-3-methoxyphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyridine-7-carboxylic acid, mp 181-183 ° C 2-trans- (2- (2,4,5-trimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, mp 224-226 ° C, 2-trens- (2- (2,4-dimethylphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 84-86 ° C 2-trans- (2- (3,4-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo- H -pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 208-209 ° C, 2-trans- (2- (4-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, m.p. 180-190 ° C, 244131 12 2-traaa- (2- (4-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 235-237 ° C, 2-Traas- (2- (2-ethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7- carboxylic acid, m.p. 178-180 ° C, 2-trans- (2- (3,5-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylan-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 170-180 ° C, (decomposition), 2-trans- (2- / 2,5-dl-ethylphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-7-carboxylic acid, m.p. 150 ° C (decomposition), 2-trans- (2- (2,5-dimethylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine- -7-carboxylic acid, m.p. 205-207 ° C, 2-trans- (2- (2-ethylphenyl) ethenyl) -3-butyl-6,7-ethylene-4-oxo-4H-pyrido (1,2-a) pyrinidine-7- carboxylic acid, m.p. 240 ° C (decomposition), 2-tert- (2- (3-methoxyphenyl) ethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyridO (1,2-a) pyrimidine-7- -carboxylic acid, m.p. 156-158 [deg.] C., 8 [alpha] - (2- (2,3-Diaethoxyphenyl) ethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyridine; 7-carboxylic acid, m.p. 197 DEG-198 DEG C. 2-trans- (2- (2-ethoxy-3-ethoxyphenyl) ethoxy) -3-butyl-6,7-aethylene-4-oxo-4H-pyrido [1,2-a] pyrimidine; -7-carboxylic acid, 1555-157 ° C, 2-trans- (2- (2,3-diethoxyphenyl) ethenyl) -3-propyl-6,7-ethylene-4-oxo-4H- pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 177-179 ° C, Example 3
Postupuje-li se podle příkladu 2, ala vychází-li se z vhodných 2-heteroaryletenylovýchderivátů,' vyrobí se 2-trens-(2-/2-tienyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrido(1 ,2--a)pyrinidin-7-karboxylová kyselina, t.t. 157 až 162 °C. PřikládáWhen proceeding according to Example 2, starting from the appropriate 2-heteroarylethenyl derivatives, 2-trens- (2- (2-thienyl / ethenyl) -3-propyl-6,7-methylene-4-oxo was prepared. -4H-pyrido (1,2-a) pyrinidine-7-carboxylic acid, m.p. Mp 157-162 ° C. Attaches
Postupuje-li se podle příkladů 2 a 3 a vychází-li se z vhodných 2-aryletenyloyýcha 2-heteroaryletenylových derivátů, vyrobí se tyto slouieniny: 2-trans-(2-/2-aetylfenyl/etenyl)-6,7-metylan-4-oxo-4H-pyrldo(1,2-a)pyrimidin-7-karboxylovákyselina, t.t. 179 až 182 °C, .2-trane-(2-/3-aetylfenyl/etenyl)-6,7-Betylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxylovákyselina, t.t. 272 až 274 °C, 2-trans-l2-/4-aetylfenyl/etenyl)-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxylovákyselina, t.t. 190 až 194 °C, 2-trene-(2-/2-aetoxyfenyl/etenyl)-6,7-Betylen-4-oxo-4K-pyrldo(1,2-a)pyrimidin-7-karboxylovákyselina, t.t. 150 °C (rozklad), 2-trans-(2-/3-astoxyfenyl/etenyl)-6,7-aetylan-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxy-Ipvá kyselina, t.ť. 204 °C (rozklad),Following Examples 2 and 3, starting from the appropriate 2-arylethenyl and 2-heteroarylethenyl derivatives, the following compounds are prepared: 2-trans- (2- (2-ethylphenyl) ethenyl) -6,7-methylan- 4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 179 DEG-182 DEG C. 2-trans- (2- (3-ethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 272-274 ° C, 2-trans-12- (4-ethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 190-194 ° C, 2-trene- (2- (2-ethoxyphenyl) ethenyl) -6,7-methylene-4-oxo-4K-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 150 ° C (decomposition), 2-trans- (2- (3-astoxyphenyl) ethenyl) -6,7-ethylan-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxy-lvaic acid , t. 204 ° C (decomposition)
Severografia, n. p., MOSTSeverografia, n. P., MOST
Cena 2,40 Kčs >3 244)31 2-trene-(2-/4-metOxyfenyl/etenyl)-6,7-metylen-4-°xo-4H-pyrido(l ,2-e)pyrimidin-7-karboxylovákyselině, t.t. 95 ež 110 °C (rozklad), 2-tren8-(2-/3-ohlorfenyl/etenyl)-6,7-metylen-4-oxo-4H-pyrido(1,2-e5pyrimidin-7-kerboxylo-vá kyselině, t.t. 209 ež 210 °C (rozkled), 2-trans-(2-/2,4-dimetylf eny l/etenyl)-6,7-metylen-4,-oxo-4H-pyrido(1 ,2-e)pyrimidin-7-kerboxy-lová kyselina, t.t. 199 ež 202 °C, 2-trens-(2-/2,5-dimetylfenyl/etenyl)-6,7-metylen-4-oxo-4H-pyrido(1 ,2-a)pyrimidin-7-karboxy«lová kyselina, t.t. 195 až 200 °C, 2-trans-(2-/2,3,4-trimetoxyfenyl/etenyl)-6,7-metylen-4-oxo-4H-pyrido(1, 2-a)pyrimidin-7--kerboxylová kyselině, t.t. 180 ež 182 °C, 2-trans-(2-/2-metylfenyl/etenyl)-3-mety1-6,7-metylen-4-oxo-4H-pyrido(1, 2-e)pyrimidin-7--kěrboxylová kyselina, t.t. 240 °C (rozkled), 2-trans-(2-/3-metylfenyl/etsnyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2-e)pyrimidin-7--kerboxylová kyselifce, t.t. 190 ež 209 °C (rozkled), 2-trana-(2-/4-metylfenyl/etenyl)-3-mety1-6,7-metylen-4-oxo-4H-pyrido(1,2-e)pyrimidin-7--karboxylová kyselina, t.t. 260 až 269 °C (rozkled), 2-trans- (2-/2-metoxyf eny 1/e tenyl) -3-metyl-6,7 -metylen-4-oxo-4H-pyrido (1,2-a) pyrimidin-7 --karboxylová kyselina, t.t. 200 až 209 °C (rozklad), 2-trens-(2-/3-metoxyfenyl/etenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2-e) pyrimidin-7--karboxylová kyselině, t.t. 200 ež 209 °C, 2-trans-(2-/4-metoXyfenyl/etenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7 --karboxylová kyselina, t.t. 234 ež 338 °C, 2-trans-(2-/2,4-dimetylfenyl/etenyl)-3-mety1-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, t.t. 220 ež 223 °C (rozkled), 2-trans-(2-/2,5-dimetylfenyl/etenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2ea)pyrimidin--7-karboxylová kyselina, t.t. 235 až 240 °C (rozklad), 2-trans-(2-/2,3-dimetoxyfenyl/etenyl)-3-mety1-6,7-metylen-4-oxo-4H-pyrido(1,2-e)pyrimidin--7-karboxylová kyselina, t.t. 207 až 209 °C (rozklad), 2-trana«{2^/2,4-dimetoxyfenyl/etenyl)-3-metyl-6,7-metylen-4-oxo-4U-pyrido(1,2-a)pyrimidin--7-karboxylová kyselina, 2-třens-(2-/2,5-dimetoxyfenyl/etenyl)-3-metyl-6,7-oetylen-í-oxo-4H-pyrido(1,2-a)pyrimidin--7•‘karboxylová kyselina, t.t. 171 až 174 °C (rozklad), 2-*1atsna-<.2-/2,4-dimetoxyfenyl/etenyl)-3-methyl-6,7-metylen-4-oxo-4H-pyrido( 1,2«*e )pyrimidin--7-karboxylová kyselina, t.t. 207 až 210 °C (rozklad), 2-trana-(2-/3,4,5-trimetoxyfenyl/etenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2-e)pyrimi-din-7-karboxylová kyselina, t.t. 175 ež 280 °C (rozkled) a 2-trane-(2-/2-tienyl/<tenyl)-3-mety1-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-kerboxy-lová kyselina, t.t. 208 až 211 °C (rozklad). 244131 Příklad 5 14 2-trans-(2-fenyletenyl)-3-metyl-6,7-metylen-4-oxo-4K-pyrido(1,2-a)pyrimidin-7-karboaty-lová kyselina (0,8 g) se zpracovává 4 hodiny a metyljodidem (0,55 g) a bezvodým uhličitanemdraselným (0,65 g) v dimetylformamidu (7 ml) za míchání při teplotě místnosti. Seakčnísměs se zředí ledovou vodou é sraženina odfiltruje. Krystalizací z acetonu se vyrobí0,5 g metylesteru 2-trans-(2-fenyletenyl)-3-metyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimi-din-7-karboxylově kyseliny, t.t. 164 až 165 °C.Price 2,40 Kčs> 3,244) 31 2-Trene- (2- / 4-methoxyphenyl / ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7- carboxylic acid, tt 95 DEG-110 DEG C. (decomposition), 2-tren8- (2- (3-chlorophenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido [1,2-e] pyrimidine-7-carboxylic acid 209-210 ° C (dec.), 2-trans- (2- / 2,4-dimethylphenyl / ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-e pyrimidine-7-carboxylic acid, mp 199-202 ° C, 2-Trens- (2- (2,5-dimethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1, 2-a) pyrimidine-7-carboxylic acid, mp 195-200 ° C, 2-trans- (2- (2,3,4-trimethoxyphenyl) ethenyl) -6,7-methylene-4-oxo-4H -pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 180-182 ° C, 2-trans- (2- (2-methylphenyl) ethenyl) -3-methyl-6,7-methylene-4 -oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, mp 240 ° C (decomposition), 2-trans- (2- (3-methylphenyl) ethynyl) -3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, m.p. 190-209 ° C (dec.), 2-tran- (2- (4-methylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, mp 260-269 ° C (dec.), 2-trans- (2- / 2- methoxyphenylphenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 200-209 ° C (decomposition), 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine- 7-carboxylic acid, m.p. 200 to 209 ° C, 2-trans- (2- (4-methoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 - carboxylic acid, m.p. M.p. 338 DEG C., 2-trans- (2- (2,4-dimethylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine; 7-carboxylic acid, m.p. 220-223 ° C (dec.), 2-trans- (2- (2,5-dimethylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2a) pyrimidine- -7-carboxylic acid, m.p. 235-240 ° C (decomposition), 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, m.p. 207-209 ° C (decomposition), 2-trans (2- [2,4-dimethoxyphenyl] ethenyl) -3-methyl-6,7-methylene-4-oxo-4U-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-tris- (2- (2,5-dimethoxyphenyl) ethenyl) -3-methyl-6,7-ethylene-1-oxo-4H-pyrido (1,2-a) pyrimidine Carboxylic acid, m.p. 171 DEG -174 DEG C. (decomposition); 2- (2- (2,4-dimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2 ' e) pyrimidine-7-carboxylic acid, m.p. 207-210 ° C (decomposition), 2-trans- (2- (3,4,5-trimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2- e) pyrimidine-7-carboxylic acid, m.p. 175 DEG-280 DEG C. (decomposed) and 2-trans- (2- (2-thienyl) phenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine -7-carboxylic acid, m.p. 208 DEG-211 DEG C. (decomposition). 244131 Example 5 14 2-trans- (2-phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4K-pyrido (1,2-a) pyrimidine-7-carboatylic acid (0.8 g) was treated with methyl iodide (0.55 g) and anhydrous potassium carbonate (0.65 g) in dimethylformamide (7 ml) for 4 hours with stirring at room temperature. The reaction mixture was diluted with ice water and the precipitate was filtered off. Crystallization from acetone yields 0.5 g of methyl 2-trans- (2-phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid. acid, tt Mp 164-165 ° C.
Analogickým postupem se vyrobí tyto alouSeniny: metylester 2-trans-(2-fenyletenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyseliny, t.t. 194 až 195 °C, metylester 2-trans-(2-fenyletenyl)-3-butyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimidin-7--karboxylová kyseliny, t.t. 112 až 113 °C, metylester 2-trans-(2-/2,5-dimetoxyfenyl/etenyl)-3-propyl-6,7-metylen-4-oxo-4H-pyrldo(1,2--a)pyrimidin-7-karboxylové kyseliny, t.t. 117 až 120 °C a metylester 2-trens-(2-/3-metoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrldo(1,2-a)pyri-midin-7-karboxylové kyseliny, t.t. 143 až 146 °C. Příklad 6The following compounds were prepared analogously: 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid methyl ester, tt 194-195 ° C, 2-trans- (2-phenylethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid methyl ester, m.p. 112-113 ° C, 2-trans- (2- / 2,5-dimethoxyphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine methyl ester -7-carboxylic acid, m.p. 117-120 ° C and 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-methyl ester 7-carboxylic acid, m.p. 143-146 ° C. Example 6
Postupuje-li se podle příkladu 5 a použije-li se etanolu nebo etyljodidu, vyrobí setato sloučenina: etylester 2-trens-(2-/3-metoxyfenyl/etenyli-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrl-midin-7-karboxylová kyseliny, t.t. 123 až 125 °C. Příklad 7 2-trans-(2-/2-metylfenyl/etenyl-3-propyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-;7 -kar boxy -lová kyselina (3,6 g) se zpracovává 8 hodin s 1-chlor-2-(dietylamino)etanem (2,7 g) abezvodým uhličitanem draselným (2,8 g) v dimetylformamidu (40 ml) za míchání při teplotě50 °C. Po zředSní vodou se vysrážená látka odfiltruje a promyje vodou do neutrální reakce.Krystalizací z isopropyleteru se vyrobí 2,1 g 2-diefcylaminoetylesteru 2-trans-(2-/2-metyl-fenyl/etenýl)-3-propyl-4-oxo-4H-pyrido(,,2-a)pyrlmidin-7-karboxylové kyseliny. Příklade 2-trans-(2-/2,3-dimetoxyfenyl/etenyl)-3-etyl-4-oxo-4H-pyrido(1,2-a)pyrimldin-7-karbO-xylová kyselina (1,2 g) se zpracovává 3 hodiny s tionylchloridem (0,6 sil), v dioxanu (20 mlpři teplotč varu reakční směsi. Směs se pak ve vakuu odpaří do sucha. Odparek se rozpustív dioxanu (60 ml) a zpracovává se 20 hodin s 2-(áiétylamlno)etanolem (Ί ,2 g) při teplotě«místnosti. Po zředění vodou se sraženina odfiltruje, rozpustí i-aeetonu (100 ml) a zpra-cuje se se stechiometrickým množstvím kyseliny chlorovodíkově v éteru. Sraženina seodfiltruje, promyje etyléterem a rozpustí se ve vodě.If Example 5 is followed and ethanol or ethyl iodide is used, the compound is prepared: ethyl 2-trens- (2- (3-methoxyphenyl) ethenyl-3-ethyl-6,7-methylene-4-oxo-4H) -pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 123-125 ° C Example 7 2-trans- (2- / 2-methylphenyl) ethenyl-3-propyl-4-oxo-4H -pyrido (1,2-a) pyrimidine-7-carboxylic acid (3.6 g) was treated with 1-chloro-2- (diethylamino) ethane (2.7 g) for 8 hours and anhydrous potassium carbonate ( 2.8 g) in dimethylformamide (40 ml) with stirring at 50 [deg.] C. After dilution with water, the precipitated material is filtered off and washed with water until neutral. Crystallization from isopropyl ether produces 2.1 g of 2-diefcylaminoethyl ester 2-trans- (2 - [2-Methyl-phenyl] -ethyl) -3-propyl-4-oxo-4H-pyrido (2-a) pyrimidine-7-carboxylic acid Example 2-trans- (2- / 2,3-dimethoxyphenyl) (ethenyl) -3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carbonic acid (1.2 g) was treated with thionyl chloride (0.6 silos) for 3 hours, dioxane (20 mL) The mixture is then evaporated to dryness in vacuo. The residue was dissolved in dioxane (60 mL) and treated with 2- (diethyl amine) ethanol (1.2 g) at room temperature for 20 hours. After dilution with water, the precipitate is filtered off, dissolved in acetone (100 ml) and treated with a stoichiometric amount of hydrochloric acid in ether. The precipitate is filtered, washed with ethyl ether and dissolved in water.
Alkalizecí uhličitanem draselným, filtrací a krystalizací z acetonu ae vyrobí 0,6 <2-(dietylamino)-etylesteru 2-trans-(2-/2,3-dimetoxyfenyl/etenyl)-3-etyl-4-oxo-4H-pyrido-(1,2-a)pyrimidin-7-karboxylově kyseliny, t.t. 148 až 150 °C. 15 244131 Př X k 1 ad 9Alkalization with potassium carbonate, filtration and crystallization from acetone to produce 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido [eta] < 2 > - (1,2-a) pyrimidine-7-carboxylic acid, m.p. 148-150 ° C. 15 244131 Ex. 1 ad 9
Trimetylsulfoxoniumjodidu(2,3 g) se zpracovává po dobu 1 hodiny s 50* hydrldemsodným (0,5 g) v dimetylformamidu (30 ml) za míchání při teplotě místnosti.'Potom sek tomuto roztoku přidá roztok 2-(dletylamlno)etylesteru 2-trans-(2-/2,3-dimetoxyfenyl/ete-nyl)-3-etyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxylové kyseliny (3,5 g) v dimetylforma-midu (20 ml). Směs se nechá reagovat 90 minut při teplotě místnosti ze míchání. Potomse směs zředí vodou a extrahuje se etylacetátem. Organická vrstva se promyje vodou a vevakuu se odpaří dosucha. Odparek (2,9 g) se vyčistí na sloupci sllikagelu při eluovápíacetonem.Trimethylsulfoxonium iodide (2.3 g) was treated with 50% aqueous (0.5 g) in dimethylformamide (30 ml) for 1 hour with stirring at room temperature. A solution of 2- (diethylamino) ethyl ester 2- was added thereto. trans- (2- / 2,3-Dimethoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid (3.5 g) in dimethylformamide (20 mL). The mixture was allowed to react for 90 minutes at room temperature from stirring. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and evaporated to dryness in a vacuum. The residue (2.9 g) was purified on a silica gel column eluting with acetone.
Vyrobí se 1,9 g 2-(dietylamino)etylesteru 2-trans-(2-/2,3-dimetoxyfenyl/etenyl)-3--etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyrimldin-7-karboxylové kyseliny, olej. ^ch2-sh3 NUK spektrum (SUSO-dg):S: 0,97 (t, -N , 0,95 až 1,30 (m, 6,7-aetylenový ^ch2-sh3 ^CH2-fiH31.9 g of 2- (diethylamino) ethyl 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido is produced (1 g). 2-a) pyrimidine-7-carboxylic acid oil. N2-sh3 NUK spectrum (SUSO-dg): S: 0.97 (t, -N, 0.95-1.30 (m, 6,7-ethylene ^ ch2-sh3 ^ CH2-fH3
2,54 (q, -ΝΐΓ ). 2,70 (t, -OCHjj-CHg-Sgj-N ^CH2-£H3 ), 2,4 ei 2,8 (m, 6,7-metylenový> proton a -Stk-CHj), 3,88 (s, -OCHj), 3,81 (s, -OC^), 4,22 (t, -O-SH^-CHj-N C ), 4,78 (dd,C-6 proton), 6,38 (d, C-9 proton), 7,18 (d, C-8 proton), 7,39 (d, Hp -vinylový proton), 8,07 (Ho -vinylový proton, 7,18 až 7,46 (m,. fenylová protony). Příklad 10 2-trans-(2-/2-metylfenyl/etenýl)-3-propyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxylo-vá kyselina (5 g) se zpracovává s hydrogenuhlifiitanem sodným (1,25 g) ve vodě (15 ml) při80 °C tak dlouho, dokud zpracování není kompletní. Ochlazením ne 5 °C vznikne sraženina,která se odfiltruje a promyje ledovou vodou. Vyrobí se tak sodná aAl 2-trans-(2-/2-metyl-fenyl/etenyl)-3-propyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-karboxylová kyseliny, t.t. vyěěínež 300 °C (3,9 g).2.54 (q, -ΝΐΓ). 2.70 (t, -OCH 2 -CH 3 -Sg 3 -N 2 CH 2 -H 3), 2.4 ei 2.8 (m, 6,7-methylene> proton and -Stk-CH 3), 3.88 (s , 3.81 (s, -OC 1), 4.22 (t, -O-H 2 -CH 2 -NC), 4.78 (dd, C-6 proton), 6.38 ( d, C-9 proton), 7.18 (d, C-8 proton), 7.39 (d, Hp-vinyl proton), 8.07 (Ho-vinyl proton, 7.18 to 7.46 (m phenyl protons Example 10 2-trans- (2- (2-methylphenyl) ethenyl) -3-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid ( 5 g) is treated with sodium bicarbonate (1.25 g) in water (15 ml) at 80 ° C until the work-up is complete, and a precipitate is formed by cooling to not more than 5 ° C, which is filtered off and washed with ice water. sodium αAl 2-trans- (2- / 2-methyl-phenyl / ethenyl) -3-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 300 ° C ( 3.9 g).
Analogickým postupem se vyrobí tyto sloučeniny: sodná sůl 2-trans-(2-fenyletenyl)-3-mstyl-4-oxo-4H-pyrido(1,2-a)pyrimidin-7-kerboxylovákyseliny, t.t. vyěěí než 300 °C a sodné sůl 2-trens-(2-/3-metoxyfsnyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido(1,2-a)pyri-midin-7-karboxylová kyseliny, t.t. vyěěí než 300 °C (rozkl.). Přikladli 2-trans-(2-/3-metoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrido-(1,2-aIpyrimldin--7-karboxylová kyseliny (1,2 g) se nechá reagovat s tionylchloridem (0,6 ml) v dioxanu(12 ml) pod zpětným chladičem 1 hodinu a potom se směs odpaří do sucha ve vakuu. Odnarek senechá reagovat s přebytkem metanolu za teploty 50 °C po dobu 30 minut, potom se roztokodpaří ve vakuu a odparek zředí ledovou vodou. Filtrací sraženiny se získá 1,2 g metyl-esteru 2-tr8na-(2-/3-metoxyfenyl/etenyl)-3-etyl-6,7-metylen-4-oxo-4H-pyrldo(1,2-a)pyri-midin-7-karboxylová kyseliny, t.t. 143 až 146 °C. Příklad 12 Následujícím způsobem se vyrábějí tablety, z nichž každá má hmotnost 150 mg a obsa-huje 50 mg.účinná složky:.The following compounds were prepared in an analogous manner: 2-trans- (2-phenylethenyl) -3-methyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid sodium salt, m.p. over 300 ° C and 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine sodium salt -7-carboxylic acid, m.p. than 300 ° C (decomposition). Example 1 2-trans- (2- / 3-methoxyphenyl / ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido- (1,2-arypyrimidine-7-carboxylic acid (1.2%) g) is reacted with thionyl chloride (0.6 ml) in dioxane (12 ml) under reflux for 1 hour, and then the mixture is evaporated to dryness under vacuum and reacted with excess methanol at 50 ° C for 30 minutes, the solution was then evaporated in vacuo and the residue diluted with ice water to give 1.2 g of methyl ester of 2-trifluoro- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo. -4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 143-146 ° C Example 12 Tablets, each weighing 150 mg and containing 50 mg active, are prepared as follows. folders:.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7915810 | 1979-05-08 | ||
| CS803213A CS244107B2 (en) | 1979-05-08 | 1980-05-07 | Method of substituted pyrdoido-(1,2-a)pyrimidines production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS244131B2 true CS244131B2 (en) | 1986-07-17 |
Family
ID=25745766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS835287A CS244131B2 (en) | 1979-05-08 | 1983-07-12 | Method of substituted pyrido-(1,2-a) pyrimidines production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS244131B2 (en) |
-
1983
- 1983-07-12 CS CS835287A patent/CS244131B2/en unknown
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