CS271499B2 - Method of new dihydropyridinamides production - Google Patents
Method of new dihydropyridinamides production Download PDFInfo
- Publication number
- CS271499B2 CS271499B2 CS892254A CS225489A CS271499B2 CS 271499 B2 CS271499 B2 CS 271499B2 CS 892254 A CS892254 A CS 892254A CS 225489 A CS225489 A CS 225489A CS 271499 B2 CS271499 B2 CS 271499B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- phenyl
- group
- dihydro
- dicarboxylic acid
- dimethylpyridine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title description 2
- -1 C2-5-alkylcarbonyl Chemical group 0.000 claims abstract description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract description 6
- 150000001408 amides Chemical class 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 239000012442 inert solvent Substances 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 1
- 229940095054 ammoniac Drugs 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 70
- 230000008018 melting Effects 0.000 description 70
- FOMJVPKCLROENX-UHFFFAOYSA-N 2,6-dimethyl-4-(2-phenylmethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OCC1=CC=CC=C1 FOMJVPKCLROENX-UHFFFAOYSA-N 0.000 description 35
- 239000006260 foam Substances 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical compound OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- RXVMQMGEMJJNQU-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=CC=C(C=C1)C1C(=C(NC(=C1C(=O)O)C)C)C(=O)O Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C1C(=C(NC(=C1C(=O)O)C)C)C(=O)O RXVMQMGEMJJNQU-UHFFFAOYSA-N 0.000 description 5
- SATCCIHHEUGXLX-UHFFFAOYSA-N ClC1=C(COC2=C(C=CC=C2)C2C(=C(NC(=C2C(=O)O)C)C)C(=O)O)C(=CC=C1)Cl Chemical compound ClC1=C(COC2=C(C=CC=C2)C2C(=C(NC(=C2C(=O)O)C)C)C(=O)O)C(=CC=C1)Cl SATCCIHHEUGXLX-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 210000003540 papillary muscle Anatomy 0.000 description 5
- YMHOVXBETVCESG-UHFFFAOYSA-N 2,6-dimethyl-4-[2-[(4-methylphenyl)methoxy]phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OCC1=CC=C(C)C=C1 YMHOVXBETVCESG-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LVLSZNPHPHHUKL-UHFFFAOYSA-N 2,6-dimethyl-4-[2-(4-methylphenyl)sulfonyloxyphenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OS(=O)(=O)C1=CC=C(C)C=C1 LVLSZNPHPHHUKL-UHFFFAOYSA-N 0.000 description 3
- CZUYZBCNCRYFIV-UHFFFAOYSA-N 2,6-dimethyl-4-[2-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OCC1=CC=CC(C(F)(F)F)=C1 CZUYZBCNCRYFIV-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- PJONVNQAKACBPL-UHFFFAOYSA-N 4-[2-[(4-fluorophenyl)methoxy]phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OCC1=CC=C(F)C=C1 PJONVNQAKACBPL-UHFFFAOYSA-N 0.000 description 3
- SOTZTDFXGPVJLX-UHFFFAOYSA-N CC(NC(C)=C(C1C(C=CC=C2)=C2OCC(C=C2)=CC=C2Cl)C(O)=O)=C1C(O)=O Chemical compound CC(NC(C)=C(C1C(C=CC=C2)=C2OCC(C=C2)=CC=C2Cl)C(O)=O)=C1C(O)=O SOTZTDFXGPVJLX-UHFFFAOYSA-N 0.000 description 3
- ZYZFNMSUWATYLQ-UHFFFAOYSA-N CC1=C(C(C(=C(N1)C)C(=O)O)C2=CC(=CC=C2)OCC3=CC=CC=C3)C(=O)O Chemical compound CC1=C(C(C(=C(N1)C)C(=O)O)C2=CC(=CC=C2)OCC3=CC=CC=C3)C(=O)O ZYZFNMSUWATYLQ-UHFFFAOYSA-N 0.000 description 3
- PIAMFPHAHNDJPK-UHFFFAOYSA-N CC=1NC(=C(C(C1C(=O)O)C1=C(C=CC=C1)OS(=O)(=O)C1=CC=CC=C1)C(=O)O)C Chemical compound CC=1NC(=C(C(C1C(=O)O)C1=C(C=CC=C1)OS(=O)(=O)C1=CC=CC=C1)C(=O)O)C PIAMFPHAHNDJPK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FEWULVMNCUKLSI-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=C(C=CC=C1)C1C(=C(NC(=C1C(=O)O)CC)CC)C(=O)O Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC=C1)C1C(=C(NC(=C1C(=O)O)CC)CC)C(=O)O FEWULVMNCUKLSI-UHFFFAOYSA-N 0.000 description 2
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
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- 239000000654 additive Substances 0.000 description 2
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
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- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
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- ZRKLVATYKFVZFX-UHFFFAOYSA-N 2,6-dimethyl-4-[2-[(3-nitrophenyl)methoxy]phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC=C1OCC1=CC=CC([N+]([O-])=O)=C1 ZRKLVATYKFVZFX-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
Předložený vynález se týká způsobu výroby nových dihydropyridinamidů, které mají cenné farmakologické vlastnosti, zejména pak schopnost ovlivňovat krevní oběh a mohou se tudíž používat jako léčiva.The present invention relates to a process for the production of novel dihydropyridinamides having valuable pharmacological properties, in particular the ability to affect blood circulation and can therefore be used as medicaments.
Je známo, že diethylester 1,4-dihydro-2,6-dimethyl-4-fenylpyridin-3,5-dikarboxylové kyseliny se získá reakcí ethylesteru benzylidenacetoctové kyseliny s ethylesterem Q-aminokrotonové kyseliny nebo s ethylesterem acetoctové kyseliny a amoniakem [srov. E.Knoevenagel, Ber. Dtsch. Chem. Ges. 31, (1898) J .It is known that 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diethyl ester is obtained by reacting ethyl benzylideneacetic acid ethyl ester with ethyl Q-aminocrotonic acid ester or ethyl acetate and ammonia [cf. E. Knoevenagel, Ber. Dtsch. Chem. Ges. 31, (1898)
Dále je známo, že určité 1,4-dihydropyridiny mají zajímavé farmakologické vlastnosti (srov. F. Bossert, W. Vater, Naturwissenschaften .58» 578 (1971)).Furthermore, certain 1,4-dihydropyridines are known to have interesting pharmacological properties (cf. F. Bossert, W. Vater, Naturwissenschaften. 58: 578 (1971)).
Předložený vynález se týká způsobu výroby nových dihydropyridinamidů obecného vzorce IThe present invention relates to a process for the preparation of the novel dihydropyridinamides of the formula I
ve kterémin which
R1 a Rg jsou stejné nebo navzájem rozdílné a znamenají přímou nebo rozvětvenou alkylovou skupinu s 1 až 6 atomy uhlíku, znamená přímou nebo rozvětvenou alkylovou skupinu s 1 až 6 atomy uhlíku, která je popřípadě přerušena v řetězci atomem kyslíku a je popřípadě substituována alkoxykarbonylovou skupinou se 2 až 6 atomy uhlíku nebo fenylovou skupinou,R 1 and R 8 are the same or different from each other and represent a straight or branched (C 1 -C 6) alkyl group, a straight or branched (C 1 -C 6) alkyl group optionally interrupted by an oxygen atom in the chain and optionally substituted by an alkoxycarbonyl group having 2 to 6 carbon atoms or a phenyl group,
jsou stejné nebo navzájem rozdílné a znamenají atom vodíku nebo alkoxyskupinu s 1 až 4 atomy uhlíku, znamenáthey are the same or different from each other and are hydrogen or C1-C4alkoxy
-0-(CH2)n - fenylovou skupinu,-O- (CH 2 ) n -phenyl,
-0-(CH2 ) - pyridylovou skupinu,-0- (CH2) - pyridyl,
-S-(CH2)n - fenylovou skupinu nebo-S- (CH 2 ) n - phenyl or
-0-S02 - fenylovou skupinu, ve kterých n znamená číslo 1 nebo 2 a fenylová část je popřípadě jednou až třikrát substituována nitroskupinou, trifluormethylovou skupinou, alkylovou skupinou s 1 až 3 atomy uhlíku neCS 271 499 82 bo atomem halogenu,-O-SO 2 -phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl, or halogen,
R6 a R7 jsou stejné nebo navzájem rozdílné a znamenajíR 6 and R 7 are the same or different from each other and are
- atom vodíku,- hydrogen atom,
- cykloalkylovou skupinu se 3 až 8 atomy uhlíku,- C 3 -C 8 -cycloalkyl,
- přímou nebo rozvětvenou alkylovou skupinu s až 12 atomy uhlíku nebo alkenylovou skupinu s až 5 atomy uhlíku, které mohou být popřípadě substituovány hydroxyskupinou, alkoxyskupinou s 1 až 4 atomy uhlíku, alkylkarbonylovou skupinou se 2 až 5 atomy uhlíku, fenylovou skupinou, dialkylaminoskupinou s 1 až 4 atomy uhlíku v obou alkylových částech, cykloalkylovou skupinou se 3 až 6 atomy uhlíku nebo pyridylovou skupinou,- a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having up to 5 carbon atoms, which may optionally be substituted by a hydroxy group, a C1-C4 alkoxy group, a C2-C5 alkylcarbonyl group, a phenyl group, a 1-dialkylamino group up to 4 carbon atoms in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl,
- fenylovou skupinu, která je popřípadě substituována karbamoylovou skupinou, acetylaminoskupinou nebo benzoylaminoskupinou nebo- a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or
- pyridylovou skupinou, jakož i jejich fyziologicky použitelných solí.a pyridyl group and their physiologically acceptable salts.
Sloučeniny obecného vzorce I, vyráběné postupem podle vynálezu, existují ve steroisomerních formách, které se chovají buá jako obraz a zrcadlový obraz (enantiomery) nebo které se nechovají jak· obraz a zrcadlový obraz (diastereomery). Vynález se týká jak antipodů, tak i racemických forem, jakož i směsí diastereomerů. Racemické formy se dají rovněž jako diastereomery rozdělit známým způsobem na stereoisomerní jednotné složky (srov. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).The compounds of formula (I) produced by the process of the invention exist in steroisomeric forms which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates to both antipodes and racemic forms as well as mixtures of diastereomers. Racemic forms can also be resolved as diastereomers in a known manner into stereoisomeric unitary components (cf. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
Fyziologicky použitelnými solemi mohou být soli sloučenin obecného vzorce I s anor-, ganickými nebo organickými kyselinami. Výhodné jsou soli s anorganickými kyselinami, jako například s kyselinou chlorovodíkovou, s kyselinou bromovodíkovou, s kyselinou fosforečnou nebo kyselinou sírovou, nebo soli s organickými karboxylovými kyselinami nebo sulfonovými kyselinami, jako například s kyseLinou octovou, kyselinou maleinovou, kyselinou fumarovou, kyselinou jablečnou, kyselinou oitronovou, kyselinou vinnou, kyselinou mléčnou, kyselinou benzoovou nebo kyselinou methansulfonovou, kyselinou ethansulfonovou, kyselinou fenylsulfonovou, kyselinou toluensulfonovou nebo kyselinou naftalendisulfonovou .Physiologically acceptable salts can be salts of the compounds of the formula I with inorganic, organic or organic acids. Preferred are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, acid oitronic acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
Výhodné jsou sloučeniny obecného vzorce I, kterémPreferred are compounds of formula I wherein:
R1 a R8 jsou stejné nebo navzájem rozdílné a znamenajíR 1 and R 8 are the same or different from each other and are
- přímou nebo rozvětvenou alkylovou skupinu s 1 až 4 atomy uhlíku,- straight or branched (C1-C4) alkyl,
R2 znamená přímou nebo rozvětvenou alkylovou skupinu s 1 až 6 atomy uhlíku, která je popřípadě přerušena v řetězci atomem kyslíku nebo/a je popřípadě substituována fenylovou skupinou,R 2 represents a straight or branched alkyl group having 1 to 6 carbon atoms which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by phenyl,
R3 a R4 jsou stejné nebo navzájem rozdílné a znamenají atom vodíku nebo alkoxyskupinu s 1 až 4 atomy uhlíku, znamenáR 3 and R 4 are identical or different and represent hydrogen or alkoxy having 1 to 4 carbon atoms means
-O-(CH2)n - fenylovou skupinu,-O- (CH 2 ) n -phenyl,
-O-(CH2)n - pyridylovou skupinu,-O- (CH 2 ) n -pyridyl,
-S-(CH2)n - fenylovou skupinu nebo-S- (CH 2 ) n - phenyl or
CS 271 499 B1CS 271 499 B1
-O-SO2 - fenylocu skupinu, ve Kterých n - znamená číslo 1 nebo 2 í fenylová část je popřípadě jedno, až třikrát substituována nitroskupinou, trifluornethylovou skupinzc, alkylovou skupinou s 1 až 3 atomy uhlíku nebo» atomem fluoru, chlorr nebo bromu,-O-SO 2 - a phenylocyl group in which n - represents the number 1 or 2; the phenyl part is optionally one to three times substituted by nitro, trifluoromethyl, C 1 -C 3 alkyl or fluorine, chlorine or bromine;
R6 a R7 jsou stejné nebD navzájem rozdílná a znamenajíR 6 and R 7 are the same or different from each other and represent
- atom vodítku nero cykloalkylovDL skupinu se 3 až 7 atomy uhlíku,- a hydrogen atom for a cycloalkyl-DL group having from 3 to 7 carbon atoms,
- přímou nettoo rozvětvenou alkylovou skupinu s až 12 atomy uhlíku nebo alkenylovou skupinu s až 5 atonv uhlíku, které mohou být popřípadě substituovány nydroxyskupinoLi, alkoxyskupinou s 1 až 4 atomy uhlíku, alkylkartronylCiOu skupinou se 2 až 5 atomy uhlíku, fenylovou skupinou, dialkylaminoskupinoui s 1 sž 4 atomy uhlíku v obou alkylových částech,a straight nettoo branched alkyl group of up to 12 carbon atoms or an alkenyl group of up to 5 carbon atoms which may be optionally substituted by hydroxy, C1-C4alkoxy, C2-C5alkylcarbonyl, phenyl, C1-C4 dialkylamino up to 4 carbon atoms in both alkyl moieties,
- fenylovoLB skupinu, která je poróípadě substituována acetylaminoskupinou nebo ienzoylaminioskup-rtou nebo- a phenyl-LB group, which is optionally substituted by acetylamino or ienzoylamino, or
- pyridylovou stopinu, jakož i jejich fyziologicky použitelné soli.- pyridyl tracein and their physiologically acceptable salts.
Zvláště výhodné jsou sloučeniny obecného vzorce I, ve kterémParticularly preferred are compounds of formula I wherein:
88
R a R jsou stejné nebo rozdílné a znamenají methylovou skupinu nebo ethylovou skupinu,R and R are the same or different and are methyl or ethyl,
R znamená přínou nebo rozvětvenou slkylovou skupinu s 1 až 6 atomy uhlíku, která je popřípadě přerušena v řetězci atomem kyslíku nebo/a je popřípadě substituována fenylovou skupinou,R is a straight or branched C 1 -C 6 alkyl group optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group,
44
R a R jsou stejné nebo rozdílné a znamenají atom vodíku, methoxyskupinu nebo ethoxyskupinu,R and R are the same or different and are hydrogen, methoxy or ethoxy,
R5 znamená -O-CHj - fenylovou skupiru, -O-CH2 - pyridylovou skupinu,R 5 is -O-CH 2 -phenyl, -O-CH 2 -pyridyl,
-S-CH2 - fenylovou skupinu nebo -&-S02 - fenylovou skupinu, přičemž fenylová část je popřípadě až dvekrát substituována stejnými nebo rozdílnými substituenty zvolenými ze skupiny tvořené nitroskupinou, trifluormethylovou skupinou, methyl rvou skupinou nebo atomem fluoru či chloru,-S-CH 2 -phenyl or -S-SO 2 -phenyl, wherein the phenyl moiety is optionally substituted up to two times with the same or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluoro or chloro,
R^ znamená atoa vodíku nebo alkylovcu skupinu s až 4 atomy uhlíku aR @ 1 represents a hydrogen atom or an alkyl group having up to 4 carbon atoms and
R7 znamenáR 7 denotes
- atom vodíku, cyklopropylovou skupinu, cyklopentylovou skupinu, cyklohexylovou skupinu, neboa hydrogen atom, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, or
- přímou nebo rozvětvenou alkylovzu skupinu s až 10 atomy uhlíku nebo alkenylovou skupinu s až 5 atoirv uhlíku, které jsou popřípadě substituovány hydroxyskupinou, alk o x skupinou s 1 až 4 atomy uhlíku, alkylkarbonylovou skupinou s 1 až 4 itomy uhlíku v alkylové části, fenylovou skupinou nebo dialkylaminosiupinou s 1 až 4 atomy uhlíku v alkylových částech., nebo- a straight or branched alkyl group having up to 10 carbon atoms or an alkenyl group having up to 5 carbon atoms optionally substituted by a hydroxy group, an alk ox group having 1 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms in the alkyl moiety, a phenyl group or a (C 1 -C 4) dialkylamino group, or
CS 271 499 B2CS 271 499 B2
R? znamenáR? means
- fenylovou skupinu, která je popřípadě substituována acetylaminoskupinou nebo benzoylaminoskupinou nebophenyl optionally substituted by acetylamino or benzoylamino, or
- (Z -, 0- nebo - pyridylovou skupinu, jakož i jejich fyziologicky použitelné soli.- (Z -, O- or - pyridyl), and their physiologically acceptable salts.
RR
Podle tohoto vynálezu se sloučeniny obecného vzorce I, ve kterém R až R mají shora uvedené významy, jakož i jejich fyziologicky použitelné soli připravují tím, že se amidy yliden-Q-ketokarboxylové kyseliny obecného vzorce VIIAccording to the invention, the compounds of the formula I in which R to R have the meanings given above and their physiologically acceptable salts are prepared by the preparation of the ylidene-Q-ketocarboxylic acid amides of the formula VII
XR7 (VII), ve kterém X R 7 (VII) wherein
R·5, r\ R5, R6, R7 a R8 mají shora uvedené významy, uvádějí v reakci s estery enaminokarboxylové kyseliny obecného vzorce VIR 5 , R 5 , R 6 , R 7 and R 8 have the meanings given above, in reaction with the enaminocarboxylic acid esters of the general formula VI
(VI), ve kterém ,(VI) in which,
Rx a R mají shora uvedeny vyznám, popřípadě v přítomnosti inertních rozpouštědel, načež se získané sloučeniny popřípadě převedou na své fyziologicky použitelné soli.R @ 1 and R @ 2 are as described above, optionally in the presence of inert solvents, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts.
CS 271 499 B2CS 271 499 B2
Postup podle vynálezu lze na jícím reakčním schématem:The process according to the invention can be illustrated by the following reaction scheme:
konkrétním příkladu výchozích látek znázornit následuH3COOCa specific example of the starting materials shown by H 3 COOC
Jako rozpouštědla přicházejí pro reakci podle vynálezu v úvahu voda nebo všechna inertní organická rozpouštědla, která se za reakčních podmínek nemění. К těm náleží výhodně alkoholy, jako methanol, ethanol, propanol, isopropylalkohol, ethery, jako diethylether, dioxan, tetrahydrofuran, glykolmonomethylether nebo glykoldimethylether, nebo amidy, jako dimethylformamid, dimethylacetamid nebo hexamethyltriamid kyseliny fosforečné, nebo ledová kyselina octová, dimethylsulfoxid, acetonitril nebo pyridin.Suitable solvents for the reaction according to the invention are water or any inert organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides, such as dimethylformamide, dimethylacetamide or hexamethyltriophosphoric triamide, or glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine. .
CS 271 499 B2CS 271 499 B2
Reakční teploty se mohou měnit v širokém rozmezí. Obecně ee pracuje při teplotách mezi +10 °C a +150 °C, výhodně při teplotách mezi +20 °C a +100 °C. Zvláště výhodně'se pracuje při teplotě varu příslušného rozpouštědla.The reaction temperatures can be varied within a wide range. In general, it is operated at temperatures between + 10 ° C and +150 ° C, preferably at temperatures between + 20 ° C and +100 ° C. It is particularly preferred to operate at the boiling point of the solvent.
Reakce může provádět za atmosférického tlaku, avšak také při zvýšeném nebo při sníženém tlaku. Obecně se pracuje při atmosférickém tlaku.The reaction can be carried out at atmospheric pressure, but also at elevated or reduced pressure. Generally, the process is carried out at atmospheric pressure.
Poměr výchozích látek, které se zúčastňují reakce podle vynálezu, je libovolný. Obecně se však pracuje za použití molárních množství reakčníoh složek.The ratio of the starting materials involved in the reaction according to the invention is arbitrary. In general, however, the reaction is carried out using molar amounts of the reactants.
Izolace a čištění sloučenin získaných postupem podle vynálezu.se provádí výhodně tak, že se rozpouštědlo oddestiluje za sníženého tlaku a zbytek získaný popřípadě teprve po ochlazení ledem v krystalickém stavu, se překrystalizuje z vhodného rozpouštědla. V některých případech může být zapotřebí alouSenlnyj která byly získány postupem podle vyndležu, ftiBtit chromatografovánfm.The isolation and purification of the compounds obtained by the process according to the invention is preferably carried out by distilling off the solvent under reduced pressure and recrystallizing the residue, if necessary only after cooling in ice, in a crystalline state from a suitable solvent. In some cases, alumina obtained by the process of the present invention may be required to be chromatographed.
Estery enaminokarboxylové kyseliny obecného vzorce VI, které ee používají při poπΐιιμιι μιηΠπ vyiidl#411 jeku výuliu4Í iélhy, jsuii bud xndiiiýint sluuosh 1 но 1 naliti йй mtiluiu pfipravovat podle známých metod [erov. F,A< Gllokman, A»C. Cope, 0. Am. Chem. Sob. £2.» 1017 (1945) J . 1 ,The enaminocarboxylic acid esters of formula (VI), which are used in the treatment of spleen gums, may be prepared according to known methods [erov. F, A <Gllokman, A »C. Cope, 0 Am. Chem. Reindeer. £ 2. »1017 (1945) J. 1 ,
Amidy yliden-O-ketokerboxylové kyseliny obecného vzoroe VIIt které ee rovněž používají jako výohozí látky při poetupu podle vynálezu jeou buá známými látkami nebo ee mohou připravovat podle známých metod ferov. G. Jones The Knoevenagel Condensation in Organic Reactions, ev. XV, str. 204 (1967)J.The ylidene-O-ketocarboxylic acid amides of the general formula (VII ) which are also used as the preferred substances in the process according to the invention are either known substances or can be prepared according to known methods of ferro. G. Jones The Knoevenagel Condensation in Organic Reactions, ev. XV, p. 204 (1967) J.
Sloučeniny obeoného vzorce I, které ae připravují postupem podle předloženého vynálezu, vykazují nspředpokládatelné spektrum cenných farmakologických účinků. Uvedené sloučeniny ovlivňují kontraktilltu srdce, tonus hladkého svalstva, jakož i hladinu elektrolytů a kapalin.The compounds of formula I which are prepared by the process of the present invention exhibit an unpredictable spectrum of valuable pharmacological effects. These compounds affect heart contractility, smooth muscle tone as well as electrolyte and fluid levels.
Uvedené sloučeniny se mohou používat v léčivech к ošetřování pathologicky změněného krevního tlaku a srdeční nedostatečnosti, jakož i jako koronární terapeutika.The compounds can be used in medicaments for the treatment of pathologically altered blood pressure and cardiac insufficiency, as well as as coronary therapeutics.
Kromě toho se mohou uvedené látky používat к léčení poruch srdečního rytmu, nedostatečnosti ledvin, cirhosy jater, ascites, plicního edému, edému mozku, edému v těhotenství, glaukomu nebo cukrovky (Oiabetee mellitus).In addition, the compounds may be used to treat disorders of the heart rhythm, renal insufficiency, liver cirrhosis, ascites, pulmonary edema, brain edema, pregnancy edema, glaucoma or diabetes (Oiabetee mellitus).
Účinnost sloučenin vyráběných postupem podle vynálezu na činnost srdce byla zjištěna na izolovaném, stimulovaném papilárním svalu srdce morčete, Za tím účelem se pokusná zvířata (morčata obojího ‘pohlaví o hmotnosti 200 g) usmrtí, otevře se jejich hrduník a vyjme se srdce. Pro pokusy se potom vypreparují z pravé srdeční komory vždy pokud možno malé papilární svaly a fixují se horizontálně v orgánové lázni. Přitom je jeden konec svalu zachycen mezi dvěma kovovými elektrodami, které současně dráždí preparát, zatímco druhý konec svalu je spojen vláknem se snímačem síly. Papilární sval se dráždí frekvencí 1 Hz nad prahovou hodnotu. Orgánová lázeň o objemu asi 2 ml se kontinuálně promývá Krebs-Henseleltovým roztokem (koncentrace v mmol: NaCl 11B; Na2COj 25; KC1 10; KH2PO^ 1,2;The activity of the compounds according to the invention on the activity of the heart was determined on an isolated, stimulated papillary muscle of the guinea pig heart. For the experiments, small papillary muscles are then removed from the right ventricle and fixed horizontally in the organ bath. Here, one end of the muscle is trapped between two metal electrodes, which simultaneously irritate the specimen, while the other end of the muscle is connected by a fiber to a force sensor. The papillary muscle is irritated at a frequency of 1 Hz above the threshold. An organ bath of about 2 ml is continuously washed with Krebs-Henselelt solution (concentration in mmol: NaCl 11B; Na 2 CO 3 25; KCl 10; KH 2 PO 4 1.2;
MgSO^ 1,2; СаС12 1,8; glukosa 10, pH 7,4) rychlostí 4 ml/min při teplotě 32 °C. Kontrakce papilárního svalu se měří isometricky přes připojený snímač síly a zaznamenává se pomocí zapisovače.MgSO 4 1.2; СаС1 2 1.8; glucose 10, pH 7.4) at a rate of 4 ml / min at 32 ° C. Papillary muscle contraction is measured isometrically through a connected force transducer and recorded using a recorder.
Látky podle vynálezu se rozpustí v Krebs-Henseleitově roztoku v koncentraci 10 ^ug/ml, popřípadě za použití pomocného rozpouštědla (dimethylsulfoxidu až do koncentrace 0,5 .The compounds of the invention are dissolved in Krebs-Henseleit solution at a concentration of 10 µg / ml, optionally using a co-solvent (dimethylsulfoxide up to a concentration of 0.5).
Amidy dihydropyridinkarboxylové kyseliny podle vynálezu vykazují přitom vztaženo na hodnoty získané při kontrolním pokusu potlačení síly kontrakce papilárního svalu o více než 10 %.The dihydropyridine carboxylic acid amides according to the invention exhibit a reduction in the papillary muscle contraction force by more than 10% relative to the values obtained in a control experiment.
CS 271 499 В 2 nové účinné látky se mohou převádět známým způsobem na obvyklé přípravky, jako jsou tablery, dražé, pilulka granulát, aerosoly, sirupy, emulze, suspenze a roztoky, za použití i-ertních, -etoxickýzh, farmaceuticky vhodných nosných látek nebo rozpouštědel. Přitom má býT terapeuticky účinná sloučenina přítomna vždy v koncentraci od asi 0,5 do 90 % hmotnostních, rztaženo na celkovou směs, tj. v množství, která jsou postačující к tomu, aby se dosáhlo uvedenénn rozsahu dávek.The new active substances can be converted in a known manner into conventional preparations such as tablets, dragees, pellet granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The therapeutically active compound is always present in a concentration of from about 0.5 to 90% by weight, based on the total mixture, i.e. in amounts which are sufficient to achieve the stated dosage range.
Přípravky se yyríaějí například smísením účinných látek s rozpouštědly nebo/a nosnými láskami, popřípadě zi použití emulgátorů nebo/a dispergátorů, přičemž v případě použití vody jako ředidla se тэтой používat popřípadě organická rozpouštědla jakožto pomocná rozpouštědla.The formulations are prepared, for example, by mixing the active compounds with solvents and / or carrier substances, optionally using emulsifiers and / or dispersants, and optionally using organic solvents as co-solvents when water is used as the diluent.
Jako pomocné látky lze uvést například: vodu, netoxická organická rozpouštědla, jako parafinické uhlovodíky Cnapříklad ropné frakce), rostlinné oleje (například směs podzemnicovébo oleje a sezamovúio oleje), alkoholy (například ethylalkohol, glycerol), nosné látky, jako například příradní kamenné moučky (například kaoliny, aluminy, mastek, křídu), syntetické kamenné moučcy (jako například vysoce disperzní kyselinu křemičitou, křemičitany)» cukry (například třtinový cukr, mléčný cukr a hroznový cukr), emulgátory (například polyoxyethylenestery mastných kyselin, polyoxyethylenestery mastných alkoholů, alkylsulfonáty, arylsulíonáty), detergenty (například lignin, sulfitové odpadní louhy, methylcelulosu, škroby a polyvinylpyrrolidon) a látky kluzné (například hořečnatou sůl kyseliny stearové, mastek, stearovou kyselinu a natriumlaurylsulfát).Excipients which may be mentioned are, for example: water, non-toxic organic solvents such as paraffinic hydrocarbons (eg petroleum fractions), vegetable oils (for example a mixture of peanut oil and sesame oil), alcohols (for example ethyl alcohol, glycerol); e.g., kaolins, alumina, talc, chalk), synthetic stone meal (such as highly disperse silicic acid, silicates) »sugars (e.g., cane sugar, milk sugar, and grape sugar), emulsifiers (e.g. polyoxyethylene fatty acid esters, fatty alcohol polyoxyethylene esters, alkylsulfonates, arylsulonates), detergents (e.g., lignin, sulphite waste liquors, methylcellulose, starches and polyvinylpyrrolidone) and glidants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
Aplikace se provádí obvyklým způsobem, výhodně perorálně nebo parenterálně, zejména perlinguálně nebo intravenosně. V případě orální aplikace mohou tablety obsahovat samozřejmě kromě uvedených nosných látek také přísady, jako sodnou sůl kyseliny citrónové, uhličitan vápenatý a dikalciumfosfát společně s různými přísadami, jako jsou škroby, výhodně bramborový škrob, želatina apod. Dále mohou obsahovat rovněž lubrikátory, jako hořečnatou sůl kyseliny stearové, natriumlaurylsulfát a mastek, které se používají jako pomocné látky při tabletování. V případě vodných suspenzí se mohou к účinným látkám pri- dávat kromě shora uvedených pomocných látek také různé látky zlepšující chuť nebo barviva.Administration is carried out in a conventional manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, the tablets may of course also contain, in addition to the aforementioned carriers, additives such as sodium citric acid, calcium carbonate and dicalcium phosphate together with various additives such as starches, preferably potato starch, gelatin and the like. stearic acid, sodium lauryl sulfate and talc, which are used as tableting aids. In the case of aqueous suspensions, in addition to the abovementioned excipients, various flavor enhancers or colorants may be added to the active ingredients.
V případě parenterální aplikace se mohou používat roztoky účinných látek za použití vhodných kapalných masných látek.For parenteral administration, solutions of the active compounds using suitable liquid meat substances may be used.
Obecně se ukázalo výhodným používat při intravenosní aplikaci množství od asi 0,001 do 1 mgAg, výhodně od asi 0,01 do 0,5 mg/kg tělesné hmotnosti, aby se dosáhlo účinných výsledků. Při perorální aplikaci činí dávka od asi 0,01 do 20 mg/kg, výhodně od 0,1 rto 10 mg/kg tělesné hmotnosti.In general, it has proven advantageous to use an amount of from about 0.001 to 1 mgAg, preferably from about 0.01 to 0.5 mg / kg body weight, for intravenous administration, in order to achieve effective results. For oral administration, the dose is from about 0.01 to 20 mg / kg, preferably from 0.1 to 10 mg / kg body weight.
Přesto může být v některých případech popřípadě nutné odklonit se od uvedených množství a to v závislosti na tělesné hmotnosti, popřípadě na způsobu aplikace, na individuálním chování vůči medikamentu, na způsobu v jakém je podáván a na době, popřípadě intervalu, ke kterému se aplikace provádí. Tak může být v některých případech dostačující, použije-li se menšího množství než to, které je uvedeno shora jako minimální, zatímco v jiných případech se musí shora uvedená horní mez překročit. V případě aplikace větších množství lze doporučit rozdělit toto množství do několika jednotlivých dávek aplikovaných během dne.However, in some cases, it may be necessary to deviate from the indicated amounts, depending on body weight, the mode of administration, the individual behavior of the medicament, the manner in which it is administered, and the time or interval at which it is administered. . Thus, in some cases it may be sufficient to use less than the minimum listed above, while in other cases the above upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide this into several individual doses administered during the day.
V následujících příkladech byly hodnoty stanovovány na hliníkové fólii pro chromatografii na tenké vrstvě (Merck), tloušťka vrstvy 0,2 mm, silikagel 60 F 254; rozpouštědlový systém: směs tDluenu a ethylacetátu v objemovém poměru 1:2.In the following examples, values were determined on aluminum foil for thin layer chromatography (Merck), layer thickness 0.2 mm, silica gel 60 F 254; solvent system: a 1: 2 mixture of toluene and ethyl acetate.
CS 271 499 02CS 271 499 02
Příklad 1Example 1
3-methylester-5-cyklopropylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
3,35 g (10 mmol) oyklopropylamidu 2-bsnzyl-oxybsnzylldeniiaetootovd kyseliny so spolu s 1,14 g (10 mmol) methylesteru 0-aminokrotonové kyseliny vaří ve 30 ml isopropylalkoholu. Poté se reakční směs ochladí a zahustí ee. Zbytek po zahuštění ee rozpustí v toluenu a roztok se znovu zahustí. Krystalický zbytek se poté rozmíchá s toluenem, produkt se odfiltruje a překrystalizuje se z malého množství acetonitrilu. Získá se 2,0 g (46,3 teorie) bezbarvých krystalů o teplotě tání 194 °C.2.35 g (10 mmol) of 2-benzyloxybenzyl-di-di-acetic acid cyclopropylamide are boiled in 30 ml of isopropyl alcohol together with 1.14 g (10 mmol) of O-aminocrotonic acid methyl ester. Then the reaction mixture was cooled and concentrated. The residue was concentrated in toluene and the solution was concentrated again. The crystalline residue is then stirred with toluene, the product is filtered off and recrystallized from a small amount of acetonitrile. 2.0 g (46.3 of theory) of colorless crystals of melting point 194 DEG C. are obtained.
Analogickým způsobem jeko je popsán ve ehora uvedeném příkladu se připraví rovněž sloučeniny uvedené v následujících příkladech.In an analogous manner to that described in the above example, the compounds of the following examples are also prepared.
Příklad 2Example 2
3-methyl08ter-5-dimethyl amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyeeliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl08ter-5-dimethyl amide
CS 271 499 B2CS 271 499 B2
Teplota tání 162 až 165 °C.Melting point 162-165 ° C.
Příklad 3Example 3
3-methylester-5-fenylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2t6-dimethylpyridin-3,5-dikarboxylové kyseliny3-methyl-5-phenylamide 4- (2-benzyloxyphenyl) -l, 4-dihydro-2 t 6-dimethylpyridine-3,5-dicarboxylic acid
Teplota tání 194 °C.Mp 194 ° C.
Příklad 4Example 4
3-methylester-5-methylaínid l,4-dihydro-2,6-dimethyl-4- [ 2-(3-trifluormethylbenzyloxy)fenyl3 pyridin-3,5-dikarboxylové kyseliny1,4-dihydro-2,6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylainide
Teplota tání 156 až 157 °C.Melting point 156-157 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 5Example 5
3-methylester-5-cyklopropylamid 1,4-dihydro-2,6-dimethyl-4-£ 2-(3-methylbenzyloxy)fenyl3 pyridin-3,5-dlkarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (3-methylbenzyloxy) phenyl] pyridine-3,5-dlcarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 176 °C.Melting point 176 ° C.
Příklad 6Example 6
3-methylester-5-cyklopropylamld 4- t2-(4-chlorbenzyloxy)-fenyl3 -l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (4-Chlorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 178 °C.Melting point 178 ° C.
CS 271 499 82CS 271 499 82
Příklad 7Example 7
3-methylester-5-(2-pyridyl)anid 4-(2-(4-chlorbenzyloxy)fenyl ] -1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- (2- (4-chlorobenzyloxy) phenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-pyridyl) anide
Teplota tání 201 až 204 °C.Mp 201-204 ° C.
Příklad 8Example 8
3-methylester-5-(2-pyridyl)aínid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine- (3-methyl ester)
3,5-dikarboxylové kyseliny3,5-dicarboxylic acids
Teplota tání 164 až 165 °C.Melting point 164-165 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 9Example 9
3-methylester-5-(2-diethylaminoethyl)amid 4- [ 2-chlorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-diethylaminoethyl) amide
Teplota tání od 00 °C.Melting point from 00 ° C.
Příklad 10Example 10
3-methylaater-5-(2-dlethylamlnoethy1)amid 4-(2-benzyloxyfenyl)-l,4-dlhydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dlhydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methylaater-5- (2-diethylamino-ethyl) -amide
Teplota tání od 95 °C.Melting point: 95 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 11Example 11
3-methylester-5-(4-karbamoylíenyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-carbamoyl-phenyl) -amide
Teplota tání nad 300 °C.Melting point above 300 ° C.
Příklad 12Example 12
3-methylester-5-(4-acetylaminofenyl)amid 4-(2-benzy1oxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-acetylaminophenyl) amide
Teplota tání 290 °C (rozklad).Melting point 290 ° C (dec.).
CS 271 499 B2CS 271 499 B2
Příklad 13Example 13
3-methyletster-5-(4-benzoylaminofenyl)amid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-ether-5- (4-benzoylaminophenyl) amide
3-methy'lester-5-(l-fenylethyl)amid (R,S)-4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (směs R,S)(R, S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R, WITH)
Teplota tání od 162 °C.Melting point: from 162 ° C.
CS 271 499 02CS 271 499 02
P ř í к 1 a d 15Example 1 a d 15
3-methylester-5-(l-íenylethyl)anúcí (R)-4-(2-benzyloxyíenyl)-l|4-dihydro-2,6-dimethyipyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl)
Teplota tání 82 °C,Melting point 82 ° C,
Příklad 16Example 16
3-methylester-5-(3-dimethylaminopropyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-dimethylaminopropyl) amide
Teplota tání 89 až 90 °C.Mp 89-90 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 17Example 17
3-methylester-5-сукlohexylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyгidin-3,5-dikarboxylově kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclohexylamide
Teplota tání 108 až 111 °C.Melting point 108-111 ° C.
Příklad 18Example 18
3-methylester-5-terč.butylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-tert-butylamide
Teplota tání 148 °C.Mp 148 ° C.
CS 21 499 82CS 21 499 82
Příklad 19Example 19
3-methylester-5-propylamid 4-C2-benzyloxyÍ5nyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4-C2-Benzyloxy (5-phenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-propylamide
Pěna, Rf = 0,37.Foam, R f = 0.37.
Příklad 20 ’Example 20 ’
3-methylester-5-(2-methylpropyl)amid A-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyгidin-3, 5-dikarboxylové kyselinyN- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methyl-propyl) -amide
Teplota tání 134 °C.Melting point 134 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 21Example 21
3-methylester-5-N-benzyl-N-terč.butylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-N-benzyl-N-tert-butylamide
Teplota tání 128 °C.Melting point 128 ° C.
Příklad 22Example 22
3-methylester-5-methylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání 105 °C.Melting point 105 ° C.
CS 271 499 02 Příklad 23CS 271 499 02 Example 23
3-methylester-5-ethylamid 4-(2-benzylOxyfenyl)-l,4-dihydro-2>6-dimethylpyridin-3,5-dikscboxylové kyseliny3-methyl-5-ethylamide, 4- (2-benzyloxyphenyl) -l, 4-dihydro-2> 6-dimethyl-3,5-dikscboxylové acid
Teplota tání 172 °C.Melting point 172 ° C.
Příklad 24Example 24
3-butylester-5-cyklopropylamid l,4-dihydro-2,6-dimethyl-4- [ 2-(2-pyridyl)methoxyfenylJ pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide
Pěna, Rf 0,1.Foam, R f 0.1.
CS 271 499 02·CS 271 499 02
Příklad 25Example 25
3-butylester-5-methylamid 1,4-dihydro-2,6-dimethyl-4- [ 2-(2-pyridy1)methoxyfenylJ pyridin-} , 5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-}, 5-dicarboxylic acid 3-butyl ester-5-methylamide
Pěna, Rf = 0,07.Foam, Rf = 0.07.
Příklad 26Example 26
3-butylester-5-(l-methylpropyl)amid 1,4-dihydro-2,6-dimethу1-4- [ 2-(2-pyridyl)methoxyfenyl] pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-methylpropyl) amide
Pěna, RfFoam, Rf
0,25.0.25.
CS 271 499 B2CS 271 499 B2
Příklad 27Example 27
3-methylester-5-cyklopropylamid 4- [2-(3,4-dichlorbenzyloxy)fenyl J-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (3,4-Dichlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 195 °C.Mp 195 ° C.
Příklad 28Example 28
3-methylester-5-cyklopropylamid 4- [ 2-(2,6-dichlorbenzyloxy)fenyl3 -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 178 °C.Melting point 178 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 29Example 29
3-methylester-5-(l-methylpropyl)amid 4- £ 2-(2,6-dichlorbenzyloxy)fenyl ] -1,4-dihydro-2)6-dimethylpyridin-3, 5-dikarboxylové kyseliny4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-methyl-propyl) -amide
Pěna, Rf = 0,36.Foam, R f = 0.36.
Příklad 30Example 30
3-methylester-5-methylamid 4- £2-(2,6-dichlorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání 113 °C .Melting point 113 ° C.
CS 271 499 82CS 271 499 82
Příklad 31Example 31
3-m ethylester-5-methylamid 4- [ 2-(3,4-dichlorbenzyloxy)fenyl ] -1,4-dihydro-2,6-dimethyl pyridin-3)5-dikarboxylové kyseliny4- [2- (3,4-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5-methylamide
Teplota tání 120 °C.Melting point 120 ° C.
Příklad 32Example 32
3-methylester-5- cyklopropylanid 4- [ 2-(3-fluorbenzyloxy)-3-methoxyfenyl1 -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylanide
Teplota tání 202 °C.Melting point 202 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 33Example 33
3-methylester-5-cyklopropylamid 4- [ 2-(2-chlorbenzyloxy)fenyl J -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (2-chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 185 °C.Mp 185 ° C.
Příklad 34Example 34
3-methylester-5-methylamid 4- [ 2-(2-chlorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (2-chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání 170 °C.Melting point 170 ° C.
CS 271 499 82CS 271 499 82
Příklad 35Example 35
3-methylester-5-(2-methylpropyl)amid 4-E 2-(3-fluorbenzyloxy)-3-methoxyfenyl ] -1 ,4-dihydro-2 >6-dimethylpyridin-3,5-dikarboxylové kyseliny3-methyl-5- (2-methylpropyl) amide with 4-E 2- (3-fluorobenzyloxy) -3-methoxyphenyl] -1, 4-dihydro-2> 6-dimethyl-pyridine-3,5-dicarboxylic acid
Teplota tání 98 °C.Melting point 98 ° C.
Příklad 36Example 36
3-methylester-5-cyklopropylamid l,4-dihydro-2,6-dimethyl-4- [2-(3-trifluormethylbenzyloxy)fenyl] pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
H^COOCH 2 COOC
Teplota tání 148 °C.Mp 148 ° C.
CS 271 499 82CS 271 499 82
Příkladě ·Example ·
3-methylester-5-(l-methylpropyl)amid 1,4-dihydro-2,6-dimethy!-4-f 2-(3-trifluormethylbenzyloxy)fenylД pyridin-3,5-dikarboxylové kyseliny1,4-dihydro-2,6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-methylpropyl) amide
Pěna, = 0,44»Foam, = 0.44 »
Příklad 38Example 38
3-methylester-5-isopropylamid 4- E2-(3-fluorbenzyloxy)-3-methoxyfenyl3 -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- E2- (3-Fluorobenzyloxy) -3-methoxyphenyl-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-isopropylamide
Teplota tání 106 °C.Melting point 106 ° C.
CS 271 499 82CS 271 499 82
Příklad 39Example 39
3-(1-methylpropyl)ester-5-cyklopropylamíd 1,4-dihydro-2,6-dimethyl-4- [ 2-(4-methylbenzyloxy)fenylJ pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-cyclopropylamide
Pěna, Rf = 0,31.Foam, R f = 0.31.
Příklad 40Example 40
3-methylester-5-cyklopropylamid 4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 197 °C.Melting point 197 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 41Example 41
3-(1-methylpropy1)ester-5-(1-methylpropyl)amid 1,4-dihydro-2,6-dimethy1-4- £ 2-(4-methylbenzyloxy)feny 1J pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5- (1-methylpropyl) amide
Teplota tání 126 °C.Melting point 126 ° C.
Příklad 42Example 42
3-(l-methylpropyl)ester-5-methylamid 1,4-di hydro-2,6-dimethy1-4- [2-(4-теthy1benzyloxy) fenylJ pyridin-3,5-dikarboxylové kyseliny1,4-dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-methylamide
Pěna, Rf = 0,48.Foam, Rf = 0.48.
CS 271 499 B2CS 271 499 B2
Příklad 43Example 43
3-ethylester-5-cyklopropylamid 1,4-dihydro-2,6-dimethy1-4- [2-(3-nitrobenzyloxy ) feny1J pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (3-nitrobenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide
Pěna, Rf = 0,24.Foam, Rf = 0.24.
Příklad 44Example 44
3-methylester-5-propylamid 4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5dikarboxylové kyseliny4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-propylamide
Teplota tání 210 °C.Melting point 210 ° C.
CS 271 499 Ξ2CS 271 499-2
Přiklad 45Example 45
3-ethylester-5-(l-fenylethyl)amid (R)-4- I2-(4-f1usrbenzyloxy)fenylJ -l,4-dihydro-2,6dimethylpyridin-3,5-dikarboxylové kyseliny(R) -4- 12- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5- (1-phenylethyl) amide
Pěna, Rf = 0,56.Foam, R f = 0.56.
Příklad 46Example 46
3-methylester-5-(2-methylpropyl)amid 4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethyIpyridin-3,5-dikarboxylové kyseliny4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide
Teplota tání 202 °C.Melting point 202 ° C.
CS 271 499 62CS 271 499 62
P ř í к 1 в d 47 ·Example 1 in d 47 ·
3-ethylester-5-cyklopropylamid 4- £2-(4-fluorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethy1pyridin-3, 5-dikarboxylové kyselipy4- [2- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide
Teplota tání 159 °C,Melting point 159 ° C,
Příklad 48Example 48
3-mathylsstsr-5-cyklopropylBmld 4- [2-(4-fluorbenzyloxy)-řenyl3 -1,4-dihydro-2,6-di msthylpyrldin-3,5-dikarboxylové kyseliny3- [2- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyrrolidine-3,5-dicarboxylic acid
Teplota tání 154 °C.Melting point 154 ° C.
CS 271 499 02CS 271 499 02
Příklad 49Example 49
3-methylester-5-(l-fenylethyl)amid (S)-4-(4-benzyloxyfenyl)-1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny (S-forma)(S) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (S-form)
Teplota tání 141 °C.Melting point 141 ° C.
Příklad 50Example 50
3-methylester-5-isopropylamid 4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-isopropylamide
Teplota tání 162 °C.Melting point 162 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 51Example 51
3-methylester-5-(1-fenylethyl)amid (R)-4-(4-benzyloxyfenyl)-1 , 4-dihydro 2,6-dimethylpyri din-3,5-dikarboxylové kyseliny (R-forma, diastereomer A)(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form, diastereomer A)
Teplota tání 196 °C.Melting point 196 ° C.
Příklad 52Example 52
3-methylester-5-cyklopropylamid 4- [2-(3-chlorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (3-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 174 °C.Melting point 174 ° C.
CS 271 499 B2CS 271 499 B2
P ř í к 1 a d 53 ·Example 1 a d 53 ·
3-methylester-5-cyklopropylamld 4- [ 2-(4-fluorbenzylthio)fenyl J-l,4-dihydro-2,6-dimethyl pyridin-3,5-dikarboxylové kyseliny4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethyl pyridine-3,5-dicarboxylic acid 3-methyl ester
Teplota tání 202 °C.Melting point 202 ° C.
Příklad .54Example .54
3-methylester-5-(l-fenylethyl)amid pyгidin-3,5-dikarboxylové kyseliny (R)-4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethy1(diastereomer B) (R-forma)(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethyl (diastereomer B) (R-) - 5- (1-phenylethyl) amide-3,5-dicarboxylic acid 3-methyl ester form)
Teplota tání 202 °C.Melting point 202 ° C.
CS 271 499 B2CS 271 499 B2
P г í к 1 a d 55Example 55
3-methylester-5-(1-fenylethy1) amid (R)-4-(4-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (R-forma, diastereomerní směs) ·(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form, diastereomeric mixture) ·
Teplota tání 110 až 166 °C.Melting point 110-166 ° C.
Příklad 56Example 56
3-methylester-5-(l-fenylethyl)amid (S)-4-(2-benzyloxyfenyl)-1>4-dihydro-2>6-dimethylpyridin-3,5-dikarboxylové kyseliny (S-forma, diastereomer A)3-methyl-5- (l-phenylethyl) amide (S) -4- (2-benzyloxyphenyl) -1> 4-dihydro-2> 6-dimethyl-pyridine-3,5-dicarboxylic acid (S-form, diastereomer A)
Teplota tání 172 °C.Melting point 172 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 57Example 57
3-methylester-5-(l-fenylethyl)amid (S)-4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyгi din-3,5-dikarboxylové kyseliny (S-forma, diastereomer B)(S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (S-form, diastereomer B) )
Pěna, = 0,53.Foam = 0.53.
Příklad 58Example 58
3-methylester-5-(l-fenylethyl)amid (R)-4- [2-(4-fluorbenzyloxy)fenyl2 -1,4-dihydro-2,6dimethylpyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- [2- (4-Fluoro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide (R-form)
Pěna, Rf =Foam, R f =
0,52.0.52.
CS 271 499 82CS 271 499 82
Příklad 59Example 59
3-butylester-5-cyklopropylamid l,4-dihydro-2,6-dimethyl-4- Г 2-(3-methylbenzyloxy)fenylj pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (3-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide
Pěna, Rf = 0,31.Foam, R f = 0.31.
Příklad 60Example 60
3-butylester-5-(l-fenylethyl)amid (R)-l,4-dihydro-2,6-dimethy 1.-4- £2-(3-methylbenzyloxy)fenylj pyridin-3,5-dikarboxylové kyseliny(R) -1,4-Dihydro-2,6-dimethyl-4- [2- (3-methyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-phenylethyl) -amide
Olej, Rf =Oil, Rf =
0,88.0.88.
CS 271 499 B2CS 271 499 B2
Příklad 61Example 61
3-methylester-5-(l-fenylethyl)amid (R)-4-£ 2-(3-chlorbenzyloxy)fenyl ] -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- [2- (3-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide form)
Pěna, Rf = 0,73.Foam, R f = 0.73.
Příklad 62Example 62
3-methylester-5-(1-fenylethyl)amid (R)-4-(3-benzyloxyfenyl)-l,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- (3-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide (R-form)
Teplota tání od 143 °C.Mp 143 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 63Example 63
3-methylester-5-cyklopropylamid 4-(3-benzyloxyfenyl)-l, 4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (3-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Příklad 64Example 64
3-methylester-5-(l-fenylethyl)amid (R)-4- [2-(4-fluorbenzylthio)fenyl J-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form)
Pěna, Rf =Foam, Rf =
0,47.0.47.
CS 271 499 02CS 271 499 02
Příklad 65Example 65
3-methylester-5-(l-fenylethyl)amid (S)-4- L2-(4-fluorbenzylthio)fenylJ-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (S-forma)(S) -4-L2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (S-form)
Příklad 66Example 66
3-methy1estar-5-allyamid 4-£ 2-(4-fluorbenzylthio)fenyl J-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny ’4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-estar-5-allyamide
Teplota tání 177 °C.Melting point 177 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 67Example 67
3-methylester-5-allyamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allyamide
Teplota tání 148 °C.Mp 148 ° C.
Příklad 68Example 68
3-methylester-5-(l-fenylethyl)amid (R)-4-(2-benzyloxyfeny1)-1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny (R-forma)(R) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide (R-form)
Teplota tání 175 °C.Melting point 175 ° C.
CS 271 499 02CS 271 499 02
Příklad 69Example 69
3-methylesteг-5-(1-fenyIethy1)amid (R)-4-(2-benzyloxyfeny)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny (R-forma, diastereomer 0)(R) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-ester-5- (1-phenyl-ethyl) -amide (R-form, diastereomer 0)
Teplota tání 169 °C.Melting point 169 ° C.
Příklad 70Example 70
3-methylester-5-(2-fenylethyl)amid 4-(2-benzy1охуfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzylphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-phenylethyl) amide
Olej.Oil.
CS 271 499 B2CS 271 499 B2
Příklad 71Example 71
3-methylester-5-benzylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyгidin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-benzylamide
Teplota tání 14Θ až 149 °C.Melting point: 14Θ to 149 ° C.
Příklad 72Example 72
3-methylester-5-ethylamid 4- C2-(4-fluorbenzylthio)fenyl ] -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- C2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 202 až 204 °C.Mp 202-204 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 73Example 73
3-methylester-5-ethylamid 4-(3-benzyloxyfeny1)-1,4-dihydro-2,6-dimethylpyгidin-3,5-dikarboxylové kyseliny4- (3-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 152 až 154 °C.Mp 152-154 ° C.
Příklad 74Example 74
УУ
3-methylester-5-ethylamid 4-(4-benzyloxyfeny1)-1,4-dihydro-2,6-dimethylpyridin-3,5dikarboxylové kyseliny4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 183 až 185 °C.Mp 183-185 ° C.
CS 271 499 B2CS 271 499 B2
P ř í к 1 a d 75Example 1 a d 75
3-methylester-5-amid 4-(2-benzyloxyfeny 1)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-amide
Teplota tání 188 °C.Mp 188 ° C.
Příklad 76Example 76
3-methylester-5-diethylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-diethylamide
Teplota tání 135 °C.Melting point 135 ° C.
CS 271 499 82CS 271 499 82
Příklad 77Example 77
3-methylester-5-cyklopropylamid 1,4-dihydro-2,6-dimethy1-4-í 2-(4-methylfenylsulfonyloxy)fenylj pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
CH3 CH 3
Teplota tání 238 až 242 °C.Mp 238-242 ° C.
Příklad 78Example 78
3-methylester-5-ethylamid l,4-dihydro-2,6-dimethyl-4- [2-(4-methylfenylsulfonyloxy)fenylJ pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 228 °C.M.p. 228 ° C.
4Ί4Ί
CS 271 499 B2CS 271 499 B2
Příklad 79Example 79
3-methylester-5-ethylamid 4- £ 2-(2,6-dichlorbenzyloxy)fenyl3 -1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 174 až 176 °C.Melting point 174-176 ° C.
Příklad 80Example 80
3-methylester-5-ethylamid 4- (2-(3,4-dichlorbenzyloxy)fenyl 3-1,4-dihydro-2,6-dimethylpyridin-3,5dikarboxylové kyseliny4- (2- (3,4-dichlorobenzyloxy) phenyl) -1,1-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 178 až 180 °C.Melting point: 178-180 ° C.
CS 271 499 B2CS 271 499 B2
Přiklad 81Example 81
3-methylester-5-ethylamid 1,4-dihydro-2,6-dimethyl-4-£2-(2-pyridylmethyloxy)fenylJpyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 159 až 161 °C.M.p. 159-161 ° C.
Příklad 82Example 82
3-methylester-5-cyklopropylamid 1,4-dihydro-2,6-dimethyl-4-f 2-(2-pyridylmethyloxy)fenylJ pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 168 až 170 °C.Melting point 168-170 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 83Example 83
3-methylester-5-methylamid l,4-dihydro-2,6-dimethyl-4-(2-fenylsulfonуloxyfenyl)pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonooxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání 171 až 173 °C.Melting point 171-173 ° C.
Příklad 84Example 84
3-methylester-5-ethylamid 1,4-dihydro-2,6-dimethyl-4-(2-fenylsulfonyloxyfenyl)pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 188 až 190 °C.Mp 188-190 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 85Example 85
3-ethy1 ester-5-ethylamíd 1,4-dihydro-4 [ 2-(4-fluorbenzyloxy)fenyl ]-2,6-dimethylpyridin-3,5-dikarboxylove kyseliny1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide
Teplota 147 až 149 °C.Temperature 147-149 ° C.
Příklad 86Example 86
3-methylester-5-ethylamid 1,4-dihydro-4- [ 2-(4-fluorbenzyloxy)fenylJ -2,6-dimethylpyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 111 až 113 °C.Melting point 111-113 ° C.
CS 271 499 62CS 271 499 62
Příklad 87Example 87
3-methylester-5-allyamid 1,4-dihydro-2,6-dimethy1-4-(2-fenylsulfonyloxyfenyl)pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-allyamide
Teplota tání 154 až 156 °C.M.p. 154-156 ° C.
Příklad 88Example 88
3-methylester-5-(4-pyridyl)amid 1,4-dihydro-2,6-dimethy1-4-(2-fenylsulfonyloxyfenyl)pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-pyridyl) amide
Teplota tání od 240 °C (rozklad),Melting point: 240 DEG C. (decomposition),
CS 271 499 B2CS 271 499 B2
Příklad 89Example 89
3-methylester-5-allylamid 4- £2-(4-chlorbenzyloxy)fenylJ -1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- [2- (4-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide
Teplota tání 145 °C.145 ° C.
Příklad 90Example 90
3-methylester-5-allylamid 4-(3-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (3-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide
Teplota tání 95 až 98 °C.Melting point 95-98 ° C.
CS 271 499 02CS 271 499 02
Příklad 91Example 91
3-methylester-5-allylamid 1,4-dihydro-2,6-dimethyl-4- [,2-( 4-methy lf enylsulf ony loxy) feny 1 ] pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [1,2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide
Teplota tání 168 až 170 °C.Melting point 168-170 ° C.
Příklad 92Example 92
3-m ethylester-5-allylamid 4- [2-(2,6-dichlorbenzyloxy)-fenyl ] -1,4-dihydro-2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5-allylamide
Teplota tání 132 až 134 °C.M.p. 132-134 ° C.
£5 271 499 В2£ 5,271,499 В2
Příklad 93Example 93
3-methylester-5-(2-hydrοχ/ethyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-hydroxy-ethyl) -amide
Teplota tání 148 až 150 °£.M.p. 148-150 ° C.
Příklad 94Example 94
3-methylester-5-eethylamid 4- r2-(3-fluorbenzyloxy)-3-methoxyfenylJ-l>4-dihydro-2,6dimethylpyridin-3,5-dikarboxylové kyseliny3-methyl-5-eethylamid 2- 4- (3-fluorobenzyloxy) -3-methoxyfenylJ-l> 4-dihydro-2,6dimethylpyridin-3,5-dicarboxylic acid
Teplota tání 171 až 173 °C.Melting point 171-173 ° C.
CS 271 499 82CS 271 499 82
Příklad 95Example 95
3-methylester-5-f 2-(4-pyridyl)ethylJ amid 4-(2-b0nzyloxytenyl)-l>4-dihydro-2,6-rdimethyl pyridin-3,5-dikarboxylové kyeeliny3-methyl-5-f 2- (4-pyridyl) ethyl 4- (2-b0nzyloxytenyl) -l> 4-dihydro-2,6-rdimethyl pyridine-3,5-dicarboxylic kyeeliny
Příklad 96Example 96
3-methylester-5-methylamid 1,4-dlhydro-2,6-dimethyl-4- £2-(3-pyridyl)methoxyfenyjpyridin-3,5-dikarboxylové kyseliny1,4-dlhydro-2,6-dimethyl-4- [2- (3-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání od 210 °C.Melting point: 210 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 97Example 97
3-methylester-5-ethylamid 1,4-dihydro-2t6-dlmethyl-4-£ 2-(3-pyridyl)methoxyfenyl3 pyridin-3,5-dikarboxylové kyseliny3-methyl-5-ethylamide, 1,4-dihydro-2 t 6-dimethyl-4- £ 2- (3-pyridyl) methoxyfenyl3 pyridine-3,5-dicarboxylic acid
Teplota táni 122 až 125 °C,Melting point 122-125 ° C,
Příklad 98Example 98
3-methylester-5-ethylamid 1,4-dihydro-2>6-dimethyl-4- C 2-(4-pyridyl)methoxyfenyl3 pyridin-3,5-dikarboxylové kyseliny3-methyl-5-ethylamide, 1,4-dihydro-2> 6-dimethyl-4- C 2- (4-pyridyl) methoxyfenyl3 pyridine-3,5-dicarboxylic acid
Teplota tání 95 až 100 °C.Melting point 95-100 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 99Example 99
3-methylester-5-methylamid 1,4-dihydro-2,6-dimethyl-4-£ 2-(4-pyridyl)methoxyfeny1J pyridin-З , 5-dikarboxy lové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-pyridyl) methoxyphenyl] pyridine-2 ', 5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání od 203 °C (rozklad).Melting point: 203 DEG C. (decomposition).
Příklad 100Example 100
3-methylester-5-(cyklopropylmethyl)amid 4.(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (cyclopropylmethyl) amide
Teplota tání 186 °C.Melting point 186 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 101Example 101
3-methylester-5-ethylamid (+)-4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(+) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 147 °C ^D° ; + 29,68, c = 0,91 (DMF).Mp 147 ° C ° D °; + 29.68, c = 0.91 (DMF).
Příklad 102Example 102
3-methylester-5-ethylamid (-)-4-(2-benzyloxyfeny1)-I,4-dihydro-2,6-dimethylpyгidin-3 , 5-dikarboxylové kyseliny(-) - 4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
Teplota tání 140 °C.Melting point 140 ° C.
Γο(]θ0 = - 29,92 °, C = 0,805 (DMF).Γο (] θ 0 = - 29.92 °, c = 0.805 (DMF).
CS 271 499 B2CS 271 499 B2
Příklad 103Example 103
3-ethylester-5-methyl amid 4-(2-benzyloxyfепу1)-1,4-dihydro-2,6-dimethylpyridin-3, 5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methyl amide
Teplota tání 179 °C.Mp 179 ° C.
Příklad 104Example 104
3-ethylester-5-ethylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide
Teplota tání 161 až 164 °C.Mp 161-164 ° C.
CS 271 499 02CS 271 499 02
Příklad 105Example 105
3-methylester-5-(2-ethoxykarbonylethy1)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2, 6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2-ethoxycarbonylethyl) amide
Rf = 0,35.R f = 0.35.
Příklad 106Example 106
3-methylester-5-(ethoxykarbonylmethyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (ethoxycarbonylmethyl) amide
CS 271 499 B2CS 271 499 B2
Přiklad 107Example 107
3-methylester-5-oktylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3 boxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridin-3-boxylic acid 3-methyl ester-5-octylamide
5-dikar-5-dikar-
Rf = 0,53.R f = 0.53.
Příklad 106Example 106
3-methyle3ter-5-nonylamid 4-(2-benzyloxyfeny1)-l,4-dihydro-2,6-dimethylpyridin-3 karboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3-carboxylic acid 3-methyl-ester-5-nonylamide
5-di -5-di -
Rf = 0,55.R f = 0.55.
CS 271 499 Β2CS 271 499-2
Příklad 109Example 109
3-methylester-5-decylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-decylamide
Teplota tání 111 °C .Melting point 111 ° C.
Příklad 110Example 110
3-methylester-5-(2-methoxyethyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methoxyethyl) amide
Teplota tání 145 °C.145 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 111Example 111
3-methylester-5-(3-methoxypropyl)amid 4-(2-benzyloxy:eny1)-l ,4-dihydro-2,6-diniethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-methoxypropyl) amide
Rf = 0,19.R f = 0.19.
Příklad 112Example 112
3-methylester-5-(2-hydroxy-1-methyl-2-fenyl)ethylamid (R, R)-4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(R, R) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5- (2-hydroxy-1-methyl-2-phenyl) ethylamide 3-methyl ester dicarboxylic acids
CS 271 499 B2CS 271 499 B2
Příklad 113Example 113
3-methyle5ter-5-(2-hydroxy-l-methylethyl)a(nld (S)-4-(2-benzyloxyfenyl)-l)4-dihydro-2)6-dimethylpyridin-3,5-dikarboxylové kyseliny3-methyle5ter-5- (2-hydroxy-l-methylethyl) and (NLD (S) -4- (2-benzyloxyphenyl) -l) 4-dihydro-2), 6-dimethylpyridine-3,5-dicarboxylic acid
Rf = 0,13 /Z)20 : + 7,34 0 (CHClj).R f = 0.13 / Z) 20: 0 + 7.34 (CHCl₃).
Příklad 114Example 114
3-methylester-5-(l-hydroxymethylpropyl)amid (S)-4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-propyl) -amide
2S 271 499 B22S 271 499 B2
Příklad 115Example 115
3-methylester-5-(1-hydroxуmethy1-2-metnýlpropyl)amid (S)-4-(2-benzyloxyfenyl)-l,4-dihydro -2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-hydroxymethyl-2-methyl-propyl) -amide
Rf = 0,19 : - 10,8 0 (CHCI,)R f = 0.19 - 10.8 0 (CHCl)
Příklad 116Example 116
3-methylester-5-(l-hydroxymethyl-2-methylbutyl)amid (S)-4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-2-methylbutyl) amide
Rf = 0,21 = - 17,37 0 (CHClj).R f = 0.21 - 17.37 0 (CHCl₃).
CS 271 499 B2 ββCS 271 499 B2 ββ
Příklad 117Example 117
3-methylester-5-(3-hydroxypropyl)amid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyгidin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-hydroxypropyl) amide
Teplota tání 205 °C.Mp 205 ° C.
Příklad 110Example 110
3-methylester-5-cyklopropylamid (-)-4-(2-benzy1oxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny(-) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide
Teplota tání 178 až 181 °C p-i20 = - 38,28 0 (c = 0,569, chloroform).Mp 178-181 ° C at 20 = - 38.28 0 (c = 0.569, chloroform).
1/J5891 / J589
CS 271 499 B2CS 271 499 B2
Příklad 119Example 119
3-methylester-5-cykloprooylaniid (+)-4-(2-benzyloxyfenyl)-l)4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny3-methyl-5-cykloprooylaniid (+) - 4- (2-benzyloxyphenyl) -l) 4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid
Teplota tání 178 až 181 °CMelting point: 178-181 ° C
1^589 = + 36,56 0 (c = 0,52, chloroform).[Α] 589 = + 36.56 0 (c = 0.52, chloroform).
Příklad 120Example 120
3-methy1ester-5-hexylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-5-hexylamide
Teplota tání 133 °C.Melting point 133 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 121Example 121
3-methylester-5-amid 4- [2-(4-methylbenzensulfonyloxy)-fenyl ] -1,4-dihydro - 2,6-dimethy1pyridin-3,5-dikarboxylové kyseliny4- [2- (4-Methylbenzenesulfonyloxy) -phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-amide
Teplota tání 205 °C .Mp 205 ° C.
Příklad 122Example 122
3-methylester-5-sek.butylamid 4-(2-benzyloxyfeny1)-l,4-dihydro-2,6-dimethylpyridin-315-dikarboxylové kyseliny3-methyl-5-sek.butylamid 4- (2-benzyloxyfeny1) -l, 4-dihydro-2,6-dimethylpyridine-3 1 5-dicarboxylic acid
Teplota tání 135 °C.Melting point 135 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 123Example 123
3-isopropylester-5-amid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-amide
P ř í kl a d 124Example 124
3-(2-methoxyethylester)-5-amid 4-(2-benzyloxyfenyl)-1, 4-dihydro-2,6-dimethy1pyridin -3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl ester) -5-amide
Teplota tání 165 °C.Melting point 165 ° C.
CS 271 499 82CS 271 499 82
Příklad 125Example 125
3-methylester-5-dutylamid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-dutylamide
Teplota tání 144 až 148 °C.Mp 144-148 ° C.
Příklad 126Example 126
3-isopropylester-5-ethylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-ethylamide
Teplota tání 135 °C.Melting point 135 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 127Example 127
3-methylester-5-(3-ethoxypropyl)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-ethoxypropyl) amide
Teplota tání 115 °C.Melting point 115 ° C.
Příklad 128Example 128
3-methylester-5-(5-hydroxypenty1)amid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (5-hydroxypentyl) -amide
Teplota tání 17Θ °C,Melting point 17 ° C,
CS 271 199 B2CS 271 199 B2
Příklad 129Example 129
3-(2-methoxyethyl)ester-5-methylamid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5-methylamide
Teplota tání 133 až 135 °C.M.p. 133-135 ° C.
Příklad 130Example 130
3-(2-methoxyethyl)ester-5-ethylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5-ethylamide
Teplota tání 111 °C.Melting point 111 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 131Example 131
3-isopropylester-5-methylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3, 5 -dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-methylamide
Teplota tání 140 až 143 °C.Melting point 140-143 ° C.
Příklad 132Example 132
3-isopropylester-5-cyklopropylamid 4-(2-benzyloxyfenyl)-1,4-dihydro-2,6-dimethylpyřídin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-cyclopropylamide
Teplota tání 132 až 135 °C.M.p. 132-135 ° C.
CS 271 499 B2CS 271 499 B2
Příklad 133Example 133
3-isopropylester-5-isopropylamid 4-(2-benzyloxyfenyl)-l, 4-dihydco-2,6-dimethylpyřídin-4- (2-Benzyloxyphenyl) -1,4-dihydco-2,6-dimethylpyridine-3-isopropyl ester-5-isopropylamide-
3,5-dikarboxylové kyseliny3,5-dicarboxylic acids
Příklad 134Example 134
3-methylester-5-ethylamid l,4-dihydro-2,6-dimethyl-4 C2-(4-methylbenzyloxy)fenyl] pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4 C2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide
CS 271 499 B2CS 271 499 B2
Příklad 135Example 135
3-methylester-5-methylamid 1,4-dihydro-2,6-dimethy1-4- Г 2-(4-methylbenzyloxy)feny1J pyridin-3,5-dikarboxylové kyseliny1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide
Teplota tání 186 °C.Melting point 186 ° C.
Příklad 136Example 136
3-(S)-(l-isopropoxykarbonylethyl)ester-5-cyklopropylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3>5-dikarboxylové kyseliny3- (S) - (l-isopropoxykarbonylethyl) ester-5-cyclopropylamide 4- (2-benzyloxyphenyl) -l, 4-dihydro-2,6-dimethylpyridine-3> 5-dicarboxylic acid
CS 271 499 62CS 271 499 62
Příklad 137Example 137
3-(2-fenethy1)ester-5-methylamid 4-(2-benzyloxyfeny1)-1,4-dihydro-2,6-dimethylpyridin-3,5-díkarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-methylamide
Příklad 138Example 138
3-(2-fenethy1)ester-5-propylamid 4(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-propylamide
CS 271 499 B2CS 271 499 B2
Příklad 139Example 139
3-(2-fenethyl)ester-5-cyklopropylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-diniethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-diethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-cyclopropylamide
t.t. 152 °C.m.p. 152 [deg.] C.
Příklad 140Example 140
3-methy1ester-5-oktylamid 4-(2-benzyloxyfenyl)-l,4-dihydro-2,6-dimethylpyridin-3,5-dikarboxylové kyseliny4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-ester-5-octylamide
0,44 ve směsi toluenu a ethylacetátu v poměru 1 : 10.44 in toluene / ethyl acetate 1: 1
CS 271 499 B2CS 271 499 B2
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873711991 DE3711991A1 (en) | 1987-04-09 | 1987-04-09 | DIHYDROPYRIDINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| CS882354A CS271486B2 (en) | 1987-04-09 | 1988-04-06 | Method of new dihydropyridinamides production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS225489A2 CS225489A2 (en) | 1990-02-12 |
| CS271499B2 true CS271499B2 (en) | 1990-10-12 |
Family
ID=25745613
Family Applications (7)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS892253A CS271498B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892254A CS271499B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892250A CS271495B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892255A CS271500B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892252A CS271497B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892251A CS271496B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892249A CS271494B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS892253A CS271498B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
Family Applications After (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS892250A CS271495B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892255A CS271500B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892252A CS271497B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892251A CS271496B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
| CS892249A CS271494B2 (en) | 1987-04-09 | 1989-04-12 | Method of new dihydropyridinamides production |
Country Status (1)
| Country | Link |
|---|---|
| CS (7) | CS271498B2 (en) |
-
1989
- 1989-04-12 CS CS892253A patent/CS271498B2/en unknown
- 1989-04-12 CS CS892254A patent/CS271499B2/en unknown
- 1989-04-12 CS CS892250A patent/CS271495B2/en unknown
- 1989-04-12 CS CS892255A patent/CS271500B2/en unknown
- 1989-04-12 CS CS892252A patent/CS271497B2/en unknown
- 1989-04-12 CS CS892251A patent/CS271496B2/en unknown
- 1989-04-12 CS CS892249A patent/CS271494B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS271497B2 (en) | 1990-10-12 |
| CS225489A2 (en) | 1990-02-12 |
| CS225189A2 (en) | 1990-02-12 |
| CS225089A2 (en) | 1990-02-12 |
| CS271495B2 (en) | 1990-10-12 |
| CS225289A2 (en) | 1990-02-12 |
| CS224989A2 (en) | 1990-02-12 |
| CS271498B2 (en) | 1990-10-12 |
| CS225589A2 (en) | 1990-02-12 |
| CS271494B2 (en) | 1990-10-12 |
| CS271500B2 (en) | 1990-10-12 |
| CS271496B2 (en) | 1990-10-12 |
| CS225389A2 (en) | 1990-02-12 |
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