DK157857B - Analogifremgangsmaade til fremstilling af pyridincarboxylsyreestere eller farmaceutisk acceptable salte deraf - Google Patents
Analogifremgangsmaade til fremstilling af pyridincarboxylsyreestere eller farmaceutisk acceptable salte deraf Download PDFInfo
- Publication number
- DK157857B DK157857B DK117783A DK117783A DK157857B DK 157857 B DK157857 B DK 157857B DK 117783 A DK117783 A DK 117783A DK 117783 A DK117783 A DK 117783A DK 157857 B DK157857 B DK 157857B
- Authority
- DK
- Denmark
- Prior art keywords
- pyridine
- dimethyl
- dicarboxylic acid
- ester
- carbon atoms
- Prior art date
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- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000686 lactone group Chemical group 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 1
- 238000007796 conventional method Methods 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 206010021143 Hypoxia Diseases 0.000 abstract description 18
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- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
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- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 31
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- LPKYPFGTCAIIIC-UHFFFAOYSA-N 5-(4-hydroxy-2-methylbutan-2-yl)oxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid Chemical compound OCCC(C)(C)OC(=O)C=1C(=NC(=C(C=1C1=CC(=CC=C1)[N+](=O)[O-])C(=O)O)C)C LPKYPFGTCAIIIC-UHFFFAOYSA-N 0.000 description 5
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
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- 241000699670 Mus sp. Species 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
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- PNUUTTVJMVKZCR-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=CC1C1=CC=CC([N+]([O-])=O)=C1 PNUUTTVJMVKZCR-UHFFFAOYSA-N 0.000 description 1
- AMWPWJANUIQUJX-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-5-[2-[3-(trifluoromethyl)phenoxy]propoxycarbonyl]pyridine-3-carboxylic acid Chemical compound C=1C=CC(C(F)(F)F)=CC=1OC(C)COC(=O)C1=C(C)N=C(C)C(C(O)=O)=C1C1=CC=CC([N+]([O-])=O)=C1 AMWPWJANUIQUJX-UHFFFAOYSA-N 0.000 description 1
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- XRMNJAKITMALKI-UHFFFAOYSA-N 2-(acetyloxymethyl)-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid Chemical compound C(C)(=O)OCC1=NC(=C(C(=C1C(=O)O)C1=CC(=CC=C1)[N+](=O)[O-])C(=O)O)C XRMNJAKITMALKI-UHFFFAOYSA-N 0.000 description 1
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- IZYXCJVHSFKXPJ-UHFFFAOYSA-N 2-hydroxyethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-7h-furo[3,4-b]pyridine-3-carboxylate Chemical compound OCCOC(=O)C=1C(C)=NC=2COC(=O)C=2C=1C1=CC=CC([N+]([O-])=O)=C1 IZYXCJVHSFKXPJ-UHFFFAOYSA-N 0.000 description 1
- YXGMQBNCRUNMGT-UHFFFAOYSA-N 2-methoxyethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-4,7-dihydro-1h-furo[3,4-b]pyridine-3-carboxylate Chemical compound COCCOC(=O)C1=C(C)NC(COC2=O)=C2C1C1=CC=CC([N+]([O-])=O)=C1 YXGMQBNCRUNMGT-UHFFFAOYSA-N 0.000 description 1
- LRYKTMIAXZIIPF-UHFFFAOYSA-N 2-methoxyethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-7H-furo[3,4-b]pyridine-3-carboxylate Chemical compound COCCOC(=O)C1=C(C)N=C2COC(=O)C2=C1C1=CC=CC([N+]([O-])=O)=C1 LRYKTMIAXZIIPF-UHFFFAOYSA-N 0.000 description 1
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- LHTGFSXVDSWGDR-UHFFFAOYSA-N 3-O-(2-methoxyethyl) 5-O-propan-2-yl 2,6-dimethyl-4-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC(C(F)(F)F)=C1 LHTGFSXVDSWGDR-UHFFFAOYSA-N 0.000 description 1
- GXRKMNZYMXYWFC-UHFFFAOYSA-N 3-o-(2-chloroethyl) 5-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCCl)=C1C1=CC=CC([N+]([O-])=O)=C1 GXRKMNZYMXYWFC-UHFFFAOYSA-N 0.000 description 1
- FWWINPMTFUIKBR-UHFFFAOYSA-N 3-o-(2-cyanoethyl) 5-o-ethyl 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]pyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)N=C(C)C(C(=O)OCCC#N)=C1C1=CC=CC=C1C(F)(F)F FWWINPMTFUIKBR-UHFFFAOYSA-N 0.000 description 1
- AKKGINDMDCGUMP-UHFFFAOYSA-N 3-o-(2-cyanoethyl) 5-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCC#N)=C1C1=CC=CC([N+]([O-])=O)=C1 AKKGINDMDCGUMP-UHFFFAOYSA-N 0.000 description 1
- JWVKHESEEIDDJE-UHFFFAOYSA-N 3-o-(2-cyanoethyl) 5-o-methyl 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]pyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCC#N)=C1C1=CC=CC=C1C(F)(F)F JWVKHESEEIDDJE-UHFFFAOYSA-N 0.000 description 1
- DCIMTQCMPVHZFX-UHFFFAOYSA-N 3-o-(2-hydroxyethyl) 5-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCO)=C1C1=CC=CC([N+]([O-])=O)=C1 DCIMTQCMPVHZFX-UHFFFAOYSA-N 0.000 description 1
- OXXOMPGVGGWPDQ-UHFFFAOYSA-N 3-o-(2-hydroxyethyl) 5-o-methyl 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]pyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCO)=C1C1=CC=CC=C1C(F)(F)F OXXOMPGVGGWPDQ-UHFFFAOYSA-N 0.000 description 1
- TYOGPJWGWZKXSL-UHFFFAOYSA-N 3-o-(2-hydroxyethyl) 5-o-methyl 4-(2-methoxyphenyl)-2,6-dimethylpyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(C)C(C(=O)OCCO)=C1C1=CC=CC=C1OC TYOGPJWGWZKXSL-UHFFFAOYSA-N 0.000 description 1
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- PIHACLJLTHYLLE-UHFFFAOYSA-N 3-o-(2-hydroxyethyl) 5-o-propan-2-yl 2,6-dimethyl-4-(4-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CC(C)OC(=O)C1=C(C)NC(C)=C(C(=O)OCCO)C1C1=CC=C(C)C=C1 PIHACLJLTHYLLE-UHFFFAOYSA-N 0.000 description 1
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- BWVUMXCLRFRMFU-UHFFFAOYSA-N 3-o-ethyl 5-o-(2-hydroxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCO)C1C1=CC=CC([N+]([O-])=O)=C1 BWVUMXCLRFRMFU-UHFFFAOYSA-N 0.000 description 1
- JWKSXQAHGAFTHO-UHFFFAOYSA-N 3-o-ethyl 5-o-(2-hydroxyethyl) 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCO)C1C1=CC=CC=C1C(F)(F)F JWKSXQAHGAFTHO-UHFFFAOYSA-N 0.000 description 1
- AHGDAPFJTIORHJ-UHFFFAOYSA-N 3-o-ethyl 5-o-(2-hydroxyethyl) 4-(2-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCO)C1C1=CC=CC=C1OC AHGDAPFJTIORHJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Description
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte pyridincarboxyl-syreestere, der kan anvendes i lægemidler, især i midler mod sygdomme, der beror på en iskæmi og/eller en hypoxi.
5 Det er allerede kendt, at man får 2,6-dimethyl~4-(2- -nitrophenyl) -pyridin-3,5-dicarboxylsyrediethylester ved chromsyreoxidation af den tilsvarende 1,4-hydro-2,6-dimethyl- 4- (2-nitrophenyl) -pyridin-3,5-dicarboxylsyrediethylester, jfr. V. A. Petrow, J. Chem. Soc., 884 (1946).
10 Det er endvidere kendt, at der ved biotransformation af vasodilaterende virksomme 4-aryl-l,4-dihydropyridinderi-vater dannes pyridiner, der er væsentligt svagere karvirksomme end de tilsvarende dihydropyridinforbindelser, jfr. S. Higuchi et al., 95. General Congress of the Japanese Phar-15 maceutical Society, April 1975, S. E. Parker og J. Weinstock, J. Med. Chem., 16, 34 (1973) og H. Medenwald, K. Schlossmann og C. Wiinsche, Arzneim.-Forsch., 22, 53 (1972).
Det er desuden kendt, at forbindelsen 1,4-dihydro--2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxylsyre-20 -isopropyl-(2-methoxyethyl)-ester tydeligt forbedrer eksperimentelt inducerede indlærings- og hukommelsesgener, jfr. DE-offentliggørelsesskrift nr. 2.815.578.
Endvidere er 4 - (3 -nitropheny 1) -pyridin-3,5-dicarboxyl-syreestere blevet anvendt som mellemprodukter ved syntesen 25 af antibakterielt virksomme pyridylquinoloner, jfr. P. M. Carbateas og G. L. Williams, J. Heterocyclic Chem., 11, 819 (1974) .
De her omhandlede hidtil ukendte pyridincarboxyl-syreestere har den almene formel 30
R
X JL COOR3 35
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2 i hvilken R betyder en pyridylgruppe eller en phenylgruppe, der eventuelt indeholder 1 eller 2 ens eller forskellige substituen-ter valgt blandt halogen, cyano, nitro trifluormethyl, 5 alkyl med 1-4 carbonatomer og alkoxy med 1-4 carbonatomer, R1 betyder en alkylgruppe med 1-4 carbonatomer eller en hydroxyalkylgruppe med 1-4 carbonatomer, r2 betyder en alkylgruppe med 1-4 carbonatomer, X betyder gruppen -C00R5, hvor R5 betegner H eller en lige-10 kædet, forgrenet eller cyclisk alkylgruppe med op til 12 carbonatomer, der eventuelt er afbrudt af 1-oxygenatom i kæden, og R3, der altid er forskellig fra R5, betyder en alkylgruppe med 1-4 carbonatomer, der eventuelt er substitueret med 15 hydroxy, cyano, halogen, trifluormethylphenoxy, halogen-phenoxy, alkoxy med 1-4 carbonatomer eller alkanoyloxy med 2-5 carbonatomer, eller R1 og X danner sammen med de C-atomer, hvortil de er bundet, en 5- til 7-leddet lactonring, 20 og ifølge opfindelsen kan der også fremstilles farmaceutisk acceptable salte deraf.
På overraskende måde udviser de her omhandlede forbindelser en kraftig hypoxi-beskyttelsesvirkning, der kommer til udtryk såvel ved en hypoxi-induceret amnæsi som ved 25 hypoxi-tolerancen. På baggrund af teknikkens stade kunne disse specielle farmakologiske virkninger ikke forventes.
De omhandlede, hidtil ukendte forbindelser må således på grund af disse egenskaber anses som en berigelse af farmacien, jfr. de i det følgende angivne resultater af sammen-30 ligningsforsøg med forbindelsen Nimodipin, der er kendt fra DE offentliggørelsesskrift nr. 2.815.578.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man (a) bringer 1,4-dihydropyridinderivater med den almene 35 formel (II) 3
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R
5 (ii)
H
i hvilken R, R1, R2, R3 og X har den ovenfor angivne betydning, til reaktion med oxiderende (dehydrogenerende) midler, 10 eventuelt i nærværelse af indifferente opløsningsmidler, ved temperaturer mellem o og 200°C, eller (b) forestrer pyridincarboxylsyrer med den almene formel (ill)
R
XYVC00H (III) R1 ^N^R2 i hvilken R, R1, R2 og X har den ovenfor angivne betydning, 20 eventuelt efter aktivering af carboxylgruppen efter fra litteraturen kendte metoder, til carboxylsyreestere med den almene formel (I), eller (c) i det tilfælde, at R1 i den almene formel (I) betyder en hydroxyalkylgruppe, underkaster de tilsvarende 25 mono- eller bis-acetoxyalkylpyridiner betingelserne for en mild og selektiv hydrolyse, eller (d) i det tilfælde, at R1 sammen med X i den almene formel (I) danner en lactonring, cycliserer hydroxyalkyl-pyridincarboxylsyrer med den almene formel (V) 30
R
HOOC-y^^, COjR3 (V) 35 i hvilken R, R2 og R3 har den ovenfor angivne betydning, og n er et tal fra 1 til 3, under indvirkning af protoner efter
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4 gængse metoder til dannelse af forbindelser med formlen (VI)
0 R
Ο-^γΛγ COOr3 (VI) 5 » i hvilken R, R2, R3 og n har den ovenfor angivne betydning, hvorefter en fremstillet forbindelse om ønsket omdannes til et farmaceutisk acceptabelt salt deraf.
10
De her omhandlede forbindelser med den almene formel (I) kan alt efter arten af substituenterne fremstilles på forskellige måder.
Særlig fordelagtig og mest bredt anvendelig har omsætningen af 1,4-dihydropyridinderivater med den almene formel (II) 15
R
x^Acoor3 ¥ J <xi) R1 Λ»Λκ2 20 med oxiderende (dehydrogenerende) midler ifølge fremgangsmåde (a) vist sig at være.
12 3 I formlen (II) har grupperne R, R , R , R og X den ovenfor angivne betydning.
De som udgangsmaterialer anvendte 1,4-dihydropyridinde-25 rivater med formlen (II) er kendt fra litteraturen eller kan fremstilles efter fra litteraturen kendte metoder, jfr. f.eks.
DE-offehtliggørelsesskrifterne nr. 2.117.571, 2.508.181 og 2.847.236.
3Q Som eksempler kan nævnes følgende forbindelser: 1.4- dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin-3,5-di-carboxylsyre-(2-hydroxyethyl)-methyl-ester, 1.4- dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin-3,5-di-carboxylsyre-(2-chlorethyl)-isopropyl-ester, 35 l,.4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridin-3,5-di-carboxylsyre-(2-cyanoethyl)-methyl-ester, 5
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l/4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin-3,5-di-carboxylsyre-(2-acetoxyethyl)-isopropyl-ester, 1.4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3 , 5-di- carboxylsyre-(2-acetoxyethyl)-methyl-ester, 5 1.4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-di-carboxylsyre-(3-hydroxypropyl)-isopropyl-ester, 1.4- dihydro-2,6-dimethyl-4-(pyridyl-2-)-pyridin-3,5-dicarb-oxylsyre-(2-hydroxyethyl)-isopropyl-ester, 10 l,4-dihydro-2,6-dimethyl-4-(pyridyl-3-)-pyridin-3,5-dicarboxyl-syre-(2-hydroxyethyl)-isopropyl-ester,
Som oxidationsmidler (dehydrogeneringsmidler) kommer i første række salpetersyre eller salpetersyrling, chrom-(VI)--oxid eller natriumdichromat, nitrogenoxider, chloranil, te-Ί5 tracyanobenzoquinon eller den anodiske oxidation i nærværelse af et egnet elektrolytsystem, f.eks. acetonitrillithiumper-chlorat, på tale.
Som fortyndingsmidler skal der i første række nævnes vand og alle indifferente organiske opløsningsmidler. Hertil 2o hører fortrinsvis benzen, toluen, acetonitril, iseddike og hexamethylphosphorsyretriamid.
Reaktionstemperaturerne kan varieres inden for et større område. I almindelighed arbejdes der mellem 0 og 200°C, fortrinsvis således, at reaktionen kan styres godt.
25 Alt efter arten af substituenterne kan det være for delagtigt som sidste syntesetrin ikke at foretage omdannelsen af 1,4-dihydropyridinderivatet med den almene formel (II) til de her omhandlede forbindelser med den almene formel (I).
Således kan også ifølge fremgangsmådevariant (b) pyri- * 30 dincarboxylsyrer med den almene formel (III) cooh 1 2 35 i hvilken R, R , R og X har den ovenfor angivne betydning, efter fra litteraturen kendte metoder omdannes til de her omhandlede pyridincarboxylsyreestere med den almene formel (I).
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Alt efter valget af substituenterne kan de her omhandlede forbindelser eksistere i stereoisomere former, der enten forholder sig som billede og spejlbillede (enantiome-re) , eller ikke forholder sig som billede og spejlbillede 5 (diastereomere). Fremstillingen af såvel antipoderne som de racemiske former samt diastereomerblandingerne er genstand for den foreliggende opfindelse. De racemiske former kan ligesom de diastereomere lade sig adskille på kendt måde i de stereoisomert ensartede bestanddele, jfr. f.eks. E. L.
10 Eliel, Stereochemistry of Carbon Compounds, McGraw Hiil, 1962.
De her omhandlede forbindelser egner sig navnlig til behandling af hypoxiske og/eller iskæmiske beskadigelser, først og fremmest i centralnervesystemet, samt sclerotisk-, 15 nekrotisk- eller aldersbetingede cerebrale insufficienser og psykopatologiske tilstande.
De fordelagtige egenskaber er godtgjort ved følgende undersøgelser: 20 a) Hypoxi-beskyttelsesvirkning i en model for hypoxi-induce-ret retrograd amnesi ved "Passive Avoidance Test"_
Der henvises til S.J. Sara & D. Lefevre, Psychophar-makologia, 25, 32-40 (1972).
I et lyst/mørkt ("clair-obscure") bur optrænes rotter 25 ved hjælp af et elektrochok til at undgå den mørke del af buret. Udsættes forsøgsdyrene derefter for en hypoxisk atmosfære (3,5 rumfangsprocent 02), ødelægges hukommelsesindholdet tilbagevirkende. De her omhandlede forbindelser antagoniserer fuldstændigt den retrograde amnesi.
30 b) Forøgelse af hvpoxi-tolerancen
Med virksomt stof og med placebo behandlede mus anbringes i et kammer, der gennemstrømmes i så lang tid med en hypoxisk gasblanding (3,5 rumfangsprocent 02), at 85% af 35 7
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kontroldyrene er døde. De her omhandlede forbindelser bevirker en forøgelse af antallet af de overlevende dyr i signifikant omfang.
5 c) Hæmning af afværgereaktionen
Mus, der holdes isoleret, udviser ved elektrisk aktivering en "aggressive-defensive behaviour". Forbindelserne fremstillet ifølge opfindelsen, der i øvrigt er uden alment sederende virkning, hæmmer fuldstændigt denne reaktion.
10 De her omhandlede forbindelser er kraftigt virksomme til beskyttelse mod hypoxi, omend de hverken øver indflydelse på blodtryk eller hjertefrekvens og heller ikke er vasoaktive i forbindelser med isolerede karstykker fra kaniner. Den påviste psykotrope virkning er navnlig af yderligere terapeu-15 tisk betydning i gerontologien.
Resultaterne af sammenligningsforsøg udført med dels den kendte forbindelse Nimodipin, jfr. DE offentliggørelsesskrift nr. 2.815.578 (l,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl) -pyridin-3,5-dicarboxylsyre-isopropyl-(2-methoxy-20 ethyl)-ester), dels med en række repræsentative forbindelser fremstillet ifølge den foreliggende opfindelse, fremgår af den følgende tabel med tilhørende forsøgsbeskrivelser.
25 30 35
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Amnesi-test (rotter) - Dosis i mg/kg p.o.
Eks. nr. 0.001 0.01 0.03 0*1 0*3 l*0i 10 100
Nimodipin (kendt) 19 51* 96 22 5 1 46 77 71 89 100 63 38 41 52 67 75 84 86 39 61 74 97 100 98 14 34 84 98 100 32 55 72 81 100 24 10 9 45 70 90 100 100 3 12 39 68 100 49 10 65 99 55 4 47 58 64 93 63 24 63 65 74 100 15 25 22 22 62 54 75 82 100 *Dosering 0,4 mg/kg p.o.
Værdierne angiver den anti-amnetiske virkning i %, 20 idet 100% betyder total ophævelse af den hypoxi-inducerede amnesi.
Forsøgsmetoderne er som følger:
Passive avoidance test Forsøgs- og testmetode 25 Hanrotter med en vægt på 180-220 g holdes i grupper på tre i plastbure med fri adgang til foder og vand. Hvert forsøgsbur består af en lys og en mørk afdeling med en aflukkelig gennemgang. Metalgittergulvet er forbundet med et elektrisk stimulationsapparat. Forsøgsdyrene anbringes i 30 den lyse afdeling og bevæger sig på grund af deres naturlige mørkepræference i løbet af 10-15 sekunder ind i den mørke afdeling. Derpå lukkes gennemgangen, og rotterne bibringes via metalstængerne en elektrisk påvirkning (2 mA i 2 sekunder, i alt 4 gange med hver gang 10 sekunders pause). Der-35 efter udtages dyrene af forsøgsburene. 4 timer senere anbringes de igen i den lyse afdeling. Det måles, hvor lang tid der forløber, inden rotterne bevæger sig ind i den mørke 9
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afdeling (max. 3 minutter).
Hypoxi-behandlinq I direkte tilslutning til optræningsgennemgangen 5 udsættes rotterne for en hypoxisk atmosfære bestående af en gasblanding indeholdende 3,8% oxygen og 96,2% nitrogen; indtil de viser snappen efter vejret (dog højst 400 sekunder) .
En opløsning af de her omhandlede forbindelser i en 10 polyethylenglycol 400/glycerol/vand-blanding indgives via en svælgsonde.
Forsøget udføres hver gang med 3 grupper på hver 15 dyr.
Gruppe A: Kontrolgruppe uden hypoxi-belastning 15 Gruppe B: Kontrolgruppe med hypoxi-belastning
Gruppe C: Stofbehandlet gruppe med hypoxi-belastning.
Den tid, som dyrene kræver til overgangen til dets mørke afdeling, måles. Tidsforskellen mellem de to kontrolgrupper sættes til 100% (A-B = 100%). Tidsforskellen mellem 20 kontrolgruppe B og den behandlede gruppe C udtrykkes i % og gælder som mål for den hypoxi-protektive, antiamnetiske virkning af den afprøvede forbindelse.
Det ses, at Nimodipin viser en typisk dihydropyridin-profil, dvs. en stejl dosis-virkningskurve, der begynder 25 ved ca. 0,1 mg/kg, har maksimum ved 1 mg/kg og allerede ved 10 mg/kg er faldet kraftigt. Derimod viser de her omhandlede forbindelser uventet fuld antiamnetisk virkning over et bredt dosisområde, der allerede begynder under 0,01 m9/k9 og holder sig til en dosis på 100 mg/kg.
30 De her omhandlede hidtil ukendte virksomme forbindel ser kan på kendt måde overføres i de gængse præparatformer, f.eks. tabletter, kapsler, dragées, piller, granulater, aerosoler, sirupper, emulsioner, suspensioner og opløsninger, under anvendelse af indifferente, ikke-toksiske, farmaceutisk 35 egnede bærestoffer eller opløsningsmidler. Herved skal den terapeutisk virksomme forbindelse i hvert enkelt tilfælde 10
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være til stede i en koncentration på fra ca. 0,5 til ca. 90 vægt% af den samlede blanding, dvs. i mængder, der er tilstrækkelige til opnåelse af det angivne doseringsspillerum.
Præparaterne fremstilles f.eks. ved strækning af de 5 virksomme stoffer med opløsningsmidler og/eller bærestoffer, eventuelt under anvendelse af emulgeringsmidler og/eller ' dispergeringsmidler, idet der f.eks. i tilfælde af anvendelse af vand som fortyndingsmiddel eventuelt kan anvendes organiske opløsningsmidler som hjælpeopløsningsmidler.
10 Som hjælpestoffer kan der f.eks. nævnes følgende:
Vand, ikke-toksiske, organiske opløsningsmidler, f.eks. paraffiner, såsom jordoliefraktioner, vegetabilske olier, såsom jordnødde- og sesamolie, alkoholer, såsom ethyl-alkohol, og glycerol, glycoler, såsom propylenglycol og 15 polyethylenglycol, faste bærestoffer, f.eks. naturlige stenmel, såsom kaoliner, lerjordarter, talkum og kridt, syntetiske stenmel, såsom højdispers kiselsyre og silicater, sukkerarter, såsom rør-, mælke- og druesukker, emulgeringsmidler, såsom polyoxyethylen-fedtsyreestere, polyoxethylen-20 -fedtalkoholethere, alkylsulfonater og arylsulfonater, dispergeringsmidler, f.eks. lignin, sulfitaffaidslud, methyl-cellulose, stivelse og polyvinylpyrrolidon, og glidemidler, f.eks. magnesiumstearat, talkum, stearinsyre og natrium-laurylsuflat.
25 Indgivelsen sker på gængs måde, fortrinsvis oralt eller parenteralt, især perlingualt eller intravenøst. I tilfælde af oral anvendlse kan tabletter naturligvis ud over de nævnte bærestoffer også indeholde tilsætninger som f.eks. natriumcitrat, calciumcarbonat og dicalciumphosphat 30 sammen med forskellige yderligere tilsætningsstoffer, f.eks. stivelse, fortrinsvis kartoffelstivelse, gelatine og lignende stoffer. Endvidere kan der til tablet fremstilling medanvendes glidemidler, f.eks. magnesiumstearat, natriumlaurylsulfat og talkum. I tilfælde af vandige suspensioner og/eller elik-35 si'rer, der er beregnet til orale anvendelser, kan der til de virksomme stoffer ud over de ovennævnte hjælpestoffer 11
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sættes forskellige smagsforbedrende stoffer eller farvestoffer.
I tilfælde af parenteral anvendelse kan der anvendes opløsninger af de virksomme stoffer under anvendelse af 5 egnede flydende bærestoffer.
I almindelighed har det vist sig at være'fordelagtigt ved intravenøs indgivelse af indgive mængder på fra ca.
0,01 til ca. 10 mg pr. kg, fortrinsvis fra ca. 0,1 til ca.
5 mg pr. kg legemsvægt pr. dag, til opnåelse af virksomme 10 resultater, og ved oral indgivelse andrager doseringen fra ca. 0,05 til ca. 20 mg pr. kg, fortrinsvis fra ca. 0,5 til ca. 5 mg pr. kg legemsvægt pr. dag.
Imidlertid kan det eventuelt være nødvendigt af afvige fra de nævnte mængder, nemlig afhængigt af forsøgsdyrets 15 legemsvægt eller arten af indgivelsesvejen, men også på grund af dyrearten og dens individuelle forhold overfor medikamentet eller arten af dettes præparatform og det tidspunkt eller det interval, til hvilket eller hvori indgivelsen sker. Det kan således i nogle tilfælde være tilstrækkeligt 20 at anvende mindre end den ovennævnte mindstemængde, medens den nævnte øvre grænse i andre tilfælde må overskrides. I tilfælde af indgivelse af større mængder kan det være an-befalelsesværdigt at fordele mængden over dagen i form af flere enkeltindgivelser. Til indgivelse i humanmedicinen 25 regnes der med det samme doseringsspillerum som ovenfor. Tilsvarende gælder herved også de ovenstående angivelser.
Fremgangsmåden ifølge opfindelsen illustreres nærmere i de følgende eksempler.
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Fremstillingseksempler Eksempel 1 5 2,6-Dimethyl-4-(3-nitropheny1)-pyridin-3,5-dicarboxyl- syre-(2-hydroxyethyl)-isopropyl-ester ^YN02 E3C\
10 E9°2C -Y^YC02CH2-CH2-0H
h.cT X 1 3 H3C^ N^ CH3 20 g (49,5 mmol) l,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridin-3,5-dicarboxylsyre-(2-hydroxyethyl)-isopropyl-15 -ester indføres i en blanding af 83 ml 96%'s salpetersyre i 660 ml vand, og der opvarmes til kogning i 1 time. Derefter afkøles der til fra 5 til 10°C og gøres svagt alkalisk med fortyndet natriumhydroxidopløsning. Den udfældede olie ekstraheres med methylenchlorid, og ekstrakterne tørres over natriumsulfat 20 og inddampes i- vakuum. Den olieagtige remanens bringes til krystallisation ved rivning med en blanding af ether og petro-leumsether, skilles fra ved sugning og omkrystalliseres fra methanol.
Smeltepunkt: 120°C. Udbytte: 13,1 g (66%) .
25
Eksempel 2 h3cn y 30 h cf°2C Yy-C02-CH2-CH2-C1
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxylsyre-35 13
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- (2-chlo.rethyl) -isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxylsyre-(2--chlorethyl)-isopropyl-ester med smp. 80°C. Udbytte: 69% af det teoretiske.
5
Eksempel 3 gN02 C0--CH--CH2-CN l l ά - Ht; N CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxylsy-Ϊ5 re-(2-cyanoethyl)-isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3 ,5-dicarboxylsyre-(2--cyanoethyl)-isopropyl-ester med smp. 93°C. Udbytte: 71% af det teoretiske.
20 Eksempel 4 2,6-Dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-syre-(2-acetoxyethyl)-isopropyl-ester i 2 H-C 0 25 ^ \ " hco2c-^X^s^' co2ch2ch2-o-c-ch3 H3c/ a X.
h3ct tj ch3 20,1 g (50 mmol) 2,6-dimethyl-4-(3-nitrophenyl)-pyridin--3,5-dicarboxylsyre-(2-hydroxyethyl)-isopropyl-ester (eksempel 1 30 opløses i 75 ml pyridin. Hertil sættes der 5,9 g (75 mmol). ace-tylchlorid. Efter afslutning af den exoterme reaktion omrøres der i 3 timer ved stuetemperatur, og reaktionsblandingen udhældes i vand og ekstraheres med . De organiske ekstrakter vaskes med fortyndet saltsyre og inddampes i vakuum efter tør-35 ring over natriumsulfat. Den resulterende olie gennemkrystalli- 14
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serer, og den sammenrøres med petroleumsether, skilles fra ved sugning og tørres. Smp. 68°C. Udbytte 20,5 g (93%) .
Eksempel 5 5 2,6r®iniethyl-4- (3-nitrophenyl) -pyridin-3,5-dicarboxyl- syre-isopropyl-(2-methoxyethyl)-ester ^γΝ°2 η3\ γ 10 HC02C C02CH2CH20CH3
S3°y IX
H3C'^'N/v'CH3
Til en kogende opløsning af 41,8 g (100 mmol) 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-15 syre-isopropyl-(2-methoxyethyl)-ester i 160 ml iseddike sættes der portionsvis 6,8 g chrom(VI)-oxid. Derefter opvarmes der i yderligere 30 minutter under tilbagesvaling, og efter afkøling udhældes der i ammoniakalsk isvand. Blandingen eks-traheres med chloroform, og ekstrakterne inddampes i vakuum 20 efter tørring over natriumsulfat. Der fås 35,9 g (86% af det teoretiske) af en olie.
Eksempel 6 S°2
J-V
02CB2CH2-0-f_XN
N-^-Cl ia3v_ « v,H3 30 Analogt med eksempel 1 fås der ved omsætning af 1,4-di- hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-syre-(2-(3-chlorphenoxy)-ethyl)-isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5--dicarboxylsyre-(2-(3-chlorphenoxy)-ethyl)-isopropyl-ester 35 med smp. 79°C. Udbytte: 85% af det teoretiske.
15
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DK 157857B
Eksempel 7 fY™2
5 H3C02G^^Vs^C02CH2CH2-0H
ffjCr" ir'-CH-j
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-10 oxylsyre-(2-hydroxyethyl)-methyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-(2-hydroxyethyl)-methyl-ester med smp. 115°C. Udbytte: 59% af det teoretiske.
Eksempel 8
JiO,
H3C02C^rCrC02CH2CH2CN
20 I
h3c-^vn^' ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-(2-cyanoethyl)-methyl-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-(2-cyanoethyl)-methyl-ester med smp. 98°C. Udbytte; 65% af det teoretiske.
30 35
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13
Eksempel 9 ^r'C02CH2CH2“Cl H3C Ν' ^CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-10 oxylsyre-(2-chlorethyl)-methyl-ester med salpetersyre for bindelsen. 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-(2-chlorethyl)-methyl-ester med smp. 60°C. Udbytte: 55% af det teoretiske.
15 Eksempel 10 WXco2W{) 20 Λ H3C ir" CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-syre-methyl-(2-(3-trifluormethylphenoxy)-ethyl)-ester med sal-25 petersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin--3,5-dicarboxylsyre-methyl-(2-(3-trifluormethylphenoxy)-ethyl)--ester med smp. 88°C. Udbytte: 89% af det teoretiske.
30 35
DK 157857B
Eksempel 11 17
O
fY N02
5 H5C2°2C ->^V-C02CH2CH2-0H
H3C N^^CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-10 syre-ethyl-(2-hydroxyethyl)-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxylsy-re-ethyl-(2-hydroxyethyl)-ester med smp. 88°C. Udbytte: 51% af det teoretiske.
15 Eksempel 12 ry co2ch2ch2-oh
——J
so Js! <JL
h3c ^n^ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarboxyl-syre-cyclopentyl-(2-hydroxyethyl)-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-cyclopentyl-(2-hydroxyethyl)-ester med smp. 112°C. Udbytte: 63% af det teoretiske.
30 35 ^yN02 18
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Eksempel 13 5 ^°2CY^y'C02CH2CH2-C1 H3C^N^CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,5-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-10 oxylsyre-(2-chlorethyl)-cyclopentyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-di-carboxylsyre-(2-chlorethyl)-cyclopentyl-ester med smp. 84°C. Udbytte: 71% af det teoretiske.
15 Eksempel 14 XN°2 co2ch2ch2-oh CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-decyl-(2-hydroxyethyl)-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-decyl-(2-hydroxyethyl)-ester med smp. 60°C. Udbytte: 71% af det teoretiske.
30 35
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19
Eksempel 15
O
H.C W
3 \ X
HCO-C v/^s^CO-CH-CH.-OH 5 S’ z ]\ til
H3C 1* A
h3c ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-phenyl-pyridin-3,5-dicarboxylsyre-(2-10 -hydroxyethyl)-isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-phenyl-pyridin-3,5-dicarboxylsyre-(2-hydroxy-ethyl)-isopropyl-ester med smp. 79°C. Udbytte: 82% af det teoretiske .
15 Eksempel 16
f^N
H5C2°2CV^::>r^ co2ch2ch2-c^n 20 JO sL· H3C n ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(pyridyl-3)-pyridin-3,5-dicarboxylsyre--(2-cyanoethyl)-ethyl-ester med salpetersyre forbindelsen 2,6-25 -dimethyl-4-(pyridyl-3)-pyridin-3,5-dicarboxylsyre-(2-cyanoethyl) -ethyl-ester med smp. 90°C. Udbytte: 52% af det teoretiske.
30 35 20
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DK 157857 B
Eksempel 17 NO,
H,C T
5 hco2c co2ch2ch2-oh
H-5C Ji /L
3 H3C CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin-3,5-dicarb-10 oxylsyre-(2-hydroxyethyl)-isopropylester med salpetersyre forbindelsen 2,6-dimethyl-4-(2-nitrophenyl)-pyridin-3,5-dicarb-oxylsyre-(2-hydroxyethyl)-isopropyl-ester med smp. 78°C. Udbytte: 83% af det teoretiske.
15 Eksempel 18 - Å hco2c ^/<y^:o2ch2-ch2-oh
20 H C I
3 H3C^N^"CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(4-chlorphenyl)-pyridin-3,5-dicarb-oxylsyre-(2-hydroxyethyl)-isopropyl-ester med salpetersyre 25 forbindelsen 2,6-dimethyl-4-(4-chlorphenyl)-pyridin-3,5-di-carboxylsyre-(2-hydroxyethyl)-isopropyl-ester med smp. 120°C. Udbytte: 88% af det teoretiske.
30 35
DK 157857 B
21
Eksempel 19
O
H3C\ X
5 C02CH2CH2-C=N
il x ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4--dihydro-2,6-dimethyl-4-(3-iodphenyl)-pyridin-3,5-dicarboxyl-10 syre-(2-cyanoethyl)-isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-iodphenyl)-pyridin-3,5-dicarboxyl-syre-(2-cyanoethyl)-isopropyl-ester med smp. 69°C. Udbytte: 75% af det teoretiske.
15 Eksempel 20
CN
a3cx U
HC02C ^C02CH2-CH2-0CH3
20 H3c ]j I
H3C^N^ ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-cyanophenyl)-pyridin-3,5-dicarboxyl-syre-isopropyl-(2-methoxyethyl)-ester med salpetersyre forbin-25 delsen 2,6-dimethyl-4-(3-cyanophenyl)-pyridin-3,5-dicarboxyl-syre-isopropyl-(2-methoxyethyl)-ester med smp. 50°C. udbytte: 73% af det téoretiske, 30 35 22
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DK 157857 B
Eksempel 21 H3Cn. k^CF3
HCO,C CO,CH,CH,C=N
5 /2 -γΤ -ΐγ 2 2/ H3C 1 >1 J H3c-^N^ ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5-di-10 carboxylsyre-(2-cyanoethyl)-methyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarboxylsyre-(2-cyanoethyl)-methyl-ester med smp. 74°C. Udbytte: 85% af det teoretiske.
15 Eksempel 22 ^^“CF3
H5C2°2GTl^rC02CH2CH2"C^N
20 h3c n ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2/6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5-di-carboxylsyre-(2-cyanoethyl)-ethyl-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarboxylsyre-(2-cyanoethyl)-ethyl-ester med smp. 68°C. Udbytte: 69% af det teoretiske.
30 35 23
Eksempel 23
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DK 157857 B
LJUfj
5 H5C202C^k.c02CH2CH20H
H3CX^'
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5-di-10 carboxylsyre-ethyl-(2-hydroxyethyl)-ester med salpetersyre for bindelsen 2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarboxylsyre-ethyl-(2-hydroxyethyl)-ester med smp. 86°C. Udbytte: 75% af det teoretiske.
15 Eksempel 24 <yJ-cP3
HjCOjCv^is^-COjCHjCHj-OH
20 h3cr n^ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5-di-carboxylsyre-(2-hydroxyethyl)-methyl-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5--dicarboxylsyre-(2-hydroxyethyl)-methyl-ester med smp. 75°C. Udbytte: 71% af det teoretiske.
30 35
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Eksempel25 24
DK 157857 B
H3C^ k^“CF3
5 ^02CYVCO2CH2CH2-OH
H3C ^
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3,5-di-10 carboxylsyre-(2-hydroxyethyl)-isopropyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(2-trifluormethylphenyl)-pyridin-3 ,5-dicarboxylsyre-(2-hydroxyethyl)-isopropyl-ester med smp. 83°C. Udbytte: 51% af det teoretiske.
15 Eksempel 26 fip h3cn y ®C02C Vv C02CH2CH2OCH3
20 H,C II J
3 H3C CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(3-trifluormethylphenyl)-pyridin-3,5-di-carboxylsyre-isopropyl-(2-methoxyethyl)-ester med salpetersy-25 re forbindelsen 2 > 6-dimethyl-4-(3-trifluormethylphenyl)-pyridin-3 ,5-dicarboxylsyre-isopropyl-(2-methoxyethyl)-ester med smp. 51°C. Udbytte: 65% af det teoretiske.
30 35 25
Eksempel 27
O
DK 157857B
XOCH3 C02CH2CH20H « CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxyl-10 syre-(2-hydroxyethyl)-methyl-ester med salpetersyre forbindel sen 2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxylsyre- (2-hydroxyethyl) -methyl -ester med smp. 90°C. Udbytte: 84% af det teoretiske.
15 Eksempel 28 0^-°CH3
H5G2°2C '^j^^C02CH2CH2“°H
20 1) <JL
h3<r^ ch3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxyl-syre-ethyl-(2-hydroxyethyl)-ester med salpetersyre forbindelsen 25 2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxylsyre- -ethyl-(2-hydroxyethyl)-ester med smp. 95°C. Udbytte: 71% af det teoretiske.
30 35 26
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Eksempel 29 H3C 0CH3 5 HC02cVvr co2ch2ch2-oh
H3C Ji A
h3c ^Ν:η3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-diearboxy1-10 syre-(2-hydroxyethyl)-isopropyl-ester med salpetersyre forbin delsen 2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxyl-syre-(2-hydroxyethyl)-isopropyl-ester med smp. 68°C. Udbytte: 85% af det teoretiske.
15 Eksempel 30 h3c och3 HCO.C CO-CH-CH--0-^ Λ 20 H3C/ J ji CF3 H3C ^ N CH3 j
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(2-methoxyphenyl)-pyridin-3,5-dicarboxyl-syre-isopropyl-(2-(3-trifluormethylphenoxy)-ethyl)-ester med 25 salpetersyre forbindelsen 2,6-dimethyl-4-(2-methoxyphenyl)-py-ridin-3,5-dicarboxylsyre-isopropyl-(2-(3-trifluormethylphenoxy) -ethyl)-ester med smp. 80°C. Udbytte: 65% af det teoretiske.
30 35
DK 157857 B
27
Eksempel 31
O
Ψ2
H-C
3 \ T
5 HC02C C02CH2CH2-0H
H-ic^ JLf H3C ^ CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(4-nitrophenyl)-pyridin-3,5-dicarboxylsy-10 re-(2-hydroxyethyl)-isopropyl-ester med salpetersyre forbindel sen 2,6-dimethyl-4-(4-nitrophenyl)-pyridin-3,5-dicarbcxylsyre--(2-hydroxyethyl)-isopropyl-ester med smp. 145°C. Udbytte: 62% af det teoretiske.
15 Eksempel 32 ch3
H^C
3 \ T
HC02C y^yC02CH2CH2-0H
20 [I JL
H3C ^ CH3
Analogt med eksempel 1 fås der ved omsætning af 1,4-di-hydro-2,6-dimethyl-4-(4-methylphenyl)-pyridin-3,5-dicarboxylsyre- (2 -hydro xyethyl) -isopropyl-ester med salpetersyre for-25 bindeisen 2,6-dimethyl-4-(4-methylphenyl)-pyridin-3,5-dicarb-oxylsyre-(2-hydroxyethyl)-isopropyl-ester med smp. 72°C. Udbytte: 56% af det teoretiske.
30 35
DK 157857 B
28
O
Eksempel 33
St»02
C02CH2CH20H
CH3 10 Analogt med eksempel 1 fås der ved omsætning af 1,4-di- hydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-5-carboxylsyre- -(2-hydroxyethyl)-methyl-ester med salpetersyre forbindelsen 2,6-dimethyl-4-(3-nitrophenyl)-pyridin-5-carboxylsyre-(2-hy- droxyethyl)-methyl-ester med smp. 120°C. Udbytte: 53% af det teoretiske.
1 o 2Q Eksempel 34 f^1rN°2 0 CO-CH_CH_OCH-j o ]T Γ 2 2 2 3 25 .
ch3
Analogt med eksempel 9 fås der ved omsætning af 1,4,5,7--tetrahydro-2-methyl-4-(3-nitrophenyl)-5-oxo-furo[3,4-b]pyri-din-3-carboxylsyre-(2-methoxyethyl)-ester med chrom(VI)-oxid 30 forbindelsen 5,7-dihydro-2-methyl-4-(3-nitrophenyl)-5-oxo-fu-ro[3,4-b]pyridin-3-carboxylsyre-(2-methoxyethyl)-ester med smp. 114°C. Udbytte: 75% af det teoretiske.
35
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DK 157857B
29
Eksempel 35
Kaliumsalt af 2-hydroxymethyl-6-methyl-4-(3-nitrophe-nyl) -pyridin-3,5-dicarboxylsyre-5- (2-hydrgxyethyl) tester 5 kl
HOOC v 2CH2CH2-OH
hoh2c-^ n^ch3 10 24 g (50 mmol) 2-acetoxymethyl-6-methyl-4-(3-nitrophe- nyl)-pyridin-3,5-dicarboxylsyre-5-(2-acetoxyethyl)-3-ethyl--ester opløses i 120 ml 1,2-dimethoxyethan og omrøres i 2 timer ved stuetemperatur efter forsigtig tilsætning af en opløsning af 6,2 g kaliumhydroxid i 120 ral vand. Derefter eks-15 traheres blandingen flere gange med methylenchlorid, den vandige fase inddampes i vakuum til tørhed, og remanensen omkrystalliseres fra isopropanol. Smp. 223°C. Udbytte: 3,6 g (17% af det teoretiske).
20 Eksempel 36 5,7-Dihydro-2-methyl-4-(3-nitrophenyl)-5-oxo-furo-[3,4-b]pyridin-3-carboxylsyre-(2-hydroxyethy1)-ester 25 0
C02CH2CH2-0H
° I 1 ^ ca3 4 g af kaliumsaltet af 2-hydroxymethyl-6-methyl-4-(3-30 -nitrophenyl)-pyridin-3,5-dicarboxylsyre-5-(2-hydroxyethyl)- -esteren (eksempel 38) opløses i 4 ml vand, og der gøres surt med koncentreret saltsyre. Efter henstand natten over ved stuetemperatur fortyndes der med vand, den udfældede olie eks-traheres med methylenchlorid, de organiske ekstrakter inddam-35 pes i vakuum efter tørring over natriumsulfat, og remanensen omkrystalliseres fra isopropanol. Smp. 130°C. Udbytte: 2,3 g (64% af det teoretiske).
Claims (3)
- 5 R X COOR3 R1 R2 i hvilken 10. betyder en pyridylgruppe eller en phenylgruppe, der eventuelt indeholder 1 eller 2 ens eller forskellige substituen-ter valgt blandt halogen, cyano, nitro, trifluormethyl, alkyl med 1-4 carbonatomer og alkoxy med 1-4 carbonatomer, R1 betyder en alkylgruppe med 1-4 carbonatomer eller en 15 hydroxyalkylgruppe med 1-4 carbonatomer, R2 betyder en alkylgruppe med 1-4 carbonatomer, X betyder gruppen -COOR5, hvor R5 betyder H eller en lige-kædet, forgrenet eller cyclisk alkylgruppe med op til 12 carbonatomer, der eventuelt er afbrudt af 1 oxygenatom i 20 kæden, og R3, der altid er forskellig fra R5, betyder en alkylgruppe med 1-4 carbonatomer, der eventuelt er substitueret med hydroxy, cyano, halogen, trifluormethylphenoxy, halogen-phenoxy, alkoxy med 1-4 carbonatomer eller alkanoyloxy med 25 2-5 carbonatomer, eller R1 og X danner sammen med de C-atomer, hvortil de er bundet, en 5- til 7-leddet lactonring, eller farmaceutisk acceptable salte deraf, kendetegnet ved, at man 30 (a) bringer 1,4-dihydropyridinderivater med den almene formel (II) R X ^Js^COOR3 (il) H 35 DK 157857B i hvilken R, R1, R2, R3 og X har den ovenfor angivne betydning, til reaktion med oxiderende (dehydrogenerende) midler, eventuelt i nærværelse af indifferente opløsningsmidler, ved temperaturer mellem 0 og 200°c, eller at man 5 (b) esterificerer pyridincarboxylsyrer med den almene formel (III) R X ^As^COOH i (III)
- 1 JL 2 10 r' i hvilken R, R1, R2 og X har den ovenfor angivne betydning, eventuelt efter aktivering af carboxylgruppen efter fra litteraturen kendte metoder, til carboxylsyreestere med 15 den almene formel (I), eller at man (c) i det tilfælde, at rI i den almene formel (I) betegner en hydroxyalkylgruppe, underkaster de tilsvarende mono- eller bisacetoxyalkylpyridiner betingelserne for en mild og selektiv hydrolyse, eller at man 20 (d) i det tilfælde, hvor R1 sammen med X i den almene formel (I) danner en lactonring, ringslutter hydroxyalkyl-pyridincarboxylsyrer med den almene formel R 25 ΗΟΟΟγΛγ C02R3 (V) H0-(CH.) <^N^R2 2 n i hvilken R, R2 og R3 har den ovenfor angivne betydning, og n betyder et tal fra 1 til 3, under indflydelse af protoner 30 efter gængse metoder til forbindelser med formlen (VI)
- 0 R COOR3 \ ji I (VI) 35 DK 157857 B i hvilken R, R2, R3 og n har den ovenfor angivne betydning, hvorefter en fremstillet forbindelse om ønsket omdannes til et farmaceutisk acceptabelt salt deraf.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19823209274 DE3209274A1 (de) | 1982-03-13 | 1982-03-13 | Pyridincarbonsaeureester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
DE3209274 | 1982-03-13 |
Publications (4)
Publication Number | Publication Date |
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DK117783D0 DK117783D0 (da) | 1983-03-11 |
DK117783A DK117783A (da) | 1983-09-14 |
DK157857B true DK157857B (da) | 1990-02-26 |
DK157857C DK157857C (da) | 1990-07-30 |
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DK117783A DK157857C (da) | 1982-03-13 | 1983-03-11 | Analogifremgangsmaade til fremstilling af pyridincarboxylsyreestere eller farmaceutisk acceptable salte deraf |
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US (1) | US4705794A (da) |
EP (1) | EP0088940B1 (da) |
JP (1) | JPS58167571A (da) |
KR (1) | KR910000637B1 (da) |
AT (1) | ATE19875T1 (da) |
AU (1) | AU564367B2 (da) |
CA (1) | CA1208216A (da) |
DE (2) | DE3209274A1 (da) |
DK (1) | DK157857C (da) |
FI (1) | FI82687C (da) |
GR (1) | GR78454B (da) |
HU (1) | HU188851B (da) |
IE (1) | IE54879B1 (da) |
IL (1) | IL68095A (da) |
NO (1) | NO162234C (da) |
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Families Citing this family (12)
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JPS58185821U (ja) * | 1982-06-02 | 1983-12-10 | 日産自動車株式会社 | ウインドシ−ルド |
DE4342196A1 (de) * | 1993-12-10 | 1995-06-14 | Bayer Ag | Neue 4-Phenyl-substituierte 1,4-Dihydropyridine |
DE3410645A1 (de) * | 1984-03-23 | 1985-09-26 | Bayer Ag, 5090 Leverkusen | L-alkylsubstituierte 1,4-dihydropyridinlactone, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
GB8530602D0 (en) * | 1985-12-12 | 1986-01-22 | Fujisawa Pharmaceutical Co | Heterocyclic compounds |
IT1204948B (it) * | 1987-03-13 | 1989-03-10 | Boheringer Biochemia Robin S P | 2-tiometil-sostituite-piridine, metodo per la loro preparazione e composizioni farmaceutiche che le contengono. |
DE3712369A1 (de) * | 1987-04-11 | 1988-10-27 | Bayer Ag | Substituierte 5-nitro-1,4-dihydropyridine, verfahren zur herstellung und ihre verwendung |
DE3712371A1 (de) * | 1987-04-11 | 1988-10-27 | Bayer Ag | Substituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung |
CA1312611C (en) * | 1987-07-01 | 1993-01-12 | Yamanouchi Pharmaceutical Co., Ltd. | Pyridine derivatives, process for production thereof and pharmaceutical composition containing them |
US5100892A (en) * | 1990-11-13 | 1992-03-31 | Glaxo Inc. | Dihydropyridine vasodilator agents |
DK0657432T3 (da) | 1993-12-10 | 2003-07-07 | Bayer Ag | Phenylsubstituerede 1,4-dihydropyridiner med cerebral aktivitet |
DE4430639A1 (de) * | 1994-08-29 | 1996-03-07 | Bayer Ag | Verwendung von 5-substituierten Pyridin- und Hexahydrochinolin-3-carbonsäurederivaten |
AU2004272078A1 (en) * | 2003-09-10 | 2005-03-24 | Synta Pharmaceuticals Corp. | Dihydropyridine compounds for treating or preventing metabolic disorders |
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GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
NZ201395A (en) * | 1981-07-30 | 1987-02-20 | Bayer Ag | Pharmaceutical compositions containing 1,4-dihydropyridines and certain of these dihydropyridines |
DE3209276A1 (de) * | 1982-03-13 | 1983-09-15 | Bayer Ag, 5090 Leverkusen | Arzneimittel mit antihypoxischer und ischaemie-protektiver wirkung |
-
1982
- 1982-03-13 DE DE19823209274 patent/DE3209274A1/de not_active Withdrawn
-
1983
- 1983-02-17 NO NO830539A patent/NO162234C/no unknown
- 1983-02-28 US US06/470,886 patent/US4705794A/en not_active Expired - Fee Related
- 1983-03-02 EP EP83102001A patent/EP0088940B1/de not_active Expired
- 1983-03-02 DE DE8383102001T patent/DE3363581D1/de not_active Expired
- 1983-03-02 AT AT83102001T patent/ATE19875T1/de active
- 1983-03-03 PT PT76328A patent/PT76328B/pt unknown
- 1983-03-07 AU AU12081/83A patent/AU564367B2/en not_active Ceased
- 1983-03-10 FI FI830810A patent/FI82687C/fi not_active IP Right Cessation
- 1983-03-10 IL IL68095A patent/IL68095A/xx unknown
- 1983-03-11 JP JP58039303A patent/JPS58167571A/ja active Granted
- 1983-03-11 PH PH28638A patent/PH19685A/en unknown
- 1983-03-11 GR GR70766A patent/GR78454B/el unknown
- 1983-03-11 IE IE535/83A patent/IE54879B1/en not_active IP Right Cessation
- 1983-03-11 DK DK117783A patent/DK157857C/da not_active IP Right Cessation
- 1983-03-11 CA CA000423460A patent/CA1208216A/en not_active Expired
- 1983-03-11 HU HU83847A patent/HU188851B/hu not_active IP Right Cessation
- 1983-03-11 ZA ZA831691A patent/ZA831691B/xx unknown
- 1983-03-11 KR KR1019830000979A patent/KR910000637B1/ko not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
FI830810L (fi) | 1983-09-14 |
FI830810A0 (fi) | 1983-03-10 |
NO830539L (no) | 1983-09-14 |
PH19685A (en) | 1986-06-13 |
KR910000637B1 (ko) | 1991-01-31 |
NO162234C (no) | 1989-11-29 |
NO162234B (no) | 1989-08-21 |
EP0088940A1 (de) | 1983-09-21 |
FI82687C (fi) | 1991-04-10 |
HU188851B (en) | 1986-05-28 |
AU1208183A (en) | 1983-09-15 |
PT76328B (en) | 1985-11-11 |
ZA831691B (en) | 1983-12-28 |
AU564367B2 (en) | 1987-08-13 |
DK117783A (da) | 1983-09-14 |
US4705794A (en) | 1987-11-10 |
IE54879B1 (en) | 1990-03-14 |
PT76328A (en) | 1983-04-01 |
JPS58167571A (ja) | 1983-10-03 |
FI82687B (fi) | 1990-12-31 |
IE830535L (en) | 1983-09-13 |
IL68095A (en) | 1986-12-31 |
GR78454B (da) | 1984-09-27 |
EP0088940B1 (de) | 1986-05-21 |
DK117783D0 (da) | 1983-03-11 |
ATE19875T1 (de) | 1986-06-15 |
JPH0551581B2 (da) | 1993-08-03 |
KR840004079A (ko) | 1984-10-06 |
DK157857C (da) | 1990-07-30 |
DE3363581D1 (en) | 1986-06-26 |
DE3209274A1 (de) | 1983-09-15 |
CA1208216A (en) | 1986-07-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PBP | Patent lapsed |