DK157013B - Analogifremgangsmaade til fremstilling af fluorholdige 1,4-dihydropyridiner eller farmaceutisk acceptable syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af fluorholdige 1,4-dihydropyridiner eller farmaceutisk acceptable syreadditionssalte deraf Download PDFInfo
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- DK157013B DK157013B DK399079AA DK399079A DK157013B DK 157013 B DK157013 B DK 157013B DK 399079A A DK399079A A DK 399079AA DK 399079 A DK399079 A DK 399079A DK 157013 B DK157013 B DK 157013B
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- carbon atoms
- acid addition
- alkyl
- acceptable acid
- substituents
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- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000002253 acid Substances 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract 3
- 239000011737 fluorine Substances 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 150000002081 enamines Chemical class 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 101100496169 Arabidopsis thaliana CLH1 gene Proteins 0.000 claims 1
- 101100044057 Mesocricetus auratus SYCP3 gene Proteins 0.000 claims 1
- 101100080600 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nse6 gene Proteins 0.000 claims 1
- 101150111293 cor-1 gene Proteins 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract 2
- 230000000694 effects Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- OIPACIYDAFNMBA-RQOWECAXSA-N C\C=C(/N)C(=O)OCC(F)(F)F Chemical compound C\C=C(/N)C(=O)OCC(F)(F)F OIPACIYDAFNMBA-RQOWECAXSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CUNSUQKHHZVKMU-UHFFFAOYSA-N 1,4-dihydropyridine-2-carboxylic acid Chemical class OC(=O)C1=CCC=CN1 CUNSUQKHHZVKMU-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- KQKQHIHGOVNAPC-UHFFFAOYSA-N 3-o-ethyl 5-o-(2,2,2-trifluoroethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC(F)(F)F)C1C1=CC=CC([N+]([O-])=O)=C1 KQKQHIHGOVNAPC-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- -1 m-nitrobenzylidene Chemical group 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 157013 B
Den foreliggende opfindelse angâr en analogifrem-gangsmâde til fremstilling af hidtil ukendte 1,4-dihydro-pyridinderivater, der indeholder perfluorerede carbonatomer i deres estergrupper. De omhandlede forbindelser kan anvendes 5 soin lægemidler, især som kredslobspâvirkende midler.
Det er allerede kendt, at man fâr 1,4-dihydropyridin-carboxylsyreestere med intéressante kredslobspâvirkende egenskaber ved omsætning af aldehyder med jS-ketocarboxyl-syreestere og enaminocarboxylsyreestere [jfr. DE-offentlig-10 gtfrelsesskrifter nr. 2.117.571 og 2.117.573], Dihydropyridin-derivater, der indeholder perfluorerede carbonatomer i deres estergrupper, er ikke tidligere beskrevet.
Den foreliggende opfindelse angâr en analogifrem-gangsmâde til fremstilling af hidtil ukendte 1,4-dihydropyri-15 dîner med mindst ét perfluoreret carbonatom i estergruppen med den almene formel *4h r3 r5OOC V ^cooch"' 0 20 Ύ\ί ^R (I) r6XnAr!
H
25 hvor R1 og R6 er ens eller forskellige og betyder alkyl med 1-4 carbonatomer, R4 betyder phenyl, der eventuelt er sub-stitueret med 1 eller 2 substituenter fra gruppen nitro, trifluormethyl, halogen, alkyl eller alkoxy hver med 1-2 carbonatomer i alkyl- eller alkoxygrupperne, R5 betyder 30 alkyl med 1-6 carbonatomer, der eventuelt er substitueret med halogen, eller R5 betyder alkoxyalkyl med op til 6 carbonatomer eller cycloalkyl med 4-7 carbonatomer, eller R5 35 2
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R3 / 9 , betyder gruppen -CH , hvor R*4 og R·5 ι hvert tilfælde \ 2 5 R2 er ens eller forskellige, hvorhos en af de to substituenter betyder hydrogen, og den anden substituent eller begge substituenter R2 og R3 i hvert tilfælde betyder en ligekædet 10 eller forgrenet alkylgruppe med op til 8 carbonatomer, for-trinsvis med op til 6 carbonatomer, der indeholder 1, 2 eller 3 perfluorerede carbonatomer med hver 2 eller 3 fluor-substituenter, hvorhos denne alkylgruppe eventuelt er afbrudt af grupperingen -CH2-O-CH2-, eller farmaceutisk acceptable 15 syreadditionssalte deraf.
Analogifremgangsmâden ifolge opfindelsen er karak-teriseret ved, at man ved temperaturer mellem 20 og 150°C, eventuelt i nærværelse af vand eller indifferente, organiske oplosningsmidler, omsætter 1 mol enamin med den almene formel 20 3 (11)
Iv R^“C=CH-C00CH 0 r6-c=ch-coor5 I 1
NH * , NH
__ 1 eller , 2d H g (Ha) (Hb) 30 hvor R1, R2, R3, R5 og R6 har den ovenfor angivne betydning med 1 mol ylidenforbindelse med den almene formel 35 3
DK 157013 B
4 COR hhv. 4 n ^C0R „3 , n R-CH=C b R-CH=C ^ R (V) 5 ^ COOR3 COOCH 0
^R
(Va) (Vb) 10 hvor R1, R2, R3, R4, R5 og R6 har den ovenfor angivne betyd-ning, hvorefter den fremstillede forbindelse med formel (I), nâr den bærer en basisk substituent, om onsket omdannes til et farmaceutisk acceptabelt syreadditionssalt. Denne omdannelse til syreadditionssalt sker ved kendte metoder 15 ved hjælp af egnede, organiske eller uorganiske syrer.
Forbindelserne med formel (I) samt deres farmaceutisk acceptable syreadditionssalte har stærke, farmakologiske virkninger. De udmærker sig især ved virkninger pâ kredsl0bet og kan fortrinsvis anvendes som coronarmidler, antihyperten- 20 sive midler og midler til for0gelse af den perifere gennem- bl0dning. Pâ grund af deres hidtil ukendte struktur, især pâ grund af tilstedeværelsen af perfluorerede carbonatomer, har de her omhandlede forbindelser fordelagtige virkninger.
Deres anvendelse udg0r derfor en berigelse af farmacien.
25
De enaminer med den almene formel (II) , der kan anvendes if0lge opfindelsen, er kendte eller kan fremstilles ud fra de tilsvarende β-diketoforbindelser og aminer ved kendte metoder [jfr. A. Pinner, Berichte 34, 4239/40 (1901)].
30 Pâ taie som fortyndingsmiddel kommer vand og aile indifferente, organiske opl0sningsmidler. Til disse h0rer fortrinsvis alkoholer, sâsom éthanol, methanol og isopropanol, ethere, sâsom dioxan, diethylether, tetrahydrofuran, glycol- monomethylether, glycoldimethylether eller iseddike, dimethyl-35 formamid, dimethylsulfoxid, acetonitril og pyridin.
4
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Reaktionstemperaturerne kan varieres inden for et st0rre omrâde. Man arbejder almindeligvis mellem 20 og 150°C, fortrinsvis ved det anvendte opl0sningsmiddels kogetemperatur.
Omsætningen kan gennemf0res ved normalt tryk, men ogsâ ved forh0jet tryk. Man arbejder almindeligvis ved normalt tryk.
Ved gennemf0relsen af den her omhandlede fremgangsmâde anvendes de forbindelser med formlerne (II) og (V), der tager del i reaktionen, fortrinsvis i omtrentlig molære mængder.
Ylidenforbindelserne med formel (V) fremstilles ved omsætning af ækvimolære mængder af et aldehyd med formlen (IV) 1 ς R4-CHO (IV) 4 hvor R har den ovenfor anf0rte betydning, med en β-keto-carboxylsyreester med formlen R6-CO-CEL-COOR5 hhv. R1-C0-CHo-C00CH (III) \r2
20 R
(Ilia) (Illb) 1 p ο ς c hvor R-1·, R , RJ, R og R har den ovenfor anf0rte betydning.
De hidtil ukendte forbindelser er forbindelser, der er anvendelige som lægemidler. De har et bredt og mangesidet 25 farmakologisk virkningsspektrum. Ved dyrefors0g kan man især pâvise nedenstâende hovedvirkninger: 1. Ved parentéral, oral og perlingual indgift bevirker forbindelserne en tydelig og længe vedvarende udvidelse af coronarkarrene.
30 Denne virkning pâ coronarkarrene forstærkes af en samtidig, nitritlignende, hjerteaflastende virkning.
De pâvirker eller ændrer hjertestofskiftet til op-nâelse af en energibesparelse.
2. Pirringsevnen af irritationsdannelses- og pirrings-35 ydelsessystemet i hjertet nedsættes, sâledes at der resulterer en antiflimmervirkning, der kan pâvises i terapeutiske doser.
3. Toniciteten af karrenes glatte muskulatur formind-skes stærkt under forbindelsernes indvirkning. Denne kar-
DK 157013B
5 spasmolytiske virkning kan finde sted i det totale karsystem eller kan manifestere sig mere eller mindre isoleret i af-grænsede karomrâder (sâsom centralnervesystemet).
4. Forbindelserne sænker blodtrykket hos normotone 5 og hypertone dyr og kan sâledes anvendes som antihypertensive midler.
5. Forbindelserne har stærk muskulær-spasmolytisk virkning, som bliver tydelig ved den glatte muskulatur i maven, tarmomrâdet, urogenitalomrâdet og ândedrætssystemet.
10 1,4-Dihydropyridiner med farmakologiske virkninger er foruden fra de ovenfor nævnte DE-of fentliggorelsesskrifter nr. 2.117.571 (svarer til DK-patentskrift nr. 132.496) og 2.117.573 ogsà kendt fra DE-offentligg0relsesskrifterne nr. 1.963.188, 2.117.572 og 2.210.672. For aile disse kendte 15 forbindelser gælder, at de mangler det eller de perfluorerede carbonatomer, som obligatorisk findes i forbindelser med formel (I) fremstillet ved analogifremgangsmâden if0lge opfindelsen.
Endvidere gælder, at de kendte forbindelser ikke er 20 sâ aktive som forbindelser med formel (I), hvad angâr op-nâelse af coronar oxygenmætning, ligesom virkningsvarigheden er kortere, eller der kræves en hojere dosis til opnâelse af samme virkningsvarighed. Dette fremgâr af nedenstâende tabel I.
6
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Tabel I
Forbindelse Eksem- Dosis C>2-Stig- Varighed kendt fra pel nr. (mg/kg iv.v) ning (%) (minutter) 5 ____________ DE-off.skr. 1 0,01 30-40 10-60 2.117.571 10 0,005 20-30 10-60 17 0,02 20-30 10-60 10 DE-off.skr.
2.210.672 1 0,3 30-40 >60 DE-off.skr.
2.117.572 14 0,01 20-30 10-60 15 _ DE-off.skr. la 0,02 30-40 10-60 1.963.188 le 0,02 30-40 >60
Opfindelsen 1 0,01 30-40 >60 20 9 0,005 20-30 >60 13 0,005 20-30 >60
Forbindelser med formel (I) udmærker sig endvidere 25 ved, at de fordger b 1odgennemstromningen i iskæmiske ekstri-miteter, medens gennemstromningen i raske ekstremiteter ikke foroges i tilsvarende grad, hvilket er en yderligere fordel, da blodgennemstromningen i den raske ekstremitet bor være sâ tæt pâ det normale som muligt. Ogsâ med hensyn 30 til denne virkning er forbindelserne med formel (I) overras-kende bedre end de kendte forbindelser, hvilket fremgâr af de resultater, som er vist i nedenstâende tabel II. Disse resultater er opnâet ved en forsogsmetode som folger:
Bedovede hunde fâr underbundet Arteria fémoralis i 35 venstre bagben, sâledes at blodtilforslen kun sker gennem kollateralkarrene. B1odgennemstromningen i dette ben, som 7
DK 157013 B
pâ denne mâde er gjort iskæmisk, mâles pâ den tilsvarende benvene med en elektromagnetisk strdmningsmâler. Til sammen-ligning mâles blodgennemstrdmningen pâ benvenen i h0jre ben med normal blodforsyning.
5
Tàhel II
Stremningsforegelse (%)
Forbindelse Eksem- Dosis kollateral normal 10 kendt fra pel nr. (mg/kg l.v.) (venstre ben) (hojre ben)
Opfindelsen 13 0,001-0,1 23-184 10-60 (0,01) (81) 15 DE-off.skr.
2.117.573 9 0,001-0,03 18-100 52-480 DE-off.skr.
2.117.572 8 0,001-0,1 30-110 92-435 20 DE-off.skr. 52 0,01 10 0 2.117.571 1 0,001-0,1 20-42 42 7 0,01 -20 (sænkning) 0
DK 157013 B
s
Fremstillinqseksempler
Eksempel 1 ,NOa Ûf CF3 CH2 OOC γ' cooca Hs CH3^N^CH3
H
3-Ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)--5-trifluorethoxycarbonyl-1,4-dihydropyridin_ 5 g aminocrotonsyretrifluorethylester opvarmes under tilbagesvaling i 3 tiraer i 500 ml éthanol med 7,3 g m-nitro-benzylidenaceteddikesyreethylester. Der afk01es, frasuges og fâs 7,8 g svagt gule krystaller med smp.: 192°C svarende til 67% af det teoretiske.
Eksempel 2
ifT
CF5 CHa 02 C C0CCHa -CH, -0CH3 CH3 CK,
H
2,6-Dimethyl-3-8-methoxyethoxycarbonyl-4-(3-nitro-phenyl)-5-trifluorethoxycarbony1-1,4-dihydropyridin_ 5 g aminocrotonsyretrifluorethylester opvarmes under tilbagesvaling i 3 timer sammen med 3,1 g m-nitrobenzyliden-aceteddikesyre-p-methoxyethylester i 500 ml propanol. Der frasuges og fâs 9,3 g svagt gule krystaller med smp.: 169°C svarende til 74% af det teoretiske.
9
DK 157013 B
Pâ analog arbejdsmâde med eksempel 1 fâs de i neden-stâende tabel anf0rte forbindelser.
R* R300C^ A^COOR1 ch3 JkcH3
H
i " “ ] “Γ I 1 Λ J v * Bemærk-
Nr. R1 R2 R3 Smp. ninger 3 ch3 <Qh CF3-CH2- 161 °c no2
4 Ca H3 '· " 158'eC
5 CH,- (py " 153°c
6 " » (CF3 }a-CH- 165°C
7 nC3H7- ” CF3-CHa- 172°C
8 isoC3H7- » ” 158°C
9 w " 173 eC
i 10 ÎS0C3H7- M CHa -CHa -0-CH2 CF3 — olieagtig, chromato- grafisk renset, M+ 486 10
DK 157013 B
Ra R3 OOC C00R1 CH*
H
Nr. R' R3 R3 ^P· ninger 11 CF3 -CHa- *p- CF 3 -CHa- 209°C ·
12 " Qrcl ' 95°C
13 CH3 " " 119°C
olieagtig, Ί z - tt ft M chromatogra- * 2 *s fisk renset, TC ensartet M+ 417 15 ch3- QrCTi " 114‘c
16 CF3-CH2- " M 131°C
17 ” 119°c ia » ' ' ' ' ' " i34°c
19 - " 114°C
soch3
Claims (2)
1. Analogifremgangsmâde til fremstilling af fluor-holdige 1,4-dihydropyridiner med den almene formel 5. o R H R3 r5ooc. Je ^cooch' , % M. v r6 h r 10 hvor R1 og R6 er ens eller forskellige og betyder alkyl med 1-4 carbonatomer, R4 betyder phenyl, der eventuelt er sub-stitueret med 1 eller 2 substituenter fra gruppen nitro, 15 trifluormethyl, halogen, alkyl eller alkoxy hver med 1-2 carbonatomer i alkyl- eller alkoxygrupperne, R5 betyder alkyl med 1-6 carbonatomer, der eventuelt er substitueret med halogen, eller R5 betyder alkoxyalkyl med op til 6 carbonatomer eller cycloalkyl med 4-7 carbonatomer, eller R5 20 betyder gruppen R2 -CH , hvor R2 og R3 i hvert tilfælde er ens eller for-\ 3
25 RJ skellige, hvorhos en af de to substituenter kan betyde hydro-gen, og den anden substituent eller begge substituenter R2 og R3 i hvert tilfælde betyder en ligekædet eller forgrenet 30 alkylgruppe med op til 8 carbonatomer, der indeholder 1, 2 eller 3 perfluorerede carbonatomer med hver 2 eller 3 fluor-substituenter, hvorhos denne alkylgruppe eventuelt er afbrudt af grupperingen -CH2-0-CH2/ eller farmaceutisk acceptable syreadditionssalte deraf, kendetegnet ved, at 35 man ved temperaturer mellem 20 og 150°C, eventuelt i nær-værelse af vand eller indifferente, organiske opl^sningsmid-1er, omsætter 1 mol enamin med den almene formel DK 157013B ^R3 R1-C=CH-COOCH ^ 2 eller r6-c=CH-COOR5 ^ 5 nh in E H (IIa) (XXb) 10 hvor R1, R2, R3, R5 og R6 har den ovenfor angivne betydning, med 1 mol ylidenforbindelse med den almene formel 15 4. cor6 . COR1 R4-CH=C R4-CH=C^ r3 (V) ^COOR3 hhv. \ xCOOCH 'T 9 ^RZ 20 (Va) (vb) hvor R1, R2, R3, R4, R5 og R6 har den ovenfor angivne betyd-25 ning, hvorefter den fremstillede forbindelse med formel (I) om 0nsket omdannes til et farmaceutisk acceptabelt syreaddi-tionssalt.
2. Analogifremgangsmàde ifolge krav l, k e n d e-30 tegnet ved, at man fremstiller den forbindelse, hvori i formel (I) R1 og R6 begge er methyl, R2 og R3 begge er hydrogen, R4 er o-chlorphenyl, og R5 er 2,2,2-trifluorethyl eller et farmaceutisk acceptabelt syreadditionssalt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2841667 | 1978-09-25 | ||
| DE19782841667 DE2841667A1 (de) | 1978-09-25 | 1978-09-25 | Fluorhaltige 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK399079A DK399079A (da) | 1980-03-26 |
| DK157013B true DK157013B (da) | 1989-10-30 |
| DK157013C DK157013C (da) | 1990-03-26 |
Family
ID=6050376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK399079A DK157013C (da) | 1978-09-25 | 1979-09-24 | Analogifremgangsmaade til fremstilling af fluorholdige 1,4-dihydropyridiner eller farmaceutisk acceptable syreadditionssalte deraf |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4256749A (da) |
| EP (1) | EP0009206B1 (da) |
| JP (2) | JPS6016934B2 (da) |
| AT (1) | ATE290T1 (da) |
| CA (1) | CA1130291A (da) |
| DE (2) | DE2841667A1 (da) |
| DK (1) | DK157013C (da) |
| ES (1) | ES484397A1 (da) |
| FI (1) | FI70887C (da) |
| GR (1) | GR74127B (da) |
| HK (1) | HK15184A (da) |
| HU (1) | HU178449B (da) |
| IE (1) | IE49462B1 (da) |
| IL (1) | IL58299A (da) |
| SG (1) | SG38783G (da) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2508446B1 (fr) * | 1981-06-25 | 1986-05-02 | Rhone Poulenc Agrochimie | Herbicides a fonctions amide et ester derives de la pyridine ainsi que leur procede de preparation et leur application |
| DE3130041A1 (de) * | 1981-07-30 | 1983-02-17 | Bayer Ag, 5090 Leverkusen | Dihydropyridine mit positiv inotroper wirkung, neue verbindungen, ihre verwendung in arzneimitteln und verfahren zu ihrer herstellung |
| JPS5897332U (ja) * | 1981-12-24 | 1983-07-02 | 株式会社昭和製作所 | 油圧緩衝器の減衰力調整機構 |
| JPS5897333U (ja) * | 1981-12-24 | 1983-07-02 | 株式会社昭和製作所 | 油圧緩衝器の減衰力調整機構 |
| DE3312283A1 (de) * | 1983-04-05 | 1984-10-18 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von unsymmetrischen 1,4-dihydropyridincarbonsaeureestern |
| DE3316510A1 (de) * | 1983-05-06 | 1984-11-08 | Bayer Ag | Parenterale formulierung von nimodipin, ein verfahren zu ihrer herstellung sowie ihre verwendung bei der bekaempfung von erkrankungen |
| US4677101A (en) * | 1983-09-26 | 1987-06-30 | Merck & Co., Inc. | Substituted dihydroazepines useful as calcium channel blockers |
| IE57810B1 (en) * | 1984-03-27 | 1993-04-21 | Delagrange Lab | 1,4-dihydropyridine derivatives,their preparation and their use |
| EP0169009A3 (en) * | 1984-07-17 | 1988-08-31 | FISONS plc | Novel dihydropyridine derivatives and their production, formulation and use as pharmaceuticals |
| DE3544211A1 (de) * | 1985-12-13 | 1987-06-19 | Bayer Ag | Neue, fluorhaltige 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| JPS62292757A (ja) * | 1986-06-12 | 1987-12-19 | Taisho Pharmaceut Co Ltd | １，４−ジヒドロピリジン誘導体 |
| US4868181A (en) * | 1986-08-04 | 1989-09-19 | E. I. Du Pont De Nemours And Company | 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity |
| JPS63160458U (da) * | 1987-04-09 | 1988-10-20 | ||
| US5177211A (en) * | 1988-01-21 | 1993-01-05 | Alter, S.A. | 4-alkyl-1,4-dihydropyridines with PAF-antagonist activity |
| EP0330470A3 (en) * | 1988-02-24 | 1992-01-02 | Ajinomoto Co., Inc. | 1,4-dihydropyridine derivatives useful against tumour cells |
| US5216172A (en) * | 1988-02-24 | 1993-06-01 | Ajinomoto Co., Inc. | 1,4-dihydropyridine-4-aryl-2,6-dimethyl-3,5-dicarboxylates useful as agents against drug resistant tumor cells |
| DE3833893A1 (de) * | 1988-10-05 | 1990-04-12 | Bayer Ag | Verwendung von basischen nitro-phenyl-dihydropyridin-amiden als arzneimittel, neue verbindungen und verfahren zu ihrer herstellung ueber neue zwischenprodukte |
| JP3040364U (ja) * | 1996-07-23 | 1997-08-19 | 清秀 中川 | 芳香含有物質の詰め替え可能な枕 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK132496B (da) * | 1971-04-10 | 1975-12-15 | Bayer Ag | Analogifremgangsmåde til fremstilling af usymmetriske 1,4-dihydropyridincarboxylsyreestere. |
| DK134600B (da) * | 1971-04-10 | 1976-12-06 | Bayer Ag | Fremgangsmade til fremstilling af usymmetriske 1,4-dihydropyridindicarboxylsyreestere |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1409865A (en) * | 1973-02-13 | 1975-10-15 | Science Union & Cie | Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them |
| DE2508181A1 (de) * | 1975-02-26 | 1976-09-09 | Bayer Ag | 1,4-dihydropyridincarbonsaeurearal- kylester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
-
1978
- 1978-09-25 DE DE19782841667 patent/DE2841667A1/de not_active Withdrawn
-
1979
- 1979-09-10 US US06/074,048 patent/US4256749A/en not_active Expired - Lifetime
- 1979-09-12 AT AT79103411T patent/ATE290T1/de active
- 1979-09-12 DE DE7979103411T patent/DE2961012D1/de not_active Expired
- 1979-09-12 EP EP79103411A patent/EP0009206B1/de not_active Expired
- 1979-09-21 FI FI792939A patent/FI70887C/fi not_active IP Right Cessation
- 1979-09-21 CA CA336,100A patent/CA1130291A/en not_active Expired
- 1979-09-21 JP JP54120911A patent/JPS6016934B2/ja not_active Expired
- 1979-09-21 IL IL58299A patent/IL58299A/xx unknown
- 1979-09-24 GR GR60102A patent/GR74127B/el unknown
- 1979-09-24 HU HU79BA3852A patent/HU178449B/hu not_active IP Right Cessation
- 1979-09-24 ES ES484397A patent/ES484397A1/es not_active Expired
- 1979-09-24 IE IE1802/79A patent/IE49462B1/en unknown
- 1979-09-24 DK DK399079A patent/DK157013C/da not_active IP Right Cessation
-
1983
- 1983-07-02 SG SG387/83A patent/SG38783G/en unknown
-
1984
- 1984-02-23 HK HK151/84A patent/HK15184A/xx unknown
- 1984-07-27 JP JP59155722A patent/JPS6069018A/ja active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK132496B (da) * | 1971-04-10 | 1975-12-15 | Bayer Ag | Analogifremgangsmåde til fremstilling af usymmetriske 1,4-dihydropyridincarboxylsyreestere. |
| DK134600B (da) * | 1971-04-10 | 1976-12-06 | Bayer Ag | Fremgangsmade til fremstilling af usymmetriske 1,4-dihydropyridindicarboxylsyreestere |
Also Published As
| Publication number | Publication date |
|---|---|
| FI70887C (fi) | 1986-10-27 |
| JPS6069018A (ja) | 1985-04-19 |
| EP0009206A3 (en) | 1980-04-16 |
| GR74127B (da) | 1984-06-06 |
| DE2841667A1 (de) | 1980-04-10 |
| EP0009206B1 (de) | 1981-10-14 |
| ES484397A1 (es) | 1980-05-16 |
| ATE290T1 (de) | 1981-10-15 |
| JPS5547657A (en) | 1980-04-04 |
| IL58299A (en) | 1983-03-31 |
| IL58299A0 (en) | 1979-12-30 |
| DK157013C (da) | 1990-03-26 |
| JPS6016934B2 (ja) | 1985-04-30 |
| FI70887B (fi) | 1986-07-18 |
| SG38783G (en) | 1984-07-27 |
| US4256749A (en) | 1981-03-17 |
| JPS6217972B2 (da) | 1987-04-21 |
| IE49462B1 (en) | 1985-10-16 |
| CA1130291A (en) | 1982-08-24 |
| FI792939A (fi) | 1980-03-26 |
| HK15184A (en) | 1984-03-02 |
| EP0009206A2 (de) | 1980-04-02 |
| DK399079A (da) | 1980-03-26 |
| HU178449B (en) | 1982-05-28 |
| IE791802L (en) | 1980-03-25 |
| DE2961012D1 (en) | 1981-12-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |