NL193066C - Methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydro pyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound. - Google Patents
Methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydro pyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound. Download PDFInfo
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- NL193066C NL193066C NL7909024A NL7909024A NL193066C NL 193066 C NL193066 C NL 193066C NL 7909024 A NL7909024 A NL 7909024A NL 7909024 A NL7909024 A NL 7909024A NL 193066 C NL193066 C NL 193066C
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- benzoxadiazol
- isopropyl
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- 150000001875 compounds Chemical class 0.000 title claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- -1 2,1,3-benzoxadiazol-4-yl Chemical group 0.000 title description 4
- JNLUMMRKXUTNAA-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-5-propan-2-yloxycarbonyl-1,4-dihydropyridine-3-carboxylic acid Chemical compound CC(C)OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC2=NON=C12 JNLUMMRKXUTNAA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 8
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical group C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 230000017531 blood circulation Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010022562 Intermittent claudication Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 208000021156 intermittent vascular claudication Diseases 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UKVYVZLTGQVOPX-IHWYPQMZSA-N (z)-3-aminobut-2-enoic acid Chemical compound C\C(N)=C\C(O)=O UKVYVZLTGQVOPX-IHWYPQMZSA-N 0.000 description 1
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical class C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- SLLFVLKNXABYGI-UHFFFAOYSA-N 1,2,3-benzoxadiazole Chemical class C1=CC=C2ON=NC2=C1 SLLFVLKNXABYGI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- COLPLFZHPXIFCQ-UHFFFAOYSA-N 1,4-dihydropyridine-3,5-dicarboxylic acid Chemical class OC(=O)C1=CNC=C(C(O)=O)C1 COLPLFZHPXIFCQ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 206010058842 Cerebrovascular insufficiency Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- DYYYPIJLRRHUPR-UHFFFAOYSA-N dimethyl 1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=CNC=C(C(=O)OC)C1 DYYYPIJLRRHUPR-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
1 1930661 193066
Methyl, isopropyl-4-(2,1,3-benzoxadiazool-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylaat en farmaceutisch preparaat dat deze verbinding bevatMethyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound
De onderhavige uitvinding heeft betrekking op een methyl, isopropyl-4-(2,1,3-benzoxadiazool-4-yl)-2,6-5 dimethyl-1,4-dihydropyridine-3,5-dicarboxylaat.The present invention relates to a methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-5 dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Dergelijke verbindingen zijn bekend uit de Europese octrooiaanvrage 150. Deze literatuurplaats heeft betrekking op verbindingen met een 1,4-dihydropyridine-structuur die op de 4-plaats met een eventueel gesubstitueerde benzoxadiazool- of benzothiadiazoolrest gesubstitueerd is. De in de voorbeelden beschreven en door een fysische constant gekenmerkte verbindingen, waaronder 3,5-dialkoxycarbonylderivaten, zijn 10 alle symmetrisch, dat wil zeggen de beschreven substituenten op de 3- en de 5-plaats van de dihydropyridi-negroep zijn steeds gelijk.Such compounds are known from European patent application 150. This literature reference relates to compounds with a 1,4-dihydropyridine structure which is substituted in the 4-position with an optionally substituted benzoxadiazole or benzothiadiazole residue. The compounds described in the examples and characterized by a physical constant, including 3,5-dialkoxycarbonyl derivatives, are all symmetrical, ie the described substituents in the 3- and 5-positions of the dihydropyridine group are always the same.
Gevonden is nu een verbinding met formule 1, van het formuleblad die bijzonder waardevolle farmacologische eigenschappen bezit. Zo is de coronaire werking krachtig ten opzichte van vergelijkbare symmetrische verbindingen en van Nifedipine en bovendien bijzonder lang. De calcium-antagonistische werking is 15 eveneens bijzonder krachtig. Verder wordt de verbinding goed getolereerd.A compound of the formula 1 of the formula sheet has now been found which has particularly valuable pharmacological properties. For example, the coronary action is powerful compared to comparable symmetrical compounds and to Nifedipine, and it is particularly long. The calcium antagonistic action is also very powerful. Furthermore, the connection is well tolerated.
De uitvinding heeft verder betrekking op een farmaceutisch preparaat dat de verbinding van de uitvinding en een farmaceutisch aanvaardbare drager of farmaceutisch aanvaardbaar verdunningsmiddel bevat.The invention further relates to a pharmaceutical composition containing the compound of the invention and a pharmaceutically acceptable carrier or pharmaceutically acceptable diluent.
Gewezen kan nog worden op de Nederlandse octrooiaanvragen 7204693 en 7303135 die betrekking hebben op asymmetrische (cyclo)alkyl-, alkenyl- of alkynylesters van 1,4-dihydropyridine-3,5-dicarbonzuren. 20 Volgens deze literatuur bezitten deze assymmetrisch gesubstitueerde 1,4-dihydropyridinen een sterkere coronairvaten verwijdende werking dan bekende symmetrisch gesubstitueerde 1,4-dihydropyridinen. Deze literatuurplaatsen beschrijven geen 1,4-dihydropyridinederivaten die op de 4-plaats met een 2,1,3 benzoxa-diazolylgroep gesubstitueerd zijn. Evenmin suggereren zij dat de specifieke, asymmetrische gesubstitueerde verbinding van de uitvinding bijzonder gewenste eigenschappen bezit en een bijzonder lange werking 25 vertoont.Reference may also be made to Dutch patent applications 7204693 and 7303135 which relate to asymmetric (cyclo) alkyl, alkenyl or alkynyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acids. According to this literature, these asymmetrically substituted 1,4-dihydropyridines have a stronger coronary vasodilatory activity than known symmetrically substituted 1,4-dihydropyridines. These references do not describe 1,4-dihydropyridine derivatives substituted in the 4-position with a 2,1,3 benzoxadiazolyl group. Nor do they suggest that the specific, asymmetric substituted compound of the invention has particularly desirable properties and exhibits a particularly long action.
De verbinding van de uitvinding kan worden bereid door de -HC=Y-groep in de verbinding met formule 2, waarin de -HC=Y-groep: i) een formylgroep, ii) een groep met formule 8 of 30 iii) een groep met formule 9, waarin Z en Z' onafhankelijk van elkaar, zuurstof of een NH-groep weergeven, voorstelt omzet in een groep met formule 3.The compound of the invention can be prepared by the -HC = Y group in the compound of formula 2, wherein the -HC = Y group: i) a formyl group, ii) a group of formula 8 or iii) a group of formula 9, wherein Z and Z 'independently represent oxygen or an NH group, represents conversion to a group of formula 3.
Deze werkwijze kan op een gebruikelijke wijze voor het bereiden van overeenkomstige dihydropyridine-derivaten, bijvoorbeeld volgens Hantzsch, worden uitgevoerd.This process can be carried out in a conventional manner for preparing corresponding dihydropyridine derivatives, for example, according to Hantzsch.
Geeft de -HC=Y-groep de formylgroep weer dan kan de verbinding van de uitvinding worden bereid door 35 de verbinding met formule 2 te laten reageren met een verbinding met formule 4, waarin R2 de hiervoor aangegeven betekenis heeft, en een verbinding met formule 7, waarin R, en R3 de hiervoor aangegeven betekenissen hebben.When the -HC = Y group represents the formyl group, the compound of the invention can be prepared by reacting the compound of formula 2 with a compound of formula 4, wherein R2 has the meaning indicated above, and a compound of formula 7, wherein R 1 and R 3 have the meanings indicated above.
Het zal duidelijk zijn dat de verbinding met formule 6 als tussenproduct tijdens de reactie van de verbinding met formule 4 en de verbinding met formule 5 kan worden gevormd. Eveneens kan een 40 verbinding met formule 2 waarin de -HC=Y groep een groep ii) of iii) weergeeft, als tussenproduct bij deze reacties worden verkregen. Ze kunnen echter volgens verschillende werkwijzen worden gevormd.It will be understood that the compound of formula 6 can be formed as an intermediate during the reaction of the compound of formula 4 and the compound of formula 5. Also, a compound of formula 2 in which the -HC = Y group represents a group ii) or iii) can be obtained as an intermediate in these reactions. However, they can be formed by various methods.
De verbinding van de uitvinding kan ook worden bereid door een verbinding met formule 2, waarin de -HC=Y groep met een groep vermeld onder ii) is, te laten reageren met de verbinding met formule 4 of 6 en, indien geschikt, met een verbinding met formule 5. Een verbinding met formule 2 waarin de -HC=Y groep 45 een groep vermeld onder iii) is kan een tussenproduct zijn.The compound of the invention can also be prepared by reacting a compound of formula 2, wherein the -HC = Y group is with a group mentioned under ii) with the compound of formula 4 or 6 and, if appropriate, with a compound of formula 5. A compound of formula 2 wherein the -HC = Y group 45 is a group mentioned under iii) may be an intermediate.
Bij de hiervoor beschreven reacties is het in bepaalde gevallen mogelijk dat meer dan één isomeer met formule 1 wordt gevormd. Indien dit het geval is, kunnen de isomeren op een gebruikelijke wijze worden gescheiden, bijvoorbeeld door kolom- of dunnelaagchromatografie. Past men als uitgangsmateriaal een verbinding met formule 2 toe waarin de -HC=Y groep een groep vermeld onder iii) is, dan is de reactie een 50 ringsluitingsreactie. Stellen Z en Z' beide zuurstof voor, dan moet ammoniak met formule 5 aanwezig zijn.In the reactions described above, it is possible in certain cases that more than one isomer of formula 1 is formed. If so, the isomers can be separated in a conventional manner, for example, by column or thin layer chromatography. When a compound of formula 2 is used as starting material in which the -HC = Y group is a group mentioned under iii), the reaction is a cyclization reaction. Z and Z 'both represent oxygen, then ammonia of formula 5 must be present.
Al de hiervoor beschreven reacties kunnen echter onder dezelfde omstandigheden worden uitgevoerd.However, all of the reactions described above can be carried out under the same conditions.
Men kan de reactie geschikt in oplossing laten verlopen. Een geschikt oplosmiddel hiervoor is water, ethanol, dioxaan, dimethylformamide, dimethylsulfoxide, pyridine of ijsazijn. Geschikte reactietemperaturen zullen tussen 20 en 160°C, bij voorkeur tussen 60 en 120°C liggen.The reaction can be conveniently run in solution. A suitable solvent for this is water, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or glacial acetic acid. Suitable reaction temperatures will be between 20 and 160 ° C, preferably between 60 and 120 ° C.
55 Voor zover het bereiden van de uitgangsmaterialen niet in het bijzonder is beschreven, zijn deze materialen bekend of kunnen op een analoge wijze aan het bereiden van bekende verbindingen worden verkregen.As far as the preparation of the starting materials is not particularly described, these materials are known or can be obtained in an analogous manner from the preparation of known compounds.
In het volgende voorbeeld is de in graden Celcius opgegeven temperatuur niet gecorrigeerd.In the following example, the temperature specified in degrees Celsius is not corrected.
VoorbeeldExample
Men kookte een mengsel van de isopropylester van a-acetyl-p-(2,1,3-benzoxadiazool-4-yl)-acrylzuur, de 5 methylester van β-aminocrotonzuur en 10 ml ethanol 3 uren onder terugvloeikoeling. Daarna dampte men het reactiemengsel in en chromatografeerde men het verkregen residu over silicagel met een mengsel van chloroform en ethylacetaat (8:1), waardoor men de verbinding van de uitvinding verkreeg. Men her-kristalliseerde de verkregen verbinding uit diisopropylether en methylcyclohexaan, waarna het smeltpunt van de gewenste verbinding tussen 131 en 153°C lag.A mixture of the isopropyl ester of α-acetyl-p- (2,1,3-benzoxadiazol-4-yl) -acrylic acid, the methyl ester of β-aminocrotonic acid and 10 ml of ethanol was refluxed for 3 hours. The reaction mixture was then evaporated and the residue obtained was chromatographed on silica gel with a mixture of chloroform and ethyl acetate (8: 1), whereby the compound of the invention was obtained. The resulting compound was recrystallized from diisopropyl ether and methylcyclohexane, after which the melting point of the desired compound was between 131 and 153 ° C.
10 De verbinding volgens de uitvinding bezit een farmacologische werking en brengt in het bijzonder een dilatatie van coronaire vaten teweeg, zoals blijkt uit de resultaten van proeven waarbij de bloedstroom naar het myocardium van een geanaesthetiseerde kat met behulp van de kogelcelmethode (Rudolph A.M. en Heymann M.A.: Circulation Research 21, 163 (1967)) na toediening van 30 tot 50 /jg/kg intraveneus of van 50 tot 150 pg/kg i.d. van de actieve verbinding werd gemeten.The compound according to the invention has a pharmacological action and in particular induces a dilation of coronary vessels, as can be seen from the results of tests involving the blood flow to the myocardium of an anesthetized cat using the bullet cell method (Rudolph AM and Heymann MA : Circulation Research 21, 163 (1967)) after administration of 30 to 50 µg / kg intravenously or from 50 to 150 µg / kg id of the active compound was measured.
15 Derhalve bezit de verbinding volgens de uitvinding eveneens een gunstige werking tegen angina pectoris, zoals blijkt uit de toeneming van de coronaire stroming van een geanaesthetiseerde kat bij toedienen van de verbinding volgens de uitvinding.Therefore, the compound of the invention also has a beneficial effect against angina pectoris, as evidenced by the increase in coronary flow of an anesthetized cat when administering the compound of the invention.
De verbinding volgens de uitvinding is daarom geïndiceerd voor toepassing bij het behandelen van coronaire insufficiëntie.The compound of the invention is therefore indicated for use in the treatment of coronary insufficiency.
20 De verbinding volgens de uitvinding doet de bloedstroom naar de ledematen, bijvoorbeeld de spieren van de benen, toenemen, zoals blijkt uit de kogelcelmethode toegepast op een geanaesthetiseerde kat bij toedienen van 30 tot 50 pg/kg i.v. of van 50 tot 150 pg/kg i.d. van de verbinding volgens de uitvinding.The compound of the invention increases blood flow to the limbs, for example the muscles of the legs, as evidenced by the bullet cell method applied to an anesthetized cat when administering 30 to 50 µg / kg i.v. or from 50 to 150 pg / kg i.d. of the compound of the invention.
De verbinding volgens de uitvinding is daardoor geïndiceerd voor toepassing bij het behandelen van claudicatio intermittens en andere perifere aandoeningen van de bloedstroom naar de spieren van de 25 ledematen.The compound of the invention is therefore indicated for use in the treatment of intermittent claudication and other peripheral disorders of blood flow to the muscles of the limbs.
Bovendien doet de verbinding volgens de uitvinding de cerebrale bloedstroming toenemen, zoals blijkt uit de resultaten van de kogelcelmethode op geanaesthetiseerde katten bij toediening van 30 tot 50 pg/kg i.v. of van 50 tot 150 pg/kg i.d. van de verbinding volgens de uitvinding.In addition, the compound of the invention increases cerebral blood flow, as evidenced by the results of the bullet cell method on anesthetized cats when administered from 30 to 50 µg / kg i.v. or from 50 to 150 pg / kg i.d. of the compound of the invention.
De verbinding volgens de uitvinding is daarom geïndiceerd voor toepassing bij het behandelen van 30 cerebrovasculaire aandoeningen.The compound of the invention is therefore indicated for use in the treatment of cerebrovascular disorders.
Verder bezit de verbinding volgens de uitvinding een calcium-antagonistische werking, zoals blijkt uit standaard proeven, bijvoorbeeld door een remming van een door calcium geïnduceerde contractie van geïsoleerde coronaire arteriën van honden gesuspendeerd in een depolariserende oplossing met een concentratie van 10‘10 tot 10'8 M van de verbinding volgens de principes van Godfraind T. en Kaba, A. Brit. 35 J. Pharm. 36, 549-560, 1969.Furthermore, the compound of the invention has a calcium antagonistic activity, as evidenced by standard tests, for example, by inhibiting a calcium-induced contraction of isolated canine coronary arteries suspended in a depolarizing solution at a concentration of 10'10 to 10 ' 8 M of the connection according to the principles of Godfraind T. and Kaba, A. Brit. J. Pharm. 36, 549-560, 1969.
De verbinding volgens de uitvinding is daarom eveneens geïndiceerd voor toepassing als spasmolytisch middel voor het behandelen van spierkrampen, Voor de hiervoor aangeduide aandoeningen zal een geïndiceerde dagelijkse dosis tussen 5 en 100 mg, geschikt als eenheidsdoseringsvorm met 1,25 mg tot 50 mg van de verbinding volgens de uitvinding 2-4 malen daags of in een langzaam vrijkomende vorm, liggen. 40 Bovendien bezit de verbinding volgens de uitvinding een antihypertensieve werking, zoals blijkt uit standaard proeven, bijvoorbeeld de Grollman-proef op ratten [zie A. Grollman, Proc. Soc. Expt. Biol, and Med. 57, 104 (1944)] bij het subcutaan toedienen van 0,1-10 mg van de verbinding volgens de uitvinding per kg lichaamsgewicht van het dier.The compound of the invention is therefore also indicated for use as a spasmolytic for the treatment of muscle cramps. For the conditions indicated above, an indicated daily dose will be between 5 and 100 mg, suitable as a unit dosage form with 1.25 mg to 50 mg of the compound according to the invention lie 2-4 times a day or in a slowly released form. In addition, the compound of the invention has an antihypertensive activity, as evidenced by standard tests, for example, the Grollman test on rats [see A. Grollman, Proc. Soc. Expt. Biol, and Med. 57, 104 (1944)] when administering 0.1-10 mg of the compound of the invention per kg body weight of the animal subcutaneously.
De verbinding volgens de uitvinding is dus eveneens geïndiceerd voor toepassing als antihypertensief 45 middel. Voor deze aandoening zal een geïndiceerde dagelijkse dosis tussen 5 en 1000 mg liggen. Deze dosis wordt geschikt in de vorm van een eenheidsdoseringsvorm met 1,25 tot 500 mm actief materiaal in afzonderlijke doses 2-4 malen daags of in een langzaam vrijkomende vorm toegediend.Thus, the compound of the invention is also indicated for use as an antihypertensive agent. For this condition, an indicated daily dose will be between 5 and 1000 mg. This dose is suitably administered in unit dosage form with 1.25 to 500 mm active material in separate doses 2-4 times daily or in a slow release form.
Een farmaceutisch preparaat dat de verbinding volgens de uitvinding bevat, kan volgens gebruikelijke methoden worden bereid en heeft bijvoorbeeld de vorm van een capsule of tablet.A pharmaceutical preparation containing the compound of the invention can be prepared by conventional methods and is, for example, in the form of a capsule or tablet.
50 De verbinding van de uitvinding wordt bij voorkeur gebruikt tegen coronaire insufficiëntie, claudicatio intermittens, cerebrovasculaire insufficiëntie en spasmolytische werking.The compound of the invention is preferably used against coronary insufficiency, intermittent claudication, cerebrovascular insufficiency and spasmolytic activity.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1283578A CH639659A5 (en) | 1978-12-18 | 1978-12-18 | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| CH1283578 | 1978-12-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NL7909024A NL7909024A (en) | 1980-06-20 |
| NL193066B NL193066B (en) | 1998-05-06 |
| NL193066C true NL193066C (en) | 1998-09-08 |
Family
ID=4386824
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL7909024A NL193066C (en) | 1978-12-18 | 1979-12-14 | Methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydro pyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound. |
| NL990014C NL990014I1 (en) | 1978-12-18 | 1999-05-11 | Methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL990014C NL990014I1 (en) | 1978-12-18 | 1999-05-11 | Methyl, isopropyl-4- (2,1,3-benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutical composition containing this compound. |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5583783A (en) |
| AU (1) | AU536055B2 (en) |
| BE (1) | BE880591A (en) |
| CH (1) | CH639659A5 (en) |
| CY (1) | CY1321A (en) |
| DE (1) | DE2949491A1 (en) |
| FR (1) | FR2444681A1 (en) |
| GB (2) | GB2103203B (en) |
| HK (1) | HK16086A (en) |
| IE (1) | IE49496B1 (en) |
| IT (1) | IT1164097B (en) |
| KE (1) | KE3593A (en) |
| MY (1) | MY8500130A (en) |
| NL (2) | NL193066C (en) |
| NZ (1) | NZ192422A (en) |
| SE (1) | SE445219B (en) |
| SG (1) | SG97585G (en) |
| ZA (1) | ZA796842B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3022030A1 (en) * | 1980-06-12 | 1981-12-17 | Bayer Ag, 5090 Leverkusen | 4-THIAZOLE or 4-IMIDAZOLE-SUBSTITUTED, 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| CH655658B (en) * | 1980-09-18 | 1986-05-15 | ||
| EP0080220B1 (en) * | 1981-11-17 | 1986-02-19 | FISONS plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| ZA83959B (en) * | 1982-03-10 | 1984-09-26 | Sandoz Ltd | 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| US4414213A (en) * | 1982-03-22 | 1983-11-08 | Mead Johnson & Company | Dihydropyridyl cyclic imidate esters and their pharmaceutical use |
| FR2528431B1 (en) * | 1982-06-15 | 1986-01-10 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
| IL68975A (en) * | 1982-06-15 | 1987-01-30 | Sandoz Ag | 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid ester derivatives in optically active form,their preparation and pharmaceutical compositions containing them |
| JPS5978186A (en) * | 1982-10-27 | 1984-05-04 | Yoshitomi Pharmaceut Ind Ltd | 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative |
| US4794111A (en) * | 1984-05-23 | 1988-12-27 | Bayer Aktiengesellschaft | Dihydropyridine preparations containing β-blockers |
| HU198844B (en) * | 1984-06-14 | 1989-12-28 | Sandoz Ag | Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| HU197201B (en) * | 1985-10-01 | 1989-03-28 | Sandoz Ag | Process for producing oral pharmaceutical compositions of controlled solubility of the active components |
| DE3542794A1 (en) * | 1985-12-04 | 1987-06-11 | Bayer Ag | ANTI-HYPERTENSIVE COMBINATION PREPARATION |
| GB8626217D0 (en) * | 1986-11-03 | 1986-12-03 | Sandoz Ltd | Pharmaceutical compositions |
| US4816263A (en) * | 1987-10-02 | 1989-03-28 | Alza Corporation | Dosage form for treating cardiovascular diseases comprising isradipine |
| KR940003492B1 (en) * | 1988-10-27 | 1994-04-23 | 주식회사 유한양행 | Process for preparation of 1,4 dihydropyridine derivatives |
| DE4222770A1 (en) * | 1992-07-10 | 1994-01-13 | Bayer Ag | Light-activated 1- (2-nitrobenzyl) -substituted 1,4-dihydropyridines |
| IL163666A0 (en) | 2002-02-22 | 2005-12-18 | New River Pharmaceuticals Inc | Active agent delivery systems and methods for protecting and administering active agents |
| WO2005023787A1 (en) * | 2003-09-10 | 2005-03-17 | Shasun Chemicals And Drugs Limited | Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde |
| CN103613584B (en) * | 2013-11-27 | 2016-04-27 | 沈阳药科大学 | The method of a kind of Isrodipine synthetic product aftertreatment |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670824C3 (en) * | 1967-03-20 | 1978-08-03 | Bayer Ag, 5090 Leverkusen | 1,4-Dihydropyridine-33-dicarboxylic acid alkyl ester |
| FR2320750A1 (en) * | 1975-08-12 | 1977-03-11 | Hexachimie | 1,4-DIHYDRO PYRIDINES AND THEIR THERAPEUTIC APPLICATION |
| DE2616991A1 (en) * | 1976-04-17 | 1977-10-27 | Bayer Ag | Thio-substd. dihydro-pyridine derivs. - coronary vasodilators and antihypertensives prepd. e.g. by reacting dicarbonyl cpds. with amines and thio-substd. ketones |
| JPS5373327A (en) * | 1976-12-13 | 1978-06-29 | Matsushita Electric Ind Co Ltd | Power source system |
| DK149855C (en) * | 1977-06-20 | 1987-04-21 | Sandoz Ag | METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINE DERIVATIVES |
-
1978
- 1978-12-18 CH CH1283578A patent/CH639659A5/en not_active IP Right Cessation
-
1979
- 1979-12-08 DE DE19792949491 patent/DE2949491A1/en active Granted
- 1979-12-11 SE SE7910188A patent/SE445219B/en not_active IP Right Cessation
- 1979-12-13 BE BE1/9643A patent/BE880591A/en not_active IP Right Cessation
- 1979-12-14 IT IT51095/79A patent/IT1164097B/en active Protection Beyond IP Right Term
- 1979-12-14 GB GB08215988A patent/GB2103203B/en not_active Expired
- 1979-12-14 NL NL7909024A patent/NL193066C/en not_active IP Right Cessation
- 1979-12-14 CY CY1321A patent/CY1321A/en unknown
- 1979-12-14 GB GB7943113A patent/GB2037766B/en not_active Expired
- 1979-12-17 JP JP16396579A patent/JPS5583783A/en active Granted
- 1979-12-17 AU AU53896/79A patent/AU536055B2/en not_active Expired
- 1979-12-17 IE IE2445/79A patent/IE49496B1/en not_active IP Right Cessation
- 1979-12-17 FR FR7930829A patent/FR2444681A1/en active Granted
- 1979-12-17 NZ NZ192422A patent/NZ192422A/en unknown
- 1979-12-18 ZA ZA00796842A patent/ZA796842B/en unknown
-
1985
- 1985-12-20 SG SG975/85A patent/SG97585G/en unknown
- 1985-12-30 MY MY130/85A patent/MY8500130A/en unknown
-
1986
- 1986-01-08 KE KE3593A patent/KE3593A/en unknown
- 1986-03-06 HK HK160/86A patent/HK16086A/en not_active IP Right Cessation
-
1999
- 1999-05-11 NL NL990014C patent/NL990014I1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE49496B1 (en) | 1985-10-16 |
| AU5389679A (en) | 1980-06-26 |
| IT7951095A0 (en) | 1979-12-14 |
| GB2103203A (en) | 1983-02-16 |
| IT1164097B (en) | 1987-04-08 |
| GB2037766A (en) | 1980-07-16 |
| JPS5583783A (en) | 1980-06-24 |
| CH639659A5 (en) | 1983-11-30 |
| SG97585G (en) | 1986-07-18 |
| NZ192422A (en) | 1982-09-14 |
| ZA796842B (en) | 1981-07-29 |
| DE2949491A1 (en) | 1980-06-26 |
| FR2444681B1 (en) | 1982-10-29 |
| NL7909024A (en) | 1980-06-20 |
| SE445219B (en) | 1986-06-09 |
| BE880591A (en) | 1980-06-13 |
| DE2949491C2 (en) | 1988-10-27 |
| CY1321A (en) | 1986-06-27 |
| GB2103203B (en) | 1983-06-08 |
| GB2037766B (en) | 1983-02-16 |
| SE7910188L (en) | 1980-06-19 |
| KE3593A (en) | 1986-02-07 |
| NL193066B (en) | 1998-05-06 |
| FR2444681A1 (en) | 1980-07-18 |
| NL990014I1 (en) | 1999-07-01 |
| JPH0369910B2 (en) | 1991-11-05 |
| HK16086A (en) | 1986-03-14 |
| MY8500130A (en) | 1985-12-31 |
| AU536055B2 (en) | 1984-04-19 |
| IE792445L (en) | 1980-06-18 |
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