DK149855B - METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINE DERIVATIVES - Google Patents
METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINE DERIVATIVES Download PDFInfo
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Description
Den foreliggende opfindelse angår en analogifremgangsmåde til frem stilling af 1,4-dihydropyridinderivater.The present invention relates to an analogous process for the preparation of 1,4-dihydropyridine derivatives.
149855149855
De ved fremgangsmåden ifølge den foreliggende opfindelse fremstilledeThey are prepared by the process of the present invention
1,4-dihydropyridinderivater er sådanne med den almene formel I1,4-dihydropyridine derivatives are those of the general formula I
R6 Κγ\ 5 KA/ ' / .COR3 y f "v R1 hvor R1 betegner hydrogen eller alkyl med 1-6 carbonatomer, R2 og R5 uafhængigt af hinanden betegner alkyl med 1-6 carbonatomer, R3 og Rft uafhængigt af hinanden betegner alkyl med 1-6 carbonatomer eller alkoxy med 1-6 carbonatomer, Rs betegner hydrogen, halogen 10 eller alkyl eller alkoxy, hver med 1-4 carbonatomer, og X betegner oxygen eller svovl.R6 represents R1 or hydrogen where R 1 represents hydrogen or alkyl of 1-6 carbon atoms, R2 and R5 independently represent alkyl of 1-6 carbon atoms, R3 and Rft independently represent alkyl of 1 -6 carbon atoms or alkoxy of 1-6 carbon atoms, R 5 represents hydrogen, halogen or alkyl or alkoxy, each having 1-4 carbon atoms, and X represents oxygen or sulfur.
Enhver af de ovenfor nævnte alkylgrupper med 1-6 carbonatomer har fortrinsvis 1-4 carbonatomer, især 1 eller 2 carbonatomer. Enhver al kyl- eller alkoxygruppe med 1-4 carbonatomer indeholder fortrinsvis 15 1 eller 2 carbonatomer. Halogen betegner flour, chlor eller brom og betegner især chlor. Når R3 og/eller Ra betegner alkoxy med 1-6 carbonatomer, betegner disse fortrinsvis ethoxy eller methoxy. R1 betegner fortrinsvis hydrogen. R2 er hensigtsmæssigt identisk med R5. R2 og/eller Rs er fortrinsvis methyl. R3 og/eller Rfc betegner 20 fortrinsvis alkoxy. R6 er især hydrogen. R6 er hensigtsmæssigt nabostillet til dihydropyridingruppen, som igen hensigtsmæssigt sidder i 4-stillingen.Any of the above-mentioned alkyl groups having 1-6 carbon atoms preferably have 1-4 carbon atoms, especially 1 or 2 carbon atoms. Any alkyl or alkoxy group having 1-4 carbon atoms preferably contains 1 or 2 carbon atoms. Halogen represents fluorine, chlorine or bromine and in particular represents chlorine. When R 3 and / or Ra represent alkoxy of 1-6 carbon atoms, they preferably represent ethoxy or methoxy. Preferably R1 represents hydrogen. R2 is suitably identical to R5. R 2 and / or R 5 are preferably methyl. R3 and / or Rfc preferably represent alkoxy. R6 is especially hydrogen. R6 is suitably adjacent to the dihydropyridine group, which in turn is suitably seated in the 4-position.
149855 2149855 2
Fremgangsmåden ifølge den foreliggende opfindelse III fremstilling af forbindelser med den ovenfor anførte almene formel I er ejendommelig ved, at gruppen -HC=Y i en forbindelse med den almene formel IIThe process of the present invention III preparation of compounds of the above general formula I is characterized in that the group -HC = Y in a compound of the general formula II
W\ h<£y 5 hvor R6 og X har den ovenfor angivne betydning, og -HC=Y betegner i) formyl, ii) en gruppe med den almene formel -HC=C-C(=Z)R2, eller COR3 10 iii) en gruppe med den almene formel COR3 ^Ht-C(=Z)R2 -HC^ ^^HC-C(=Z')R5 I t 15 COR*Where R6 and X have the meaning given above and -HC = Y represents i) formyl, ii) a group of the general formula -HC = CC (= Z) R2, or COR3 iii) a group of the general formula COR3 ^ Ht-C (= Z) R2 -HC ^^ HC-C (= Z ') R5 I t COR *
hvor Z og Z' betegner oxygen, eller den ene af Z og Z' betegner oxygen, og den anden betegner NR1, og R1-Rs har den ovenfor angivne betydning, ved en reaktion af Hantzsch-typen og ved omsætning med én eller flere forbindelser med den almene formel IV og/eller 20 V og/eller VI og/eller VIIwherein Z and Z 'represent oxygen, or one of Z and Z' represents oxygen, and the other represents NR 1, and R 1 -R 5 is as defined above, by a Hantzsch-type reaction and by reaction with one or more compounds with the general formula IV and / or 20 V and / or VI and / or VII
rsco-ch2-co-r* IVrsco-ch2-co-r * IV
H^R1 VH ^ R1 V
Rs-C(NH-R1)=CH-CO-R* VIRs-C (NH-R1) = CH-CO-R * VI
R2-C(NH-Rx)=CH-CO-R3 VIIR2-C (NH-Rx) = CH-CO-R3 VII
149855 3149855 3
hvor F^-R5 har den ovenfor angivne betydning, omdannes til en gruppe med den almene formel IIIwherein F 1 -R 5 has the meaning given above is converted to a group of general formula III
r4°c'v^sv/ cor3 *5 AA2r4 ° c'v ^ sv / cor3 * 5 AA2
Ri hvor Rl-R5 har den ovenfor angivne betydning.R 1 where R 1 -R 5 has the meaning given above.
5 Som beskrevet ovenfor udføres fremgangsmåden ifølge opfindelsen på konventionel måde for analoge dihydropyridinsynteser, nemlig ved fremgangsmåden efter Hantzsch, jfr. A. Hantzsch, Ann. 215, 1, s. 72 (1882); Ber. 18, s. 1744 (1885); Ber. 19, s. 289 (1886). Som anført i The Merck Index. 10. udgave, s. ONR-39, Merck & Co., Rahway, 10 foregår syntese af 1,4-dihydropyridiner ifølge Hantzsch fx ved, at to mol af en β-dicarbonylforbindelse kondenseres med ét mol af et aldehyd i nærværelse af ammoniak i overensstemmelse med følgende reaktionsskema: CH, I 3As described above, the process of the invention is carried out in a conventional manner for analogous dihydropyridine syntheses, namely by the method of Hantzsch, cf. A. Hantzsch, Ann. 215, 1, pp. 72 (1882); Ber. 18, pp. 1744 (1885); Ber. 19, pp. 289 (1886). As stated in The Merck Index. 10th Edition, p. ONR-39, Merck & Co., Rahway, 10 Synthesis of 1,4-dihydropyridines according to Hantzsch, for example, by condensing two moles of a β-dicarbonyl compound with one mole of an aldehyde in the presence of ammonia according to the following reaction scheme: CH, I 3
CH3 jPCH3 jP
CK + fH2C00Et __ Etooc-c CHqCOOEtCK + fH2C00Et __ Etooc-c CHqCOOEt
Ar I * I + I * O C0CH3 CH3CO COCHg CH- CH EtOOCN^>C,COOEt __ EtOOC-CH CHCOOEt | li CHgCO COCHj -* ®3 4 U98B5Ar I * I + I * O C0CH3 CH3CO COCHg CH- CH EtOOCN ^> C, COOEt __ EtOOC-CH CHCOOEt | li CHgCO COCHj - * ®3 4 U98B5
Når gruppen -HC=Y er formyl, og når det er ønskeligt at fremstille en forbindelse med den almene formel I, hvor R2 er identisk med R5, og R3 er identisk med R4, er det hensigtsmæssigt at omsætte en forbindelse med den almene formel II med en forbindelse med den 5 almene formel IVWhen the group -HC = Y is formyl and when it is desirable to prepare a compound of general formula I wherein R2 is identical to R5 and R3 is identical to R4, it is convenient to react with a compound of general formula II with a compound of the general formula IV
rsco-ch2-co-r4 IVrsco-ch2-co-r4 IV
hvor R4 og R5 har den ovenfor angivne betydning, i nærværelse af en forbindelse med den almene formel Vwherein R4 and R5 are as defined above, in the presence of a compound of general formula V
h^NR1 Vh ^ NR1 V
10 hvor R1 har den ovenfor angivne betydning.10 wherein R1 has the meaning given above.
Fortrinsvis er der mindst 2 mol til stede af forbindelsen med den almene formel IV pr. mol af forbindelsen med den almene formel II. Alternativt kan en forbindelse med den almene formel II omsættes med en forbindelse med den almene formel VIPreferably, at least 2 moles of the compound of general formula IV are present. moles of the compound of general formula II. Alternatively, a compound of general formula II may be reacted with a compound of general formula VI
15 R5-C(NH-Rx)=CH-CO-R4 VIR5-C (NH-Rx) = CH-CO-R4 VI
hvor R1, R4 og R5 har den ovenfor angivne betydning.wherein R1, R4 and R5 have the meaning given above.
Fortrinsvis er der mindst to mol til stede af en forbindelse med den almene formel VI pr. mol af en forbindelse med den almene formel II.Preferably, at least two moles of a compound of the general formula VI are present. moles of a compound of general formula II.
R1 betegner også fortrinsvis hydrogen.R 1 also preferably represents hydrogen.
20 Når gruppen -HC=Y er formyl og fortrinsvis, når det er ønsket at fremstille en forbindelse med den almene formel I, hvor R2 er forskellig fra R5, og/elfer R3 er forskellig fra R4, er det også muligt at omsætte en sådan forbindelse med den almene formel ΙΓ 25 τί HC=0 149855 5When the group -HC = Y is formyl and preferably when it is desired to prepare a compound of general formula I wherein R 2 is different from R 5 and / or R 3 is different from R 4, it is also possible to react such a compound with the general formula ΙΓ 25 τί HC = 0 149855 5
med en forbindelse med den almene formel IV og en forbindelse med den almene formel VIIwith a compound of general formula IV and a compound of general formula VII
R2-C(NH-R1)=CH-CO-R3 VIIR2-C (NH-R1) = CH-CO-R3 VII
hvor R2, R1 og R3 har den ovenfor angivne betydning.wherein R 2, R 1 and R 3 have the meaning given above.
5 Det vil forstis, at en forbindelse med den almene formel VI kan dannes som et mellemprodukt under reaktionen mellem en forbindelse med den almene formel IV og en forbindelse med den almene formel V.It will be appreciated that a compound of the general formula VI can be formed as an intermediate in the reaction between a compound of the general formula IV and a compound of the general formula V.
En forbindelse med den almene formel II, hvor -HC=Y er en gruppe ii) eller iii), kan dannes som et mellemprodukt af de ovenfor anførte 10 reaktioner. De kan imidlertid fremstilles ved andre fremgangsmåder.A compound of general formula II wherein -HC = Y is a group ii) or iii) can be formed as an intermediate of the above reactions. However, they can be prepared by other methods.
Alternativt eller især til fremstilling af en forbindelse med den almene formel I, hvor R2 er forskellig fra R5, og/eller R3 er forskellig fra R1*, er det hensigtsmæssigt at omsætte en forbindelse med den almene formel II, hvor gruppen -HC=Y er en gruppe ii), med en forbindelse 15 med den almene formel IV eller VI, og hvor det er hensigtsmæssigt med en forbindelse med den almene formel V. En forbindelse med den almene formel II, hvor gruppen -HC=Y er en gruppe iii), kan være et mellemprodukt.Alternatively or in particular to prepare a compound of general formula I wherein R 2 is different from R 5 and / or R 3 is different from R 1, it is convenient to react with a compound of general formula II wherein the group -HC = Y is a group ii), with a compound of general formula IV or VI, and where appropriate a compound of general formula V. A compound of general formula II wherein the group -HC = Y is a group iii ) can be an intermediate.
I de ovenfor anførte reaktioner er det i visse tilfælde muligt, når R2, 20 R3, R" og R5 ikke er identiske, at der fremstilles mere end én isomer af den almene formel I. Hvis dette er tilfældet, kan disse adskilles på konventionel måde, fx ved tyndtlagschromatografi.In the above reactions, in some cases, when R 2, R 20, R 3 and R 5 are not identical, more than one isomer of the general formula I is prepared, if this is the case, they can be separated in conventional manner. , for example, by thin layer chromatography.
Når udgangsmaterialet er en forbindelse med den almene formel II, hvor -HC=Y er en gruppe iii), er reaktionen en ringslutning. Når Z 25 og Z' begge betegner oxygen, så skal der være en amin med den almene formel V til stede.When the starting material is a compound of general formula II wherein -HC = Y is a group iii), the reaction is a cyclization. When Z 25 and Z 'both represent oxygen, then an amine of the general formula V must be present.
Alle de ovenfor nævnte reaktioner kan imidlertid udføres under de samme betingelser.However, all of the above reactions can be carried out under the same conditions.
6 1488556 148855
Reaktionen kan hensigtsmæssigt udføres i opløsning. Et egnet opløsningsmiddel er vand, ethanol, dioxan, dimethylformamid, dimethyl-sulfoxid, pyridin eller iseddike. Egnede reaktionstemperaturer kan være fra 20 til 160°C, fortrinsvis fra 60 til 120°C.The reaction may conveniently be carried out in solution. A suitable solvent is water, ethanol, dioxane, dimethylformamide, dimethylsulfoxide, pyridine or glacial acetic acid. Suitable reaction temperatures can be from 20 to 160 ° C, preferably from 60 to 120 ° C.
5 For så vidt fremstillingen af udgangsmaterialerne ikke specielt er beskrevet, er disse forbindelser kendte eller kan fremstilles analogt med kendte forbindelser.As far as the preparation of the starting materials is not specifically described, these compounds are known or can be prepared analogously to known compounds.
Fremgangsmåden ifølge den foreliggende opfindelse belyses nærmere ved følgende eksempler, hvor temperaturangivelserne er ukorrigerede.The process of the present invention is further illustrated by the following examples, wherein the temperature indications are uncorrected.
10 EKSEMPEL 1 4- C2,1,3-Benzoxadiazol-4-yI) -2,6-dimethyl-l ,4-dihydropyridin-3,5-di-carboxylsyrediethylester.Example 1 4- C2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
3,2 g 2,l,3-benzoxadiazol-4-aldehyd, 5,7 g acetoeddikesyreethylester, 2,5 ml koncentreret ammoniak og 10 ml ethanol tilbagesvales i 6 timer.3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acid ethyl ester, 2.5 ml of concentrated ammonia and 10 ml of ethanol are refluxed for 6 hours.
15 Blandingen inddampes derpå, og den som remanens vundne olie chro-matograferes på silicagel med chloroform/ethylacetat (9:1) til dannelse af titelforbindeisen. Produktet omkrystalliseres af toluen, smeltepunkt 153-155°C.The mixture is then evaporated and the oil recovered as the residue is chromatographed on silica gel with chloroform / ethyl acetate (9: 1) to give the title compound ice. The product is recrystallized from toluene, mp 153-155 ° C.
Under anvendelse af samme fremgangsmåde som beskrevet i eksempel 1 20 og ud fra tilsvarende udgangsforbindelser, fx en forbindelse med den almene formel II, hvor -HC=Y er en gruppe i) og forbindelser med den almene formel IV og V, og for eksemplerne 12 og 13 en forbindelse med den almene formel. II, hvor -HC=Y er en gruppe ii), hvor Z betegner oxygen, og en forbindelse med den almene formel VI, kan 25 fremstilles de nedenfor stående forbindelser med den almene formel I, hvor n betegner dihydropyridingruppens stilling: 149855 7Using the same procedure as described in Example 1 20 and from corresponding starting compounds, for example, a compound of general formula II wherein -HC = Y is a group i) and compounds of general formulas IV and V, and for Examples 12 and 13 a compound of the general formula. II where -HC = Y is a group ii) where Z represents oxygen and a compound of general formula VI, the following compounds of general formula I may be prepared, where n represents the position of the dihydropyridine group:
Eks. R1 R2 R3 R* Rs R6 X n SmeltepunktEx. R1 R2 R3 R * Rs R6 X n Melting point
nr. °CNo. ° C
2 H CH3 OC2H5 OC2H5 CH3 H S 4 146-148 5 3 H CH3 OC(CH3)3 OC(CH3)3 CH3 H S 4 193-199 4 H CH3 OCH3 OCH3 CH3 7-CI O 4 207-211 5 H CH3 OCH3 OCH3 CH3 H S 4 215-216 6 H CH3 OC2H5 OC2H5 CH3 5-OCHg S 4 201-203 7 H CH3 OC2H5 OC2H5 CH3 7-CI S 4 135-155 10 8 H CH3 OC2H5 OC2H5 CH3 H S 5 152-153 9 H CH3 OC2H5 OC2H5 CH3 4-CI S 5 198-200 10 H CH3 CH3 CH3 CH3 H S 4 128,5-130 11 H CH3 CH3 CH3 CH3 H 0 4 218-222 12 H CH3 CH3 CH3 CH3 H 0 4 186-188 15 13 H CH3 CH3 OC2H5 CH3 H S 4 146-1482 H CH3 OC2H5 OC2H5 CH3 HS 4 146-148 5 3 H CH3 OC (CH3) 3 OC (CH3) 3 CH3 HS 4 193-199 4 H CH3 OCH3 OCH3 CH3 7-CI O 4 207-211 5 H CH3 OCH3 OCH3 CH3 HS 4 215-216 6 H CH3 OC2H5 OC2H5 CH3 5-OCHg S 4 201-203 7 H CH3 OC2H5 OC2H5 CH3 7-CI S 4 135-155 10 8 H CH3 OC2H5 OC2H5 CH3 HS 5 152-153 9 H CH3 OC2H5 OC2H5 CH3 4-CI S 5 198-200 10 H CH3 CH3 CH3 CH3 HS 4 128.5-130 11 H CH3 CH3 CH3 CH3 H 0 4 218-222 12 H CH3 CH3 CH3 CH3 H 0 4 186-188 15 13 H CH3 CH3 OC2H5 CH3 HS 4 146-148
Forbindelserne med den almene formel I udviser farmakologisk aktivitet. De fører især til en dilatering af coronarkarrene, som det påvises med resultaterne af tests til måling af blood-flowet til myo-20 cardium på en anæstetiseret kat ved "microsphere"-metoden efter administration af det aktive stof intravenøst eller intradermalt. Forbindelserne med den almene formel I har også en gunstig effekt mod angina pectoris, som det vises ved forøgelsen af coronarflowet i en anæstetiseret kat efter administration af det aktive stof. Nedenstående 25 tabel viser ændringer af blodtryk samt aorta- og coronarblodstrøm i anæstetiserede katte ved indgivelse af repræsentative forbindelser med den almene formel I: Ændring af blodtryk, aorta- og coronarblodstrøm i % ± 5%The compounds of general formula I exhibit pharmacological activity. In particular, they lead to dilation of the coronary vessels, as demonstrated by the results of tests to measure the blood flow to myo-20 cardium on an anesthetized cat by the "microsphere" method after administration of the active substance intravenously or intradermally. The compounds of general formula I also have a beneficial effect against angina pectoris, as shown by the increase of coronary flow in an anesthetized cat after administration of the active substance. The following table shows changes in blood pressure as well as aortic and coronary blood flow in anesthetized cats by administration of representative compounds of general formula I: Change in blood pressure, aortic and coronary blood flow in% ± 5%
Eksempel Blodtryk Aortablod- Coronar- Dosis i yg/kg 30 nr. strøm* blodstrøm* -30 20 30 43 2 -20 10 20 ' 43 U9855Example Blood pressure Aortic blood Coronary Dose in yg / kg 30 no. Flow * blood flow * -30 20 30 43 2 -20 10 20 '43 U9855
Eksempel Blodtryk Aortablod- Coronar- Dosis i yg/kg nr. strøm* blodstrøm* 5 -10 10 10 43 5 9 -10 10 10 40 10 -10 10 10 43 12 -20 20 20 43 * Bestemt ved hjælp af mi krosf æremetoden ifølge A.M. Rudolf og 10 M.A. Heymann, Circulation Research, 21, s. 163-184 (1967, modificeret af R.P. Hof, F. Wyler og G. Stalder, Basic. res.Example Blood pressure Aortic blood Coronary Dose in yg / kg no current * blood flow * 5 -10 10 10 43 5 9 -10 10 10 40 10 -10 10 10 43 12 -20 20 20 43 * Determined by means of the cross-venous method according to AM Rudolf and 10 M.A. Heymann, Circulation Research, 21, pp. 163-184 (1967, modified by R. P. Hof, F. Wyler and G. Stalder, Basic Res.
Cardiol. 75, s. 747-756 (1980).Cardiol. 75, pp. 747-756 (1980).
Forbindelserne med den almene formel I er derfor indicerede til anvendelse ved behandlingen af coronarinsufficiens. Til denne anven-15 delse er en given daglig dosis på fra ca. 5 til 100 mg, hensigtsmæssigt administreret i delte doser to til fire gange daglig i enhedsdosisformer, som indeholder ca. 1,25 til ca. 50 mg, eller i retardform.The compounds of general formula I are therefore indicated for use in the treatment of coronary insufficiency. For this use, a given daily dose of from ca. 5 to 100 mg, conveniently administered in divided doses two to four times daily in unit dosage forms containing ca. 1.25 to approx. 50 mg, or in retard form.
Endvidere besidder forbindelserne med den almene formel I antihyper-tensiv virkning, som det indiceres i standardtests, fx ved Grollman-20 rottetesten [se A. Grollman, Proc. Soc. Expt. Biol. og Med. 57, 104 (1944)] ved subcutan administration af fra 0,1 til 10 mg/kg af dyrets legemsvægt af forbindelserne.Furthermore, the compounds of the general Formula I possess antihypertensive activity as indicated in standard tests, for example, in the Grollman 20 rat test [see A. Grollman, Proc. Soc. Expt. Biol. and with. 57, 104 (1944)] by subcutaneous administration of from 0.1 to 10 mg / kg of the animal body weight of the compounds.
Forbindelserne er derfor endvidere indiceret til anvendelse som anti-hypertensive midler. Til denne anvendelse er en daglig dosis på fra 25 ca. 5 til ca. 1000 mg indiceret, hensigtsmæssigt administreret i delte doser 2-4 gange daglig i enhedsdosisformer, som indeholder fra ca.Therefore, the compounds are also indicated for use as antihypertensive agents. For this use, a daily dose of about 25 5 to approx. 1000 mg indicated, conveniently administered in divided doses 2-4 times daily in unit dosage forms containing from ca.
1,25 mg til ca. 500 mg, eller i retardform.1.25 mg to approx. 500 mg, or in retard form.
Forbindelserne med den almene formel I kan administreres i form af et farmaceutisk præparat. Sådanne præparater kan fremstilles ved kon-30 ventionelle teknikker i konventionelle former, fx kapsler eller tabletter.The compounds of general formula I may be administered in the form of a pharmaceutical composition. Such compositions may be prepared by conventional techniques in conventional forms, e.g., capsules or tablets.
Claims (2)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH752077 | 1977-06-20 | ||
| CH752077 | 1977-06-20 | ||
| CH286578 | 1978-03-16 | ||
| CH286578 | 1978-03-16 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK262578A DK262578A (en) | 1978-12-21 |
| DK149855B true DK149855B (en) | 1986-10-13 |
| DK149855C DK149855C (en) | 1987-04-21 |
Family
ID=25691589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK262578A DK149855C (en) | 1977-06-20 | 1978-06-12 | METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINE DERIVATIVES |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0000150B1 (en) |
| JP (1) | JPS54103876A (en) |
| AT (1) | AT376220B (en) |
| AU (1) | AU524000B2 (en) |
| CA (1) | CA1105463A (en) |
| CY (1) | CY1239A (en) |
| DE (1) | DE2860708D1 (en) |
| DK (1) | DK149855C (en) |
| ES (1) | ES470917A1 (en) |
| FI (1) | FI64938C (en) |
| HK (1) | HK65184A (en) |
| IE (1) | IE47212B1 (en) |
| IL (1) | IL54948A (en) |
| IT (1) | IT1105364B (en) |
| LU (1) | LU88342I2 (en) |
| MY (1) | MY8500041A (en) |
| NL (1) | NL930126I2 (en) |
| NZ (1) | NZ187617A (en) |
| PT (1) | PT68191A (en) |
| SG (1) | SG20584G (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH639659A5 (en) * | 1978-12-18 | 1983-11-30 | Sandoz Ag | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| FI793848A (en) * | 1978-12-18 | 1980-06-19 | Sandoz Ag | BENZOXADIAZOLER OCH BENZOTHIADIAZOLER DERAS FRAMSTAELLNING OCH PHARMACEUTICAL COMPOSITION INNEHAOLLANDE DESSA |
| BE886259A (en) * | 1979-11-23 | 1981-05-20 | Sandoz Sa | NOVEL DRUGS BASED ON 1,4-DIHYDROPYRIDINE DERIVATIVES FOR THE TREATMENT OF CEREBROVASCULAR DEFICIENCY OR WITH SPAMOLYTIC ACTION |
| CH655658B (en) * | 1980-09-18 | 1986-05-15 | ||
| FI813460L (en) * | 1980-11-10 | 1982-05-11 | Sandoz Ag | NYA 4- (2,1,3-BENZOXADIAZOL-4-YL) -1,4-DIHYDRO-PYRIDIN DERIVATIVES DERAS FRAMSTAELLNINGSFOERFARANDE OCH DESSA INNEHAOLLANDE PHARMACEUTICAL COMPOSITION |
| DE3269219D1 (en) * | 1981-11-17 | 1986-03-27 | Fisons Plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| DE3207982A1 (en) * | 1982-03-05 | 1983-09-08 | Bayer Ag, 5090 Leverkusen | NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS |
| ZA83959B (en) * | 1982-03-10 | 1984-09-26 | Sandoz Ltd | 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| DE3208628A1 (en) * | 1982-03-10 | 1983-09-22 | Bayer Ag, 5090 Leverkusen | NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| FR2528431B1 (en) * | 1982-06-15 | 1986-01-10 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
| FR2554109A1 (en) * | 1983-11-01 | 1985-05-03 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS AS MEDICAMENTS |
| IE57810B1 (en) * | 1984-03-27 | 1993-04-21 | Delagrange Lab | 1,4-dihydropyridine derivatives,their preparation and their use |
| HU198844B (en) * | 1984-06-14 | 1989-12-28 | Sandoz Ag | Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient |
| GB8428552D0 (en) * | 1984-11-12 | 1984-12-19 | Sandoz Ltd | Organic compounds |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| GB8616047D0 (en) * | 1986-07-01 | 1986-08-06 | Sandoz Ltd | A 1 4-dihydropyridine derivatives |
| KR20040088519A (en) | 2002-02-22 | 2004-10-16 | 뉴 리버 파마슈티칼스, 인크. | Active Agent Delivery Systems and Methods for Protecting and Administering Active Agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
-
1978
- 1978-06-12 FI FI781867A patent/FI64938C/en not_active IP Right Cessation
- 1978-06-12 DK DK262578A patent/DK149855C/en not_active IP Right Cessation
- 1978-06-15 CY CY1239A patent/CY1239A/en unknown
- 1978-06-15 EP EP78100165A patent/EP0000150B1/en not_active Expired
- 1978-06-15 DE DE7878100165T patent/DE2860708D1/en not_active Expired
- 1978-06-19 ES ES470917A patent/ES470917A1/en not_active Expired
- 1978-06-19 IE IE1231/78A patent/IE47212B1/en not_active IP Right Cessation
- 1978-06-19 AU AU37252/78A patent/AU524000B2/en not_active Expired
- 1978-06-19 IT IT49939/78A patent/IT1105364B/en active Protection Beyond IP Right Term
- 1978-06-19 CA CA305,727A patent/CA1105463A/en not_active Expired
- 1978-06-19 JP JP7332778A patent/JPS54103876A/en active Granted
- 1978-06-19 IL IL54948A patent/IL54948A/en unknown
- 1978-06-19 AT AT0443178A patent/AT376220B/en not_active IP Right Cessation
- 1978-06-19 PT PT68191A patent/PT68191A/en unknown
- 1978-06-19 NZ NZ187617A patent/NZ187617A/en unknown
-
1984
- 1984-03-05 SG SG205/84A patent/SG20584G/en unknown
- 1984-08-23 HK HK651/84A patent/HK65184A/en not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY41/85A patent/MY8500041A/en unknown
-
1993
- 1993-06-30 LU LU88342C patent/LU88342I2/en unknown
- 1993-07-01 NL NL930126C patent/NL930126I2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU3725278A (en) | 1980-01-03 |
| FI781867A (en) | 1978-12-21 |
| ATA443178A (en) | 1984-03-15 |
| LU88342I2 (en) | 1994-05-04 |
| IL54948A0 (en) | 1978-08-31 |
| EP0000150A1 (en) | 1979-01-10 |
| CY1239A (en) | 1984-06-29 |
| IE781231L (en) | 1978-12-20 |
| PT68191A (en) | 1978-07-01 |
| JPS54103876A (en) | 1979-08-15 |
| IT7849939A0 (en) | 1978-06-19 |
| FI64938B (en) | 1983-10-31 |
| AT376220B (en) | 1984-10-25 |
| FI64938C (en) | 1984-02-10 |
| CA1105463A (en) | 1981-07-21 |
| HK65184A (en) | 1984-08-31 |
| MY8500041A (en) | 1985-12-31 |
| SG20584G (en) | 1985-03-08 |
| NL930126I1 (en) | 1993-11-01 |
| DE2860708D1 (en) | 1981-08-27 |
| DK262578A (en) | 1978-12-21 |
| NL930126I2 (en) | 1995-02-16 |
| IE47212B1 (en) | 1984-01-25 |
| NZ187617A (en) | 1980-12-19 |
| AU524000B2 (en) | 1982-08-26 |
| IT1105364B (en) | 1985-10-28 |
| EP0000150B1 (en) | 1981-05-20 |
| DK149855C (en) | 1987-04-21 |
| JPS6360755B2 (en) | 1988-11-25 |
| IL54948A (en) | 1982-01-31 |
| ES470917A1 (en) | 1979-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1993 00031, 930624 |
|
| CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1993 00031, 930624 |
|
| PUP | Patent expired |