CA1136631A - 1,4-dihydropyridine compounds, their production and their medicinal use - Google Patents
1,4-dihydropyridine compounds, their production and their medicinal useInfo
- Publication number
- CA1136631A CA1136631A CA000379456A CA379456A CA1136631A CA 1136631 A CA1136631 A CA 1136631A CA 000379456 A CA000379456 A CA 000379456A CA 379456 A CA379456 A CA 379456A CA 1136631 A CA1136631 A CA 1136631A
- Authority
- CA
- Canada
- Prior art keywords
- ester
- process according
- dimethyl
- methyl
- acetoacetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
-
- 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
-
- 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
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to 1,4-dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in the 4-position. Also included in the invention are methods for the preparation of said compounds. The invention further relates to compositions containing said 1,4-dihydropyridines and the use of said compounds and compositions for their circulation influencing effects.
The invention relates to 1,4-dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in the 4-position. Also included in the invention are methods for the preparation of said compounds. The invention further relates to compositions containing said 1,4-dihydropyridines and the use of said compounds and compositions for their circulation influencing effects.
Description
3~
.The prese.nt invention reIates to ce.rtain new l,4-dihydropyridine. compounds,. to.proces.ses~ for their production and to their use as medicaments for influencing the. circulati.on.
It is already known that 1,4-dihydropyridine .derivatives have.circulati.on-influencing properties. Thus for examp.le,.2,.6-dime.thyl-4-(2'-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarbo.xylic ac.id dime.thyl e.ster, a compound known under the Trade Mark "Nifedipin", (see German Patent Specification 1,607,827) is known as a compound which has a coronary-vasodilating act.i:on.
According to the pre.sent invention we provide compounds which are 1,4-dihydropyr.idines. of the general formula R4 , R3 CH (I) R202C ~ C02R
or a salt thereof, H
in which Rl and R2 are ide.ntical or different and denote a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, R3 denotes a hydrogen atom, a methyl group or a phenyl radical and R4 represe.nts a phenyl or phenoxy radical, which optionally carry 1 or more substituents selected from nitro, halogen, methyl and methoxy.
1,4-Dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in the 4-position have not previously been described.
The compounds of the present invention possess 3 circulation-influencing properties, and in particular dilate .
... ..
Le A 20 954 ii3'~
.
..t.he: coronary ves.seIs and lower. the:b.Iood pressure.
Ac.cording to the pres:ent invention we.further provide a p.rocess for the production of compounds of the inventi.on in which a) an aldehyde of the general formula CH /
C (II) H / ~ O
in which R3 and R4 have. the abo.vementio.ned meaning, is reacted with ammonia and an acetoac.etic acid ester of the general formula O O
1~ tl CH3-c-cH2-c-oR (III) in which l has the abovementioned meaning, in an orga~ic solvent, b) an aldehyde of general formula (II), as defined above, is reacted with an enamino-ester of the general formula CH3-C CH-COORl (IV) in which Rl has the abovementioned meaning, in an organic solvent, or c) an ylidene compound of the general formula R3 cooR2 CH-CH=C ( ) in which R2, R3 and R4 have the ab.ovementioned meanings, Le- A 20 954 1~3Çi63~L
.is reac.t.ed with'an enamino-es.ter' of the ge.neral formula (IV), as defined ab.o.ve, in an organic so.lven.t..
The organic solvent used' can be an alcohol, dioxane, glacial acetic acid,. ethyl acetate, dimethylform-amide or ac.e.tonitrile. The re.act.ion temperatures can bevaried.over a wlde range, p.referabIy b.etween 20C and 150C.
More.prefer.ably,. t.he re.action is carried out.at the boiling .point. of. the solvent..
The starting materials which can be: us.ed are mostly known comp.ounds, or can be prepared in accordance with.known proces.ses.
As examples of aldehy.des..of. the formula (II) there may be mentioned: 2-(3-methoxyphenyl)-propionaldehyde,
.The prese.nt invention reIates to ce.rtain new l,4-dihydropyridine. compounds,. to.proces.ses~ for their production and to their use as medicaments for influencing the. circulati.on.
It is already known that 1,4-dihydropyridine .derivatives have.circulati.on-influencing properties. Thus for examp.le,.2,.6-dime.thyl-4-(2'-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarbo.xylic ac.id dime.thyl e.ster, a compound known under the Trade Mark "Nifedipin", (see German Patent Specification 1,607,827) is known as a compound which has a coronary-vasodilating act.i:on.
According to the pre.sent invention we provide compounds which are 1,4-dihydropyr.idines. of the general formula R4 , R3 CH (I) R202C ~ C02R
or a salt thereof, H
in which Rl and R2 are ide.ntical or different and denote a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, R3 denotes a hydrogen atom, a methyl group or a phenyl radical and R4 represe.nts a phenyl or phenoxy radical, which optionally carry 1 or more substituents selected from nitro, halogen, methyl and methoxy.
1,4-Dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in the 4-position have not previously been described.
The compounds of the present invention possess 3 circulation-influencing properties, and in particular dilate .
... ..
Le A 20 954 ii3'~
.
..t.he: coronary ves.seIs and lower. the:b.Iood pressure.
Ac.cording to the pres:ent invention we.further provide a p.rocess for the production of compounds of the inventi.on in which a) an aldehyde of the general formula CH /
C (II) H / ~ O
in which R3 and R4 have. the abo.vementio.ned meaning, is reacted with ammonia and an acetoac.etic acid ester of the general formula O O
1~ tl CH3-c-cH2-c-oR (III) in which l has the abovementioned meaning, in an orga~ic solvent, b) an aldehyde of general formula (II), as defined above, is reacted with an enamino-ester of the general formula CH3-C CH-COORl (IV) in which Rl has the abovementioned meaning, in an organic solvent, or c) an ylidene compound of the general formula R3 cooR2 CH-CH=C ( ) in which R2, R3 and R4 have the ab.ovementioned meanings, Le- A 20 954 1~3Çi63~L
.is reac.t.ed with'an enamino-es.ter' of the ge.neral formula (IV), as defined ab.o.ve, in an organic so.lven.t..
The organic solvent used' can be an alcohol, dioxane, glacial acetic acid,. ethyl acetate, dimethylform-amide or ac.e.tonitrile. The re.act.ion temperatures can bevaried.over a wlde range, p.referabIy b.etween 20C and 150C.
More.prefer.ably,. t.he re.action is carried out.at the boiling .point. of. the solvent..
The starting materials which can be: us.ed are mostly known comp.ounds, or can be prepared in accordance with.known proces.ses.
As examples of aldehy.des..of. the formula (II) there may be mentioned: 2-(3-methoxyphenyl)-propionaldehyde,
2-(4'-meth.oxyp.henyl)-propionaldehy:de, 2-.(3',4'-dimethoxy-phenyl)-propionaldehyde, 3,4-dimethoxyphenylacetaldehyde, 2-(4~-chlorophenyl)-propionaldehyde, 2-(2''-chIorophenyl)-propionaldehyde, 2-chlorophenylacetaldehyde, 4-chloro-phenylacetaldehyde, 2-(3-nitrophenyl)-propionaldehyde, diphenylacetaldehyde, 2,6-~imethoxyphenoxyacetaldehyde and 2,.6-dichlorophenoxyacltaldehyde.
Examples of acetoacetic acid esters of formula (III) suitable for use in reaction variant (a) are methyl aceto-acetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate, butyl acetoacetate, sec.-butyl acetoacetate and isobutyl acetoacetate.
The enamino esters of t~eformula (IV), suitable for use in reaction variant (b), are obtained from the corres-ponding acetoacetic acid esters of the formula (III) by react-ion wi.th. ammonia.
As stated above,. the invention also relates to the use in human and veterinary medicine as circulation-influencing agents of the compounds of the invention.
The present invention provides a pharmaceutical composition containing as active ingredient a compound 35. of..the inven.tion in..admixture.wi:th a solid.or li.q.uefi.ed ..
:Le A~20 954 :~
63~.
, gaseous ~iluent, or in admixture wi:th a liquid diluent other than a solve.n.t. of a mole.cular weight less. than 200 (preferably less than 350) exce.pt in the presence of a surface active agent.
The inve.ntion furth.er p.rovides a pharmaceutical composition containing as active ingredient a compound of. the inve.ntion in t.he form of a s.terile and/or physio-logically is.otonic aque.ous so.lut.ion.
The invention also provides a medicame.nt in dosage unit form comprising a compound of. the invention.
The invention also prov.ides a medicament in the form of tablets (including lo.zenges. and granules), dragees, capsules, pills, ampoules or suppositories comprising a comp.ound cf the invention.
"Medicament" as used in this Sp.ecification means physically discrete coherent port.ions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means phys.ically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of ~ the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respect.ively.
The pharmaceutical composition according to the invention may,.for example,. take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingred-ient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions .~e.g. granulates.).adap.ted.to.be formed into tab.Iet.s., . . . . .
~e ~ 20-954 ~i36631 - . 5 . dragees:,: capsules and pills include.:the::following:
(a) fillers and extenders,. e.g. starch, sugars, mannitol, and silicic acid, (b) binding age.nts, e.g. carboxymethyl cellulo.se and other cellulose derivatives, alginates, .gelatine and poiyvinyl pyrrolidone; (c) mois.turizing agents, e.g. gly.cerol; (d). disinte:grating agents:,. e.g. agar-agar, calc.ium carbonate and sodium bicarbonate; (e) agents for r.etarding. dis.s-o:lution e.g. paraffin; (f) resorption accelerators,. e.g. quaternary ammonium compounds; (g) surface active agents,. e.g. cet:y.l alcohol, glycerol mono-stearate; (h) adsorpt.ive. carriers,. e.g. kaolin and benton-ite; (i) lubricants., e.g.. talc,. calc.ium and magnesium stearate and solid polyethyl glycols.
The tab.lets.,. dragees,. cap.sules. and pills formed from 15`.the pharmac.eutical compositions of. the invention can have the customary coatings,. envelopes and prote.ct.ive matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient. only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dilue~ts-The diluents to be used in pharmaceutical compositionsadapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high es.ters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, par~ffins,..starch.,. tragacanth.,.cellulo.se..der.ivatives., Le A 20-954 . . .
.. . . ..
.polyethy:lene glycols, s-ilicones:, bentonite~s, siIicic ac.id, talc and zinc oxide. or mixtures of the.se:sub.stances.
The pharmaceuticaI compositions which are powders and sprays. can, for examp.le, contain the usual diluents, . e.g. lac.to.se,. talc, silic.ic.ac.id, aluminium hydroxide, calc.ium silic.ate., and polyamide:powder or mixt-ures of . the:s.e.s.ub.s.tances.. Aerosol sprays. can, for example,. contain . the usual propellants,. e.g.. chIorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example,. cQntain the customary diluents (wi.th, of c.ourse,. the ab.o.ve-ment.i.oned exclusion of solvents. having a mole.cular weight be.low 200 e.xcept in the presence of a surface-active agent):, s.uch as solv-e.nts,. disso.lving age.nts. and e.mulsifiers; specific examples of s.uch diluents are water,. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acet.ate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,. dimethyl-formamide, oils (for example ground nut oil), glyce.rol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxy-ethylene sorbite and sorbitane es.ters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
Examples of acetoacetic acid esters of formula (III) suitable for use in reaction variant (a) are methyl aceto-acetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate, butyl acetoacetate, sec.-butyl acetoacetate and isobutyl acetoacetate.
The enamino esters of t~eformula (IV), suitable for use in reaction variant (b), are obtained from the corres-ponding acetoacetic acid esters of the formula (III) by react-ion wi.th. ammonia.
As stated above,. the invention also relates to the use in human and veterinary medicine as circulation-influencing agents of the compounds of the invention.
The present invention provides a pharmaceutical composition containing as active ingredient a compound 35. of..the inven.tion in..admixture.wi:th a solid.or li.q.uefi.ed ..
:Le A~20 954 :~
63~.
, gaseous ~iluent, or in admixture wi:th a liquid diluent other than a solve.n.t. of a mole.cular weight less. than 200 (preferably less than 350) exce.pt in the presence of a surface active agent.
The inve.ntion furth.er p.rovides a pharmaceutical composition containing as active ingredient a compound of. the inve.ntion in t.he form of a s.terile and/or physio-logically is.otonic aque.ous so.lut.ion.
The invention also provides a medicame.nt in dosage unit form comprising a compound of. the invention.
The invention also prov.ides a medicament in the form of tablets (including lo.zenges. and granules), dragees, capsules, pills, ampoules or suppositories comprising a comp.ound cf the invention.
"Medicament" as used in this Sp.ecification means physically discrete coherent port.ions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means phys.ically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of ~ the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respect.ively.
The pharmaceutical composition according to the invention may,.for example,. take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingred-ient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions .~e.g. granulates.).adap.ted.to.be formed into tab.Iet.s., . . . . .
~e ~ 20-954 ~i36631 - . 5 . dragees:,: capsules and pills include.:the::following:
(a) fillers and extenders,. e.g. starch, sugars, mannitol, and silicic acid, (b) binding age.nts, e.g. carboxymethyl cellulo.se and other cellulose derivatives, alginates, .gelatine and poiyvinyl pyrrolidone; (c) mois.turizing agents, e.g. gly.cerol; (d). disinte:grating agents:,. e.g. agar-agar, calc.ium carbonate and sodium bicarbonate; (e) agents for r.etarding. dis.s-o:lution e.g. paraffin; (f) resorption accelerators,. e.g. quaternary ammonium compounds; (g) surface active agents,. e.g. cet:y.l alcohol, glycerol mono-stearate; (h) adsorpt.ive. carriers,. e.g. kaolin and benton-ite; (i) lubricants., e.g.. talc,. calc.ium and magnesium stearate and solid polyethyl glycols.
The tab.lets.,. dragees,. cap.sules. and pills formed from 15`.the pharmac.eutical compositions of. the invention can have the customary coatings,. envelopes and prote.ct.ive matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient. only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dilue~ts-The diluents to be used in pharmaceutical compositionsadapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high es.ters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, par~ffins,..starch.,. tragacanth.,.cellulo.se..der.ivatives., Le A 20-954 . . .
.. . . ..
.polyethy:lene glycols, s-ilicones:, bentonite~s, siIicic ac.id, talc and zinc oxide. or mixtures of the.se:sub.stances.
The pharmaceuticaI compositions which are powders and sprays. can, for examp.le, contain the usual diluents, . e.g. lac.to.se,. talc, silic.ic.ac.id, aluminium hydroxide, calc.ium silic.ate., and polyamide:powder or mixt-ures of . the:s.e.s.ub.s.tances.. Aerosol sprays. can, for example,. contain . the usual propellants,. e.g.. chIorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example,. cQntain the customary diluents (wi.th, of c.ourse,. the ab.o.ve-ment.i.oned exclusion of solvents. having a mole.cular weight be.low 200 e.xcept in the presence of a surface-active agent):, s.uch as solv-e.nts,. disso.lving age.nts. and e.mulsifiers; specific examples of s.uch diluents are water,. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acet.ate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,. dimethyl-formamide, oils (for example ground nut oil), glyce.rol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxy-ethylene sorbite and sorbitane es.ters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
-3 All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
.. ..
Le A 20 954 .
The pharmaceut:ical compos.itions ac.cording t~:the invention generally contain from 0.5. to.95% o~ the active ingredient by wei.ght. of the totaI composition.
In addition to a compound of the invention,. the pharmaceut.i.cal compositions and medicaments ac.cording to the invention can also contain other pharmaceutically active. comp.ounds. They may also contain a plurality of .compounds of the invent.i.on.
Any di.lue.nt in the medicaments of the present invention may be any of those mentioned ab.ove in relation to the pharmaceutical compositi.ons of.t.he p.re.sent invention.
Such medicaments.may i.nclude so.lvents.of mole.cular weight less than 200 as sole diluent..
The. disc.rete. cohere.nt portions. constituting the medicament according to.the inventi.on will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the follow-ing: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may.be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the compositi.on into the medicament .(e.g.. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the 35 ;.form of a medicament .according.to.the inve.nti.on.
.
: Le A 20 954 .~
113663~L
It is envisaged that these'active comp:ounds ~ill be administered perorally, parenterally (for example intra-muscularly, intraperitoneally, subcutaneously and intra-venously), rectally or locally.
The following Examples illustrate processes for the production of compounds according to the present invention.
Exa~ple 1 2,6-Dimethyl-4-[1-t3-methoxyphenyl)-ethyl~-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester.
~ OCH3 CH-CH
C~3 ~ 3 (Reaction variant (a)).
16.4 g of 2-(3-methoxyphenyl)-propionaldehyde, 23.2 g of methyl acetoacetate and 2.1 ml of NH3 (33%
strength) in 50 cm of ethanol were heated under reflux for
.. ..
Le A 20 954 .
The pharmaceut:ical compos.itions ac.cording t~:the invention generally contain from 0.5. to.95% o~ the active ingredient by wei.ght. of the totaI composition.
In addition to a compound of the invention,. the pharmaceut.i.cal compositions and medicaments ac.cording to the invention can also contain other pharmaceutically active. comp.ounds. They may also contain a plurality of .compounds of the invent.i.on.
Any di.lue.nt in the medicaments of the present invention may be any of those mentioned ab.ove in relation to the pharmaceutical compositi.ons of.t.he p.re.sent invention.
Such medicaments.may i.nclude so.lvents.of mole.cular weight less than 200 as sole diluent..
The. disc.rete. cohere.nt portions. constituting the medicament according to.the inventi.on will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the follow-ing: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may.be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the compositi.on into the medicament .(e.g.. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the 35 ;.form of a medicament .according.to.the inve.nti.on.
.
: Le A 20 954 .~
113663~L
It is envisaged that these'active comp:ounds ~ill be administered perorally, parenterally (for example intra-muscularly, intraperitoneally, subcutaneously and intra-venously), rectally or locally.
The following Examples illustrate processes for the production of compounds according to the present invention.
Exa~ple 1 2,6-Dimethyl-4-[1-t3-methoxyphenyl)-ethyl~-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester.
~ OCH3 CH-CH
C~3 ~ 3 (Reaction variant (a)).
16.4 g of 2-(3-methoxyphenyl)-propionaldehyde, 23.2 g of methyl acetoacetate and 2.1 ml of NH3 (33%
strength) in 50 cm of ethanol were heated under reflux for
4 hours. After the mixture had cooled, the product cry-stallised out. It was purified by recrystallisation from ethanol.
Yield: 26.7 g (75%) - Melting point: 145 to 147C
The following compounds of the present invention were obtained analogously: 2,6-dimethyl-4-~1-(3-methoxy-phenyl)-ethyll-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, 2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl~-1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester, 2,6-dimethyl-4- rl-(2-chlorophenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, 2,6-dimethyl-4-[1-(2-chlorophenyl)-ethyl~-1,4-dihydropyridine-3,5-dicarboxylic acid dipropyl ester and 2,6-dimethyl-4-[1-(3-nitr.ophenyl).-e.thyl¦-1,4.-.dihydropyr.ldlne-3.,5-dicar.boxylic :Le A '2'0'9'54 1~36631 acid dimethyl ester.
Example 2 2,6-Dimethyl-4-(2'-chIorophenylmethyl)-1,4:-dihydropyridine-3,5-dicarboxylic acid dimethyl ester ~ Cl CH3~2C~C02CH3 (Reaction variant (b)) 3 H
15.4 g of 2-chIorophenylacetaldehyde and 23 g of methyl ~-aminocrotonate in 50 ml of ethanol were heated under reflux for 4 hours. Af.ter the mixture had cooled, the product precipitated. It was recrystallised from methanol.
Yield: 21 g (60%) Melting point: 178C to 179C.
The following compounds of the present invention were obtained analogously: 2,6-dimethyl-4-(2'-chlorophenyl)-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, 2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dipropyl ester.
Examp-le 3 2,6-Dimethyl-4-(4'-methoxyphenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-isopropyl ester.
~ OCH3 CH302C ~ 2 ~ ~H
25. (~eaction variant :(c)) . H
. .
Le A 20 954 , 10 --.'24..8 g of 2-(4'-methoxyphenyl)-.ethylideneaceto-acetic acid me.thyl es.ter and 14.3 g of isop.ropyl ~-amino-crotonate in 100 cm of. ethanol were he:ated under reflux for 4 hours. When the mi.xture had cooled, the product
Yield: 26.7 g (75%) - Melting point: 145 to 147C
The following compounds of the present invention were obtained analogously: 2,6-dimethyl-4-~1-(3-methoxy-phenyl)-ethyll-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, 2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl~-1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester, 2,6-dimethyl-4- rl-(2-chlorophenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, 2,6-dimethyl-4-[1-(2-chlorophenyl)-ethyl~-1,4-dihydropyridine-3,5-dicarboxylic acid dipropyl ester and 2,6-dimethyl-4-[1-(3-nitr.ophenyl).-e.thyl¦-1,4.-.dihydropyr.ldlne-3.,5-dicar.boxylic :Le A '2'0'9'54 1~36631 acid dimethyl ester.
Example 2 2,6-Dimethyl-4-(2'-chIorophenylmethyl)-1,4:-dihydropyridine-3,5-dicarboxylic acid dimethyl ester ~ Cl CH3~2C~C02CH3 (Reaction variant (b)) 3 H
15.4 g of 2-chIorophenylacetaldehyde and 23 g of methyl ~-aminocrotonate in 50 ml of ethanol were heated under reflux for 4 hours. Af.ter the mixture had cooled, the product precipitated. It was recrystallised from methanol.
Yield: 21 g (60%) Melting point: 178C to 179C.
The following compounds of the present invention were obtained analogously: 2,6-dimethyl-4-(2'-chlorophenyl)-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester, 2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dipropyl ester.
Examp-le 3 2,6-Dimethyl-4-(4'-methoxyphenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-isopropyl ester.
~ OCH3 CH302C ~ 2 ~ ~H
25. (~eaction variant :(c)) . H
. .
Le A 20 954 , 10 --.'24..8 g of 2-(4'-methoxyphenyl)-.ethylideneaceto-acetic acid me.thyl es.ter and 14.3 g of isop.ropyl ~-amino-crotonate in 100 cm of. ethanol were he:ated under reflux for 4 hours. When the mi.xture had cooled, the product
5 was filter.ed off and recrystallised from ethanol.
YieId: 18.6 g .(50%) Mel.ting point: 163C to 165C
The.:following comp.ound of. the present invention was obtained analogously: 2,.6-dimethyl-4-(3',4'-dimethoxy-10 phenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3.-ethyl e.s.ter 5-isopropyl e.ster.
Example' 4 2,.6-Dimethyl-4-diphenylmethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl es.ter CH
2 5 2 ~~ C02C2H5 CH3--l~NJ 3 ~Reaction variant (b)) 9.6 g of diphenylacetaldehyde and 26 g of ethyl ~-aminocrotonate in 50 cm3 of ethanol were heated under reflux for 8 hours. After the mixture had cooled, the 20 product precipitated. It was washed with ether and recrystallised from ethanol.
Yield: 10.4 g (25%) Melting point: 140C.
Examp:le' 5 25 2,6-Dimethyl-4-(2',6'-dimethylphenoxymethyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester :Le A 20 954 3 ~ 3 2 5 2 ~ C02C2H5 (Re.action variant (b)) 16.4 g of 2,.6-dimethylphe.noxyac.eta.ldehyde and.26 g of. ethyl ~-aminocrotonate in 50 cm3 of..ethanol were heated -5 . under reflux for 4 hours. . Af.ter the mixture had cooled, the product precipitated, and was recrystallis.ed from ethanol.
Yield: 31.3% (55%) Melting point: 106C to 107C.
The following compound of the present invention was obtained analogously: 2,.6-dimethyl-4-(2',6'-dichloro-phenoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester.
Among the new 1,4-dihydropyridine salts of the invention, those salts that are pharmaceutically acceptable are particularly important and are preferred.
The new free 1,4-dihydropyridines of the general formula (I) and their salts can be interconverted in any suitable manner; methods for s.uch interconversion are known in the art.
The present invention also comprises pharmaceutic-ally ac.ceptable bioprecursors of the active compounds of the present invention.
For the purposes of this specification the term .25 'pharmac.e.ut.i.cally ac.ce.p.tab.le. b.i.opre.cursor'. of an.act.ive Le A 20 954 - 12.-, ..comp:ound of th:e inve.ntion means a compound having astructural formula dif.ferent from the :active comp:ound b.ut which nonetheles:s, upon administration to an animal or human being is converted in the patientis body to the active comp.ound.
Le ~ 20 954 . .
YieId: 18.6 g .(50%) Mel.ting point: 163C to 165C
The.:following comp.ound of. the present invention was obtained analogously: 2,.6-dimethyl-4-(3',4'-dimethoxy-10 phenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3.-ethyl e.s.ter 5-isopropyl e.ster.
Example' 4 2,.6-Dimethyl-4-diphenylmethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl es.ter CH
2 5 2 ~~ C02C2H5 CH3--l~NJ 3 ~Reaction variant (b)) 9.6 g of diphenylacetaldehyde and 26 g of ethyl ~-aminocrotonate in 50 cm3 of ethanol were heated under reflux for 8 hours. After the mixture had cooled, the 20 product precipitated. It was washed with ether and recrystallised from ethanol.
Yield: 10.4 g (25%) Melting point: 140C.
Examp:le' 5 25 2,6-Dimethyl-4-(2',6'-dimethylphenoxymethyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester :Le A 20 954 3 ~ 3 2 5 2 ~ C02C2H5 (Re.action variant (b)) 16.4 g of 2,.6-dimethylphe.noxyac.eta.ldehyde and.26 g of. ethyl ~-aminocrotonate in 50 cm3 of..ethanol were heated -5 . under reflux for 4 hours. . Af.ter the mixture had cooled, the product precipitated, and was recrystallis.ed from ethanol.
Yield: 31.3% (55%) Melting point: 106C to 107C.
The following compound of the present invention was obtained analogously: 2,.6-dimethyl-4-(2',6'-dichloro-phenoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester.
Among the new 1,4-dihydropyridine salts of the invention, those salts that are pharmaceutically acceptable are particularly important and are preferred.
The new free 1,4-dihydropyridines of the general formula (I) and their salts can be interconverted in any suitable manner; methods for s.uch interconversion are known in the art.
The present invention also comprises pharmaceutic-ally ac.ceptable bioprecursors of the active compounds of the present invention.
For the purposes of this specification the term .25 'pharmac.e.ut.i.cally ac.ce.p.tab.le. b.i.opre.cursor'. of an.act.ive Le A 20 954 - 12.-, ..comp:ound of th:e inve.ntion means a compound having astructural formula dif.ferent from the :active comp:ound b.ut which nonetheles:s, upon administration to an animal or human being is converted in the patientis body to the active comp.ound.
Le ~ 20 954 . .
Claims (23)
PROPERTY OF PRIVILEGE IS CLAIMED ARE DEFINED ASSFOLLOWS:
1. A process for preparing a 1,4-dihydropyridine of the formula (I) or a pharmaceutically acceptable salt thereof, in which R1 and R2 are identical or different and denote a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, R3 represents a hydrogen atom, a methyl group or a phenyl radical and R4 represents a phenyl or phenoxy radical which phenyl or phenoxy radical optionally carries one or more substitutents selected from nitro, halogen, methyl and methoxy, which process comprises a) reacting an aldehyde of the formula (II) in which R3 and R4 have the meanings given above, with ammonia and an acetoacetic acid ester of the formula (III) in which R1 has the meaning given above, in an organic solvent, b) reacting an aldehyde of formula (II), as defined above, with an enamino-ester of the formula (IV) in which R1 has the meaning given above, in an organic solvent, or c) reacting an ylidene compound of the formula (V) in which R2, R3 and R4 have the meanings given, with an enamino-ester of the formula IV, as defined above, in an organic solvent and, if required, converting the obtained compound of formula I into a pharmaceutically acceptable salt thereof.
2. A process according to claim 1 a), b), or c), in which the reaction is carried out in an alcohol, dioxane, glacial acetic acid, ethyl acetate, dimethylformamide or acetonitrile.
3. A process according to claim 1 a), b), c) or 2, in which the reaction is carried out at between 20°C and 150°C.
4. A process according to claim 1, wherein the aldehyde of formula II is selected from the group consisting of 2-(3-methoxyphenyl)-propionaldehyde, 2-(4'-methoxyphenyl)-propionaldehyde, 2-(3',4'-dimethoxyphenyl)-propionaldehyde, 3,4-dimethoxyphenylacetaldehyde, 2-(4'-chlorophenyl)-propionaldehyde, 2-(2'-chlorophenyl)-propionaldehyde, 2-chlorophenylacetaldehyde, 4-chlorophenylacetal-dehyde, 2-(3-nitrophenyl)-propionaldehyde, diphenylacetaldehyde, 2,6-dimethoxyphenoxyacetaldehyde and 2,6-dichlorophenoxyacetaldehyde.
5. A process according to claim 1 or 4 wherein the acetoacetic acid ester of formula III is selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate, butyl acetoace-tate, sec.-butyl acetoacetate and isobutyl acetoacetate.
6. A process according to claim 1 wherein the enamino compound of formula IV is obtained by reacting ammonia with an acetoacetic acid ester selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate, butyl acetoacetate, sec.-butyl acetoacetate and isobutyl acetoacetate.
7. A process according to claim 1, 2 or 3 wherein R1 and R2 are both methyl radicals or ethyl radicals or one of Rl and R2 is a methyl radical and the other is an isopropyl radical, R3 is hydrogen or a methyl or phenyl radical and R4 is a 3-methoxyphenyl, 2-chlorophenyl, 4-methoxyphenyl, phenyl or 2,6-dimethylphenoxy radical.
8. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
9. A process according to claim 1, 2 or 3 wherein R1, R2 and R3 are methyl radicals and R4 is a 3-methoxy-phenyl radical.
10. A process for preparing 2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester which comprises reflu-xing 2-(3-methoxyphenyl)-propionaldehyde with methyl acetoacetate and ammonia in ethanol.
11. The compound 2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl]-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester when prepared by a process according to claim 10 or an obvious chemical equivalent thereof.
12. A process according to claim 1, 2 or 3 wherein R1 and R2 are both methyl radicals, R3 is hydrogen and R4 is a 2-chlorophenyl radical.
13. A process for preparing 2,6-dimethyl-4-(2'-chlorophenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester which comprises refluxing 2-chlorophenylacetaldehyde with methyl .beta.-aminocrotonate in ethanol.
14. The compound 2,6-dimethyl-4-(2'-chlorophenylmethyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid dimethyl ester when prepared by a process according to claim 13 or an obvious chemical equivalent thereof.
15. A process according to claim 1, 2 or 3 wherein one of R1 and R2 is an isopropyl radical and the other is a methyl radical, R3 is hydrogen and R4 is a 4-methoxyphenyl radical.
16. A process for preparing 2,6-dimethyl-4-(4'-methoxyphenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-isopropyl ester which comprises refluxing 2-(4'-methoxyphenyl)- ethylideneacetoacetic acid methyl ester with isopropyl .beta.-aminocrotonate in ethanol.
17. The compound 2,6-dimethyl-4-(4'-methoxyphenylmethyl)-1,4-dihydropyri-dine-3,5-dicarboxylic acid 3-methyl ester 5-isopropyl ester when prepared by a process according to claim 16 or an obvious chemical equivalent thereof.
18, A process according to claim 1, 2 or 3 wherein R1 and R2 are both ethyl radicals and R3 and R4 are both phenyl radicals.
19. A process for preparing 2,6-dimethyl-4-diphenylmethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester which comprises refluxing diphenyl-acetaldehyde with ethyl .beta.-aminocrotonate in ethanol.
20. The compound 2,6-dimethyl-4-diphenylmethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.
21. A process according to claim 1, 2 or 3 wherein R1 and R2 are both ethyl radicals, R3 is hydrogen and R4 is a 2,6-dimethylphenoxy radical.
22. A process for preparing 2,6-dimethyl-4-(2',6'-dimethylphenoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which comprises refluxing 2,6-dimethylphenoxyacetaldehyde with ethyl .beta.-aminocrotonate in ethanol.
23. The compound 2,6-dimethyl-4-(2',6'-dimethylphenoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester when prepared by a process according to claim 22 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3021958.0 | 1980-06-12 | ||
| DE3021958A DE3021958A1 (en) | 1980-06-12 | 1980-06-12 | 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1136631A true CA1136631A (en) | 1982-11-30 |
Family
ID=6104387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000379456A Expired CA1136631A (en) | 1980-06-12 | 1981-06-10 | 1,4-dihydropyridine compounds, their production and their medicinal use |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4364952A (en) |
| EP (1) | EP0042093A3 (en) |
| JP (1) | JPS5728050A (en) |
| CA (1) | CA1136631A (en) |
| DE (1) | DE3021958A1 (en) |
| ES (1) | ES8203842A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60109519A (en) * | 1983-11-17 | 1985-06-15 | Nippon Shinyaku Co Ltd | "nifedipine(r)" composition and production thereof |
| JPS61180835A (en) * | 1985-02-05 | 1986-08-13 | Matsushita Electric Ind Co Ltd | Kerosine burning equipment |
| DE3544692A1 (en) * | 1985-12-18 | 1987-06-19 | Bayer Ag | DIHYDROPYRIDINE SPRAY, METHOD FOR THE PRODUCTION THEREOF AND ITS PHARMACEUTICAL USE |
| US5204339A (en) * | 1986-01-31 | 1993-04-20 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
| JPS62248923A (en) * | 1986-04-21 | 1987-10-29 | Gunji Sasaki | Malodor preventive device in kerosene stove |
| US4920101A (en) * | 1987-09-30 | 1990-04-24 | Nelson Research & Development Co. | Compositions comprising 1-oxo- or thiohydrocarbyl substituted azacycloaklkanes |
| US4879275A (en) * | 1987-09-30 | 1989-11-07 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agent |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670827C3 (en) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine |
| DE2003146A1 (en) * | 1970-01-24 | 1971-07-29 | Bayer Ag | New 1,4-dihydropyridine derivatives |
| DE2005116C3 (en) * | 1970-02-05 | 1980-02-14 | Bayer Ag, 5090 Leverkusen | Symmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid esters |
-
1980
- 1980-06-12 DE DE3021958A patent/DE3021958A1/en not_active Withdrawn
-
1981
- 1981-05-29 US US06/268,417 patent/US4364952A/en not_active Expired - Fee Related
- 1981-06-01 EP EP81104164A patent/EP0042093A3/en not_active Withdrawn
- 1981-06-09 JP JP8759781A patent/JPS5728050A/en active Pending
- 1981-06-10 CA CA000379456A patent/CA1136631A/en not_active Expired
- 1981-06-11 ES ES502951A patent/ES8203842A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES502951A0 (en) | 1982-04-01 |
| JPS5728050A (en) | 1982-02-15 |
| DE3021958A1 (en) | 1981-12-24 |
| EP0042093A3 (en) | 1982-07-14 |
| EP0042093A2 (en) | 1981-12-23 |
| US4364952A (en) | 1982-12-21 |
| ES8203842A1 (en) | 1982-04-01 |
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