CA1185182A - Pharmaceutical compositions containing diethyl-2- methyl-6-propyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate - Google Patents
Pharmaceutical compositions containing diethyl-2- methyl-6-propyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylateInfo
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- CA1185182A CA1185182A CA000447060A CA447060A CA1185182A CA 1185182 A CA1185182 A CA 1185182A CA 000447060 A CA000447060 A CA 000447060A CA 447060 A CA447060 A CA 447060A CA 1185182 A CA1185182 A CA 1185182A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- 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
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- 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
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- Hydrogenated Pyridines (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to pharmaceutical compositions containing diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The compositions display circulation influencing properties.
The invention relates to pharmaceutical compositions containing diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The compositions display circulation influencing properties.
Description
5:~
Our Patent Application Serial No. 377,32fi relates to certain 1,4-dihydro-pyridine compounds having different subs~ituents in the 2-position and 6-position, to several processes for their production and to their use in agents which influence the circulation. ~his application is divided ou~
of Application Serial No. 377>326 and also relates to a l,~-dihydro-pyridine compound.
It has already been disclosed that 1,~-dihydro-2,6-dimethyl-~1-phenyl-pyridine-3,5-dicarboxylic acid diethyl esters are obtained when benzylidene-acetoacetic acid ethyl ester is reacted with ~-aminocrotonic acid e-thyl ester or acetoacetic acid ethyl ester and ammonia ~see E. Knoevenagel, Bcr~ dtsch.
chem. Ges. 31, 7~3 (1898)~.
Further, it is known that certain l,~-dihydropyridines possess inter-esting pharmacological properties (see F. Bossert and W. Vater, Naturl~issen-schaften 58, 578 (1971)~.
Further, dihydropyridines which carry different ester groups in the 3-position and 5-position are known (see DE-OS (German Published Specification)
Our Patent Application Serial No. 377,32fi relates to certain 1,4-dihydro-pyridine compounds having different subs~ituents in the 2-position and 6-position, to several processes for their production and to their use in agents which influence the circulation. ~his application is divided ou~
of Application Serial No. 377>326 and also relates to a l,~-dihydro-pyridine compound.
It has already been disclosed that 1,~-dihydro-2,6-dimethyl-~1-phenyl-pyridine-3,5-dicarboxylic acid diethyl esters are obtained when benzylidene-acetoacetic acid ethyl ester is reacted with ~-aminocrotonic acid e-thyl ester or acetoacetic acid ethyl ester and ammonia ~see E. Knoevenagel, Bcr~ dtsch.
chem. Ges. 31, 7~3 (1898)~.
Further, it is known that certain l,~-dihydropyridines possess inter-esting pharmacological properties (see F. Bossert and W. Vater, Naturl~issen-schaften 58, 578 (1971)~.
Further, dihydropyridines which carry different ester groups in the 3-position and 5-position are known (see DE-OS (German Published Specification)
2,117,571). l,~-Dihydropyridines with identical ester groups in the 3-position and 5-position and diEferent substi~uents in the 2-position and 6-position have hitherto not been disclosed.
According to Application Serial No. 377,326 there are provided compo~md~ which are l,~l-dihydro-pyridines of the genera:L Eormula R
\/l /
R2 , R
in which R represents a phenyl radical optionally containing 1 or 2 identical or different substituents selected from me-thoxyJ halogen, trifluoromethyl, nitro and cyano; Rl represents a straight-chain or branched alkyl radical with up to 8 carbon atoms which is optionally interrupted by 1 or 2 oxygen atoms in the chain, and/or which is optionally substituted by a phenyl radical; p2 and R4 are always differen~ and each represents a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, benzyl or cyclohexylmethyl; with the exception of the compound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
The compound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl~-1,4-dihydropyridine-3,5-dicarboxylate is disclosed as an intermediate in United States Patent No. 4,021,434. The United States patent contains no suggestion oE any medicinal utility for the compound. The compound displays circulation influencing properties similar to the novel l,4-dihydropyridine compounds whlch are the sub~ect of our Patent Application Serial No. 377,326, i.e. the compounds of formula I above. Accordingly the present invention provides a pharmaceutical composition containing diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydro-pyridine--3,5-dicarboxylate as active ingredient, in admixture with a suitable carrier or diluent.
The 1,4-dihydropyridine compounds of Application Serial No. 337,326 and of this application can be prepared by a process in which (A) an ylidene-~-keto-ester of the general Eormula coR2 /
R-C~=C Il COOR
in which R, R and R2 have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R~-C=CII-COORl I III
in which Rl and R4 have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (B) an ylidene-~-keto-ester of the general formula II, as defined above, is reacted with ammonia and a ~-ketocarboxylic acid ester of the general formula V
in which R~ and Rl have the abovementioned meanings, optionally in -the presence of an inert organic solvent, or (C) an yl.idene-~-keto-ester of the general :Eormula = COR~
R-CII=C VI
COOR
in which R, Rl and R~ have the a~ovementioned meanings, is reacted with an - 2a -enaminocarboxylic acid es-ter of the general formul.a R2-C=CH-COOR
~ VII
~H2 in which R and R have the abovementioned meanlngs, opti.onally in the presence of an inert organic solvent, or (D) an ylidene-~-keto-ester oE the general formula VI, as defined above, is reacted with ammonia and a ~-ketocarboxylic acid ester of the general formula VIII
in which R and R have the abovementioned meanings, optionall~ in -the presence :LO of an inert organic solvent, or (E) an aldehyde of the general :Formula R-C IX
~0 in which R has the abovementioned meaning, is reacted with an enaminocarboxylic acid ester of the genera:L Eormula III, as deEined above, and a ~-ke-tocarboxylic acid ester of the general formula VIII, as deEined above, optionall.y in the presence of an inert organic solvent, or (F) an aldehyde of the general formula I~, as definecl above, is reacted with an enaminocarboxylic acid ester of the general formu:La VII, as defined above, and a ~-ketocarboxylic acid ester of the generGIl formu:La V, as defined above, optionally in the presence o~ an inert organic solvent, o:r (G) when a compound of formula I i.s required, in wh:ich -the radicals R, R and R do not carry any functional groups which can undergo modi:Eication under hydrogenating conditions, and R is different from hydrogen, and R repre-sents a hydrogen atorn, a 2-dialkylarnino-3,4-dihydro-pyridine vf -the general forrnula R 02C ~ C2R
2 1 N ~ X
R
in which R, Rl and R2 have the abovementioned mean:ings and do not carry any :Functional groups which undergo modiFication under hydrogenating conditions, and ~5 and R6 represent Cl to C6 alkyl groups or -together complete a heterocyclic ring with the exocyclic nitrogen atom~ is catalytically hydrogenated in the presence of a noble metal catalyst.
~ he compounds of Application Serial No. 337,326 and o-t this application possess valuable pharmacological properties. By virtue of their circulation-in:Fll.lencing action they can be used as anti-hypertensive agents, as vasodilators, as cerebral therclpeutic ageilts and as coronary -therapeu-tic agents, and they are thus to be regarded as an enrichment of pha.rmacy.
The process variants (A)~ (B), (C), (D), ~E), (~:) and (G) :For the production of the compounds acco:rding to the invention are illus-trated by the following equations, in which in each case, the end-product o formula (1) is 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-di.carboxylic acid diethyl ester and 1,4-dihydro-2-methyl-4-~3'-trifluoro]nethyl-phenyl)-pyridine-
According to Application Serial No. 377,326 there are provided compo~md~ which are l,~l-dihydro-pyridines of the genera:L Eormula R
\/l /
R2 , R
in which R represents a phenyl radical optionally containing 1 or 2 identical or different substituents selected from me-thoxyJ halogen, trifluoromethyl, nitro and cyano; Rl represents a straight-chain or branched alkyl radical with up to 8 carbon atoms which is optionally interrupted by 1 or 2 oxygen atoms in the chain, and/or which is optionally substituted by a phenyl radical; p2 and R4 are always differen~ and each represents a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, benzyl or cyclohexylmethyl; with the exception of the compound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
The compound diethyl 2-methyl-6-propyl-4-(3-nitrophenyl~-1,4-dihydropyridine-3,5-dicarboxylate is disclosed as an intermediate in United States Patent No. 4,021,434. The United States patent contains no suggestion oE any medicinal utility for the compound. The compound displays circulation influencing properties similar to the novel l,4-dihydropyridine compounds whlch are the sub~ect of our Patent Application Serial No. 377,326, i.e. the compounds of formula I above. Accordingly the present invention provides a pharmaceutical composition containing diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydro-pyridine--3,5-dicarboxylate as active ingredient, in admixture with a suitable carrier or diluent.
The 1,4-dihydropyridine compounds of Application Serial No. 337,326 and of this application can be prepared by a process in which (A) an ylidene-~-keto-ester of the general Eormula coR2 /
R-C~=C Il COOR
in which R, R and R2 have the abovementioned meanings, is reacted with an enaminocarboxylic acid ester of the general formula R~-C=CII-COORl I III
in which Rl and R4 have the abovementioned meanings, optionally in the presence of an inert organic solvent, or (B) an ylidene-~-keto-ester of the general formula II, as defined above, is reacted with ammonia and a ~-ketocarboxylic acid ester of the general formula V
in which R~ and Rl have the abovementioned meanings, optionally in -the presence of an inert organic solvent, or (C) an yl.idene-~-keto-ester of the general :Eormula = COR~
R-CII=C VI
COOR
in which R, Rl and R~ have the a~ovementioned meanings, is reacted with an - 2a -enaminocarboxylic acid es-ter of the general formul.a R2-C=CH-COOR
~ VII
~H2 in which R and R have the abovementioned meanlngs, opti.onally in the presence of an inert organic solvent, or (D) an ylidene-~-keto-ester oE the general formula VI, as defined above, is reacted with ammonia and a ~-ketocarboxylic acid ester of the general formula VIII
in which R and R have the abovementioned meanings, optionall~ in -the presence :LO of an inert organic solvent, or (E) an aldehyde of the general :Formula R-C IX
~0 in which R has the abovementioned meaning, is reacted with an enaminocarboxylic acid ester of the genera:L Eormula III, as deEined above, and a ~-ke-tocarboxylic acid ester of the general formula VIII, as deEined above, optionall.y in the presence of an inert organic solvent, or (F) an aldehyde of the general formula I~, as definecl above, is reacted with an enaminocarboxylic acid ester of the general formu:La VII, as defined above, and a ~-ketocarboxylic acid ester of the generGIl formu:La V, as defined above, optionally in the presence o~ an inert organic solvent, o:r (G) when a compound of formula I i.s required, in wh:ich -the radicals R, R and R do not carry any functional groups which can undergo modi:Eication under hydrogenating conditions, and R is different from hydrogen, and R repre-sents a hydrogen atorn, a 2-dialkylarnino-3,4-dihydro-pyridine vf -the general forrnula R 02C ~ C2R
2 1 N ~ X
R
in which R, Rl and R2 have the abovementioned mean:ings and do not carry any :Functional groups which undergo modiFication under hydrogenating conditions, and ~5 and R6 represent Cl to C6 alkyl groups or -together complete a heterocyclic ring with the exocyclic nitrogen atom~ is catalytically hydrogenated in the presence of a noble metal catalyst.
~ he compounds of Application Serial No. 337,326 and o-t this application possess valuable pharmacological properties. By virtue of their circulation-in:Fll.lencing action they can be used as anti-hypertensive agents, as vasodilators, as cerebral therclpeutic ageilts and as coronary -therapeu-tic agents, and they are thus to be regarded as an enrichment of pha.rmacy.
The process variants (A)~ (B), (C), (D), ~E), (~:) and (G) :For the production of the compounds acco:rding to the invention are illus-trated by the following equations, in which in each case, the end-product o formula (1) is 1,4-dihydro-2-ethyl-6-methyl-4-(3'-nitrophenyl)-pyridine-3,5-di.carboxylic acid diethyl ester and 1,4-dihydro-2-methyl-4-~3'-trifluoro]nethyl-phenyl)-pyridine-
3,5-dicarboxylic acid diethyl ester:
A) ~ / N2 ~ ~ N02 ~5C22C ~ C2C2l~5 1-15C202C ~ -('2('2115 1-1 C~ l12N 2 5 -~12 113(. N ~ ~ C2115 2 5C22C ~ COzC2~ls ~5C22C ~ H H2C -21120 ~ H C N 2 5 !. -- 6 C) [~ N2 [~ NO2 H5C202C ~HH~CO2C2Hs HgC202CXl~ Co2c2Hs H3 C NH2 C2 H5 -H2 o ~13 C ~ c2 ~5 D ) [~ NO2 [~ NO2 H5C202C~cH H~ CO2C2HsH5C202C~, C2C2~ls + I ~ N
,C~ O C2 H5 ~ ~2 H2 H3 C H C2 H5 NH~
E) ~ ~ NO2 O'lH ~
Hs C2 ()2 C~cH H ~ COz C2 Hs Hs C2 02 C h CO2 C2 H5 ~ H2N C2H5 -2 H20HlC ~H C2Hs ~ NO2 F) ~ ~NO2 O H CO2C2 Hs HsC202C~ H H2C' _ -EDH5C20~Cl~CO~(,2~5 H, C NH2 C2 H5 ' H Ou~ C~ H5 Le A ? 3?2 ~ ~ CF3 5 2 2 ~ AcOH ~ ~ 2 2 5 Specific details of the various process variants are as follows:
Process variant A
The ylidene-R-keto-esters of the ~ormul.a II used as the starti.ng material are known from the literature or can be prepared accordinc3 to methods known from the literature (see, for example, G. Jones "The Knoevenagel Condensa-tion" in Orc3. Reactions, Vol. XV, 20~ et seq. (1967)).
As examples of esters of formula II there may be mentioned: benzyli-dene-formylacetic acid methyl es-ter, benzylideneacetoacetic acid methyl ester, 2'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid n-butyl ester, 2'-methoxybenzylideneacetoacetic acid isohutyl ester, 3'-nitrobenzylideneacetoacetic acid isopropyl ester, 3'-nitrobenzylideneacetoacetic acid 2-methoxyethyl ester, 2'-nitrobenzylideneacetoacetic acid isobutyl ester, 2'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-propoxy-ethyl ester, 3'-nitrobenzylideneacetoacetic acid benzyl ester, 3'-slitrobenzyliclcneacetoacetic acid 2-phellyl-ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-pllenoxy-ethyl ester, 2'-cyanobenzylideneacetoacetic acid ethyl ester, 2'-cyanobenzylidcnc-proL~ionylacetic acid ethyl ester, 2'-nitrobenzylidelleproL~iollyl~cetic acici methyl ester, 3'-nitrobenæylidenepropionylacetic acicl cthyl ester, 3'-nitrobenzyllderlc-propionylacetic acid 2-methoxycthyl estcr, 3'-nitrobcnzylidclle~)ropiollylacctic acid isopropyl estcr, 2'-nitrobcnzylidcncproE~iol)ylacctic acid isobutyl estcr, 2'-chlorobenzylidenepropionyl acetic acid methyl ester, 2'-cyanobenzylidene-isob~tanoylacetic acid e-thyl ester, 3'-nitrobenzylideneisobutanoylacetic acid ethyl ester, 2'-nitrobenzylideneisobutanoylacetic acid methyl es-ter, 2'-nitro-benzylideneisobu-tanoylacetic acid isobutyl ester, 3'-nitrobenzylideneisobutanoyl-acetic acid 2-methoxy-ethyl ester, 3'-ni-troben~ylidene-~-phenylacetoacetic acidethyl ester, 2'-nitrobenzylidene-~-phenylacetoace-tic acid methyl ester, 2'-nitrobenzylidene-y-phenylacetoacetic acid isobutyl ester, 3'-nitroben~ylidene-y-phenylacetoacetic acid isopropyl ester, 3'-nitrobenzylidene-~-phenylaceto-acetic acid 2-methoxy-ethyl ester and 2'-triEluoromethylbenzylidene-y-phenyl-acetoacetic acid ethyl ester.
Preferred starting compounds of formula III are those in which R has the same meanin~ as in the preferred compounds of formula II an~l R represents a hydro~en atom or represents a straight-chain or branched alkyl radical with 1 to ~, especially 1 to 4 carbon atoms, in which a hydro~en atom can be replaced by a satura-ted or unsaturated cyclic hydrocarbon radical with up to 6 carbon atoms, especially a phenyl radical.
The enaminocarboxylic acid esters of the formula III used as startin~
materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J.Amer. chem. Soc. 67, 1017 (1945~)-As examples of compounds of formula III therc may be mentioned:
B-amino-crotonic acid methyl ester, B-amino-crotonic acid ethyl cster, B-amino-B-ethyl-acrylic acid mcthyl ester, B-amino-B-ethyl-acrylic acid cthyl cster, B-amino-B-ethyl-acrylic acid isopropyl estcr, B-amino-B-cthyl-acrylic acid lleopentyl estcr, B-amillo-B-ethyl-acrylic acid bcnzyl ester, B-amino-~-cthyl-acrylic acid 2-phcnylethyl cstcr, B-amino-B-cthyl-acrylic acid 2-phclloxycthyl estcr, B-amino-B-propyl-acrylic acid methyl cstcr, g-amino-e-isopropyl-acrylic acid methyl estcr, B-~nino-B n-butyl-acrylic acid methyl cstcr, B-amino-B-isobutyl-acrylic acid methyl ester, ~-amino-~-cyclohexylmethyl-acrylic acid methyl ester, ~-amino-~-benzyl-acrylic acid methyl ester and ~-amino-~-(2-phenylethyl)-acrylic acid ethyl ester.
Sui-table diluen-ts are any of the inert organic solvents. These include as preferences alcohols (such as ethanol, methanol and isopropanol), e-thers (such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether and glycol dimethyl ether), glacial acetic acid, dime-thylEormamide, dimethyl-sulphoxide, acetonitrile, pyridine and hexamethylphosphorotriamide.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, preferably between 20 and 100 C, especially at the boiling poin-t of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, one mole of an ylidene-~-keto-ester of the formula II is reacted with one mole of an enamino-earboxylic acid ester of the formula II in a suitable solvent. The substances according to the invention are preferably isolated and purified by distilling off the solvent in vacuo and recrystallizing the residue, which may only be obtained in a crystalline form after cooling with ice, from a suitable solvent.
Procesc variant ~
Preferred ylidene-3-keto-ester starting compounds of the formula II
are those mentioned as preferred for reaction variant A.
Preferred starting compounds of formula V are those in which the radieals R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formula III.
Examples of the ylidene-~-~eto-esters of the formula II, used as starting materials, have already been listed under process variant A.
The ~-~etocarbo~ylic acid esters oE the Eormula V used as starting _ g _ materials are known fxom -the literature and can be prepared in accordance with methods known from the literature (see example, Do Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercap-tanen" ('7Reaction of Dike-tene with Alcohols, Phenols and Mercaptans"), in Houben-Weyl, Methoden der Organischen chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y. Oikawa, K. Sugano and 0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).
As examples of esters of formula V there may be mentioned: aceto~
acetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid n~butyl ester, acetoacetic acid isopropyl ester, acetoacetic acid benzyl ester, aceto-acetic acid 2-phenyl-ethyl ester, acetoacetic acid 2-phenoxyethyl ester, propionylacetic acid methyl ester, propionylacetic acid ethyl ester, propiony]-acetic acid isopropyl ester, propionylacetic acid benzyl ester, propionylacetic acid 2-phenyl-ethyl ester, propionylacetic acid 2-phenoxyethyl ester, isobutano-ylacetic acid methyl ester, y-cyclohexylacetoacetic acid ethyl ester and ~-phenylacetoacetic acid methyl ester.
Suitable diluents are any of the inert organic solvents. These include, as ~references, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general~ the reaction is carried out at between 20 and 150 C, but preferably at the bciling point of the particular solvent.
The reaction can be carried out under norma~ pressurea but also undcr elevatcd pressure. In gelleral, it is carried out under normal ~rcssure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulac II and V, are each employed in molar amoullts. The aminc uscd is advantageously added in an c~cess of 1 to 2 moles. The compounds according to the invention can easily be purificd by recrystallization from a suitablc solvcnt.
Process variant C
Preferred starting materials of formulae VI and VII, are those in which the radicals R, R , R and R have the meanings mentioned for the preferred starting materials of formulae II and III under process vzriant A.
The ylidene-~-keto-esters of the formula VI, used as starting materials, are known from the li-terature or can be prepared in accordance with methods known from the literature (see, for example, G. Jones (The Knoevenage Condensation" in Org. Reactions, Vol. XV, 204 et seq. (1967)).
As examples of esters of formula VI there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula II.
The enaminocarboxylic acid esters of the formula VII used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J. Amer. Chem. Soc. 67, 10]7 ~1945)).
As examples oE esters of formula VII there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula III.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial ran~e.
In general, the reaction is carried out at between 20 and 150 C, prcferably botween 20 and 100 C, especially at the boiling point of the particular solvent.
The reaction can be carricd out under normal pressur~ but also under clovatcd pressurc. In general, it is carricd out under normal pressurc.
In carrying out the proccss according to the invention, onc molc of thc ylidcne-B-~cto-cster of the formula VI is rcactcd with one molc of cn~millo-carboxylic acid cstcr of the formula VII in a suitable solvent.
Process variant D
Preferred ylidene-~-keto-ester starting compounds oE the formula VI
are those mentioned as preferred for reaction variant C.
Preferred s-tarting compounds of formula VIII, are those in which the radicals R and R have -the meaning mentioned under process variant A in respect of preferred compounds oE formula II.
Examples of the ylidene-~-keto-esters of -the formula VI used as starting compounds have already been listed under process variant C.
The ~-ketocarboxylic acid esters of -the formula VIII ~lsed as star-ting materials are known from the literature or can be prepared in accordance with methods known from the literature (see for examp]e, D. Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("Reaction of Diketene with ~lcohols, Phenols and Mercaptans"), in ~louben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. VII~4, 230 e-t seq. (1968); and Y.
Oikawa, K. Sugano and O. Yonemi-tsu, J. Org. Chem. 43, 2087 (1978)).
As examples of esters of formula VIII there may be mentioned those esters specifically mentioned under process variant B as examples of esters of formula V.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substalltial range.
In general, the reaction is carricd out at betweell 20 and 150 C, but preferably at the ~oiling pOillt of the particular solvent.
Thc reactlon can be carried out ullder non~al pressure but also ullder elevatecl prcssurc. In general, it is carricd out undcr normal pressure.
In carrying out thc i~rocess according to thc invelltioll, the com~oullds participating in thc rcactioll, of the formulae VI and VIII, are eaell cmployccl in molar amounts. Thc amillc used ~s advalltagcously addcd ill arl cxccss o 1 to 2 moles.
_ocess variant E
PreEerred ester starting compounds of -the formula III are those mentioned as preEerred for reaction variant A~ Preferred ester starting com-pounds of the formula VIII are those mentioned as preferred for reaction variant D.
Preferred starting compounds of formula IX are those in which the radicals R, R , R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formulae II and III.
The aldehydes of the formula IX, used as s-tar-ti.ncJ materials, are known from ~he literature or can be prepared in accordance with methods known from the literature (see, Eor example, E. Mosettig, Org. Reactions VIII, 218 et seq.
~195~)).
As examples of aldehydes of formula IX there may be mentioned:
benzaldehyde, 2-, 3- or ~-methoxybenzaldehyde, 2-, 3- or ~-chloro-, bromo- or fluoro-benzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde, 2-, 3- or 4-nitro-benzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2,3- or 2,6-dichlorobenzaldehyde, 2,~- or 2,6-dinitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, ~-chloro-2 nitrobsnzaldehyde, 2-nitro-~-methoxybenzaldehyde, 2-nitro-~l-cyanobenzaldehyde, 2-chloro-~-cyanobenzaldehyde and 3-chloro-~-trifluoromethylbenzaldehyde.
Examples of the enaminocarboxylic acid esters of the formula III, used as starting compounds have already bcen listed under process variant A, and examples of the ~-kctocarboxylic acid csters of the formula VIII, used as starting compounds have already been listcd under proccss variant D.
Suitablc diluents are any of the incrt organic solvents. Thcse include, as preferences, those mentioned for reactioll variant A.
Thc reaction tcmperatures can be varied within a substalltial rangc.
In gcncral, thc reactioll is carricd out at bctwccn 20 and 150 C, but pre~crJbly at the hoiliny point of -the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the inven-tion, the compounds participating in the reaction, of the formulae IX, III and VIII, are each employed in molar amounts.
Process variant F
Preferred aldehyde starting compounds of the formula IX are those mentioned as preferred for reaction varian-t E.
Preferred ester starting compounds of -the formula V are those men-tioned as preEerred Eor reaction variant B, preferred ester starting compounds of formula VII are those mentioned as preferred for reaction variant C.
Examples oE the aldehydes of the formula IX used as starting compounds are listed under prorcess variant E, examples of the enaminocarboxylic acid esters of the formula VII are listed under process variant C and examples of the ~-ketoearboxylic aeid esters of the formula V are listed under process variant ~.
Suitable diluents axe any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a s~lbstantial range.
In general, the reaction is carried out atbetween20 and lS0 C, but preferably at th~ boiling point of the particular solvent.
The reaction can be carried out under nor~nl pressure but al.so under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds partieipatillg in the reaction, of the Eormulae IX, VII and V, are each employed in molar amounts.
Process variant G
PreEerred startiny compounds of formula X are those in which the 5~
radieals R, R and R have the meanings mentioned under process variant ~, in respeet of preferred compounds of formula II with the restriction that the radicals R, R and R do not con-tain any func-tional groups which can undergo ehange under hydro~enating conditions, and provided R is different from hydro-yen and R represents a hydrogen a-tom, and in which, R and R , which can be identical or different, represent an alkyl radical with 1 to ~ carbon atoms, espeeially with 1 or 2 carbon atoms, or the radicals R and R together with the exocyelie nitrogen atom form a 5-membered to 7-membered he-teroeyclic ring.
The 2-dialkylamino-3,4--dihydropyridines of the formula X, used as starting materials, are known Erom the literature or can be prepared according to methods known from the literature (see H. Meyer, F. sossert and H. ~lorstmann, I,iebigs Ann. Chem. 1~395 (1977)).
As examples of starting compounds of formula X there may be mentioned:
2-dimethyl-amino-3,4-dihydro-6-methyl-4-(3-chlorophenyl)-pyridine-3,5-dicarboxyl-ic acid diethyl estert 2-dimethylamino-3,4-dihydro-6-ethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylie aeid diethyl ester, 2-dimethylamino-3,4-dihydro-6-propyl-~-(2'-methoxyphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester, 2-(pyrrolidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester, 2-(pyrrolidin-1-yl)-3,4-dihydro-6-ethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylic acid diethyl ester, 2-(piperidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester and 2-(piperidill-1-yl)-3,4-dihydro-6-methyl-~1-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester.
Prcferrcd noble metal catalysts arc platinum and platirlum dioxide and a pre~erred solvellt is ~laeial acetic acid.
Th~ reaetion temperature ean be varicd t~ithin a substalltial rangc.
In general, thc reaction is carried out at bctwcen 10 and 100 C, but prefcrably at room tcmperaturc.
The reac~ion can be carried out under normal pressure but also under elevated pressure. The use of slightly supera~mospheric pressure is particularly advantageous.
In carrying out thc process according to the invention, the 3,~-dihydrvpyridine derivative of the formula X, used as starting substance, is hydrogenated in the presence of a sui-table noble metal catalyst, in glacial acetic acid until the ~uimolar amo~mto~ hydrogen has been taken -up.
Depending on the choice of the starting substances, the compounds according to the invention may exist in stereoisomeric forms, whicll e:ither are related to one another like an image and its mirror image (cnantiomers~ or are not related to one another like an image and its mirror image (diastereomers~. Both the antipodes and the racemic forms, and also the diastereomer mixtures, form a subject of the present inven~ion. The racemic forms, like the diastereomers, can be separated in a known manner into the individual steroisomer components (see for example, E.L. ElielJ
Stereo-chemistry of Carbon Compounds, McGraw Hill, 1962).
The l,~-dihydropyridine compounds have a broad and diverse pharmacological action spectrurm.
In de-tail, -the Eollowing main actions can be demonstrated in animal experiments:
(1) On parenteral, oral and perlingual administra-tion -the compounds produee a distinct and long-lasting dilation of the coronary vessels. This action on the coronary vessels is intensified by a simul-taneous nitrite-like effeet of reducing the load on the heart. They influence or modify the heart metabolism in the sense of an energy saving.
(2) The exeitability of the stimulus formation and excitation con-duction system within the heart is lowered, so that an anti-fibrilla-tion action demonstrable at therapeutic doses results.
(3) The tone of the smooth muscle of the vessels is greatly reduced under the action of the compounds. This vascular-spasmolytic action can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular regions (such as, for example, the central nervous system). The compounds are there'core particularly suitable as cerebral thera-peutie agents.
A) ~ / N2 ~ ~ N02 ~5C22C ~ C2C2l~5 1-15C202C ~ -('2('2115 1-1 C~ l12N 2 5 -~12 113(. N ~ ~ C2115 2 5C22C ~ COzC2~ls ~5C22C ~ H H2C -21120 ~ H C N 2 5 !. -- 6 C) [~ N2 [~ NO2 H5C202C ~HH~CO2C2Hs HgC202CXl~ Co2c2Hs H3 C NH2 C2 H5 -H2 o ~13 C ~ c2 ~5 D ) [~ NO2 [~ NO2 H5C202C~cH H~ CO2C2HsH5C202C~, C2C2~ls + I ~ N
,C~ O C2 H5 ~ ~2 H2 H3 C H C2 H5 NH~
E) ~ ~ NO2 O'lH ~
Hs C2 ()2 C~cH H ~ COz C2 Hs Hs C2 02 C h CO2 C2 H5 ~ H2N C2H5 -2 H20HlC ~H C2Hs ~ NO2 F) ~ ~NO2 O H CO2C2 Hs HsC202C~ H H2C' _ -EDH5C20~Cl~CO~(,2~5 H, C NH2 C2 H5 ' H Ou~ C~ H5 Le A ? 3?2 ~ ~ CF3 5 2 2 ~ AcOH ~ ~ 2 2 5 Specific details of the various process variants are as follows:
Process variant A
The ylidene-R-keto-esters of the ~ormul.a II used as the starti.ng material are known from the literature or can be prepared accordinc3 to methods known from the literature (see, for example, G. Jones "The Knoevenagel Condensa-tion" in Orc3. Reactions, Vol. XV, 20~ et seq. (1967)).
As examples of esters of formula II there may be mentioned: benzyli-dene-formylacetic acid methyl es-ter, benzylideneacetoacetic acid methyl ester, 2'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid n-butyl ester, 2'-methoxybenzylideneacetoacetic acid isohutyl ester, 3'-nitrobenzylideneacetoacetic acid isopropyl ester, 3'-nitrobenzylideneacetoacetic acid 2-methoxyethyl ester, 2'-nitrobenzylideneacetoacetic acid isobutyl ester, 2'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitrobenzylideneacetoacetic acid ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-propoxy-ethyl ester, 3'-nitrobenzylideneacetoacetic acid benzyl ester, 3'-slitrobenzyliclcneacetoacetic acid 2-phellyl-ethyl ester, 3'-nitrobenzylideneacetoacetic acid 2-pllenoxy-ethyl ester, 2'-cyanobenzylideneacetoacetic acid ethyl ester, 2'-cyanobenzylidcnc-proL~ionylacetic acid ethyl ester, 2'-nitrobenzylidelleproL~iollyl~cetic acici methyl ester, 3'-nitrobenæylidenepropionylacetic acicl cthyl ester, 3'-nitrobenzyllderlc-propionylacetic acid 2-methoxycthyl estcr, 3'-nitrobcnzylidclle~)ropiollylacctic acid isopropyl estcr, 2'-nitrobcnzylidcncproE~iol)ylacctic acid isobutyl estcr, 2'-chlorobenzylidenepropionyl acetic acid methyl ester, 2'-cyanobenzylidene-isob~tanoylacetic acid e-thyl ester, 3'-nitrobenzylideneisobutanoylacetic acid ethyl ester, 2'-nitrobenzylideneisobutanoylacetic acid methyl es-ter, 2'-nitro-benzylideneisobu-tanoylacetic acid isobutyl ester, 3'-nitrobenzylideneisobutanoyl-acetic acid 2-methoxy-ethyl ester, 3'-ni-troben~ylidene-~-phenylacetoacetic acidethyl ester, 2'-nitrobenzylidene-~-phenylacetoace-tic acid methyl ester, 2'-nitrobenzylidene-y-phenylacetoacetic acid isobutyl ester, 3'-nitroben~ylidene-y-phenylacetoacetic acid isopropyl ester, 3'-nitrobenzylidene-~-phenylaceto-acetic acid 2-methoxy-ethyl ester and 2'-triEluoromethylbenzylidene-y-phenyl-acetoacetic acid ethyl ester.
Preferred starting compounds of formula III are those in which R has the same meanin~ as in the preferred compounds of formula II an~l R represents a hydro~en atom or represents a straight-chain or branched alkyl radical with 1 to ~, especially 1 to 4 carbon atoms, in which a hydro~en atom can be replaced by a satura-ted or unsaturated cyclic hydrocarbon radical with up to 6 carbon atoms, especially a phenyl radical.
The enaminocarboxylic acid esters of the formula III used as startin~
materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J.Amer. chem. Soc. 67, 1017 (1945~)-As examples of compounds of formula III therc may be mentioned:
B-amino-crotonic acid methyl ester, B-amino-crotonic acid ethyl cster, B-amino-B-ethyl-acrylic acid mcthyl ester, B-amino-B-ethyl-acrylic acid cthyl cster, B-amino-B-ethyl-acrylic acid isopropyl estcr, B-amino-B-cthyl-acrylic acid lleopentyl estcr, B-amillo-B-ethyl-acrylic acid bcnzyl ester, B-amino-~-cthyl-acrylic acid 2-phcnylethyl cstcr, B-amino-B-cthyl-acrylic acid 2-phclloxycthyl estcr, B-amino-B-propyl-acrylic acid methyl cstcr, g-amino-e-isopropyl-acrylic acid methyl estcr, B-~nino-B n-butyl-acrylic acid methyl cstcr, B-amino-B-isobutyl-acrylic acid methyl ester, ~-amino-~-cyclohexylmethyl-acrylic acid methyl ester, ~-amino-~-benzyl-acrylic acid methyl ester and ~-amino-~-(2-phenylethyl)-acrylic acid ethyl ester.
Sui-table diluen-ts are any of the inert organic solvents. These include as preferences alcohols (such as ethanol, methanol and isopropanol), e-thers (such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether and glycol dimethyl ether), glacial acetic acid, dime-thylEormamide, dimethyl-sulphoxide, acetonitrile, pyridine and hexamethylphosphorotriamide.
The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out at between 20 and 150 C, preferably between 20 and 100 C, especially at the boiling poin-t of the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, one mole of an ylidene-~-keto-ester of the formula II is reacted with one mole of an enamino-earboxylic acid ester of the formula II in a suitable solvent. The substances according to the invention are preferably isolated and purified by distilling off the solvent in vacuo and recrystallizing the residue, which may only be obtained in a crystalline form after cooling with ice, from a suitable solvent.
Procesc variant ~
Preferred ylidene-3-keto-ester starting compounds of the formula II
are those mentioned as preferred for reaction variant A.
Preferred starting compounds of formula V are those in which the radieals R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formula III.
Examples of the ylidene-~-~eto-esters of the formula II, used as starting materials, have already been listed under process variant A.
The ~-~etocarbo~ylic acid esters oE the Eormula V used as starting _ g _ materials are known fxom -the literature and can be prepared in accordance with methods known from the literature (see example, Do Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercap-tanen" ('7Reaction of Dike-tene with Alcohols, Phenols and Mercaptans"), in Houben-Weyl, Methoden der Organischen chemie (Methods of Organic Chemistry), Vol. VII/4, 230 et seq. (1968); and Y. Oikawa, K. Sugano and 0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).
As examples of esters of formula V there may be mentioned: aceto~
acetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid n~butyl ester, acetoacetic acid isopropyl ester, acetoacetic acid benzyl ester, aceto-acetic acid 2-phenyl-ethyl ester, acetoacetic acid 2-phenoxyethyl ester, propionylacetic acid methyl ester, propionylacetic acid ethyl ester, propiony]-acetic acid isopropyl ester, propionylacetic acid benzyl ester, propionylacetic acid 2-phenyl-ethyl ester, propionylacetic acid 2-phenoxyethyl ester, isobutano-ylacetic acid methyl ester, y-cyclohexylacetoacetic acid ethyl ester and ~-phenylacetoacetic acid methyl ester.
Suitable diluents are any of the inert organic solvents. These include, as ~references, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial range.
In general~ the reaction is carried out at between 20 and 150 C, but preferably at the bciling point of the particular solvent.
The reaction can be carried out under norma~ pressurea but also undcr elevatcd pressure. In gelleral, it is carried out under normal ~rcssure.
In carrying out the process according to the invention, the compounds participating in the reaction, of the formulac II and V, are each employed in molar amoullts. The aminc uscd is advantageously added in an c~cess of 1 to 2 moles. The compounds according to the invention can easily be purificd by recrystallization from a suitablc solvcnt.
Process variant C
Preferred starting materials of formulae VI and VII, are those in which the radicals R, R , R and R have the meanings mentioned for the preferred starting materials of formulae II and III under process vzriant A.
The ylidene-~-keto-esters of the formula VI, used as starting materials, are known from the li-terature or can be prepared in accordance with methods known from the literature (see, for example, G. Jones (The Knoevenage Condensation" in Org. Reactions, Vol. XV, 204 et seq. (1967)).
As examples of esters of formula VI there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula II.
The enaminocarboxylic acid esters of the formula VII used as starting materials are known from the literature or can be prepared in accordance with methods known from the literature (see A.C. Cope, J. Amer. Chem. Soc. 67, 10]7 ~1945)).
As examples oE esters of formula VII there may be mentioned those esters specifically mentioned under process variant A as examples of esters of formula III.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substantial ran~e.
In general, the reaction is carried out at between 20 and 150 C, prcferably botween 20 and 100 C, especially at the boiling point of the particular solvent.
The reaction can be carricd out under normal pressur~ but also under clovatcd pressurc. In general, it is carricd out under normal pressurc.
In carrying out the proccss according to the invention, onc molc of thc ylidcne-B-~cto-cster of the formula VI is rcactcd with one molc of cn~millo-carboxylic acid cstcr of the formula VII in a suitable solvent.
Process variant D
Preferred ylidene-~-keto-ester starting compounds oE the formula VI
are those mentioned as preferred for reaction variant C.
Preferred s-tarting compounds of formula VIII, are those in which the radicals R and R have -the meaning mentioned under process variant A in respect of preferred compounds oE formula II.
Examples of the ylidene-~-keto-esters of -the formula VI used as starting compounds have already been listed under process variant C.
The ~-ketocarboxylic acid esters of -the formula VIII ~lsed as star-ting materials are known from the literature or can be prepared in accordance with methods known from the literature (see for examp]e, D. Borrmann "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" ("Reaction of Diketene with ~lcohols, Phenols and Mercaptans"), in ~louben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. VII~4, 230 e-t seq. (1968); and Y.
Oikawa, K. Sugano and O. Yonemi-tsu, J. Org. Chem. 43, 2087 (1978)).
As examples of esters of formula VIII there may be mentioned those esters specifically mentioned under process variant B as examples of esters of formula V.
Suitable diluents are any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a substalltial range.
In general, the reaction is carricd out at betweell 20 and 150 C, but preferably at the ~oiling pOillt of the particular solvent.
Thc reactlon can be carried out ullder non~al pressure but also ullder elevatecl prcssurc. In general, it is carricd out undcr normal pressure.
In carrying out thc i~rocess according to thc invelltioll, the com~oullds participating in thc rcactioll, of the formulae VI and VIII, are eaell cmployccl in molar amounts. Thc amillc used ~s advalltagcously addcd ill arl cxccss o 1 to 2 moles.
_ocess variant E
PreEerred ester starting compounds of -the formula III are those mentioned as preEerred for reaction variant A~ Preferred ester starting com-pounds of the formula VIII are those mentioned as preferred for reaction variant D.
Preferred starting compounds of formula IX are those in which the radicals R, R , R and R have the meanings mentioned under process variant A, in respect of preferred compounds of formulae II and III.
The aldehydes of the formula IX, used as s-tar-ti.ncJ materials, are known from ~he literature or can be prepared in accordance with methods known from the literature (see, Eor example, E. Mosettig, Org. Reactions VIII, 218 et seq.
~195~)).
As examples of aldehydes of formula IX there may be mentioned:
benzaldehyde, 2-, 3- or ~-methoxybenzaldehyde, 2-, 3- or ~-chloro-, bromo- or fluoro-benzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde, 2-, 3- or 4-nitro-benzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2,3- or 2,6-dichlorobenzaldehyde, 2,~- or 2,6-dinitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, ~-chloro-2 nitrobsnzaldehyde, 2-nitro-~-methoxybenzaldehyde, 2-nitro-~l-cyanobenzaldehyde, 2-chloro-~-cyanobenzaldehyde and 3-chloro-~-trifluoromethylbenzaldehyde.
Examples of the enaminocarboxylic acid esters of the formula III, used as starting compounds have already bcen listed under process variant A, and examples of the ~-kctocarboxylic acid csters of the formula VIII, used as starting compounds have already been listcd under proccss variant D.
Suitablc diluents are any of the incrt organic solvents. Thcse include, as preferences, those mentioned for reactioll variant A.
Thc reaction tcmperatures can be varied within a substalltial rangc.
In gcncral, thc reactioll is carricd out at bctwccn 20 and 150 C, but pre~crJbly at the hoiliny point of -the particular solvent.
The reaction can be carried out under normal pressure but also under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the inven-tion, the compounds participating in the reaction, of the formulae IX, III and VIII, are each employed in molar amounts.
Process variant F
Preferred aldehyde starting compounds of the formula IX are those mentioned as preferred for reaction varian-t E.
Preferred ester starting compounds of -the formula V are those men-tioned as preEerred Eor reaction variant B, preferred ester starting compounds of formula VII are those mentioned as preferred for reaction variant C.
Examples oE the aldehydes of the formula IX used as starting compounds are listed under prorcess variant E, examples of the enaminocarboxylic acid esters of the formula VII are listed under process variant C and examples of the ~-ketoearboxylic aeid esters of the formula V are listed under process variant ~.
Suitable diluents axe any of the inert organic solvents. These include, as preferences, those mentioned for reaction variant A.
The reaction temperatures can be varied within a s~lbstantial range.
In general, the reaction is carried out atbetween20 and lS0 C, but preferably at th~ boiling point of the particular solvent.
The reaction can be carried out under nor~nl pressure but al.so under elevated pressure. In general, it is carried out under normal pressure.
In carrying out the process according to the invention, the compounds partieipatillg in the reaction, of the Eormulae IX, VII and V, are each employed in molar amounts.
Process variant G
PreEerred startiny compounds of formula X are those in which the 5~
radieals R, R and R have the meanings mentioned under process variant ~, in respeet of preferred compounds of formula II with the restriction that the radicals R, R and R do not con-tain any func-tional groups which can undergo ehange under hydro~enating conditions, and provided R is different from hydro-yen and R represents a hydrogen a-tom, and in which, R and R , which can be identical or different, represent an alkyl radical with 1 to ~ carbon atoms, espeeially with 1 or 2 carbon atoms, or the radicals R and R together with the exocyelie nitrogen atom form a 5-membered to 7-membered he-teroeyclic ring.
The 2-dialkylamino-3,4--dihydropyridines of the formula X, used as starting materials, are known Erom the literature or can be prepared according to methods known from the literature (see H. Meyer, F. sossert and H. ~lorstmann, I,iebigs Ann. Chem. 1~395 (1977)).
As examples of starting compounds of formula X there may be mentioned:
2-dimethyl-amino-3,4-dihydro-6-methyl-4-(3-chlorophenyl)-pyridine-3,5-dicarboxyl-ic acid diethyl estert 2-dimethylamino-3,4-dihydro-6-ethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylie aeid diethyl ester, 2-dimethylamino-3,4-dihydro-6-propyl-~-(2'-methoxyphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester, 2-(pyrrolidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester, 2-(pyrrolidin-1-yl)-3,4-dihydro-6-ethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylic acid diethyl ester, 2-(piperidin-l-yl)-3,4-dihydro-6-methyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-diearboxylie aeid diethyl ester and 2-(piperidill-1-yl)-3,4-dihydro-6-methyl-~1-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester.
Prcferrcd noble metal catalysts arc platinum and platirlum dioxide and a pre~erred solvellt is ~laeial acetic acid.
Th~ reaetion temperature ean be varicd t~ithin a substalltial rangc.
In general, thc reaction is carried out at bctwcen 10 and 100 C, but prefcrably at room tcmperaturc.
The reac~ion can be carried out under normal pressure but also under elevated pressure. The use of slightly supera~mospheric pressure is particularly advantageous.
In carrying out thc process according to the invention, the 3,~-dihydrvpyridine derivative of the formula X, used as starting substance, is hydrogenated in the presence of a sui-table noble metal catalyst, in glacial acetic acid until the ~uimolar amo~mto~ hydrogen has been taken -up.
Depending on the choice of the starting substances, the compounds according to the invention may exist in stereoisomeric forms, whicll e:ither are related to one another like an image and its mirror image (cnantiomers~ or are not related to one another like an image and its mirror image (diastereomers~. Both the antipodes and the racemic forms, and also the diastereomer mixtures, form a subject of the present inven~ion. The racemic forms, like the diastereomers, can be separated in a known manner into the individual steroisomer components (see for example, E.L. ElielJ
Stereo-chemistry of Carbon Compounds, McGraw Hill, 1962).
The l,~-dihydropyridine compounds have a broad and diverse pharmacological action spectrurm.
In de-tail, -the Eollowing main actions can be demonstrated in animal experiments:
(1) On parenteral, oral and perlingual administra-tion -the compounds produee a distinct and long-lasting dilation of the coronary vessels. This action on the coronary vessels is intensified by a simul-taneous nitrite-like effeet of reducing the load on the heart. They influence or modify the heart metabolism in the sense of an energy saving.
(2) The exeitability of the stimulus formation and excitation con-duction system within the heart is lowered, so that an anti-fibrilla-tion action demonstrable at therapeutic doses results.
(3) The tone of the smooth muscle of the vessels is greatly reduced under the action of the compounds. This vascular-spasmolytic action can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular regions (such as, for example, the central nervous system). The compounds are there'core particularly suitable as cerebral thera-peutie agents.
(4) The compounds lower the blood pressure of normotonlc and hyper-tonie animals and ean thus be used as anti-hypertensive agents.
(5) The eompounds have strongly muscular-spasmolytic actions which maniEest themselves on the smooth muscle oE the stomach, the intestinal tract, the urogenital tract and the respiratory system.
On the basis of these properties, the compounds accorcling to the inven-tion are particularly suitable Eor the prophylaxis and therapy of acute ancl chronic isehaemic heart disease in the broadest sense, for the theral~y oE
hy~ortension and for the troatmellt of cerebral ancl peripheral circulation disordors.
As stated abo~e, the ir.vention also relates tc the use in human and veterinary medicine of the compounds of the inventior..
~ he present invention provides a pharmaceutical com~osition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent~ or in admixture with a liquid diluent other than a solvent of a molecular weîght less than 200 (preferabiy less than 350) except in the presence of a surface active agent.
The invention further prov des a pharmaceutical composition ccntaining as active ingredient a compound of the nvention in t~e fcrm of a sterile and/or physiologically isotcnic aqueous solutior..
The invention also provides a medicament in dosage unit form comprising 2 compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a co~.pound of the invention.
"~edicament'l as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dos2ge unit form" as used in this Specification means physically discrete coherent units suitatle for medical admlnistratior.
each containing a daily dose or a multip'e (bp to four times) or ~ubmultiple (dowr. to a fortieth) of a daily dose of the compound of the invention in association with a carrier ~nd/or enclosed within ar. envelope. ~Ihether the medicament contains a àaily dose or, for ex2mple, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be acministered or.ce or, for ex2mple, twice, three times cr fcur times a day respectively.
~ e pharmaceutical com~osition according to the invention m2y, for example~ take the form cf ointments, gels, pastes, creams, sprays (ir.cludir.g .
Le A 2C ~22 .
aerosols), lotions, suspensions, solutions an~ emulsions of the active ingredient in aqueous or non-aqueous diluen~s~ syr~ps~ ~rar.ulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adap~ed to be ~ormed in~o tablets, dragees, capsules and pills include the ~ollowing:
(a) ~illers and ex~enders~ eOg. starch, sugars, mannitol, ar.d silicic acid; ~b) binding agents9 e.g. carboxyIr.ethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvir.yl pyrrolidone;
(c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbor.ate; (e) ager.ts ~or retardin~ dissolution e.g paraffin; (f) resorption accelerators, e.~.
quaternary ~I~.oniu~. compounds;~(g) surface active agents, e.g. cetyl alcohol, g1ycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite;
(i) lubricants, eOg. talc, calcium and ~ragnesium stearate and solid polyethyl glycols~
The tablets, dragees, capsules artd pills ~ormed from the pharmaceutical compositior.s of the inventior.
can have the custor.ary coatings, envelopes ar.d protective ~atrices, ~hich may contain opacif-ers. They can be so constituted that they release the ~ctive ingredient only or preferably in a part cular part of the intestinal tract, possi~ly over a period o~ ti~e. ~he coatirgs, envelopes and protective matrices Ir.ay be made, for example, of pclymeric substances or ~laxes.
The ingredient can ~lso be made up in tr,icrcencap~
sulated rorm together with one or several of the above-~entioned diluents.
The diluer.ts to be used in phar~.aceutical corrpositions adapted to be ror~.ed into suppositor.es can~ for example, ~e the usual hater-solu~le diluents, suc~.
as pclyethyler.e ~lycols and fats (e.g. cocoa c l ar.c high esters (e.g. C14-alcchol with C16~atty acid)) or rr.ixtures of these diluer.ts.
Le A 20 322 _ _ ~ he phar~aceutical compositions which are ointments~
pastes~ creams and ~els can, for example, contain the usual diluents, e.g. animal and vegetable ~ats, waxes, paraffins9 starch, tragacanth9 cellulose derivatives, polyethylene ~lycols, silicones 3 bentonites, silicic acid, ~alc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can9 for exa~ple~ contain the usual diluents, e g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances~ Aerosol sprays can, for ex~mple, contain the usual propellants, e.g. chlorofluorohydro~
carbons.
The pharmaceutical compositions which are solutions and emulsions car., for example, contain the customary diluents (with, of course~ the above ~entioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent)~
such as solvents, dissolving agents and emulsifiers;
specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbor.ate, ethyl acetate9 berzyl alcohol, benzyl benzoate, prcpylene glycol, l,3-butylene glycol, dimethyl~ormamide, oils (for example ground nut oil), glycerol, tetrahydrc-f`urfuryl alcohol, polyethylene glycols ar.d fatty aci~ esters of sorbitol or mixtures thereof.
For parenteral administratior., solutior.s and emulsions should be sterile9 ar.d, i, appropriate9 blood-isotor.icO
The pharmaceutical composit ons ~hich are suspensions can ccnta_n the usual diluents, such as li~uld diluer.ts, e.~. water, et~.yl alcohcl, pro~ylene ~lycol3 surface-acti~e a~ents (e.g ethoxylated sostearyl alcohcls~ polyoxyethylene sorb te ar.d sorbitane esters), mic~ocrystalline cellulose~ aluminium ~.eta-hydroxide, benton te, a~ar-agar ar.d tragacar.th or mixtures thereor.
Le A 20 ~2Z
s~
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservative as well as perfumes ard flavourinG
additions (e.g. peppermint oil anà eucalyptus oil~
and sweetening agents (e~g. saccharin).
The pharmaceutical compositions accoxding to the invention generally contain from 0.5 to 90%
of the active ingredient by weight of the total composition.
In addition to a cor~nd of the inventlon, the pharmaceutical compositions and medica~ents according to the i.nventi.on can also contain other pharmaceutically active compounds. They may also contain a plural ty of ccmpounds of the in~-ention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of` molecular weight less than 200 as sole diluent.
The discrete coherent portions constituting the r.~.edicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administratior. and may be, for example, any of the followin~: tablets (ir.cluding lozen~es and granula~es) 3 pills, dragees, capsules, suppcsitories and a~.poules. Some of these forms may ~e made ~Ip for delayed release of the active ingreAient.
Some, such as capsules, include a protective envelope which ren~ers the portions of the medicament physically discrete and coherent.
~ .e preferred dail~ dose for administraticr cf the ~e~icaments of t~.e inventlon is 2.5mg to 25Gm~ of acti~e ingredient in the case of intravenous 2dmir.istr2tion and 25mg to 250~g of active in~redient in the case of oral administratior..
Le A 2G- 322 The production of the above-~lentioned pharmaceutical compositions and medicaments is carried out by any method known in the art~ for exam~le, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition te.g. a granulate) and then forming the composition into the medicament - (e.~. tablets).
This invention further provides a method of combating (i.ncluding prevention, relief and cure of) the above mentioned diseases in human and non-human ani~als3 which comprises administering tothe animals a compound of the invention alone or in admixture with a dlluent or in the form of a medicament according to the inventior..
It is envisaged that these active compounds will be administered perorally, Farenterally (f'or example intramuscularly, intraperitoneally, sub-cutaneously and intravenously), rectally or locallyl preferably orally or parenterally, especially perlingually or intravenously. Preferred pharmaceutical compositions and medicaments are theref'ore those adapted for administration such as oral or parenteral administration.
Administration in the method of the invention is preferably oral or parenteral administration In general it has proved advantageous to administer amounts of from O.OOlmg to lOm~/kg, preferably 0~05~g to 5mg/kg, of body weight per day in the case of intravenous administratior., and 0.05mg to 20mg/kg, preferably 0.5mg to 5mg/k~ of body wei~ht per day, ir. the case Or oral administration, to achieve effective results.
Nevertheless, it can at times be necessar~ to deviate from those dosage rates, and in particul~r to do so as a function of the nature and body we ght of the human or animal subject to be treated, the individual reaction of this su~ject to the tre2tment, the tJpe of formulation in hhich the active in~redient is admir.istered and the mode in which the administration is carried out, and t~.e point in t~.e progress Or Le A 2~ 322 the disease or interval at which it is to be administered. Thus i-t may in some casessuffice to use less than the above-mentioned minimum dosage rate~ whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
The following Examples illustrate processes for the production of 1,4 dihydropyridine compounds.
~ e 1.
1,4-Di]lydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-375-dicarboxylic acid dimethyl ester.
~N02 113C02C ~ C2CH3 Process variant A
_.~.. _ A solution of 1~.7 g (75 mmoles) of 2'-nitro-benzylideneacetoacetic acid methyl ester and 9.7 g (75 mmoles) of ~-amino-~ ethyl-acrylic acicl methyl ester in 100 ml of methanol was heated to the boil,uncler nitrogenJ
tor 1~ hollrs. AEter the reaction mixture had cooled, the solvent was distilled oE:E _ vacuo and_ the oily residue was triturated with a small amount of ether, whereupon the crude product soon solidified.
It was filtered off and recrys-tallised from methanol, Melting point: 157C; yield: 16,9 g (6~%).
~ E~
~C202C ~r~ CO2C2 I ~
~3 ~; ~ H C3 .i7 (n) Analogously to Example 1, reac-tion of 2'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2 propyl-6-me-thyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 110C (ethanol), Yie~d: 48% of theory.
Example 3 o2 (CH~)2HC02C ~ C02-CH(C~)2 ~,C 1`' `'2--~
Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid isopropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropanol gave 1,4-dihydro-2-e-thyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 140C (ethanol)~
Yield: 28,~ of theory.
Le A 20 322 ~s~
Exam~ 4 ~ ~0~
H3C02C ~ CO~C~
H3C N CH2 ~
Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid methyl ester with ~ amino-~
benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180C (rnethanol).
Yield: 31% of theory.
Example ~ -~, NO2 -H,C0zC ~ C0zCH~
H, C ~ [ C2 H5 Analogously to Example 1, reac-tion of 3'~nitro-benzylideneacetoace-tic acid methyl ester with ~-amino-~-ethyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl ester of melting poin-t 159C
(methanol).
Yield: 60~ of theory.
Exam~le 6 H5C22C ~ " ~, C2C2Hs ~ ~
~3C ~i C3~7(n~
h . Le A 20_~22 Analogously -to Example 1, reaction of 3'-ni-tro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-methyl-4-(3-ni-trophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 1~6C (ethanol).
Yield: 70% of theory.
Example 7 ~ NO2 ( CH s ) 2 HC02 C ~[ CO2 CH( CH3 ) 2 H5 C r~ ~`2 r5 Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid iso~ropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropan-ol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 108C (methanol).
Yield: 22% of theory le 8 ,~ NO2 H3C0-~2C-H2C02C ~ C0z-CH2-CH2-OCH.
C ~I
H
Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid 2-methoxyethyl ester with 3-amino-3-ethyl-acrylic acid 2-methoxyethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid bis-(2-methoxy-ethyl) ester of melting point 86C.(methanol).
Yield: 55% of theory Le A 20 322 ~35 ~;-J
2 C2 C~ CC2 ~ 2 ~
~.yC N ~2H~
H
Analogously to Example 1, reac-tion of 3'-nitro-benzylideneace-toacetic acid benzyl ester with ~-amino~3-e-thyl-acrylic acid benzyl ester in ethanol gave 1,4-dihydro-2-e-thyl-6-me-thyl-4-(3-nitrophenyl)-pyridine-3~5-dicarboxy-lic acid dibenzyl ester o~ melting point 102C (e-thanol).
Yield: 65% of theory.
Example 10 ~, NO2 ~ ' ~, Cz 2 C ~, CC~ C,~ .15 H,C ~`~ CH2 ~
Analogously to Example 1, reaction of 3'-ni-tro-benzylideneacetoace-tic acid ethyl ester with ~-amino-~cyclohexylmethyl--acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-cyclohexylmethyl-6 methyl-4-(3-nitro-phenyl)-pyridine-3~5-dicarboxylic acid diethyl ester o~
melting point 153C (ethanol).
Yield: 69% of theory.
;J2 ' ~
H~ C02 C ~,C02 C~.
~ C ~ ~ Cri2 ~
Analogously to Example 1j reaction of 3'-nitro-benzylideneacetoacetic acid methyl ester with ~-amino-~-Le A 20 322 benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-me-thyl~4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 166 C
(ethanol).
Yield: 630~o of theory.
[ ~ Cl H3 C02 C ~[ C02 C~i H3C H C2~g Analogously to Example 17 reaction of 2'-chloro-benzylideneacetoacetic acid methyl es-ter with ~-amino-~-10 e-thyl-acrylic acid methyl ester in methanol gave l,4-dihy-dro-2-ethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-di-carboxylic acid dimethyl ester of melting point 147C
(methanol).
Yield: 36% of theory.
15 Example 13 l 11 ~ Cl HS C2 O2 C ~ 2 C2 -~
~ ~l H3C ~ C, ~ (n) Analogously to Example 1, reaction of 2l-chloro-benzylideneacetoacetic acid ethyl ester with ~ amino~
propyl-acryllc acid ethyl ester in e-thanol gave l,4-dihydro-20 2-propyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5 dicar-boxylic acid diethyl ester of melting point 100C (ethanol).
Yield: 27% of theory.
Example 14 ~f Cl H C ~ C~
Le A 20 322 _ _ s~
Analogously to Example 1, reac-tion of 2' chloro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-cyclohexylmethyl-acrylic acid ethyl ester in ethanol gave l,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 117C (e-thanol).
Yield: 29% of theory.
Exam~le 15 ~ CN
H~Cz02C ~CO2CzH5 H~C ~ C2Hs Analogously to Example 1, reaction of 2'-cyano benzylideneacetoacetic acid ethyl ester wi-th ~-amino-~-e-thyl-acrylic acid ethyl ester in ethanol ga~e 1,4-di-hydro-2-ethyl-6-methyl-4~(2-cyanophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting polnt 12~C
(ethanol), Yield: 47% of theory.
Example 16 ~' ~ CF3 H5C20z~ ~ C0~C2~5 H3C N C~U7(h) Analogously -to Example 1, reaction of 2'-tI`i-~luoromethylbenzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-me-thyl-4-(2-trifluorome-thyl-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 95C (isopropanol).
Yield: 48% of -theory.
Le A 20 ~22 2.~
~c*
Hs C2 2 C ~ ~~ C2 r,~
J~ I
HIC ~ r2 -q5 Analogously -to Example 1, reaction of 2'--tri-fluoromethylbenzylideneacetoace-tic acid ethyl es-ter wi-th ~-amino-~-ethyl.-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2 ethyl-6-methyl-4-(2-trifluorome-thylphenyl)-pyr.idine-3,5-dicarboxylic acid diethyl es-ter o~ mel-ting poin-t 81C (isopropanol).
Yield: 62% of theory.
Example 18 02C ~ CO C2 l I
H~C ~ ~ ' ~ _u~ ~?
Analogously to Example 1, reaction o~ 2'-nitro-beriz.ylideneacetoacetic acid ethyl ester with ~-amino-~-isopropyl-acrylic acid ethyl ester in ethanol ga~e 1~4-15 dihydro-2-isopropyl-6-methyl-4 (2-nitrophenyl)-pyridine--3,5-dicarboxylic acid diethyl ester of mel-ting point 117C (eth~nol).
Yield: 28~ of -theory, Exam~le 19 W`-~JO 2 H5Cl03C 1 co.c. ~s ll ~
H3C ~ C2~5 Le A 20 322 Analogously to Example 1, reac-tion of 2'-nitro-benzylideneacetoacetic acid ethyl es-ter with ~-amino-~-ethyl~acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3 7 5-dicarboxylic acid diethyl es-ter of melting point 124C
(e-thanol).
Yield: 35% of theory.
1,4-Dihydro-2-methyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl es-ter C~~
HsC20~C~"CO2c2~s ~3C H
Process variant G
4.5 g (10 mmols) of 3,4-dihydro-6~methyl-2-(pyrrolidin-1-yl)-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester were hydrogenated in 150 ml of glacial acetic acid over platinum-(IV) oxide, in a shaking apparatus, at 3.5 atmospheres gauge, until the equivalent amo~t of hydrogen had been taken up (about 2 hours). The ca-talyst was -then filtered off and the filtrate was concentrated in vacuo. The residue was taken up in chloroform and chroma-tographed over a silica gel column (chloroform/ethyl acetate =
10:1), an analytically pure product, of melting point 95-96C, being obtained af-ter concentrating the eluate.
Yield: 28% of theory.
Le A 20 322 __ I T
1--I 0 0 N In ~
., ,-o o~
~r~ ~rl t~l r-- ~~
O O O
'r'l ~ Z ~O 2 r~
~rl h O ~ O Q O ~0 ~0 o O
_, a ~q r~
~ ~ ~ _ ~ ~
O ~
---- r~
O O
r-~ bO
~ O
~ 0~
rl h 'O P~
~1 O r~
Le A 20 322 ~o ~ D (`J
-~ c o ~ c~
o o ~ ~ ~ ~
F ~ ~ C,~
.,~
, t~
~r o ~1 = = _ _ 0 ~1 ~ + ~ r~ r~ r~l r~
O ~ ~
r-l ~1 ~ ~i o O
b~ ~d , .
O
,~,, a) h X ~;~;
Le A 20 322 5~12 The present invention also co~.prises pharmaceutically acceptable bioprecursors o~ the active ccmpounds of the present invention.
For the purposes of this specification the term 'pharmaceuticall~ acceptable bioprecursor''of an active compound of the invention means a compound having a structural formula di~ferent from the active compound but ~Jhich nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.
Le ~'20 ~22 . .
- 3~1 -
On the basis of these properties, the compounds accorcling to the inven-tion are particularly suitable Eor the prophylaxis and therapy of acute ancl chronic isehaemic heart disease in the broadest sense, for the theral~y oE
hy~ortension and for the troatmellt of cerebral ancl peripheral circulation disordors.
As stated abo~e, the ir.vention also relates tc the use in human and veterinary medicine of the compounds of the inventior..
~ he present invention provides a pharmaceutical com~osition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent~ or in admixture with a liquid diluent other than a solvent of a molecular weîght less than 200 (preferabiy less than 350) except in the presence of a surface active agent.
The invention further prov des a pharmaceutical composition ccntaining as active ingredient a compound of the nvention in t~e fcrm of a sterile and/or physiologically isotcnic aqueous solutior..
The invention also provides a medicament in dosage unit form comprising 2 compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a co~.pound of the invention.
"~edicament'l as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dos2ge unit form" as used in this Specification means physically discrete coherent units suitatle for medical admlnistratior.
each containing a daily dose or a multip'e (bp to four times) or ~ubmultiple (dowr. to a fortieth) of a daily dose of the compound of the invention in association with a carrier ~nd/or enclosed within ar. envelope. ~Ihether the medicament contains a àaily dose or, for ex2mple, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be acministered or.ce or, for ex2mple, twice, three times cr fcur times a day respectively.
~ e pharmaceutical com~osition according to the invention m2y, for example~ take the form cf ointments, gels, pastes, creams, sprays (ir.cludir.g .
Le A 2C ~22 .
aerosols), lotions, suspensions, solutions an~ emulsions of the active ingredient in aqueous or non-aqueous diluen~s~ syr~ps~ ~rar.ulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adap~ed to be ~ormed in~o tablets, dragees, capsules and pills include the ~ollowing:
(a) ~illers and ex~enders~ eOg. starch, sugars, mannitol, ar.d silicic acid; ~b) binding agents9 e.g. carboxyIr.ethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvir.yl pyrrolidone;
(c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbor.ate; (e) ager.ts ~or retardin~ dissolution e.g paraffin; (f) resorption accelerators, e.~.
quaternary ~I~.oniu~. compounds;~(g) surface active agents, e.g. cetyl alcohol, g1ycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite;
(i) lubricants, eOg. talc, calcium and ~ragnesium stearate and solid polyethyl glycols~
The tablets, dragees, capsules artd pills ~ormed from the pharmaceutical compositior.s of the inventior.
can have the custor.ary coatings, envelopes ar.d protective ~atrices, ~hich may contain opacif-ers. They can be so constituted that they release the ~ctive ingredient only or preferably in a part cular part of the intestinal tract, possi~ly over a period o~ ti~e. ~he coatirgs, envelopes and protective matrices Ir.ay be made, for example, of pclymeric substances or ~laxes.
The ingredient can ~lso be made up in tr,icrcencap~
sulated rorm together with one or several of the above-~entioned diluents.
The diluer.ts to be used in phar~.aceutical corrpositions adapted to be ror~.ed into suppositor.es can~ for example, ~e the usual hater-solu~le diluents, suc~.
as pclyethyler.e ~lycols and fats (e.g. cocoa c l ar.c high esters (e.g. C14-alcchol with C16~atty acid)) or rr.ixtures of these diluer.ts.
Le A 20 322 _ _ ~ he phar~aceutical compositions which are ointments~
pastes~ creams and ~els can, for example, contain the usual diluents, e.g. animal and vegetable ~ats, waxes, paraffins9 starch, tragacanth9 cellulose derivatives, polyethylene ~lycols, silicones 3 bentonites, silicic acid, ~alc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can9 for exa~ple~ contain the usual diluents, e g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances~ Aerosol sprays can, for ex~mple, contain the usual propellants, e.g. chlorofluorohydro~
carbons.
The pharmaceutical compositions which are solutions and emulsions car., for example, contain the customary diluents (with, of course~ the above ~entioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent)~
such as solvents, dissolving agents and emulsifiers;
specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbor.ate, ethyl acetate9 berzyl alcohol, benzyl benzoate, prcpylene glycol, l,3-butylene glycol, dimethyl~ormamide, oils (for example ground nut oil), glycerol, tetrahydrc-f`urfuryl alcohol, polyethylene glycols ar.d fatty aci~ esters of sorbitol or mixtures thereof.
For parenteral administratior., solutior.s and emulsions should be sterile9 ar.d, i, appropriate9 blood-isotor.icO
The pharmaceutical composit ons ~hich are suspensions can ccnta_n the usual diluents, such as li~uld diluer.ts, e.~. water, et~.yl alcohcl, pro~ylene ~lycol3 surface-acti~e a~ents (e.g ethoxylated sostearyl alcohcls~ polyoxyethylene sorb te ar.d sorbitane esters), mic~ocrystalline cellulose~ aluminium ~.eta-hydroxide, benton te, a~ar-agar ar.d tragacar.th or mixtures thereor.
Le A 20 ~2Z
s~
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservative as well as perfumes ard flavourinG
additions (e.g. peppermint oil anà eucalyptus oil~
and sweetening agents (e~g. saccharin).
The pharmaceutical compositions accoxding to the invention generally contain from 0.5 to 90%
of the active ingredient by weight of the total composition.
In addition to a cor~nd of the inventlon, the pharmaceutical compositions and medica~ents according to the i.nventi.on can also contain other pharmaceutically active compounds. They may also contain a plural ty of ccmpounds of the in~-ention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of` molecular weight less than 200 as sole diluent.
The discrete coherent portions constituting the r.~.edicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administratior. and may be, for example, any of the followin~: tablets (ir.cluding lozen~es and granula~es) 3 pills, dragees, capsules, suppcsitories and a~.poules. Some of these forms may ~e made ~Ip for delayed release of the active ingreAient.
Some, such as capsules, include a protective envelope which ren~ers the portions of the medicament physically discrete and coherent.
~ .e preferred dail~ dose for administraticr cf the ~e~icaments of t~.e inventlon is 2.5mg to 25Gm~ of acti~e ingredient in the case of intravenous 2dmir.istr2tion and 25mg to 250~g of active in~redient in the case of oral administratior..
Le A 2G- 322 The production of the above-~lentioned pharmaceutical compositions and medicaments is carried out by any method known in the art~ for exam~le, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition te.g. a granulate) and then forming the composition into the medicament - (e.~. tablets).
This invention further provides a method of combating (i.ncluding prevention, relief and cure of) the above mentioned diseases in human and non-human ani~als3 which comprises administering tothe animals a compound of the invention alone or in admixture with a dlluent or in the form of a medicament according to the inventior..
It is envisaged that these active compounds will be administered perorally, Farenterally (f'or example intramuscularly, intraperitoneally, sub-cutaneously and intravenously), rectally or locallyl preferably orally or parenterally, especially perlingually or intravenously. Preferred pharmaceutical compositions and medicaments are theref'ore those adapted for administration such as oral or parenteral administration.
Administration in the method of the invention is preferably oral or parenteral administration In general it has proved advantageous to administer amounts of from O.OOlmg to lOm~/kg, preferably 0~05~g to 5mg/kg, of body weight per day in the case of intravenous administratior., and 0.05mg to 20mg/kg, preferably 0.5mg to 5mg/k~ of body wei~ht per day, ir. the case Or oral administration, to achieve effective results.
Nevertheless, it can at times be necessar~ to deviate from those dosage rates, and in particul~r to do so as a function of the nature and body we ght of the human or animal subject to be treated, the individual reaction of this su~ject to the tre2tment, the tJpe of formulation in hhich the active in~redient is admir.istered and the mode in which the administration is carried out, and t~.e point in t~.e progress Or Le A 2~ 322 the disease or interval at which it is to be administered. Thus i-t may in some casessuffice to use less than the above-mentioned minimum dosage rate~ whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
The following Examples illustrate processes for the production of 1,4 dihydropyridine compounds.
~ e 1.
1,4-Di]lydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-375-dicarboxylic acid dimethyl ester.
~N02 113C02C ~ C2CH3 Process variant A
_.~.. _ A solution of 1~.7 g (75 mmoles) of 2'-nitro-benzylideneacetoacetic acid methyl ester and 9.7 g (75 mmoles) of ~-amino-~ ethyl-acrylic acicl methyl ester in 100 ml of methanol was heated to the boil,uncler nitrogenJ
tor 1~ hollrs. AEter the reaction mixture had cooled, the solvent was distilled oE:E _ vacuo and_ the oily residue was triturated with a small amount of ether, whereupon the crude product soon solidified.
It was filtered off and recrys-tallised from methanol, Melting point: 157C; yield: 16,9 g (6~%).
~ E~
~C202C ~r~ CO2C2 I ~
~3 ~; ~ H C3 .i7 (n) Analogously to Example 1, reac-tion of 2'-nitro-benzylideneacetoacetic acid ethyl ester with ~-amino-~propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2 propyl-6-me-thyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 110C (ethanol), Yie~d: 48% of theory.
Example 3 o2 (CH~)2HC02C ~ C02-CH(C~)2 ~,C 1`' `'2--~
Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid isopropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropanol gave 1,4-dihydro-2-e-thyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 140C (ethanol)~
Yield: 28,~ of theory.
Le A 20 322 ~s~
Exam~ 4 ~ ~0~
H3C02C ~ CO~C~
H3C N CH2 ~
Analogously to Example 1, reaction of 2'-nitro-benzylideneacetoacetic acid methyl ester with ~ amino-~
benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-methyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180C (rnethanol).
Yield: 31% of theory.
Example ~ -~, NO2 -H,C0zC ~ C0zCH~
H, C ~ [ C2 H5 Analogously to Example 1, reac-tion of 3'~nitro-benzylideneacetoace-tic acid methyl ester with ~-amino-~-ethyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl ester of melting poin-t 159C
(methanol).
Yield: 60~ of theory.
Exam~le 6 H5C22C ~ " ~, C2C2Hs ~ ~
~3C ~i C3~7(n~
h . Le A 20_~22 Analogously -to Example 1, reaction of 3'-ni-tro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-methyl-4-(3-ni-trophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 1~6C (ethanol).
Yield: 70% of theory.
Example 7 ~ NO2 ( CH s ) 2 HC02 C ~[ CO2 CH( CH3 ) 2 H5 C r~ ~`2 r5 Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid iso~ropyl ester with ~-amino-~-ethyl-acrylic acid isopropyl ester in isopropan-ol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 108C (methanol).
Yield: 22% of theory le 8 ,~ NO2 H3C0-~2C-H2C02C ~ C0z-CH2-CH2-OCH.
C ~I
H
Analogously to Example 1, reaction of 3'-nitro-benzylideneacetoacetic acid 2-methoxyethyl ester with 3-amino-3-ethyl-acrylic acid 2-methoxyethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid bis-(2-methoxy-ethyl) ester of melting point 86C.(methanol).
Yield: 55% of theory Le A 20 322 ~35 ~;-J
2 C2 C~ CC2 ~ 2 ~
~.yC N ~2H~
H
Analogously to Example 1, reac-tion of 3'-nitro-benzylideneace-toacetic acid benzyl ester with ~-amino~3-e-thyl-acrylic acid benzyl ester in ethanol gave 1,4-dihydro-2-e-thyl-6-me-thyl-4-(3-nitrophenyl)-pyridine-3~5-dicarboxy-lic acid dibenzyl ester o~ melting point 102C (e-thanol).
Yield: 65% of theory.
Example 10 ~, NO2 ~ ' ~, Cz 2 C ~, CC~ C,~ .15 H,C ~`~ CH2 ~
Analogously to Example 1, reaction of 3'-ni-tro-benzylideneacetoace-tic acid ethyl ester with ~-amino-~cyclohexylmethyl--acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-cyclohexylmethyl-6 methyl-4-(3-nitro-phenyl)-pyridine-3~5-dicarboxylic acid diethyl ester o~
melting point 153C (ethanol).
Yield: 69% of theory.
;J2 ' ~
H~ C02 C ~,C02 C~.
~ C ~ ~ Cri2 ~
Analogously to Example 1j reaction of 3'-nitro-benzylideneacetoacetic acid methyl ester with ~-amino-~-Le A 20 322 benzyl-acrylic acid methyl ester in methanol gave 1,4-dihydro-2-benzyl-6-me-thyl~4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester of melting point 166 C
(ethanol).
Yield: 630~o of theory.
[ ~ Cl H3 C02 C ~[ C02 C~i H3C H C2~g Analogously to Example 17 reaction of 2'-chloro-benzylideneacetoacetic acid methyl es-ter with ~-amino-~-10 e-thyl-acrylic acid methyl ester in methanol gave l,4-dihy-dro-2-ethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-di-carboxylic acid dimethyl ester of melting point 147C
(methanol).
Yield: 36% of theory.
15 Example 13 l 11 ~ Cl HS C2 O2 C ~ 2 C2 -~
~ ~l H3C ~ C, ~ (n) Analogously to Example 1, reaction of 2l-chloro-benzylideneacetoacetic acid ethyl ester with ~ amino~
propyl-acryllc acid ethyl ester in e-thanol gave l,4-dihydro-20 2-propyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5 dicar-boxylic acid diethyl ester of melting point 100C (ethanol).
Yield: 27% of theory.
Example 14 ~f Cl H C ~ C~
Le A 20 322 _ _ s~
Analogously to Example 1, reac-tion of 2' chloro-benzylideneacetoacetic acid ethyl ester with ~-amino-~-cyclohexylmethyl-acrylic acid ethyl ester in ethanol gave l,4-dihydro-2-cyclohexylmethyl-6-methyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 117C (e-thanol).
Yield: 29% of theory.
Exam~le 15 ~ CN
H~Cz02C ~CO2CzH5 H~C ~ C2Hs Analogously to Example 1, reaction of 2'-cyano benzylideneacetoacetic acid ethyl ester wi-th ~-amino-~-e-thyl-acrylic acid ethyl ester in ethanol ga~e 1,4-di-hydro-2-ethyl-6-methyl-4~(2-cyanophenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting polnt 12~C
(ethanol), Yield: 47% of theory.
Example 16 ~' ~ CF3 H5C20z~ ~ C0~C2~5 H3C N C~U7(h) Analogously -to Example 1, reaction of 2'-tI`i-~luoromethylbenzylideneacetoacetic acid ethyl ester with ~-amino-~-propyl-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-propyl-6-me-thyl-4-(2-trifluorome-thyl-phenyl)-pyridine-3,5-dicarboxylic acid diethyl ester of melting point 95C (isopropanol).
Yield: 48% of -theory.
Le A 20 ~22 2.~
~c*
Hs C2 2 C ~ ~~ C2 r,~
J~ I
HIC ~ r2 -q5 Analogously -to Example 1, reaction of 2'--tri-fluoromethylbenzylideneacetoace-tic acid ethyl es-ter wi-th ~-amino-~-ethyl.-acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2 ethyl-6-methyl-4-(2-trifluorome-thylphenyl)-pyr.idine-3,5-dicarboxylic acid diethyl es-ter o~ mel-ting poin-t 81C (isopropanol).
Yield: 62% of theory.
Example 18 02C ~ CO C2 l I
H~C ~ ~ ' ~ _u~ ~?
Analogously to Example 1, reaction o~ 2'-nitro-beriz.ylideneacetoacetic acid ethyl ester with ~-amino-~-isopropyl-acrylic acid ethyl ester in ethanol ga~e 1~4-15 dihydro-2-isopropyl-6-methyl-4 (2-nitrophenyl)-pyridine--3,5-dicarboxylic acid diethyl ester of mel-ting point 117C (eth~nol).
Yield: 28~ of -theory, Exam~le 19 W`-~JO 2 H5Cl03C 1 co.c. ~s ll ~
H3C ~ C2~5 Le A 20 322 Analogously to Example 1, reac-tion of 2'-nitro-benzylideneacetoacetic acid ethyl es-ter with ~-amino-~-ethyl~acrylic acid ethyl ester in ethanol gave 1,4-dihydro-2-ethyl-6-methyl-4-(2-nitrophenyl)-pyridine-3 7 5-dicarboxylic acid diethyl es-ter of melting point 124C
(e-thanol).
Yield: 35% of theory.
1,4-Dihydro-2-methyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl es-ter C~~
HsC20~C~"CO2c2~s ~3C H
Process variant G
4.5 g (10 mmols) of 3,4-dihydro-6~methyl-2-(pyrrolidin-1-yl)-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester were hydrogenated in 150 ml of glacial acetic acid over platinum-(IV) oxide, in a shaking apparatus, at 3.5 atmospheres gauge, until the equivalent amo~t of hydrogen had been taken up (about 2 hours). The ca-talyst was -then filtered off and the filtrate was concentrated in vacuo. The residue was taken up in chloroform and chroma-tographed over a silica gel column (chloroform/ethyl acetate =
10:1), an analytically pure product, of melting point 95-96C, being obtained af-ter concentrating the eluate.
Yield: 28% of theory.
Le A 20 322 __ I T
1--I 0 0 N In ~
., ,-o o~
~r~ ~rl t~l r-- ~~
O O O
'r'l ~ Z ~O 2 r~
~rl h O ~ O Q O ~0 ~0 o O
_, a ~q r~
~ ~ ~ _ ~ ~
O ~
---- r~
O O
r-~ bO
~ O
~ 0~
rl h 'O P~
~1 O r~
Le A 20 322 ~o ~ D (`J
-~ c o ~ c~
o o ~ ~ ~ ~
F ~ ~ C,~
.,~
, t~
~r o ~1 = = _ _ 0 ~1 ~ + ~ r~ r~ r~l r~
O ~ ~
r-l ~1 ~ ~i o O
b~ ~d , .
O
,~,, a) h X ~;~;
Le A 20 322 5~12 The present invention also co~.prises pharmaceutically acceptable bioprecursors o~ the active ccmpounds of the present invention.
For the purposes of this specification the term 'pharmaceuticall~ acceptable bioprecursor''of an active compound of the invention means a compound having a structural formula di~ferent from the active compound but ~Jhich nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.
Le ~'20 ~22 . .
- 3~1 -
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition which comprises diethyl 2-methyl -6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in admixture with a suitable carrier or diluent.
2. A composition according to claim 1 wherein the carrier or diluent is a solid or liquefied gaseous diluent or a liquid diluent other than a solvent of molecular weight less than 200 or a liquid diluent in the presence of a surface active agent.
3. A composition according to claim 1 which is in the form of a sterile and/or physiologically isotomic aqueous solution.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3018259.3 | 1980-05-13 | ||
| DE19803018259 DE3018259A1 (en) | 1980-05-13 | 1980-05-13 | 1,4-DIHYDROPYRIDINE WITH DIFFERENT SUBSTITUENTS IN 2- AND 6-POSITIONS, METHODS FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
| CA000377326A CA1175438A (en) | 1980-05-13 | 1981-05-11 | 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position, their production, and their medicinal use |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377326A Division CA1175438A (en) | 1980-05-13 | 1981-05-11 | 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position, their production, and their medicinal use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1185182A true CA1185182A (en) | 1985-04-09 |
Family
ID=6102290
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377326A Expired CA1175438A (en) | 1980-05-13 | 1981-05-11 | 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position, their production, and their medicinal use |
| CA000447060A Expired CA1185182A (en) | 1980-05-13 | 1984-02-08 | Pharmaceutical compositions containing diethyl-2- methyl-6-propyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377326A Expired CA1175438A (en) | 1980-05-13 | 1981-05-11 | 1,4-dihydropyridine compounds having different substituents in the 2-position and 6-position, their production, and their medicinal use |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0039863B1 (en) |
| JP (1) | JPS577468A (en) |
| AT (1) | ATE5718T1 (en) |
| AU (1) | AU541935B2 (en) |
| CA (2) | CA1175438A (en) |
| DE (2) | DE3018259A1 (en) |
| DK (1) | DK210281A (en) |
| ES (2) | ES8300093A1 (en) |
| FI (1) | FI811437L (en) |
| GR (1) | GR74910B (en) |
| HU (1) | HU184434B (en) |
| IE (1) | IE51267B1 (en) |
| IL (1) | IL62841A (en) |
| NO (1) | NO811424L (en) |
| PH (1) | PH18747A (en) |
| PT (1) | PT72964B (en) |
| ZA (1) | ZA813141B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DE3208628A1 (en) * | 1982-03-10 | 1983-09-22 | Bayer Ag, 5090 Leverkusen | NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| US4414213A (en) * | 1982-03-22 | 1983-11-08 | Mead Johnson & Company | Dihydropyridyl cyclic imidate esters and their pharmaceutical use |
| JPS58208271A (en) * | 1982-04-30 | 1983-12-03 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| JPS6094963A (en) * | 1983-10-31 | 1985-05-28 | Teijin Ltd | 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative and production thereof |
| NZ212895A (en) * | 1984-08-22 | 1988-07-28 | Glaxo Spa | 1,4-dihydropyridine derivatives and pharmaceutical compositions |
| DE3447169A1 (en) * | 1984-12-22 | 1986-07-03 | Bayer Ag, 5090 Leverkusen | OPTICALLY ACTIVE NITRODIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
| JPS625958A (en) * | 1985-07-03 | 1987-01-12 | Suntory Ltd | 1,4-dihydropyridine derivative, production thereof and remedy for circulatory disease |
| US4761420A (en) * | 1986-06-13 | 1988-08-02 | Laboratoires Syntex S.A. | Antihypertensive dihydropyridine derivatives |
| US5075324A (en) * | 1986-12-24 | 1991-12-24 | Boehringer Biochemia Robin S.P.A. | Aralkyl-1,4-dihydropyridines, a method for their preparation and pharmaceutical composition containing them |
| US5158963A (en) * | 1989-08-02 | 1992-10-27 | Kaken Pharmaceutical Co., Ltd. | 1-4-dihydropyridine derivative, process for preparing the same and pharmaceutical composition containing the same |
| EP0461264A4 (en) * | 1989-12-29 | 1992-02-19 | Kaken Pharmaceutical Co., Ltd. | Ethynylphenyl derivative, production thereof, and remedy for diseases of circulatory organs containing the same as active ingredient |
| ATE234286T1 (en) * | 1993-12-10 | 2003-03-15 | Bayer Ag | PHENYL-SUBSTITUTED 1,4-DIHYDROPYRIDINES WITH CEREBRAL ACTIVITY |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1792764C3 (en) * | 1967-03-20 | 1981-04-23 | Bayer Ag, 5090 Leverkusen | Coronary drugs |
| GB1430961A (en) * | 1972-01-22 | 1976-04-07 | Yamanouchi Pharma Co Ltd | 1-substituted-1,4-dihyddrypyridine derivatives |
| DE2508181A1 (en) * | 1975-02-26 | 1976-09-09 | Bayer Ag | 1,4-DIHYDROPYRIDINCARBONIC ACID ARAL KYLESTER, METHOD FOR MANUFACTURING AND USING THEY AS A MEDICINAL PRODUCT |
| GB1591089A (en) * | 1976-12-17 | 1981-06-10 | Fujisawa Pharmaceutical Co | 1,4-dihydropyridine derivatives and process for preparation thereof |
| SE7910521L (en) * | 1979-12-20 | 1981-06-21 | Haessle Ab | NEW 2-METHYL-6-SUBSTITUTED-4- (2,3-DISUBSTITUTED PHENYL) -1,4-DIHYDROPYRIDINE-3,5-DIESTERS WITH HYPOTHESIVE PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION |
-
1980
- 1980-05-13 DE DE19803018259 patent/DE3018259A1/en not_active Withdrawn
-
1981
- 1981-04-27 NO NO811424A patent/NO811424L/en unknown
- 1981-05-04 EP EP81103338A patent/EP0039863B1/en not_active Expired
- 1981-05-04 DE DE8181103338T patent/DE3161760D1/en not_active Expired
- 1981-05-04 PT PT72964A patent/PT72964B/en unknown
- 1981-05-04 AT AT81103338T patent/ATE5718T1/en not_active IP Right Cessation
- 1981-05-08 JP JP6841081A patent/JPS577468A/en active Pending
- 1981-05-11 CA CA000377326A patent/CA1175438A/en not_active Expired
- 1981-05-11 FI FI811437A patent/FI811437L/en not_active Application Discontinuation
- 1981-05-11 GR GR64908A patent/GR74910B/el unknown
- 1981-05-11 PH PH25616A patent/PH18747A/en unknown
- 1981-05-11 IL IL62841A patent/IL62841A/en unknown
- 1981-05-12 AU AU70473/81A patent/AU541935B2/en not_active Ceased
- 1981-05-12 IE IE1061/81A patent/IE51267B1/en unknown
- 1981-05-12 ES ES502132A patent/ES8300093A1/en not_active Expired
- 1981-05-12 ZA ZA00813141A patent/ZA813141B/en unknown
- 1981-05-12 DK DK210281A patent/DK210281A/en not_active Application Discontinuation
- 1981-05-13 HU HU811323A patent/HU184434B/en unknown
-
1982
- 1982-05-27 ES ES512592A patent/ES512592A0/en active Granted
-
1984
- 1984-02-08 CA CA000447060A patent/CA1185182A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES8304082A1 (en) | 1983-02-16 |
| EP0039863B1 (en) | 1983-12-28 |
| IL62841A0 (en) | 1981-07-31 |
| DK210281A (en) | 1981-11-14 |
| AU541935B2 (en) | 1985-01-31 |
| HU184434B (en) | 1984-08-28 |
| IE51267B1 (en) | 1986-11-26 |
| DE3018259A1 (en) | 1981-11-19 |
| AU7047381A (en) | 1981-11-19 |
| JPS577468A (en) | 1982-01-14 |
| GR74910B (en) | 1984-07-12 |
| NO811424L (en) | 1981-11-16 |
| IE811061L (en) | 1981-11-13 |
| CA1175438A (en) | 1984-10-02 |
| DE3161760D1 (en) | 1984-02-02 |
| ES502132A0 (en) | 1982-10-01 |
| ZA813141B (en) | 1982-04-28 |
| IL62841A (en) | 1984-11-30 |
| PH18747A (en) | 1985-09-19 |
| ES8300093A1 (en) | 1982-10-01 |
| PT72964A (en) | 1981-06-01 |
| PT72964B (en) | 1982-06-25 |
| FI811437L (en) | 1981-11-14 |
| ATE5718T1 (en) | 1984-01-15 |
| EP0039863A1 (en) | 1981-11-18 |
| ES512592A0 (en) | 1983-02-16 |
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