WO1986003748A1 - Nouveaux derives de piperazine - Google Patents

Nouveaux derives de piperazine Download PDF

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Publication number
WO1986003748A1
WO1986003748A1 PCT/EP1985/000708 EP8500708W WO8603748A1 WO 1986003748 A1 WO1986003748 A1 WO 1986003748A1 EP 8500708 W EP8500708 W EP 8500708W WO 8603748 A1 WO8603748 A1 WO 8603748A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
ester
formula
methyl
piperazinyl
Prior art date
Application number
PCT/EP1985/000708
Other languages
German (de)
English (en)
Inventor
Wolf-Rüdiger Ulrich
Herman Amschler
Klaus Eistetter
Manfrid Eltze
Dieter Flockerzi
Kurt Klemm
Norbert Kolassa
Karl Sanders
Christian Schudt
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gesellschaft M filed Critical Byk Gulden Lomberg Chemische Fabrik Gesellschaft M
Priority to JP50026986A priority Critical patent/JPS62501972A/ja
Publication of WO1986003748A1 publication Critical patent/WO1986003748A1/fr
Priority to DK397786A priority patent/DK397786D0/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new piperazine derivatives, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry for the production of medicaments.
  • the invention relates to new piperazine derivatives of the formula I.
  • R1, R2 and R3 are the same or different and are hydrogen, C 1 -C 6 - are alkyl, C 3 -C 7 -alkoxyalkyl, aryl, aryl-C 1 -C 6 -alkyl or aryloxy-C 1 -C 6 -alkyl, R4 is C 1 -C 4 -alkoxy wholly or predominantly substituted by fluorine, R5 Aryl, heteroaryl, aryl-C 1 -C 4 alkyl, heteroaryl-C 1 -C 4 alkyl,
  • Di-heteroaryl-C 1 -C 4 alkyl means and A means straight-chain or branched C 2 -C 5 alkylene, which by
  • C 1 -C 4 alkoxy or aryl may be substituted and their salts.
  • C 1 -C 6 -alkyl is straight-chain or branched and means, for example, hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular Ethyl or methyl radical.
  • C 3 -C 7 alkoxyalkyl is, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or especially methoxyethyl radical.
  • Aryl generally stands for phenyl or substituted phenyl with one or two identical or different substituents from the group halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkoxycarbonyl, C 2 -C 5 -acyl, amino and mono- or di-C 1 -C 4 -alkylamino.
  • Aryl-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryl.
  • Aryl-C 1 -C 6 -alkyl is, for example, phenethyl, 3- (4-chlorophenyl) propyl or in particular benzyl.
  • Aryloxy-C 1 -C 6 -alkyl is C 1 -C 6 -alkyl which is substituted by aryloxy.
  • Aryloxy-C 1 -C 6 alkyl is, for example, phenoxyethyl.
  • Halogen means bromine, fluorine and especially chlorine.
  • C 1 -C 4 alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl or in particular methyl radical.
  • C 1 -C 4 alkoxy contains, in addition to the oxygen atom, one of the above-mentioned C 4 alkyl radicals. The methoxy and ethoxy radicals are preferred.
  • C 1 -C 4 alkoxycarbonyl contains one of the C 1 -C 4 alkoxy radicals mentioned above.
  • the methoxycarbonyl and the ethoxycarbonyl radical are preferred.
  • C 2 -C 5 acyl contains one of the C 1 -C 4 alkyl radicals mentioned above.
  • the acetyl radical is preferred.
  • mono- or di-C 1 -C 4 -alkylamino contains one or two of the above-mentioned C 1 -C 4 -alkyl radicals.
  • Di-C 1 -C 4 -alkylamino is preferred, and here in particular oimethyl-, diethyl- or diisopropylamino.
  • C 1 -C 4 alkoxy which is wholly or predominantly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
  • Heteroaryl for the purposes of the present invention represents the radicals pyridyl-, in particular 2-pyridyl-, and pyrimidyl-, in particular 2-pyrimidyl-, which are substituted by one or two identical or different substituents from the group halogen, trifluoromethyl, C 1 -C 4 -alkyl and
  • C 1 -C 4 alkoxy may be substituted.
  • ArylC 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by aryl.
  • ArylC 1 -C 4 alkyl is, for example, 2-phenylethyl, 2- (2,4-dimethoxyphenyl) ethyl, benzyl or 4-chlorobenzyl.
  • Heteroaryl C 1 -C 4 alkyl is C 1 -C 4 alkyl which is substituted by heteroaryl.
  • Heteroaryl C 1 -C 4 alkyl is, for example, 2- (2-pyridyl) ethyl.
  • Diaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two aryl radicals.
  • Diaryl-C 1 -C 4 -alkyl is especially oiphenylmethyl (benzhydryl), or substituted benzhydryl, such as 4,4'-difluorobenz hydryl, 4, 4 '-dimethylbenzhydryl, 4, 4' -dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl.
  • Heteroaryl-aryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by heteroaryl and aryl.
  • Heteroaryl-aryl-C 1 -C 4 -alkyl is, for example, 2-pyridyl-phenylmethyl.
  • Di-heteroaryl-C 1 -C 4 -alkyl is C 1 -C 4 -alkyl which is substituted by two heteroaryl radicals.
  • Di-heteroaryl-C 1 -C 4 -alkyl is, for example, di-pyrid-2-yl-methyl.
  • Straight-chain or branched C 2 -C 5 -alkylene is, for example, tetramethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene, 2-ethylpropylene and in particular ethylene or propylene.
  • C 2 -C 5 alkylene substituted by C 1 -C 4 alkoxy is, for example, 1-methoxypropylene, 2-ethoxypropylene or 1, 2-dimethoxyethylene.
  • Aryl-substituted C 2 -C 5 -alkylene is, for example, 1-phenylethylene or 2- (4-chlorophenyl) propylene.
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrylic acid Tienilic acid or 4-chloro-sulfamoyl-benzoic acid.
  • R1, R2 and R3 are the same or different and are C 1 - C 6 - alkyl or C 3 -C 7 - mean alkoxyalkyl,
  • R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine
  • R5 is phenyl, 2-pyridyl or 2-pyrimidyl which is substituted by one or two identical or different substituents from the group hydrogen, halogen, trifluoromethyl, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy and
  • A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • A means ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • A means ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • A means ethylene or propylene, and their salts.
  • a further embodiment (embodiment b) of the invention are compounds of the formula I in which
  • R1, R2 and R3 are the same or different and are C 1 -C 6 alkyl or C 3 -C 7 alkoxyalkyl,
  • R4 is completely or predominantly C 1 -C 4 -alkoxy substituted by fluorine
  • A means straight-chain or branched C 2 -C 5 alkylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy, R5 benzhydryl, 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl,
  • 4,4'-dimethoxybenzhydryl or 4,4'-dichlorobenzhydryl and A is ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • R4 is 1, 1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy
  • R5 is benzhydryl and A is ethylene or propylene, and their salts.
  • R3 is methyl, ethyl or methoxyethyl
  • A means ethylene or propylene, and their salts.
  • the compounds of the formula I have chirality centers at the 4-position in 1,4-dihydropyridine and optionally in part A.
  • the invention therefore includes both the enantiomers and diastereomers as well as their mixtures and racemates.
  • Another object of the invention is a process for the preparation of the compounds according to the invention and their salts.
  • the process is characterized in that
  • Embodiments of the process are those in which in the formulas II to X the substituents or symbols R1, R2, R3, R4, R5 and A have the meanings given in the subclaims and dependent claims and Z together with the carbonyl group to which it is bound is a carboxyl group or a reactive carboxylic acid derivative.
  • the method according to variants a to f is preferred as inert organic solvents.
  • examples include alcohols, such as ethanol, methanol, isopropanol or, in particular, t-butanol, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or hexamethylphosphoric triamide, or chlorinated hydrocarbons such as methylene chloride Chloroform or tetrachlorethylene.
  • alcohols such as ethanol, methanol, isopropanol or, in particular, t-butanol
  • ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such
  • reaction temperatures can vary within a wide range. In general, the reaction is carried out at temperatures between 20 ° C. and 150 ° C., preferably between 20 ° C. and 100 ° C., in particular at the boiling point of the solvent used.
  • the process can be carried out at atmospheric pressure or at elevated pressure, working at atmospheric pressure being the rule and elevated pressure being used in particular in the case of reactions with ammonia.
  • the substances involved in the reaction are generally used in molar amounts, but - depending on the reaction condition - an excess (if desired, for example in ammonia in variants b and d) is also used can be.
  • variants a to f When carrying out the process according to variant g, similar reaction conditions are used as for variants a to f, but - depending on the nature of the substituent Z - additional measures may be necessary.
  • Z represents a hydroxyl group
  • the reaction should preferably be carried out in the presence of a water-releasing or water-binding condensing agent (such as dicyclohexylcarbodiimide).
  • Z represents a halogen atom (e.g. a chlorine atom)
  • the reaction can, if desired, be carried out in the presence of a base (e.g. a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate).
  • a base e.g. a tertiary organic amine such as triethylamine or an inorganic carbonate such as sodium carbonate.
  • the substances according to the invention are isolated and purified in a manner known per se, for. B. such that the solvent in Vacuum was distilled off and the residue obtained was recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.
  • Salts obtained can be obtained by alkalization, e.g. with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.
  • the starting compounds are known from the literature or can be prepared analogously to methods known from the literature.
  • the cinnamic acid derivatives II and the benzylidenecarboxylic acid derivatives VI can be prepared, for example, in analogy to G. Jones ["The Knoevenagel Condensation” in Org. Reactions, Vol. XV, 204f (1967)].
  • the enamine derivatives III and the enamines V are, for example, analogous to A.C. Cope [J. Amer. Chem. Soc. 67, 1017 (1945)].
  • ⁇ -ketocarboxylic acid derivatives IV and keto compounds VII can, according to D.
  • Mp. Means melting point
  • decomp. means decomposition
  • Example 2 Analogously to Example 1, 5.6 g of the free base are made from 5 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] propan-1-ol, 2 ml of a 50% strength diketene solution in acetone, 3.2 g Obtain 3-aminocrotonic acid (2-methoxyethyl) ester and 3.44 g of 2-difluoromethoxybenzaldehyde as a solid foam, which is converted into the crystalline fumarate with 1.03 g of fumaric acid. Yield: 5.8 g of mp 149-151 ° C (dec.). 3.
  • the compounds of the formula I according to the invention and their salts have valuable properties which make them commercially usable. They are particularly effective vasodilators with coronary therapeutic properties.
  • the pharmacological activity of the compounds according to the invention which is paired with a low toxicity, is particularly evident in a slowly occurring, strong and long-lasting drop in blood pressure.
  • the compounds according to the invention have peripheral, coronary, cerebral and renal vasodilator and salidiuretic properties.
  • the compounds according to the invention differ surprisingly and advantageously from the compounds of the prior art in their excellent activity, which is paired with low toxicity and the absence of significant side effects.
  • advantageous properties are: the extent of the reduction in blood pressure, the prolonged persistence of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small and disappearing heart rate increase after repeated administration, the excellent bioavailability, the great therapeutic breadth, the lack of central side effects, that Lack of kinetic interactions with other substances, the lack of tolerance development, the balanced physical properties and the great stability.
  • the excellent activity of the compounds of formula I and their salts according to the invention permits their use in human medicine, with primary (essential) and secondary hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction etc.), peripheral and cere as indications bral circulation disorders (stroke, temporary cerebral circulatory disorders, renal artery narrowing etc.), cardiac insufficiency and diseases that are based on increased water and sodium retention.
  • coronary heart diseases coronary insufficiency, angina pectoris, myocardial infarction etc.
  • peripheral and cere as indications bral circulation disorders (stroke, temporary cerebral circulatory disorders, renal artery narrowing etc.)
  • cardiac insufficiency and diseases that are based on increased water and sodium retention.
  • Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the above-mentioned diseases.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I.
  • the invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (for example Cyclodex trine) can be used.
  • the active substances can be administered orally or parenterally (in particular perlingually, intravenously or percutaneously).
  • the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • similar or generally lower doses in particular when the active compounds are administered intravenously
  • the dose is slowly switched to a higher dose. After the desired therapeutic success has been reached, the dose is reduced again.
  • the pharmaceutical preparations can also include one or more other pharmacologically active constituents of other groups of medicaments, such as other vasodilators, antihypertensives, ⁇ -receptor blockers, B-receptor blockers, ACE inhibitors , Nitro compounds, cardiotonics, diuretics, saluretics, alkaloids, etc., such as nifedipine, dihydralazine, prazosin, propranolol, labetalol, captopril, isosorbide dinitrate, digoxin, mefruside, clopamide, spironolactone, chlorthalidone, furosididridiniazine, furosididrochloride, furosididrochloride, furosidide hydrochloride, polyhydric chloride, furosidol chloride, furosidol chloride, furosidol chloride, furosidol chloride, furos
  • the antihypertensive activity of the compounds according to the invention can be demonstrated on the model of the spontaneously hypertensive rat.
  • the compounds listed below are given in the doses given on four consecutive days on 6 rats (strain SHR / N / Ibm / Bm ⁇ , 250-350 g) with genetically determined high pressure (systolic blood pressure> 180 mmHg) administered once a day by gavage. Blood pressure is measured 6 and, if necessary, 2 or 24 hours after substance administration.
  • the blood pressure measurement is carried out in a heat chamber at 36 ° C in order to achieve better circulation in the tail artery.
  • the animals are placed in perforated perforated metal cages and measured 20-40 minutes after warming up.
  • an annular cuff with an inflatable rubber membrane to prevent blood flow and an annular piezo crystal sensor to record the pulse waves are pushed onto the tail.
  • the cuff pressure is continuously reduced.
  • the return of the pulse waves during pressure relief is automatically recognized and printed out as systolic blood pressure (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat.
  • the animals are trained for 14 days before the substance test.
  • blood pressure pre-values are collected.
  • Groups of animals receiving substance are tested against a control group.
  • the examined connections are identified by consecutive numbers, which are assigned as follows:
  • Table I shows for the representatives of the compounds according to the invention the percentage reduction in blood pressure (BP) after oral administration in the rat.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des dérivés de pipérazine ont la formule générale (I), dans laquelle R1, R2 et R3 sont identiques ou différents et représentent hydrogène, C1-C6-alcoyle, C3-C7-alkoxyalcoyle, aryle, aryle-C1-C6-alcoyle ou aryloxy-C1-C6-alcoyle, R4 représente C1-C4-alkoxy substitué entièrement ou pour la plupart avec du fluor, R5 représent aryle, hétéroaryle, aryle-C1-C4-alcoyle, hétéroaryle-C1-C4-alcoyle, diaryle-C1-C4-alcoyle, hétéroaryle-aryle-C1-C4-alcoyle ou di-hétéroaryle-C1-C4-alcoyle. Ces dérivés et leurs sels constituent de nouvelles compositions pour le traitement et la prophylaxie de maladies dues à des troubles de la circulation.
PCT/EP1985/000708 1984-12-21 1985-12-16 Nouveaux derives de piperazine WO1986003748A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP50026986A JPS62501972A (ja) 1984-12-21 1985-12-16 新規ピペラジン誘導体
DK397786A DK397786D0 (da) 1984-12-21 1986-08-20 Piperazinderivater

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH610984 1984-12-21
CH611084 1984-12-21
CH6109/84-8 1984-12-21
CH6110/84-4 1984-12-21

Publications (1)

Publication Number Publication Date
WO1986003748A1 true WO1986003748A1 (fr) 1986-07-03

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Application Number Title Priority Date Filing Date
PCT/EP1985/000708 WO1986003748A1 (fr) 1984-12-21 1985-12-16 Nouveaux derives de piperazine

Country Status (5)

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EP (1) EP0205511A1 (fr)
JP (1) JPS62501972A (fr)
AU (1) AU5312086A (fr)
DK (1) DK397786D0 (fr)
WO (1) WO1986003748A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0255710A2 (fr) * 1986-08-04 1988-02-10 The Du Pont Merck Pharmaceutical Company Dérivés de dihydropyridines avec une activité agonistique pour le calcium et alpha-1-antagonistique
WO1988007525A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Enantiomeres de 1,4-dihydropyridine
WO1988007531A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes optiquement actifs
EP0314038A1 (fr) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2414501A1 (fr) * 1978-01-11 1979-08-10 Inst Organicheskogo Sinteza Ak 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4-dihydropyridine
EP0094159A1 (fr) * 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dérivés de la dihydropyridine, leur préparation et leur application
EP0097821A2 (fr) * 1982-06-03 1984-01-11 Pierrel S.p.A. Dihydropyridines douées d'une activité antagoniste pour le calcium, leur procédé de préparation et leur application dans des compositions pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2414501A1 (fr) * 1978-01-11 1979-08-10 Inst Organicheskogo Sinteza Ak 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4-dihydropyridine
EP0094159A1 (fr) * 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dérivés de la dihydropyridine, leur préparation et leur application
EP0097821A2 (fr) * 1982-06-03 1984-01-11 Pierrel S.p.A. Dihydropyridines douées d'une activité antagoniste pour le calcium, leur procédé de préparation et leur application dans des compositions pharmaceutiques

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0255710A2 (fr) * 1986-08-04 1988-02-10 The Du Pont Merck Pharmaceutical Company Dérivés de dihydropyridines avec une activité agonistique pour le calcium et alpha-1-antagonistique
EP0255710A3 (fr) * 1986-08-04 1989-01-04 The Du Pont Merck Pharmaceutical Company Dérivés de dihydropyridines avec une activité agonistique pour le calcium et alpha-1-antagonistique
WO1988007525A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Enantiomeres de 1,4-dihydropyridine
WO1988007531A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes optiquement actifs
EP0296316A1 (fr) * 1987-03-27 1988-12-28 Byk Gulden Lomberg Chemische Fabrik GmbH Enantiomères de dihydro-1,4-pyridine
EP0314038A1 (fr) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines
WO1989003824A1 (fr) * 1987-10-27 1989-05-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyrrolidines

Also Published As

Publication number Publication date
AU5312086A (en) 1986-07-22
DK397786A (da) 1986-08-20
JPS62501972A (ja) 1987-08-06
EP0205511A1 (fr) 1986-12-30
DK397786D0 (da) 1986-08-20

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