WO1982000822A1 - Acides oxyrane-carboxyliques substitues, leur preparation et leur utilisation comme medicaments - Google Patents

Acides oxyrane-carboxyliques substitues, leur preparation et leur utilisation comme medicaments Download PDF

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Publication number
WO1982000822A1
WO1982000822A1 PCT/EP1981/000137 EP8100137W WO8200822A1 WO 1982000822 A1 WO1982000822 A1 WO 1982000822A1 EP 8100137 W EP8100137 W EP 8100137W WO 8200822 A1 WO8200822 A1 WO 8200822A1
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denotes
integer
salts
acids
oxirane
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PCT/EP1981/000137
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English (en)
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Gulden Lomberg Chem Fab Gmbh Byk
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Eistetter K
Rapp E
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Publication of WO1982000822A1 publication Critical patent/WO1982000822A1/fr
Priority to DK190382A priority Critical patent/DK190382A/da

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings 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, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups

Definitions

  • the invention relates to epoxycycloalkylalkane- carboxylic acids, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry as intermediate products and for the preparation of medicaments.
  • the invention relates to epoxycycloalkylalkane- carboxylic acids of the general formula I
  • R denotes a hydrogen atom or a lower alkyl group
  • Y denotes an oxygen atom (-O-) or a methylene group (-CH 2 -)
  • m denotes an integer from 0 to 6
  • n denotes an integer from 0 to 6
  • p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y represents an oxygen atom, and the sum of the numbers m, n and p is an integer from 6 to 15), and to the salts of the carboxylic acids.
  • Suatable lower alkyl groups are straight-chain or branched alkyl radicals having 1 to 4 carbon atoms : straight-chain alkyl radicals are the methyl, ethyl, n- propyl and n-butyl radicals, of which the methyl radical and the ethyl radical are preferred.
  • Examples of branched alkyl radicals are the isopropyl, isobutyl and sec. -butyl radical, ⁇ f which the isopropyl radical is preferred.
  • Suitable salts are salts with inorganic and organic bases.
  • Pharmacologically unacceptable salts are converted by methods which are in themselves known into pharmacologically, that is to say biologically, acceptable salts, which are preferred amongst the salts according to the invention.
  • Cations which are used for the formation of salts are above all the cations of the alkali metals, alkaline earth metals or earth metals, however, the corresponding cations of organic nitrogen bases, such as amines, aminoalkanois, amino-sugars, basic aminoacids and the like are also used.
  • Examples which may be mentioned are the salts with lithium, sodium, potassium, magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, N-lower alkylpiperazines (for example N-methylpiperazine) , methylcyclo- hexylamine , benzylaaine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-amincmethane, 2—amino-2-methylpropanol, 2-amino-2-methyl-l, 3- ⁇ ropanediol, glucamine, N-methylglucamine, giucosamine, N- methylglucosamine, lysine, omithine, arginine and quinoline.
  • N-lower alkylpiperazines for example N-methylpiperazine
  • methylcyclo- hexylamine methylcyclo- hexylamine
  • benzylaaine ethanolamine
  • Epoxycycloalkylalkanecarboxyiic acids of the general formula I* are Epoxycycloalkylalkanecarboxyiic acids of the general formula I*
  • Y* denotes a methylene group (-CH 2 -)
  • m* denotes an integer from 1 to 6
  • n* denotes the number 1
  • p* denotes an integer from 4 to 7 (and the sum of the numbers m*, n* and p* is an integer from 6 to 11)
  • the salts of the carboxylic acids form an embodiment of the invention.
  • Epoxycycloalkylalkanecarboxylic acids of the general formula I** are Epoxycycloalkylalkanecarboxylic acids of the general formula I**
  • R** denotes a hydrogen atom or a lower alkyl group
  • Y** denotes an oxygen atom (-O-)
  • m** denotes an integer from 2 to 6
  • n** denotes an integer from 0 to 4
  • p** denotes an integer from 4 to 7 (and the sum of the numbers m**, n** and p* * is an integer from 6 to 11)
  • the salts of the carboxylic acids form a further embodiment of the invention.
  • the epoxycycloalkylalkanecarboxylic acids of the general formula I and/or of the embodiments I* and I** possess a centre of chirality.
  • the invention therefore includes both the racemates and the enantio mers and mixtures thereof. .
  • the compounds according to the invention have valuable pharmacological properties which enable them to be exploited commercially. They have a strong hyog lycaemic and hypokateonaemic action, which is of a comparatively short duration.
  • the epoxycycloalkylalkanecarbcxylic acids are suitable for the treatment and prophylaxis , in human and veterinary medicine , of diseases caused by disturbances of the metabolism of glucose and fats.
  • diseases caused by disturbances of the metabolism of glucose and fats.
  • conditions which are treated are prediabetic conditions, for preventing the manifestation of diabetes, manifest diabetes, for example adult diabetes, labile diabetes in young people and all pathological conditions which are associated with a pathologically increased production of ketonic substances.
  • the invention also relates, therefore, to a process for combating the said diseases by administering the compounds according to the invention.
  • the invention also relates to the use of the compounds according to the invention in combating the said dis ⁇
  • the invention further relates to medicaments containing one or more of the epoxycycloaikyialkane- carboxylic acids of the general formula I
  • R denotes a hydrogen atom or a lower alkyl group
  • Y denotes an oxygen atom (-O-) or a methylene group (-CH 2 -)
  • m denotes an integer from 0 to 6
  • n denotes an integer from 0 to 6
  • p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y represents an oxygen atom, and the sum of the numbers m, n and p is an integer from 6 to 15), and/or the pharmacologically acceptable salts of the acids with inorganic or organic bases.
  • Embodiments of the medicaments are those containing epoxycycloalkylalkanecarboxylic acids of the embodiments I* and I** and/or the pharmacologically acceptable salts of the acids with inorganic or organic bases.
  • the invention relates additionally to the use of the compounds according to the invention for the preparation of medicaments for combating the said diseases.
  • the medicaments are prepared in accordance with processes which are in themselves known.
  • the new compounds can be used as such or, if appropriate, in combination with suitable phamaceuti cal excipients.
  • the new pharmaceutical formulations contain pharmaceutical excipients in addition to the active compounds, the content of active compound in these mixtures is 1 to 95, preferably 15 to 85 , per cent by weight of the total mixture.
  • the active compounds in any desired form, for example a systemic form in the field of human medicine, with the proviso that the formation and/or maintenance of adequate levels of active compounds in the blood or tissue is ensured.
  • This can be achieved, for example, by oral or parenteral administration in suitable doses
  • the pharmaceutical formulation of the active compound is advantageously in the form of unit doses appropriate for the desired administration.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, of a granular material, of a solution, of an emulsion or of a suspension.
  • Unit dose for the purpose of the present invention means a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical excipient, the content of active compound in the unit dose corresponding to a fraction or multiple of a therapeutic individual dose.
  • An individual dose preferably contains the amount of active compound which is given in one administration and usually corresponds to a whole daily dose or a half, one-third or one-quarter of the daily dose. If only a fraction, such as a half or one-quarter, of the unit dose is required for an individual therapeutic administration, the unit dose is advantageously divisible, for example in the form of a tablet with a breaking groove.
  • the pharmaceutical formulations according to the invention contain about 2 to 200 mg, advantageously 10 to 100 mg and in particular 20 to 60 mg, of active compound.
  • the active compound or compounds In general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are given orally, in a daily dose of about 0.1 to about 30, preferably 0.3 to 15 and in particular 0.6 to 3, mg/kg of body weight, if ancropriate in the form of several , preferably 1 to 3 , individual admini strations in order to achieve the desired results .
  • An individual administration contains the active compound or compounds in amounts of about 0.05 to about 10 , preferably 0.1 to 5 and in particular 0. 3 to 1 , mg/ kg of body weight .
  • Similar dosages can be used in the case of a paranteral treatment, for example an intravenous or intra muscular administration.
  • About 0.3 to 1 mg of active compound/kg of body weight is administered in this therapy .
  • the dose may be increased to 0.3 to 15 , in case of need to 0.3 to 30 mg of accive compound/kg of body weight.
  • the pharmaceutical formulation is in general administered, for therapeutic purposes , at fixed points in time , such as 1 to 4 times daily , for example after each meal and/or in the evening. In acute cases , medication takes place at varying points in time .
  • the pharmaceutical formulations as a rule con sist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable medicinal excipients which are used as an adalxture or diluent in solid, semi-solid or liquid form, or as a means of encasing, for example in the form of a capsule, a tablet coating, a sachet or some other container for the therapeutically active ingredient.
  • An excipient can, for example, serve as a promoter of the absorption of the,medicament by the body, as a formulating auxili ary, as a sweetener, as a flavour correctant, as a colorant or as a preservative.
  • Examples of forms which may be used orally are tablets, dragees, hard and soft capsules, for example capsules made of gelatine, dispersible powders, granules, aqueous and oily suspensions, emulsions or solutions.
  • Tablets may contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or xylitol; granulating agents and dispersing agents, for example calcium phosphate or alginates; binders, for example starch, gelatine or gum acacia; and lubricants, for example aluminium stearate or magnesium stearate, talc or silicone oil.
  • the tablets may additionally be provided with a coating, which can also be such that delayed dissolution and resorption of the medicament in the gastro-intestinal tract and hence, for example, better toleration, a protracted effect or a retarded effect are achieved.
  • Gelatine capsules may contain the medicament mixed with a solid diluent, for example calcium carbonate or kaolin, or an oily diluent, for example paraffin oil.
  • Aqueous suspensions may contain suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginata, polyvinylpyrrolidone, gum tragacanth or gum acacia; dispersing agents and wetting agents, for example poly oxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; preservatives, for example methyl hydroxybenzoate or propyl hydroxybenzoate ; flavouring agents; and sweeteners, for example saccharin or sodium cyclamate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginata, polyvinylpyrrolidone, gum tragacanth or gum acacia
  • dispersing agents and wetting agents for example poly oxyethylene stearate, heptadecaethyleneoxycetanol,
  • Oily suspensions may contain, for example, paraffin oil and thickeners, such as beeswax, hard paraffin or cetyl alcohol; and furthermore sweeteners, flavouring agents and antioxidants.
  • paraffin oil and thickeners such as beeswax, hard paraffin or cetyl alcohol
  • sweeteners such as beeswax, hard paraffin or cetyl alcohol
  • flavouring agents such as beeswax, hard paraffin or cetyl alcohol
  • Water-dispersible powders and granules may contain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those mentioned above, as well as with sweeteners, flavouring agents and colorants.
  • Emulsions ma ⁇ contain, for example, paraffin oil, in addition to emulsifying agents, such as gum acacia, gum tragacanth, phosphatides, sorbitane monooleate or polyoxyethylene sorbitane monooleate, and sweeteners and flavouring agents.
  • emulsifying agents such as gum acacia, gum tragacanth, phosphatides, sorbitane monooleate or polyoxyethylene sorbitane monooleate, and sweeteners and flavouring agents.
  • sterile injectable aqueous suspensions for example iso tonic salt solutions or other solutions which can contain dispersing agents or wetting agents and/or pharmacologically acceptable diluents, for example propylene glycol or butylene glycol, are used.
  • the active compound or compounds can also be formulated in a micro-encapsulated form, if appropriate together with one or more of the excipients or additives indicated.
  • the pharmaceutical formulations can also contain one or more pharmacologically active ingredients from other groups of medicaments, such as antidiabetics (sulphonamides, sulphonylureas and others), for example carbutamide, tolbutamide, chlorpropamide, glibenclamide, glibomuride, glisoxepide, gliquidone or glymidine, or hypolipidaemics, such as nicotinic acid and its derivatives and salts.
  • antidiabetics sulphonamides, sulphonylureas and others
  • carbutamide tolbutamide
  • chlorpropamide glibenclamide
  • glibomuride glisoxepide
  • gliquidone or glymidine glymidine
  • hypolipidaemics such as nicotinic acid and its derivatives and salts.
  • the invention further relates to a process for the preparation of epoxycycloalkylalkanecarboxylic acids of the general formula I
  • R denotes a hydrogen atom or a lower alkyl group
  • Y denotes an oxygen atom (-O-) or a methylene group (-CH 2 -)
  • m denotes an integer from 0 to 6
  • n denotes an integer from 0 to 6
  • p denotes an integer from-2 to 11 (and m cannot be 0 or 1 if Y is an oxygen atorn, and the sum of the numbers m, n and p is an integer from 6 to 15)
  • the salts of the carboxylic acids which is characterised in that a substituted ⁇ -methylenecarboxylic acid of the general formula II
  • R, Y, m, n and p have the meanings indicated above, is oxidised and, if appropriate, the resulting lower alkyl esters are then saponified and, if desired, subsequently converted into the salts or the resulting acids are converted into the salts or lower alkyl esters.
  • the oxidation ⁇ f the ⁇ -methylenecarboxylic acids II is effected under conditions such as are known to the expert for the oxidation ⁇ f carbon-carbon double bonds to give epoxides .
  • suitable oxidising agents are peroxo compounds , such as hydrogen peroxide , peracetic acid, trifluoroperacetic acid, 3 ,5-dinitro perbenzoic acid or preferably m-chloroperbenzoic acid or perraleic acid.
  • the reaction is exoediently carried out in inert sol ven ts , for exampl e aromatic or chlorinated hydro carbons. such as benzene, toluene, methylene dichloride or chloroform.
  • the reaction temperatures are between 0° and the boiling point of the solvent, preferably between 20° and 70°C.
  • the sapbnification of the lower alkyl esters is effected in a manner which is in itself known.
  • aqueous or alcoholic (for example ethanolic) alkali metal hydroxide for example potassium hydroxide
  • inert diluent such as dioxan, tetrahydrofuran or toluene.
  • the alkaline reactant used is the inorganic or organic base forming the salt which is desired.
  • they are esterified with lower alkanols in the presence of strong acids, such as sulphuric acid or p-toluene sulphonic acid, or acid ion exchangers under conditions in whichdecarboxylation does not take place, or are esterified with dialkyl sulphates or alkyl halides in the presence of diazabicycloundecere or diazabicyclo nonene in inert solvents, such as benzene, toluene or acetone.
  • the compounds of the general formula I are normally produced in the form of racemic mixtures which are separated into the enantiomers by means of known processes.
  • the racemate is converted by means of an optically active resolving agent into diastereomers which are subsequently separated by selective crystallisation and are converted into the corresponding optical isomers.
  • optically active resolving agents used are optically active bases, such as 1-1-phenylethylamine, d-1-phenylethylamine, cinchonidine or d-ephedrine, from which salts of the acids of the general formula I are prepared, or optically active alcohols, such as borneol or menthol, from which esters of the acids of the general formula I are prepared.
  • R*, Y*, m*, n* and p* and R**, Y**, m**, n** and p**, respectively, have the meaning indicated above, are employed in order to prepare the epoxycycloalkyl- alkanecarboxylic acids of the embodiments I* and I**.
  • ⁇ -methylenecarboxyiic acids of the general formulae II, II* and II** can be prepared by methods which are in themselves known. They are valuable intermediate products for the synthesis ⁇ f the carboxylic acids I, I* and I**.
  • Y, m, n and p have the meaning indicated above and R' denotes a lower alkyl group, with formaldehyde in pyridine in the presence of secondary amines, prefer ably piperidine, and, if appropriate, subsequently saponifying the resulting lower alkyl esters.
  • the preparation ⁇ f the malonic acid half-esters IIX is effected by methods such as are familiar to the expert, for example by reacting dialkyl malonates IV with cyclcalkylalkyl compounds V and partially saponifying the resulting malonic acid diesters VT in accordance with the following reaction scheme
  • R', Y, m, n and p have the meaning indicated above and X denotes a leaving group, for example a chlorine or bromine atom or a mesyloxy or p-toluenesulphonyloxy group.
  • cycloalkylalkyl compounds V and their embodiments V* and V** are known compounds or are prepared in accordance with known processes.
  • compounds V in which Y represents a methylene group (-CH 2 -) can be prepared from known starting compounds by conventional chain lengthening reactions.
  • cycloalkylalkyl compounds V of any desired chain length can be prepared starting from cycloalkyl halides, by reacting the latter with alkali metal cyanides or by a Grignard reaction with carbon dioxide or ethylene oxide, converting the product formed into the corresponding cycloalkylalkyl halogen compound and subsequently lengthening the chain further, if necessary carrying out 'this reaction several times (for example a malonic ester synthesis with subsequent decarboxylation, reduction and conversion of the alcohol formed into the halogen compound) .
  • n, p and X have the meanings indicated above, Hal represents a halogen atom and m represents an integer from 2 to 6 [in this connection see also J. Augstein et al. (J.Med.Chem. 8 (1965) 356-367 ) , J.D. Genzer et al. (J.Amer.Chem.Soc. 73 (1951) 3,159-3,162) and Sh. Mamedov et al. , (Zh.Obshch.Khim. 32, 799 (1962), 33, 3,166 (1963)].
  • cycloalkyl compounds VII and VIII are known or are prepared (as described above) in a known manner, for example by chain lengthening.
  • the alcohols VIII or the diois IX are preferably converted into the (mono)alcoholates.
  • the conversion of the alcohols XI into the compounds V in which X represents, for example, a chlorine atom is effected, for example, by reaction with thionyl chloride.
  • Example 1a are obtained by the procedure described in Example 1a) from 11.2 g of 6-(2-cyclohexylethoxy)-2-methylene hexaroic acid ethyl ester and 13.7 g of m-chloroper benzoic acid in 100 ml of methylene chloride .
  • 3-cycloundecylpropan-l-ol is obtained as follows: hydroxymethyicycioundecane is reacted with thionyl chloride to give chloromethyl- cycloundecane, which is reacted with malonic acid diethyl ester in the presence of sodium ethylate to give (cycloundecylmethyi)-nalonic acid diethyl ester, which, after saponifying the ester group and decarb ⁇ xylating the corresponding malonic acid, gives 3-cyclcundecyl- propionic acid.
  • 3-Cycloundecylpropionic acid is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-cycloundecylpropanol.
  • 5-cycloheptyl ⁇ entyl bromide are obtained in the form of a light yellow oil [bp 135-138°C at 12 mm Hg (1600 Pa ) ] by the procedure described in Example 12 e) from 35.3 g ⁇ f 5-cyclohe ⁇ tylpentan-1-ol, 57 ml of 48% strength hydrobromic acid, 0,2 g of red phosphorus and 12 ml of concentrated sulphuric acid.
  • the starting material 5-cycloheptylpentan-1-ol is obtained as follows: cycloheptylpropylmalonic acid ethyl ester is heated to 180oC for one hour.
  • Example 17 Sodium 2- (5-Cyclohexylpentyl) -oxirane—2-carbcxylate 1.5 g of 2- (5-cyclohexylpentyl) -oxirane-2-carboxylic acid ethyl ester are stirrad for 2 hours at room temperature with 5,6 ml of 1 N sodium hydroxide solution and 5 ml of tetrahydrofuran. The mixture is concentrated to half its volume and the fatty gleaming plates of the title compound which have been precipitated are filtered off.
  • the dry granules are compressed to give tablets with a diameter of 8 mm, a weight of 250 mg and a hardness of 5-6 kg.
  • the epoxycycloalkylalkanecarboxylic acids of formula I according to the invention lower the level of. glucose and of ketones in the blood.
  • Their chemical structure differs from that of beta-cytotropic substances (for example sulfonylureas) which have an action on the pancreas, and their mode of action differs fundamentally from that of these substances in that they have an extra-pancreatic action. They are superior to commercial preparations (for example Buformin and Phenfomin) having an extra-pancreatic action .
  • Table I reflects investigations of the effect of representative compounds according to the invention on the blood glucose concentration of fasting, metabolically healthy rats.
  • Column A in each case gives the maximum lowering of the blood glucose concentration of rats which have been fasted (in %, relative to the control group) which is observed in the course of 6 hours after single oral administration of 0.6 mmole of substance/kg of body weight.
  • Column B provides data relating to acute toxicity (LDD 50 ; mice, peroral administration).
  • the pharmacological properties were determined by the following methods : 1. Determination of glucose in the blood after a single oral administration.
  • Young male Sprague-Dawley rats (body weight: 150 to 200g) are used.
  • the animals (6 animals per dose) are kept in Makrolon cages with up to 4 animals per cage (ambient temperature : 23oC , relative atmosceric humidity : 55 % fixed day/night rhythm [12/12 hours], standard diet: Altromin ® .
  • the rats are deprived of the feed 18 hours before the first sample ⁇ f blood is taken. Water is available ad libitum. Samples of blood are taken from the postorbital plexus by puncture immediately before and 2, 4 and 6 hours after administration of the substance .
  • NMRI mice body weight: 22 to 26 g
  • the reed (Altromin ® for the animals (5 animals per dose) is reduced to 50g/50 animals and water is available ad libitum.
  • Various doses of the substances (volume: 10 ml/ kg) are administered orally by means ⁇ f a stomach tube.
  • the observation time is 7 days.
  • the LD 50 that is to say the dose at which 50 % of the animals die, is determined graphically from the dose/response curve.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

Acides epoxycycloalkylalkane-carboxyliques de formule generale I (FORMULE) ou R represente un atome d'hydrogene ou un groupe alkyle inferieur, Y represente un atome d'oxygene (- O-) ou un groupe methylene (-CH2), m represente un nombre entier de 0 a 6, n represente un nombre entier de 0 a 6 et p represente un nombre entier de 2 a 11 (et m ne peut valoir ni 0 ni 1 si Y represente un atome d, oxygene, et la somme de m, n et p est un nombre entier de 6 a 15), ainsi que les sels des acides carboxyliques, sont de nouveaux composes. Ils ont une action hypoglycemique sur des animaux a sang chaud. Sont egalement decrits les procedes de preparation de ces nouveaux composes.
PCT/EP1981/000137 1980-08-29 1981-08-24 Acides oxyrane-carboxyliques substitues, leur preparation et leur utilisation comme medicaments WO1982000822A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK190382A DK190382A (da) 1980-08-29 1982-04-28 Epoxycycloalkancarboxylsyrer og fremgangsmaade til fremstilling deraf

Applications Claiming Priority (4)

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DE3032668800829 1980-08-29
DE3032668 1980-08-29
CH124381 1981-02-25
CH1243/81 1981-02-25

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EP (1) EP0046961B1 (fr)
JP (1) JPS57501478A (fr)
AU (1) AU542157B2 (fr)
DE (1) DE3168902D1 (fr)
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FR2776292B1 (fr) * 1998-03-20 2004-09-10 Oncopharm Cephalotaxanes porteurs de chaine laterale et leur procede de synthese
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Publication number Priority date Publication date Assignee Title
GB1551078A (en) * 1975-09-22 1979-08-22 Mcneilab Inc Alkyl-substituted glycidates and thioglycidates
EP0025192A2 (fr) * 1979-09-07 1981-03-18 Byk Gulden Lomberg Chemische Fabrik GmbH Acides oxiranne-carboxyliques substitués, procédé pour leur préparation, leur utilisation et médicaments les contenant

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DE3168902D1 (en) 1985-03-28
JPS57501478A (fr) 1982-08-19
DK190382A (da) 1982-04-28
US4430339A (en) 1984-02-07
AU542157B2 (en) 1985-02-07
EP0046961B1 (fr) 1985-02-13
AU7535881A (en) 1982-04-05
EP0046961A1 (fr) 1982-03-10

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