CA1163644A - Process for the preparation of epoxycycloalkylalkanecarboxylic acids - Google Patents
Process for the preparation of epoxycycloalkylalkanecarboxylic acidsInfo
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- CA1163644A CA1163644A CA000397723A CA397723A CA1163644A CA 1163644 A CA1163644 A CA 1163644A CA 000397723 A CA000397723 A CA 000397723A CA 397723 A CA397723 A CA 397723A CA 1163644 A CA1163644 A CA 1163644A
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- oxirane
- ethyl ester
- integer
- ester
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Abstract
Abstract A process for the preparation of new epoxycycloalkylalkane-carboxylic acids of the general formula I
Description
, Process for the preparation of Epoxycycloalkylalkane-carboxylic acids The invention relates to epoxycycloalkylalkane-carboxylic acids, processes for their preparation, 5 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-1~ carboxylic acids of the general formula I
o ~ (CH2)m - Y (CH2)n ~ 2 p (I) 15 wherein R denotes a hydrogen atom or a lower alkyl group, Y denotes an oxygen atom (-O-) or a methylene group (-CH2-~, m denotes an integer from O to 6, n denotes an integer from O to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y represents an oxygen 20 atom~and the 9um of the numbers m, n and p is an integer ; from 6 to 15), and to the salts of the carboxylic acids.
Suitable 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-25 propyl and n-butyl radicals, of which the methyl radical and the ethyl radlcal are preferred.- Examples of branched alkyl radicals are the isopropyl, isobutyl and sec.-butyl radical, of which the isopropyl radical is preferred.
~. :, ,, ::
~ 1 636 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, 5 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 10 bases, such as amines, aminoalkanols, amino-sugars, basic aminoacids and the like are also used.
Examples which may be mentioned are the salts with lithium, sodium, potassium, ma~nesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, 15 morpholine, piperidine, piperazine, N-lower alkylpipera-zines (for example N-methylpiperazine), methylcyclo-hexylamine, benzylamine, ethanolami~e, diethanolamine, triethanolamine, tris-(hydroxymethyl)-aminomethane,
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-1~ carboxylic acids of the general formula I
o ~ (CH2)m - Y (CH2)n ~ 2 p (I) 15 wherein R denotes a hydrogen atom or a lower alkyl group, Y denotes an oxygen atom (-O-) or a methylene group (-CH2-~, m denotes an integer from O to 6, n denotes an integer from O to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y represents an oxygen 20 atom~and the 9um of the numbers m, n and p is an integer ; from 6 to 15), and to the salts of the carboxylic acids.
Suitable 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-25 propyl and n-butyl radicals, of which the methyl radical and the ethyl radlcal are preferred.- Examples of branched alkyl radicals are the isopropyl, isobutyl and sec.-butyl radical, of which the isopropyl radical is preferred.
~. :, ,, ::
~ 1 636 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, 5 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 10 bases, such as amines, aminoalkanols, amino-sugars, basic aminoacids and the like are also used.
Examples which may be mentioned are the salts with lithium, sodium, potassium, ma~nesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, 15 morpholine, piperidine, piperazine, N-lower alkylpipera-zines (for example N-methylpiperazine), methylcyclo-hexylamine, benzylamine, ethanolami~e, diethanolamine, triethanolamine, tris-(hydroxymethyl)-aminomethane,
2-amino-2-methylpropanol, 2-amino-2-methyl-l,3-propane-20 diol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine and quinoline.
Epox~cycloalkylalkanecarboxylic acids of the general formula I*
(CH2)m* Y ~(CH2)n*--C~ (CH2)p~ (I*) C~-O-R*
~ wherein R* denotes a hydrogen atom or a lower alkyl 1 1 636~4 group, Y* denotes a methylene group (-CH2-), m* denotes an integer from l to 6, n* denotes the number l and p~
denotes an integer from 4 to 7 (and the sum of the numbers m*, n* and p* is an integer from 6 to ll), and 5 also the salts of the carboxylic acids form an embodi-ment of the invention.
Epoxycycloalkylalkanecarboxylic acids of the general formula I**
0l! Y (CH2)m** Y* (CH2)~* C (CH2)p** (I**) \ C0-0-R**
wherein R** denotes a hydrogen atom or a lower alkyl group, Y** denotes an oxygen atom (-O-), m** denotes an 15 integer ~rom 2 to 6, n** denotes an integer from 0 to 4 and p** denotes an integer from 4 to 7 (and the sum of the numbers m**, n** and p** is an integer from 6 to ll), and also the salts of the carboxylic acids form a further embodiment of the invention.
The following may be mentioned as examples of representatives of the compounds according to the inven-tion: 2-(4-cyclohexylbutyl)-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclopropylpentyl)-oxirane-2-carboxy-lic acid methyl ester, 2-(3-cyclooctylpropyl)-oxirane-25 2-carboxylic acid ethyl ester, 2-(8-cyclopentyloctyl)-oxirane-2-carboxylic acid methyl ester, 2-(2-cyclo-undecylethyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(3-cyclododecylpropyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclohexylhexyl)-oxirane-2-carboxylic .
.
1 ~ 63644 acid n-butyl ester, 2-(lO-cyclopentyldecyl)-oxirane-2-carboxylic acid ethyl ester, 2-(2-cycloheptylethyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(7-cyclo-- butylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-cyclononylmethyl-oxirane-2-carboxylic acid sec.-butyl ester9 2-(9-cyclopropylnonyl)-oxirane-2-carboxy-lic acid methyl ester, 2-(3-cyclodecylpropyl)-oxirane-2-carboxylic acid n-butyl ester, 2-cyclododecylmethyl-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclohexyl-pentyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(4-cyclooctylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(4-cyclopentylbutyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(6-cycloheptylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cyclobutylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclooctyl-pentyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(7-cycloheptylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cyclododecylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclooctylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cycloheptylpentyl)-oxirane-2 carboxylic acid sec.-butyl ester, 2-(2-cyclo-hexylethyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclopentylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(7-cyclohexylheptyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(4-cyclobutylbutyl)-oxirane-2-carboxylic acid n-butyl ester, 2-(2-cyclononylethyl)-oxirane-2-Garboxylic acid ethyl este:r, 2-(4-cyclo-dodecylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(6-cyclobutylhexyl)-oxirane-2-carboxylic acid ~, 30 1 ~ 63644 isopropyl ester, 2-(7~cyclooctylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(2-cyclopentylethyl)-oxirane-2-carboxylic acid ethyl ester, 2-(8-cyclohexyl-octyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(4-cycloheptylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(7-cyclopentylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(6-cyclobutylhexyl)-oxirane-2-carboxylic acid ethyl ester, 2-(2-cyclooctylethyl)-oxirane-2-carboxylic acid n-propyl ester, 2-[3-(2-cyclohexyl-ethoxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(3-cyclobutylpropoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(2-cycloheptylethox~)-butyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[3-(3-cyclopentylpropoxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-[3-(cyclohexyloxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(4-cyclopropylbutoxy)-hexyl]-oxirane-2-carboxylic acid methyl ester, 2-[5-(cyclopentyloxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclooctylmethoxy)-ethyl~-oxirane-2-carboxy-lic acid isopropyl ester, 2-[3-(2-cyclononylethoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(cyclododecylmethoxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(3-cyclopropylpropoxy)-hexyl]-oxirane-2-carboxylic acid n-butyl ester, 2-~5-(4-cyclobutyl-25 butoxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[3-(2-cyclododecylethoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(6-cyclopentylhexyloxy)-ethyl]-oxirane-2-carboxylic acid n-propyl ester, 2-[~-(cyclo-- hexylmethoxy)-hexyl]-oxirane-2-carboxylic acid isopropyl -~-`` t 1 ~36 ester, 2-[5-(cycloheptyloxy)-pentylJ-oxirane-2-carboxy-lic acid methyl ester, 2-~3-(cycloundecyloxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[4-(cyclo-octylmethoxy)-butyl]-oxirane-2-carboxylic acid n-butyl 5 ester, 2-[2-(5-cyclobutylpentyloxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclononylmethoxy)-ethyl]-oxirane-2-carboxylic acid n-propyl ester, 2-~5-(2-cycloheptylethoxy) pentyl]-oxirane-2-carboxylic acid methyl ester, 2-[~-(2-cyclopropylethoxy)-hexyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[3-(6-cyclopentyl-hexyloxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(3-cyclohexylpropoxy)-butyl]-oxirane-2-carboxylic acid n-propyl ester, 2-[5-(cycloheptyl-methoxy)-pentyl]-oxirane-2-carboxylic acid methyl ester, 2-[6-(cyclooctyloxy)-hexyl]-oxirane-2-carboxylic acid ethyl ester, 2-[4-(cyclononyloxy)-butyl]-oxirane-2-carboxylic acid sec.-butyl ester, 2-[2-(4-cyclohexyl-butoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(2-cyclopentylethoxy)-butyl]-oxiràne-2-carboxylic acid ethyl ester, 2-[4-(cyclopentylmethoxy)-butyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[5-(cyclo-hexyloxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[3-(3-cycloheptylpropoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[3-(cyclododecyloxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-t4-(2-cyclooctylethoxy)-butyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-~4-cycloheptylbutoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(4-cyclopentyl-butoxy)-ethyl]-oxirane-2-carboxylic acid isopropyl l l63614 ester, 2-~2-(5-cyclohexylpentyloxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(cycloheptyloxy)-hexyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[2-(3-cyclooctylpropoxy)-ethyl]-oxirane-2-carboxylic acid 5 n-butyl ester, 2-[2-(2-cyclohexylethoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-~2-(2-cycloheptyl-ethoxy)-ethyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[4-~cycloheptyloxy)-butyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclooctyloxy)-ethyl]-oxirane-10 2carboxylic acid methyl ester, 2-[3-(cyclopentyloxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-[6-(cyclopentylmethoxy)-hexyl]-oxirane-2-carboxylic acid ethyl ester, the corresponding oxirane-2-carboxylic acids and their salts with inorganic and org~nic bases.
15 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 stx~g ~glycaemic and ~x~eb~mic action, which is of a co~ratively short duration.
Because of their advantageous activity, the 25 epoxycycloalkylalkanecarboxylic acids, according to the invention, of the general formula I and/or of the ~mbodiments I* and I** and also the pharmacologically acceptable salts are suitable for the treatment and 30 prophylaxis, in human and veterinary medicine, of ` 1 1 636~4 diseases caused by disturbances of the metabolism of glucose and fats. Examples of 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 in~ention also relates, therefore, to a process for combating the said diseases by administer-ing the compounds according to the invention me invention also relates to the use of the compounds according to the in~ention in combating the said dis-eases.
The in~ention ~urther relates to medicaments conta1ning one or more of the epoxycycloalkylalkane-carboxylic acids of the general formula I
0 ~ (CHz)m - Y - (CH2)n - C ~ H2)p tI) ~ \ C0-0-R
wherein R denotes a hydrogen atom or a lower alkyl group, Y denotes an oxygen atom (-0-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to ll (and m cannot be 0 or l if Y represents an oxygen atom7and the sum of the numbers m, n and p is an integer from 6 to 15), and/or the pharmacologic-~ ally acceptable salts of the acids with inorganic or ~0 ~ 1 63644 g organic bases.
Embodiments of the medicaments are those con-taining 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 pre-paration of medicaments for combating the said 1 0 diseases.
The medicaments are prepared in accordance with processes which are in themsel~es known. As medica-ments, the new compounds can be used as such or, if appropriate, in combination with suitable pharmaceuti-c 1 eXcipients. If the ne~ pharmaceutical formula-tions contain pharmaceutical excipients in addition to the active compounds, the content of active compound in these m~xtures is 1 to 95, preferably 15 to 85, per cent by weight of the total mixture.
In accordance with the invention it is possible to use t~e active compounds in any desired form, for ex-ampIe a systemic form, in the field of human medicine,with the pro~iso 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 adm7nistration in suit-able doses. The pharmaceutical formulation of the active compound is advantageously in the form of unit doses appropriate for the desired administration A
~ ~ 63644 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 con-tains an individual amount of the active ingredient in combination with a pharmaceutical excipient, the con-tent of active compound in the t~ni t dose corresponding 10 to a fraction or multiple of a therapeutic individual dose An individual dose preferably contains the amount o~ active compound which is given in one a~m;ni-stration and usually corresponds to a whole daily dose or a half, one-third or one-quarter of the daily dose.
15 If only a fraction, such as a half or one-quarter, of the l1n1t dose is required for an individual therapeutic a~ministration, the unit dose is advantageously divis-ible, for example in the form of a tablet with a breaking groove.
When in the form of unit doses and intended, for example, for administration to humans, the pharma-ceutical formulations according to the invention con-tain about 2 to 200 mg, advantageously lO to lO0 mg and in particular 20 to 60 mg, of active compound.
In general, it has proved adv2ntageous 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 appropriate in the .
1 3 63~4 form of several, preferably 1 to ~, individual admini-strations in order to achieve the desired results.
An individual administration contains the active com-pound or compounds in amounts of about 0.05 to about lO, preferably O.l to 5 and in particular 0.3 to l, mg/
kg of body weight Similar dosages can be used in the case of a p~renter~1 treatment, for example an intravenous or intrsmncx~iL3r administration. About 0.3 to 1 m~ of active compound~kg of bcdy weight is administerel .in this therapy. As the case may be, the dose may be increased to 0.3 to 15, in case of nee~ ~o 0.3 to 30 mg of active ccnyx~Dnd/kg of body weight. In the case o~ long-term medication, the pharmar ceutical formulation is in gener~1 a~m;nistered, 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. Under certain circu~stances, it may be necessary to deviate from the dosages mentioned, and in particular to do so in accord-ance with the nature, body weight and age of the indivi-dual to be treated, the nature and severity of the illness, the nature of the formulation and of the administration of the medicament, and the time or interval over which administration takes place.
Thus, in some cases it can suffice to manage with less than the abovementioned amount of active compound, while in other cases it is necessary to exceed the amount of active compound mentioned above The optimum dosage and method of administration of the ` i ~ 636~4 active compounds required in each particular case can be determined by the expert in accordance with his expert knowledge.
The pharmaceutical formulations as a rule con-sist of the active compounds according to the inventionand non-toxic, pharmaceutically acceptable medicinal excipients, which are used as an admixture 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 activs 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, gran-ules, aqueous and oily suspensions, emulsions or solu-tions.
Tablets may contain inert diluents, for example c~lcium 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 1 1 6364~
medicament in the gastro-intestinal tract and hence, for example, better toleration, a protracted effect or a retarded effect are achie~ed. 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 alginate, 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; pre~ervatives, for example methyl hydroxybenzoate or propyl hydroxybenzoate;
fla~ouring agents; and sweeteners, for example saccharin or sodium cyclamate.
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.
Water-dispersible powders and granules may con-tain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those ~5 mentioned above, as well as with sweeteners, flavouring agents and colorants.
Emulsions may contain, for example, paraffin oil, in addition to emulsifying agents, such as gum - acacia, gum tragacanth, phosphatides, sorbitane - ' '~ :' .
Epox~cycloalkylalkanecarboxylic acids of the general formula I*
(CH2)m* Y ~(CH2)n*--C~ (CH2)p~ (I*) C~-O-R*
~ wherein R* denotes a hydrogen atom or a lower alkyl 1 1 636~4 group, Y* denotes a methylene group (-CH2-), m* denotes an integer from l to 6, n* denotes the number l and p~
denotes an integer from 4 to 7 (and the sum of the numbers m*, n* and p* is an integer from 6 to ll), and 5 also the salts of the carboxylic acids form an embodi-ment of the invention.
Epoxycycloalkylalkanecarboxylic acids of the general formula I**
0l! Y (CH2)m** Y* (CH2)~* C (CH2)p** (I**) \ C0-0-R**
wherein R** denotes a hydrogen atom or a lower alkyl group, Y** denotes an oxygen atom (-O-), m** denotes an 15 integer ~rom 2 to 6, n** denotes an integer from 0 to 4 and p** denotes an integer from 4 to 7 (and the sum of the numbers m**, n** and p** is an integer from 6 to ll), and also the salts of the carboxylic acids form a further embodiment of the invention.
The following may be mentioned as examples of representatives of the compounds according to the inven-tion: 2-(4-cyclohexylbutyl)-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclopropylpentyl)-oxirane-2-carboxy-lic acid methyl ester, 2-(3-cyclooctylpropyl)-oxirane-25 2-carboxylic acid ethyl ester, 2-(8-cyclopentyloctyl)-oxirane-2-carboxylic acid methyl ester, 2-(2-cyclo-undecylethyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(3-cyclododecylpropyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclohexylhexyl)-oxirane-2-carboxylic .
.
1 ~ 63644 acid n-butyl ester, 2-(lO-cyclopentyldecyl)-oxirane-2-carboxylic acid ethyl ester, 2-(2-cycloheptylethyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(7-cyclo-- butylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-cyclononylmethyl-oxirane-2-carboxylic acid sec.-butyl ester9 2-(9-cyclopropylnonyl)-oxirane-2-carboxy-lic acid methyl ester, 2-(3-cyclodecylpropyl)-oxirane-2-carboxylic acid n-butyl ester, 2-cyclododecylmethyl-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclohexyl-pentyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(4-cyclooctylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(4-cyclopentylbutyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(6-cycloheptylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cyclobutylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-(5-cyclooctyl-pentyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(7-cycloheptylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cyclododecylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclooctylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(5-cycloheptylpentyl)-oxirane-2 carboxylic acid sec.-butyl ester, 2-(2-cyclo-hexylethyl)-oxirane-2-carboxylic acid ethyl ester, 2-(6-cyclopentylhexyl)-oxirane-2-carboxylic acid methyl ester, 2-(7-cyclohexylheptyl)-oxirane-2-carboxylic acid isopropyl ester, 2-(4-cyclobutylbutyl)-oxirane-2-carboxylic acid n-butyl ester, 2-(2-cyclononylethyl)-oxirane-2-Garboxylic acid ethyl este:r, 2-(4-cyclo-dodecylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(6-cyclobutylhexyl)-oxirane-2-carboxylic acid ~, 30 1 ~ 63644 isopropyl ester, 2-(7~cyclooctylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(2-cyclopentylethyl)-oxirane-2-carboxylic acid ethyl ester, 2-(8-cyclohexyl-octyl)-oxirane-2-carboxylic acid n-propyl ester, 2-(4-cycloheptylbutyl)-oxirane-2-carboxylic acid methyl ester, 2-(7-cyclopentylheptyl)-oxirane-2-carboxylic acid methyl ester, 2-(6-cyclobutylhexyl)-oxirane-2-carboxylic acid ethyl ester, 2-(2-cyclooctylethyl)-oxirane-2-carboxylic acid n-propyl ester, 2-[3-(2-cyclohexyl-ethoxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(3-cyclobutylpropoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(2-cycloheptylethox~)-butyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[3-(3-cyclopentylpropoxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-[3-(cyclohexyloxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(4-cyclopropylbutoxy)-hexyl]-oxirane-2-carboxylic acid methyl ester, 2-[5-(cyclopentyloxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclooctylmethoxy)-ethyl~-oxirane-2-carboxy-lic acid isopropyl ester, 2-[3-(2-cyclononylethoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(cyclododecylmethoxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(3-cyclopropylpropoxy)-hexyl]-oxirane-2-carboxylic acid n-butyl ester, 2-~5-(4-cyclobutyl-25 butoxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[3-(2-cyclododecylethoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(6-cyclopentylhexyloxy)-ethyl]-oxirane-2-carboxylic acid n-propyl ester, 2-[~-(cyclo-- hexylmethoxy)-hexyl]-oxirane-2-carboxylic acid isopropyl -~-`` t 1 ~36 ester, 2-[5-(cycloheptyloxy)-pentylJ-oxirane-2-carboxy-lic acid methyl ester, 2-~3-(cycloundecyloxy)-propyl]-oxirane-2-carboxylic acid ethyl ester, 2-[4-(cyclo-octylmethoxy)-butyl]-oxirane-2-carboxylic acid n-butyl 5 ester, 2-[2-(5-cyclobutylpentyloxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclononylmethoxy)-ethyl]-oxirane-2-carboxylic acid n-propyl ester, 2-~5-(2-cycloheptylethoxy) pentyl]-oxirane-2-carboxylic acid methyl ester, 2-[~-(2-cyclopropylethoxy)-hexyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[3-(6-cyclopentyl-hexyloxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(3-cyclohexylpropoxy)-butyl]-oxirane-2-carboxylic acid n-propyl ester, 2-[5-(cycloheptyl-methoxy)-pentyl]-oxirane-2-carboxylic acid methyl ester, 2-[6-(cyclooctyloxy)-hexyl]-oxirane-2-carboxylic acid ethyl ester, 2-[4-(cyclononyloxy)-butyl]-oxirane-2-carboxylic acid sec.-butyl ester, 2-[2-(4-cyclohexyl-butoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[4-(2-cyclopentylethoxy)-butyl]-oxiràne-2-carboxylic acid ethyl ester, 2-[4-(cyclopentylmethoxy)-butyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[5-(cyclo-hexyloxy)-pentyl]-oxirane-2-carboxylic acid ethyl ester, 2-[3-(3-cycloheptylpropoxy)-propyl]-oxirane-2-carboxylic acid methyl ester, 2-[3-(cyclododecyloxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-t4-(2-cyclooctylethoxy)-butyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-~4-cycloheptylbutoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-[2-(4-cyclopentyl-butoxy)-ethyl]-oxirane-2-carboxylic acid isopropyl l l63614 ester, 2-~2-(5-cyclohexylpentyloxy)-ethyl]-oxirane-2-carboxylic acid ethyl ester, 2-[6-(cycloheptyloxy)-hexyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[2-(3-cyclooctylpropoxy)-ethyl]-oxirane-2-carboxylic acid 5 n-butyl ester, 2-[2-(2-cyclohexylethoxy)-ethyl]-oxirane-2-carboxylic acid methyl ester, 2-~2-(2-cycloheptyl-ethoxy)-ethyl]-oxirane-2-carboxylic acid isopropyl ester, 2-[4-~cycloheptyloxy)-butyl]-oxirane-2-carboxylic acid ethyl ester, 2-[2-(cyclooctyloxy)-ethyl]-oxirane-10 2carboxylic acid methyl ester, 2-[3-(cyclopentyloxy)-propyl]-oxirane-2-carboxylic acid n-butyl ester, 2-[6-(cyclopentylmethoxy)-hexyl]-oxirane-2-carboxylic acid ethyl ester, the corresponding oxirane-2-carboxylic acids and their salts with inorganic and org~nic bases.
15 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 stx~g ~glycaemic and ~x~eb~mic action, which is of a co~ratively short duration.
Because of their advantageous activity, the 25 epoxycycloalkylalkanecarboxylic acids, according to the invention, of the general formula I and/or of the ~mbodiments I* and I** and also the pharmacologically acceptable salts are suitable for the treatment and 30 prophylaxis, in human and veterinary medicine, of ` 1 1 636~4 diseases caused by disturbances of the metabolism of glucose and fats. Examples of 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 in~ention also relates, therefore, to a process for combating the said diseases by administer-ing the compounds according to the invention me invention also relates to the use of the compounds according to the in~ention in combating the said dis-eases.
The in~ention ~urther relates to medicaments conta1ning one or more of the epoxycycloalkylalkane-carboxylic acids of the general formula I
0 ~ (CHz)m - Y - (CH2)n - C ~ H2)p tI) ~ \ C0-0-R
wherein R denotes a hydrogen atom or a lower alkyl group, Y denotes an oxygen atom (-0-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to ll (and m cannot be 0 or l if Y represents an oxygen atom7and the sum of the numbers m, n and p is an integer from 6 to 15), and/or the pharmacologic-~ ally acceptable salts of the acids with inorganic or ~0 ~ 1 63644 g organic bases.
Embodiments of the medicaments are those con-taining 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 pre-paration of medicaments for combating the said 1 0 diseases.
The medicaments are prepared in accordance with processes which are in themsel~es known. As medica-ments, the new compounds can be used as such or, if appropriate, in combination with suitable pharmaceuti-c 1 eXcipients. If the ne~ pharmaceutical formula-tions contain pharmaceutical excipients in addition to the active compounds, the content of active compound in these m~xtures is 1 to 95, preferably 15 to 85, per cent by weight of the total mixture.
In accordance with the invention it is possible to use t~e active compounds in any desired form, for ex-ampIe a systemic form, in the field of human medicine,with the pro~iso 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 adm7nistration in suit-able doses. The pharmaceutical formulation of the active compound is advantageously in the form of unit doses appropriate for the desired administration A
~ ~ 63644 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 con-tains an individual amount of the active ingredient in combination with a pharmaceutical excipient, the con-tent of active compound in the t~ni t dose corresponding 10 to a fraction or multiple of a therapeutic individual dose An individual dose preferably contains the amount o~ active compound which is given in one a~m;ni-stration and usually corresponds to a whole daily dose or a half, one-third or one-quarter of the daily dose.
15 If only a fraction, such as a half or one-quarter, of the l1n1t dose is required for an individual therapeutic a~ministration, the unit dose is advantageously divis-ible, for example in the form of a tablet with a breaking groove.
When in the form of unit doses and intended, for example, for administration to humans, the pharma-ceutical formulations according to the invention con-tain about 2 to 200 mg, advantageously lO to lO0 mg and in particular 20 to 60 mg, of active compound.
In general, it has proved adv2ntageous 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 appropriate in the .
1 3 63~4 form of several, preferably 1 to ~, individual admini-strations in order to achieve the desired results.
An individual administration contains the active com-pound or compounds in amounts of about 0.05 to about lO, preferably O.l to 5 and in particular 0.3 to l, mg/
kg of body weight Similar dosages can be used in the case of a p~renter~1 treatment, for example an intravenous or intrsmncx~iL3r administration. About 0.3 to 1 m~ of active compound~kg of bcdy weight is administerel .in this therapy. As the case may be, the dose may be increased to 0.3 to 15, in case of nee~ ~o 0.3 to 30 mg of active ccnyx~Dnd/kg of body weight. In the case o~ long-term medication, the pharmar ceutical formulation is in gener~1 a~m;nistered, 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. Under certain circu~stances, it may be necessary to deviate from the dosages mentioned, and in particular to do so in accord-ance with the nature, body weight and age of the indivi-dual to be treated, the nature and severity of the illness, the nature of the formulation and of the administration of the medicament, and the time or interval over which administration takes place.
Thus, in some cases it can suffice to manage with less than the abovementioned amount of active compound, while in other cases it is necessary to exceed the amount of active compound mentioned above The optimum dosage and method of administration of the ` i ~ 636~4 active compounds required in each particular case can be determined by the expert in accordance with his expert knowledge.
The pharmaceutical formulations as a rule con-sist of the active compounds according to the inventionand non-toxic, pharmaceutically acceptable medicinal excipients, which are used as an admixture 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 activs 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, gran-ules, aqueous and oily suspensions, emulsions or solu-tions.
Tablets may contain inert diluents, for example c~lcium 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 1 1 6364~
medicament in the gastro-intestinal tract and hence, for example, better toleration, a protracted effect or a retarded effect are achie~ed. 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 alginate, 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; pre~ervatives, for example methyl hydroxybenzoate or propyl hydroxybenzoate;
fla~ouring agents; and sweeteners, for example saccharin or sodium cyclamate.
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.
Water-dispersible powders and granules may con-tain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those ~5 mentioned above, as well as with sweeteners, flavouring agents and colorants.
Emulsions may contain, for example, paraffin oil, in addition to emulsifying agents, such as gum - acacia, gum tragacanth, phosphatides, sorbitane - ' '~ :' .
3 ~ 4 4
4 --monooleate or polyoxyethylene sorbitane monooleate, and sweeteners and flavouring agents.
For parenteral administration of the medicaments, sterile injecta~le aqueous susp~nsion~ for example iso-tonic salt solutions or other solutions which can con-tain dispersing agents or wetting agents and/or pharmacologically acceptable diluents, for example propylene glycol or butylene glycol, are used.
m eactivecompound orcompoundsca~ ~o b~ formulated in a micro-encapsulated form, if appropriate together with one or more of the excipients or additives indi-cated.
In addition to the epoxycycloalkylalkanecarboxy-- lic acids according to the invention, in which the sub-stituents have the meaning indicated above, and/or their salts, 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, glibornuride, glisoxepide, gliquidone or glymidine, or hypolipidaemics, such as nicotinic acid and its deriva-tives and salts.
The in~ention further relates to a process for the preparation of epoxycycloalkylalkanecarboxylic acids of the general formula I
Lx(cHz~m Y (CH2~n--C~
Cp-O-R
; ~ 3 1~364 4 wherein R denotes a hy~ogen atom or a lower alkyl group, Y denotes an oxygen atom (-0-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y is an oxygen ato~ and the sum of the numbers m, n and p is an integer from 6 to 15), and also the salts of the carboxylic acids, which is characterised in that a substituted ~-methylenecarboxylic acid of the general 10 formula II
r /(CH2 )m--Y--(C~2 )n C~H2 )p (II ) CH2--~
~C0-0-R
15 wherein R, Y, m, n and p have the meanings indicated above, is oxidised and, if appropriate, the resulting lower alkyl esters are then saponi~ied and, if desired, subsequently converted into the salts or the resulting acids are converted into the salts or lower alkyl 20 esters.
m e oxidation of the ~-methylenecarboxylic acids II is effected under conditions such as are known to thè
expert for the oxidation of carbon-carbon double bonds to give epoxides. Examples of suitable oxidising 25agents are peroxo compounds, such as hydrogen peroxide, peracetic acid, trifluoroperacetic acid, 3,5-dinitro-perbenzoic acid or preferably mrchlor~p~*~nzoic acid or pE~leic acid.
The reaction is expediently carried out in inert sol-- vents, for example aromatic or chlorinated hydrocarbons, .. . .
^J ~ G364 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 70C, The saponification of the lower alkyl esters is effected in a manner which is in itself known. It is carried out at room temperature, for example using an aqueous or alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solu-tion, if appropriate with the addition of an inert diluent, such as dioxan~ tetrahydrofuran or toluene.
The conversion of the acids of the general formula I (R =-H) and/or o~ the embodiments I* and I**
into the salts can be effected by direct alkaline hydrolysis of the acid derivatives I (R = lower alkyl ? .
The alkaline reactant used is the inorganic or organic base forming the salt which is desired. However, the salts are ~lso obtained by reacting the acids I
(R =-H) with the stoichiometric equi~alent of a suitable base, for example sodium hydroxide or sodium ethylate, or readily soluble salts are con~erted by double decomposition into sparingly soluble salts, or any desired salts are converted into pharmacologically acceptable salts.
The conversion of the carboxylic acids of the general formula I (R =-H) and/or of the embodiments I*
and I** into the lower alkyl esters (R = lower alkyl) is effected in a conventional manner. For example, they are esterified with lower alkanols in the presence .
636~4 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 diazabicycloundeceneor diazabicyclo-nonene in inert solvents, such as benzene, toluene or acetone.
The compounds of the general formula I are norm~lly produced in the form of racemic mixtures which are separated into the enantiomers by means of known processes. For example, the racemate is converted by means of an optically active resolving agent into diastereomers which are subsequently separated by selective crystallisation and are converted ~nto the corresponding optical isomers. Examples of optically active resolving agents used are optically active bases, such as l-l-phenylethylamine, d-l-phenylethylamine, cinchonidine or d-ephedrine, from which salts of the acids of the general formula I are prepared, or optic-ally active alcohols, such as borneol or menthol, fromwhich esters of the acids of the general formula I are prepared. It is also possible to resolvè racemic mixtures into the optical isomers by chromatography on optically active adsorbents. Alternatively, the a-methylenecarboxylic acids II are first reacted with anoptically active resolving agent, for example borneol or menthol, and the resulting products are oxidised to give the corresponding mixtures of diastereomers of the carboxylic acid esters, from which the optical isomers ~ 30 ...., -, .
1 ~ 63~44 of the acids I are then obtained in a conventional manner a-Methylenecarboxylic acids of the general formulae II* and II**
/(C~2)m*~ Y*--tCH2)n* ~ C~H2)P* (II*) CO O R~
/(CH2)m*~Y -tCH2 )n*~C~2 p \CO-O-R**
- wherein R*, 7*, 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 embo ~ments I* and I**.
The a-methylenecarboxylic acids of the general formulae II, II* and II** can be prepared by methods which are in themselves known. m ey are valuable intermediate products for the synthesis of the carboxylic acids I, I* and I**.
: me preparation of the -methylenecarboxylic acids II is effected, for example, analogously to the method of H. Stetter and H. Kuhlmann ~Synthesis 1979, 29] by reacting malonic acid half-esters of the general formula III
, 1 1 ~36~1 HOOC ~ ~ (III) / (CH2) - Y - (CH2) - CH (CH~) wherein 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 saponi~ying the resulting lower alkyl esters;
The preparation of the malonic acid half-esters III is effected by methods such as are familiar to the expert, for example by reacting dialkyl malonates IV
with cycloalkylalkyl compounds V and partially saponi-fying the resulting malonic acid diesters VI in accord-ance with the following reaction scheme 15 R'-O-OC~ ~__~
CH2 ~ X-(~H2)m-Y-(CH2)n-C~H (,CH2)p R'-O-OC/ (V) -(IY) R'-O-OC
. /CH-(CH2)m-Y-(CH2~"-C ~ CH2)p ~ III
R'-O-OC (VIj wherein 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-toluene-sulphonyloxy group Correspondingly substituted s-tarting compounds III* or III**, IV* or IV**, V* or V**, respectively, in which the substituents Y*, m*, n* and p* or Y~*, m**, n** and p**, respectively, have the meanings .
~ ~ 6364~1 indicated above, R'* denotes a lower alkyl group, R'**
denotes a methyl or ethyl group and X* or X** denotes a chlorine or bromine atom or a mesyloxy or p-toluene-- sulphonyloxy group, are employed for the preparation of the a-methylenecarboxylic acids II* or II**.
The cycloalkylalkyl compounds ~ and their embodiments V* and V** are known compounds or are pre-pared in accordance with known processes.
For example, compounds V in which Y represents a methylene group (-CH2-), can be prepared from known starting compounds by conventional chain lengthening reactions. Thus, for example, cycloalkylalkyl com-pounds Y 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 cycloaikylalkyl 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 conver-sion of the alcohol formed into the halogen compound).
Compounds V in which Y represents an oxygen atom (-0-), can be prepared in various ways, for example in accordance with the following reaction scheme . .
-- 2~ --Hal - (CH2 )n - C~cH2 )p HO - (CH2 )n - C~cH2 )p ~YII) (YIII) ¦ H0-(CH2)m-0H ¦ X~(CH2)m~
~ (IX) 1 (X) tlO-(CH2)m~0~(CH2)n C~7~2)p 3 X-(CH2)m-0-(~H2)n-C=CH2)p ~XI) (Y~
wherein n, p and ~ have the meanings indicated above, Hal represents a halogen atom and m represents an inte-ger from 2 to 6 [in this connection see also J, Augstein et al, (J,Med,Chem, 8 (1965) ~56-367), J,D, Genzer et al, (J,Amer,Chem,Soc, 73 (1951) 3,159-3,162) and Sh, Mamedov et al,, (Zh,Obshch,Khim, ~2, 799 (1962), ~, 3,166 (1963)], The cycloalkyl co~pounds VII and VIII are known or are prepared (as described above) in a known manner, for example by chain lengthening, For the reaction with the halogen compounds VII
or X, the alcohols VIII or the diols IX are preferably converted into the (mono)alcoholates, The conver-sion 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, The examples which follow serve to illustrate the invention without limiting it, Bp denotes boil-ing point and mp denotes melting point, Tempera-ture data are quoted in C, ' 30 ~ .
` 1 1 636~4 Examples Example 1 2-t3-CyclohexylpropYl)-oxirane-2-carboxylic acid ethyl ester a~ 2-(3-CyclohexYl~ yl)-oxirane-2-carboxYlic acid ethyl ester 7.9 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester and 12.2 g of m-chloroperbenzoic acid in 100 ml of methylene chloride are boiled under reflux for 21 hours The mixture is cooled to 0C, the precipitate is filtered off and washed with 50 ml of methylene chloride and the combined filtrates are con-centrated. The turbid, oily residue is dissolved in 60 ml of acetone and dilute sodium carbonate solution is added, while cooling with ice, until a pH value of 9 is reached. 100 ml of water are also added and the mixture is-extracted with 3 times 100 ml of diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated and the oily residue 2~ is distilled This gives 4.9 g of the title com-pound, bp 100 - 108C at 0.02 mm Hg (2 7 Pa) b) 5-CYclohexYl-2-methYlenevaleric acid ethvl ester 51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester, 6 4 g of para~ormaldehyde, 50 ml of pyridine and 2.1 g of piperidine are warmed to 60C. When the evolution of carbon dioxide is complete (approx. 1 hour), the mixture is stirred for a further hour at 60C and is poured into 800 ml of water and the mixture is extracted with 4 times 200 ml of petroleum ether The combined 1 1 636~4 organic phases are washed with 200 ml of water, 200 ml of 2N hydrochloric acid, 200 ml of water and 200 ml of saturated sodium bicarbonate solution and are dried over sodium sulphate and concentrated. The residue is purified by chromatography on a silica gel column.
(Migrating agent 80:20 petroleum ether/ethyl acetate).
This gives 36.7 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester in the form of a nearly colourless oil.
c) (3-CvclohexvlProPYl)-malonic acid ethyl ester A solution of 13.5 g of potassium hydroxide in 160 ml of ethanol is added dropwise in the course of one hour and while stirring to 68 g o~ (3-cyclohexyl-propyl)-malonic acid diethyl ester (prepared analogously to Example 4d), dissolved in 160 ml of ethanol. After 15 st~rring for 24 hours at room temperature, the mixture is concentrated considerably in vacuo and the residue is dissolved in 400 ml of water and extracted with 300 ml of diethyl ether 40 ml of half-concentrated hydrochloric acid are added to the aqueous phase, while ~ cooling with ice, and the mixture is extracted with ~
times 300 ml of diethyl ether The combined organ~c phases are dried over sodium sulphate and concentrated.
This gives 51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester in the form of a viscous, yellowish oil.
25 E~ample 2 2-(4~C~clohex~lbutvl)-oxirane-2-carboxYlic acid ethyl ester a) 2-(4-C~clohexYlbutvl~-oxirane-2-carboxYlic acid ethvl ester ~ ~ 63~4~
3,8 g of the title compound are obtained in the fo~m of a colourless oil, bp 110 - 118C at 0.01 mm Hg (1,3 Pa) by the procedure described in Example la) from 6.4 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester and 9.3 g of m-chloroperbenzoic acid in 80 ml of methylene chloride.
b) 6-Cyclohexyl-2-methylenehexanoic acid ethyl ester 16.6 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) ~rom 26 g of (4-cyclohexylbutyl)-malonic acid ethyl ester, 3.1 g of paraformaldehyde, 19 ml of pyridine and 1.2 ml o~ piperidine, c) (4-CYclohexvlbutYl)-malonic acid ethYl ester 26.1 g of (4-cyclohexylbutyl)-malonic acid ethyl ester are obta~ned in the form of a viscous, yellowish oil by the procedure described in Example lc) from 35 g of (4-cyclohexylbutyl)-malonic acid diethyl ester (prepared analogously to Example 4d) and 6.7 g of potassium hydroxide in 150 ml of ethanol.
Example 3 2-(5-CyclohexvlPentYl~-oxirane-2-carboxYlic acid ethyl ester -a) 2-(5-CyclohexYlpentYl)-oxirane-2-carboxy~lic acid ethyl esteP
For parenteral administration of the medicaments, sterile injecta~le aqueous susp~nsion~ for example iso-tonic salt solutions or other solutions which can con-tain dispersing agents or wetting agents and/or pharmacologically acceptable diluents, for example propylene glycol or butylene glycol, are used.
m eactivecompound orcompoundsca~ ~o b~ formulated in a micro-encapsulated form, if appropriate together with one or more of the excipients or additives indi-cated.
In addition to the epoxycycloalkylalkanecarboxy-- lic acids according to the invention, in which the sub-stituents have the meaning indicated above, and/or their salts, 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, glibornuride, glisoxepide, gliquidone or glymidine, or hypolipidaemics, such as nicotinic acid and its deriva-tives and salts.
The in~ention further relates to a process for the preparation of epoxycycloalkylalkanecarboxylic acids of the general formula I
Lx(cHz~m Y (CH2~n--C~
Cp-O-R
; ~ 3 1~364 4 wherein R denotes a hy~ogen atom or a lower alkyl group, Y denotes an oxygen atom (-0-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y is an oxygen ato~ and the sum of the numbers m, n and p is an integer from 6 to 15), and also the salts of the carboxylic acids, which is characterised in that a substituted ~-methylenecarboxylic acid of the general 10 formula II
r /(CH2 )m--Y--(C~2 )n C~H2 )p (II ) CH2--~
~C0-0-R
15 wherein R, Y, m, n and p have the meanings indicated above, is oxidised and, if appropriate, the resulting lower alkyl esters are then saponi~ied and, if desired, subsequently converted into the salts or the resulting acids are converted into the salts or lower alkyl 20 esters.
m e oxidation of the ~-methylenecarboxylic acids II is effected under conditions such as are known to thè
expert for the oxidation of carbon-carbon double bonds to give epoxides. Examples of suitable oxidising 25agents are peroxo compounds, such as hydrogen peroxide, peracetic acid, trifluoroperacetic acid, 3,5-dinitro-perbenzoic acid or preferably mrchlor~p~*~nzoic acid or pE~leic acid.
The reaction is expediently carried out in inert sol-- vents, for example aromatic or chlorinated hydrocarbons, .. . .
^J ~ G364 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 70C, The saponification of the lower alkyl esters is effected in a manner which is in itself known. It is carried out at room temperature, for example using an aqueous or alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solu-tion, if appropriate with the addition of an inert diluent, such as dioxan~ tetrahydrofuran or toluene.
The conversion of the acids of the general formula I (R =-H) and/or o~ the embodiments I* and I**
into the salts can be effected by direct alkaline hydrolysis of the acid derivatives I (R = lower alkyl ? .
The alkaline reactant used is the inorganic or organic base forming the salt which is desired. However, the salts are ~lso obtained by reacting the acids I
(R =-H) with the stoichiometric equi~alent of a suitable base, for example sodium hydroxide or sodium ethylate, or readily soluble salts are con~erted by double decomposition into sparingly soluble salts, or any desired salts are converted into pharmacologically acceptable salts.
The conversion of the carboxylic acids of the general formula I (R =-H) and/or of the embodiments I*
and I** into the lower alkyl esters (R = lower alkyl) is effected in a conventional manner. For example, they are esterified with lower alkanols in the presence .
636~4 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 diazabicycloundeceneor diazabicyclo-nonene in inert solvents, such as benzene, toluene or acetone.
The compounds of the general formula I are norm~lly produced in the form of racemic mixtures which are separated into the enantiomers by means of known processes. For example, the racemate is converted by means of an optically active resolving agent into diastereomers which are subsequently separated by selective crystallisation and are converted ~nto the corresponding optical isomers. Examples of optically active resolving agents used are optically active bases, such as l-l-phenylethylamine, d-l-phenylethylamine, cinchonidine or d-ephedrine, from which salts of the acids of the general formula I are prepared, or optic-ally active alcohols, such as borneol or menthol, fromwhich esters of the acids of the general formula I are prepared. It is also possible to resolvè racemic mixtures into the optical isomers by chromatography on optically active adsorbents. Alternatively, the a-methylenecarboxylic acids II are first reacted with anoptically active resolving agent, for example borneol or menthol, and the resulting products are oxidised to give the corresponding mixtures of diastereomers of the carboxylic acid esters, from which the optical isomers ~ 30 ...., -, .
1 ~ 63~44 of the acids I are then obtained in a conventional manner a-Methylenecarboxylic acids of the general formulae II* and II**
/(C~2)m*~ Y*--tCH2)n* ~ C~H2)P* (II*) CO O R~
/(CH2)m*~Y -tCH2 )n*~C~2 p \CO-O-R**
- wherein R*, 7*, 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 embo ~ments I* and I**.
The a-methylenecarboxylic acids of the general formulae II, II* and II** can be prepared by methods which are in themselves known. m ey are valuable intermediate products for the synthesis of the carboxylic acids I, I* and I**.
: me preparation of the -methylenecarboxylic acids II is effected, for example, analogously to the method of H. Stetter and H. Kuhlmann ~Synthesis 1979, 29] by reacting malonic acid half-esters of the general formula III
, 1 1 ~36~1 HOOC ~ ~ (III) / (CH2) - Y - (CH2) - CH (CH~) wherein 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 saponi~ying the resulting lower alkyl esters;
The preparation of the malonic acid half-esters III is effected by methods such as are familiar to the expert, for example by reacting dialkyl malonates IV
with cycloalkylalkyl compounds V and partially saponi-fying the resulting malonic acid diesters VI in accord-ance with the following reaction scheme 15 R'-O-OC~ ~__~
CH2 ~ X-(~H2)m-Y-(CH2)n-C~H (,CH2)p R'-O-OC/ (V) -(IY) R'-O-OC
. /CH-(CH2)m-Y-(CH2~"-C ~ CH2)p ~ III
R'-O-OC (VIj wherein 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-toluene-sulphonyloxy group Correspondingly substituted s-tarting compounds III* or III**, IV* or IV**, V* or V**, respectively, in which the substituents Y*, m*, n* and p* or Y~*, m**, n** and p**, respectively, have the meanings .
~ ~ 6364~1 indicated above, R'* denotes a lower alkyl group, R'**
denotes a methyl or ethyl group and X* or X** denotes a chlorine or bromine atom or a mesyloxy or p-toluene-- sulphonyloxy group, are employed for the preparation of the a-methylenecarboxylic acids II* or II**.
The cycloalkylalkyl compounds ~ and their embodiments V* and V** are known compounds or are pre-pared in accordance with known processes.
For example, compounds V in which Y represents a methylene group (-CH2-), can be prepared from known starting compounds by conventional chain lengthening reactions. Thus, for example, cycloalkylalkyl com-pounds Y 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 cycloaikylalkyl 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 conver-sion of the alcohol formed into the halogen compound).
Compounds V in which Y represents an oxygen atom (-0-), can be prepared in various ways, for example in accordance with the following reaction scheme . .
-- 2~ --Hal - (CH2 )n - C~cH2 )p HO - (CH2 )n - C~cH2 )p ~YII) (YIII) ¦ H0-(CH2)m-0H ¦ X~(CH2)m~
~ (IX) 1 (X) tlO-(CH2)m~0~(CH2)n C~7~2)p 3 X-(CH2)m-0-(~H2)n-C=CH2)p ~XI) (Y~
wherein n, p and ~ have the meanings indicated above, Hal represents a halogen atom and m represents an inte-ger from 2 to 6 [in this connection see also J, Augstein et al, (J,Med,Chem, 8 (1965) ~56-367), J,D, Genzer et al, (J,Amer,Chem,Soc, 73 (1951) 3,159-3,162) and Sh, Mamedov et al,, (Zh,Obshch,Khim, ~2, 799 (1962), ~, 3,166 (1963)], The cycloalkyl co~pounds VII and VIII are known or are prepared (as described above) in a known manner, for example by chain lengthening, For the reaction with the halogen compounds VII
or X, the alcohols VIII or the diols IX are preferably converted into the (mono)alcoholates, The conver-sion 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, The examples which follow serve to illustrate the invention without limiting it, Bp denotes boil-ing point and mp denotes melting point, Tempera-ture data are quoted in C, ' 30 ~ .
` 1 1 636~4 Examples Example 1 2-t3-CyclohexylpropYl)-oxirane-2-carboxylic acid ethyl ester a~ 2-(3-CyclohexYl~ yl)-oxirane-2-carboxYlic acid ethyl ester 7.9 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester and 12.2 g of m-chloroperbenzoic acid in 100 ml of methylene chloride are boiled under reflux for 21 hours The mixture is cooled to 0C, the precipitate is filtered off and washed with 50 ml of methylene chloride and the combined filtrates are con-centrated. The turbid, oily residue is dissolved in 60 ml of acetone and dilute sodium carbonate solution is added, while cooling with ice, until a pH value of 9 is reached. 100 ml of water are also added and the mixture is-extracted with 3 times 100 ml of diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated and the oily residue 2~ is distilled This gives 4.9 g of the title com-pound, bp 100 - 108C at 0.02 mm Hg (2 7 Pa) b) 5-CYclohexYl-2-methYlenevaleric acid ethvl ester 51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester, 6 4 g of para~ormaldehyde, 50 ml of pyridine and 2.1 g of piperidine are warmed to 60C. When the evolution of carbon dioxide is complete (approx. 1 hour), the mixture is stirred for a further hour at 60C and is poured into 800 ml of water and the mixture is extracted with 4 times 200 ml of petroleum ether The combined 1 1 636~4 organic phases are washed with 200 ml of water, 200 ml of 2N hydrochloric acid, 200 ml of water and 200 ml of saturated sodium bicarbonate solution and are dried over sodium sulphate and concentrated. The residue is purified by chromatography on a silica gel column.
(Migrating agent 80:20 petroleum ether/ethyl acetate).
This gives 36.7 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester in the form of a nearly colourless oil.
c) (3-CvclohexvlProPYl)-malonic acid ethyl ester A solution of 13.5 g of potassium hydroxide in 160 ml of ethanol is added dropwise in the course of one hour and while stirring to 68 g o~ (3-cyclohexyl-propyl)-malonic acid diethyl ester (prepared analogously to Example 4d), dissolved in 160 ml of ethanol. After 15 st~rring for 24 hours at room temperature, the mixture is concentrated considerably in vacuo and the residue is dissolved in 400 ml of water and extracted with 300 ml of diethyl ether 40 ml of half-concentrated hydrochloric acid are added to the aqueous phase, while ~ cooling with ice, and the mixture is extracted with ~
times 300 ml of diethyl ether The combined organ~c phases are dried over sodium sulphate and concentrated.
This gives 51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester in the form of a viscous, yellowish oil.
25 E~ample 2 2-(4~C~clohex~lbutvl)-oxirane-2-carboxYlic acid ethyl ester a) 2-(4-C~clohexYlbutvl~-oxirane-2-carboxYlic acid ethvl ester ~ ~ 63~4~
3,8 g of the title compound are obtained in the fo~m of a colourless oil, bp 110 - 118C at 0.01 mm Hg (1,3 Pa) by the procedure described in Example la) from 6.4 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester and 9.3 g of m-chloroperbenzoic acid in 80 ml of methylene chloride.
b) 6-Cyclohexyl-2-methylenehexanoic acid ethyl ester 16.6 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) ~rom 26 g of (4-cyclohexylbutyl)-malonic acid ethyl ester, 3.1 g of paraformaldehyde, 19 ml of pyridine and 1.2 ml o~ piperidine, c) (4-CYclohexvlbutYl)-malonic acid ethYl ester 26.1 g of (4-cyclohexylbutyl)-malonic acid ethyl ester are obta~ned in the form of a viscous, yellowish oil by the procedure described in Example lc) from 35 g of (4-cyclohexylbutyl)-malonic acid diethyl ester (prepared analogously to Example 4d) and 6.7 g of potassium hydroxide in 150 ml of ethanol.
Example 3 2-(5-CyclohexvlPentYl~-oxirane-2-carboxYlic acid ethyl ester -a) 2-(5-CyclohexYlpentYl)-oxirane-2-carboxy~lic acid ethyl esteP
5.3 g of the title compound, bp 115 - 123C at 0.005 mm Hg (0 7 Pa), are obtained by the procedure ~. .
1 3 ~3644 described in Example la) from 9.9 g of 7-cyclohexyl-2-methyleneheptanoic acid ethyl ester and 13.6 g of m-chloroperbenzoic acid in 100 ml of methylene chloride.
- b) 7-CvclohexYl-2-methyleneheptanoic acid ethyl ester 23.6 g of 7-cyclohexyl-2-methyleneheptanoic acid ethyl ester are obtained in the form of a colourless oil by the procedure described in Example lb) from 35.5 g of (5-cyclohexylpentyl)-malonic acid ethyl ester, 4.0 g of - paraformaldehyde, 25 ml of pyridine and 1.5 ml of piperi-dine. ~Mlgrating agent 1:1 petroleum ether/methylene chloride).
c) (5-CvclohexYl~entyl)-malonic acid ethYl ester 35.5 g of (5-cyclohexylpentyl)-malonic acid ethyl ester are obtained in the form of a viscous, yellowish oil by the procedure described in Example lc) from 47.2 g of (5-cyclohexylpentyl)-malonic acid di-ethyl ester (prepared analogously to Example 4d) and 8.6 g of potassium hydroxide in 200 ml of ethanol.
Example 4 2-[4-(CyclohexYloxY)-butvl~-oxirane-2-carboxylic acid ethyl ester a) 2-~4-(vclohexYloxY)-butYl]-oxirane-2-carboxvlic acid ethyl ester 2.4 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Examplç la~ from 4 9 g of 6-cyclohexyloxy-2-methyl-enehexanoic acid ethyl ester and 7 g of m-chloroper-benzoic acid in 50 ml of methylene chloride.
~ 1 636~4 b) 6-Cyclohexyloxy-2-methylenehexanoic acid ethyl ester 4.9 g of 6-cyclohexyloxy-2-methylenehexanoic acid ethyl ester, in the form of a colourless oil, which is puri~ied by chromatography on silica gel (mig~ating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 7 4 g of ~4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester, 0.85 g of paraformaldehyde, 5.2 ml of pyridine and 0.3 ml of piperidine.
c) ~-(CyclohexYloxv)-butYll-malonic acid ethYl ester 7 4 g of ~4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester are obtained by the procedure described in Example lc) from 10.5 g of ~4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester and 1,9 g of potassium hydroxide in 50 ml of ethanol.
d) [4-(CvclohexYloxv)-butYl]-malonic acid diethyl ester 15 g of malonic acid diethyl ester are added dropwise at 50C to a solution of sodium ethylate, freshly prepared from 1.5 g of sodium and 30 ml of ethanol. This temperature is maintained for 1 hour and 11.7 g of 4-cyclohexyloxybutyl bromide are then added dropwise. When the addition is complete, the mixture is stirred for ~ hours at 60C and is concen-trated considera~ly, 100 ml of ice waterare added to the residue and the mixture is extracted 3 times with a `
total of 150 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is removed by distillation in vacuo, together with excess malonic acid diethyl ester. This gives ' ~' ' ~7 --10.5 g of t4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester in the form of a pale yellow oily residue.
Example 5 2-~4-(2-Cyclohexylethoxy~-butyl]-oxirane-2-carboxylic acid ethYl ester a) 2 1 -(2-CYclohexylethoxy~-butyl]-oxirane-2-carboxylic acid ethYl ester 5.3 g of the title compound, in the form of an oil, which is purified by chromatography on silica gel ~ (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example la) from 11.2 g of 6-(2-cyclohexylethoxy)-2-methylene-hexanoic acid ethyl ester and 13.7 g of m-chloroper-. benzoic acid in 100 ml of methylene chloride.
b) 6-(2-CvclohexYlethoxv~-2-methvlenehexanoic acid ethvl ester 11.2 g of 6-t2-cyclohexylethoxy)-2-methylene-hexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb from 16,5 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid ethyl ester, 1.97 g of paraformaldehyde, 12 ml of pyridine and 0.7 ml of piperidine c) ~4-(2-CYclohe~y_ethoxY)-butYl]-malonic acid ethyl ester 16.5 g of [4-(2-cyclohexylethoxy)-butyl~-malonic acid ethyl ester are obtained in the form of a thick, yellow oil by the procedure descriped in ~ ~ 63644 Example lc) from 22 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid diethyl ester and 3.6 g of potassium hydroxide in 150 ml of ethanol.
d) ~4-(2-CYclohexYlethoxY)-butYl]-malonic acid diethvl ester 22 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid diethyl ester are obtained in the form of a yellow oil by the procedure described in Example 4d) from 27.7 g of 4-(2-cyclohexylethoxy)-butyl bromide, 25.3 g Of malonic acid diethyl ester and a solution of 2.9 g of sodium in 150 ml of ethanol.
Exam~le 6 2-(7-CyclohexYlheptYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(7-CYclohexYlheptYl)-oxirane-2-carboxYlic acid ethvl ester 5 25 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Example la) from 9.2 g of 9-cyclohexyl-2-methylene-nonanoic acid ethyl ester and 11.3 g of m-chloroper-benzoic acid in 100 ml of methylene chloride.
b) 9-CYclohexvl-2-methYleneno~anoic acid eth~l ester 9 2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from ~ 1 ~3644 16.2 g of (7-cyclohexylheptyl)-malonic acid ethyl ester, 1.86 g o~ paraformaldehyde, 11 5 ml of pyridine and 0.6 ml of piperidine.
c) (7-CyclohexvlhePtYl)-malonic acid ethYl ester 16.3 g of (7-cyclohexylheptyl)-malonic acid ethyl ester are obtained in the form of a yellow, thic~
oil by the procedure described in Example lc) from 21 6 g of (7-cyclohexylheptyl)-m~lonic acid diethyl ester (prepared analogously to Example 4d) and 3.55 g of potassium hydroxide in 150 ml of ethanol.
Example 7 2-(6-CvclopropYlhexYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(6-CvcloPro~Ylhexyl)-oxirane-2-carboxylic acid ethYl ester 1,18 g of the title compound, in the form of a yellowish oil, which is purified by chromatographY on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Example la) from 2.5 g of 8-cyclopropyl-2-met~ylene-octanoic acid ethyl ester and 3.85 g of m-chloroper-benzoic acid in 30 ml of methylene chloride.
b) 8-CYcloproPyl-2-methyleneoctanoic acid ethYl ester 2 5 g of 8-cyclopropyl-2-methyleneoctanoic acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating , agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from - 4 53 g of t6-cyclopropylhexyl)-malonic acid ethyl ester, ~ , .
1 1~3~4 0.64 g of paraformaldehyde, 4 ml of pyridine and 0,2 ml of piperidine.
c) (6-Cyclopropvlhexyl)-malonic acid ethyl ester - 4.53 g of (6-cyclopropylhexyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 6.4 g of (6-cyclopropylhexyl)-malonic acid diethyl ester and 1.26 g of potassium hydroxide in 40 ml of ethanol, d) (6-CyclopropYlhexvl)-malonic a.cid diethYl ester
1 3 ~3644 described in Example la) from 9.9 g of 7-cyclohexyl-2-methyleneheptanoic acid ethyl ester and 13.6 g of m-chloroperbenzoic acid in 100 ml of methylene chloride.
- b) 7-CvclohexYl-2-methyleneheptanoic acid ethyl ester 23.6 g of 7-cyclohexyl-2-methyleneheptanoic acid ethyl ester are obtained in the form of a colourless oil by the procedure described in Example lb) from 35.5 g of (5-cyclohexylpentyl)-malonic acid ethyl ester, 4.0 g of - paraformaldehyde, 25 ml of pyridine and 1.5 ml of piperi-dine. ~Mlgrating agent 1:1 petroleum ether/methylene chloride).
c) (5-CvclohexYl~entyl)-malonic acid ethYl ester 35.5 g of (5-cyclohexylpentyl)-malonic acid ethyl ester are obtained in the form of a viscous, yellowish oil by the procedure described in Example lc) from 47.2 g of (5-cyclohexylpentyl)-malonic acid di-ethyl ester (prepared analogously to Example 4d) and 8.6 g of potassium hydroxide in 200 ml of ethanol.
Example 4 2-[4-(CyclohexYloxY)-butvl~-oxirane-2-carboxylic acid ethyl ester a) 2-~4-(vclohexYloxY)-butYl]-oxirane-2-carboxvlic acid ethyl ester 2.4 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Examplç la~ from 4 9 g of 6-cyclohexyloxy-2-methyl-enehexanoic acid ethyl ester and 7 g of m-chloroper-benzoic acid in 50 ml of methylene chloride.
~ 1 636~4 b) 6-Cyclohexyloxy-2-methylenehexanoic acid ethyl ester 4.9 g of 6-cyclohexyloxy-2-methylenehexanoic acid ethyl ester, in the form of a colourless oil, which is puri~ied by chromatography on silica gel (mig~ating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 7 4 g of ~4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester, 0.85 g of paraformaldehyde, 5.2 ml of pyridine and 0.3 ml of piperidine.
c) ~-(CyclohexYloxv)-butYll-malonic acid ethYl ester 7 4 g of ~4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester are obtained by the procedure described in Example lc) from 10.5 g of ~4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester and 1,9 g of potassium hydroxide in 50 ml of ethanol.
d) [4-(CvclohexYloxv)-butYl]-malonic acid diethyl ester 15 g of malonic acid diethyl ester are added dropwise at 50C to a solution of sodium ethylate, freshly prepared from 1.5 g of sodium and 30 ml of ethanol. This temperature is maintained for 1 hour and 11.7 g of 4-cyclohexyloxybutyl bromide are then added dropwise. When the addition is complete, the mixture is stirred for ~ hours at 60C and is concen-trated considera~ly, 100 ml of ice waterare added to the residue and the mixture is extracted 3 times with a `
total of 150 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is removed by distillation in vacuo, together with excess malonic acid diethyl ester. This gives ' ~' ' ~7 --10.5 g of t4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester in the form of a pale yellow oily residue.
Example 5 2-~4-(2-Cyclohexylethoxy~-butyl]-oxirane-2-carboxylic acid ethYl ester a) 2 1 -(2-CYclohexylethoxy~-butyl]-oxirane-2-carboxylic acid ethYl ester 5.3 g of the title compound, in the form of an oil, which is purified by chromatography on silica gel ~ (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example la) from 11.2 g of 6-(2-cyclohexylethoxy)-2-methylene-hexanoic acid ethyl ester and 13.7 g of m-chloroper-. benzoic acid in 100 ml of methylene chloride.
b) 6-(2-CvclohexYlethoxv~-2-methvlenehexanoic acid ethvl ester 11.2 g of 6-t2-cyclohexylethoxy)-2-methylene-hexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb from 16,5 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid ethyl ester, 1.97 g of paraformaldehyde, 12 ml of pyridine and 0.7 ml of piperidine c) ~4-(2-CYclohe~y_ethoxY)-butYl]-malonic acid ethyl ester 16.5 g of [4-(2-cyclohexylethoxy)-butyl~-malonic acid ethyl ester are obtained in the form of a thick, yellow oil by the procedure descriped in ~ ~ 63644 Example lc) from 22 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid diethyl ester and 3.6 g of potassium hydroxide in 150 ml of ethanol.
d) ~4-(2-CYclohexYlethoxY)-butYl]-malonic acid diethvl ester 22 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid diethyl ester are obtained in the form of a yellow oil by the procedure described in Example 4d) from 27.7 g of 4-(2-cyclohexylethoxy)-butyl bromide, 25.3 g Of malonic acid diethyl ester and a solution of 2.9 g of sodium in 150 ml of ethanol.
Exam~le 6 2-(7-CyclohexYlheptYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(7-CYclohexYlheptYl)-oxirane-2-carboxYlic acid ethvl ester 5 25 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Example la) from 9.2 g of 9-cyclohexyl-2-methylene-nonanoic acid ethyl ester and 11.3 g of m-chloroper-benzoic acid in 100 ml of methylene chloride.
b) 9-CYclohexvl-2-methYleneno~anoic acid eth~l ester 9 2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from ~ 1 ~3644 16.2 g of (7-cyclohexylheptyl)-malonic acid ethyl ester, 1.86 g o~ paraformaldehyde, 11 5 ml of pyridine and 0.6 ml of piperidine.
c) (7-CyclohexvlhePtYl)-malonic acid ethYl ester 16.3 g of (7-cyclohexylheptyl)-malonic acid ethyl ester are obtained in the form of a yellow, thic~
oil by the procedure described in Example lc) from 21 6 g of (7-cyclohexylheptyl)-m~lonic acid diethyl ester (prepared analogously to Example 4d) and 3.55 g of potassium hydroxide in 150 ml of ethanol.
Example 7 2-(6-CvclopropYlhexYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(6-CvcloPro~Ylhexyl)-oxirane-2-carboxylic acid ethYl ester 1,18 g of the title compound, in the form of a yellowish oil, which is purified by chromatographY on silica gel (migrating agent: 90:10 petroleum ether/
ethyl acetate), are obtained by the procedure described in Example la) from 2.5 g of 8-cyclopropyl-2-met~ylene-octanoic acid ethyl ester and 3.85 g of m-chloroper-benzoic acid in 30 ml of methylene chloride.
b) 8-CYcloproPyl-2-methyleneoctanoic acid ethYl ester 2 5 g of 8-cyclopropyl-2-methyleneoctanoic acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating , agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from - 4 53 g of t6-cyclopropylhexyl)-malonic acid ethyl ester, ~ , .
1 1~3~4 0.64 g of paraformaldehyde, 4 ml of pyridine and 0,2 ml of piperidine.
c) (6-Cyclopropvlhexyl)-malonic acid ethyl ester - 4.53 g of (6-cyclopropylhexyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 6.4 g of (6-cyclopropylhexyl)-malonic acid diethyl ester and 1.26 g of potassium hydroxide in 40 ml of ethanol, d) (6-CyclopropYlhexvl)-malonic a.cid diethYl ester
6.4 g of (6-cyclopropylhexyl)-malonic acid diethyl ester are obtained in the form of a yellow oil by the procedure described in Example 4d) from 6,8 g of 6-cyclopropylhexyl bromide, 7,95 g of m~lonic acid diethyl ester 2nd a solution of 0,91 g of sodium in 40 ml of ethanol, Example 8 2-(3-CYclopentYlpropyl)-oxirane-2-carboxylic acid ethvl ester a) 2-(3-CYclopentvlpropvl)-oxirane-2-carboxvlic acid ethyl ester 19 g of the title compound are obtained in the form of a colourless oil, bp, 89 - 93C at 0,04 mm Hg (5,3 Pa), by the procedure described in Example la) from 20 g of 5-cyclopentyl-2-methylenevaleric acid ethyl ester and 24,2 g of m-chloroperbenzoic acid in 250 ml of methylene chloride.
b) 5-Cvclopentyl-2-methYlenevaleric acid ethyl ester 20,2 g of 5-cyclopentyl-2-methylenevaleric acid ethyl ester, bp, 63 - 65C at 0,01 mm Hg (1,3 Pa), are : ~ .
' ' .
`~ 1 636~4 obtained by the procedure described in Example lb) from 43.8 g of (3-cyclopentylpropyl)-malonic acid ethyl ester, 5 7 g of paraformaldehyde, 45 ml of pyridine and 1.55 g of piperidine.
c) (~-CyclopentYlpropyl)-malonic acid ethyl ester 43.8 g of (3-cyclopentylpropyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 72.8 g of t3-cYolopentylpropyl)-malonic acid diethyl ester (pre-pared analogously to Example 4d) and 17.7 g of potassium hydroxide in 580 ml of ethanol, Example 9 2-(4-CyclopentYlbutYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-14-Cvclo~entvlbutyl)-oxirane-2-carboxYlic acid ethvl ester 4 0 g of the title compound are obtained in the form of a colourless oil, bp 100 - 107C at 0.03 mm Hg (4 Pa), by the procedure described in Example la) from 8.5 g of 6-cyclopentyl-2-methylenehexanoic acid ethyl ester and 13.1 g of m-chloroperbenzoic acid in 120 ml of methylene chloride.
b) 6-Cvclopentyl-2~methylenehexanoic acid ethYl ester 8.5 g of 6-cyclopentyl-2-methylenehexanoic acid ethyl ester, bp 80 - 87C at 0.01 mm Hg (1.3 Pa), are obtained by the procedure described in Example lb) from 18,3-g of (4-cyclopentylbutyl)-malonic acid ethyl ester, 2.6 g of paraformaldehyde, 20 ml of pyridine and 0.9 ml of piperidine.
~ ~ 636~4 c) (4-Cyclopentylbutyl)-malonic acid ethyl ester 18.3 g of (4-cyclopentylbutyl)-malonic acid ethyl ester are obtained in the form of a viscous oil by the procedure described in Example lc) from 29.9 g of (4-cyclopentylbutyl)-malonic acid diethyl ester (prepared analogoùsly to Example 4d) and 5 9 g of potassium hydroxide in 200 ml of ethanol.
Example 10 2-(6-CYclopentylhexvl)-oxirane-2-carboxylic acid ethyl ester a) 2-(6-CYcloPentYlhexvl)-oxirane-2-carboxYlic acid ethvl ester 5,33 g of the title compound, in the form of a nearly colourless oil, which is purified by chromato-graphy on silica gel (migrating agent: 90:10 petroleumet~er/ethyl acetate), are obtained by the procedure des-cribed in Example la) from 11.4 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester and 15.6 g of m-chloroperbenzoic acid in 120 ml of methylene chloride.
b) 8-CYclopentvl-2-methvleneoctanoic acid ethvl ester 11 5 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 22.1 g of (6-cyclopentylhexyl)-malonic acid ethyl ester, 2 8 g of paraformaldehyde, 22 ml of pyridine and 1 ml of piperidine.
~ ~ 63644 c) (6-Cyclopentylhexyl)-malonic acid ethyl ester 22.l g of (6-cyclopentylhexyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 37,9 g of (6-cyclopentylhexy~)-malonic acid diethyl ester and 6,8 g of potassium hydroxide in 200 ml of ethanol, d) (6-Cyclopentylhexvl)-malonic acid diethyl ester 38 g of (6-cyclopentylhexyl)-malonic acid diethyl ester are obtained in the form of an oil by the procedure described in Example 4d) from 48,9 g of 6-cyclopentylhexyl bromide, 50,3 g of malonic acid diethyl ester and a solution of 5,8 g of sodium in 300 ml of ethanol, Example ll .
2-(3-Cvclohe~tylproPYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(3-CYclohePtYlPropyl)-oxirane-2-carboxylic acid ethyl ester 9,3 g of the title compound, bp 107-110C at 0,08 ~m:Hg.. ~10,6 Pa), are obtained by the procedure des-cribed in Example la) from 18,2 g of 5-cycloheptyl-2-methylenevaleric acid ethyl ester and 26,3 g of m-`
chloroperbenzoic acid in 200 ml of methylene chloride, b) 5-CYclohePtYl-2-methvlenevaleric acid ethYl ester 18,2 g of 5-cycloheptyl-2-methylene~aleric acid ethyl ester, bp 89 - 98C at O,Ol mm Hg (l,3 Pa), are obtained by the procedure described in Example lb) from 33,3 g of (3-cycloheptylpropyl)-malonic acid ethyl ester, 4,43 g of paraformaldehyde, 35 ml of pyridine and l,6 ml ` 1 3636~4 of piperidine.
c) (~-CvcloheptYlpropvl)-malonic acid ethyl ester 33.3 g of (3-cycloheptylpropyl)-m~lonic acid ethyl ester are obtained in the form of a yellow o-il by the procedure described in Example lc) from 49.7 g of (3-cycloheptylpropyl)-malonic acid diethyl ester and 9.33 g of potassium hydroxide in 300 ml of ethanol~
d) (3-CYclohePtylproPYl)-m-lonic acid diethYl ester 49.8 g of (3-cycloheptylpropyl)-malonic acid diethyl ester, bp"12Q-122C at OrO8 mm Hg ~1:0.6 P~), are obtained by the procedure described in Example 4d) from 63 g of 3-cycloheptylpropyl bromide, 69 g of malonic acid diethyl ester anda solution of 7.9 g of sodium in 400 ml of ethanol.
EX~mple 12 2-(3-CYclooctylpro~Y1)-oxirane-2-carboxylic~ acid ethYl ester a) 2-(3-Cyclooct~lpropYl)-oxirane-2-carboxylic acid ethyl ester 2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel ~migrating agent: 90:lO petroleum ether/
ethyl acetate), are obtained by the pro~edure described in Example la) from 5.42 g of 5-cyclooctyl-2-methylene-~5 valeric acid ethyl ester and 5.55 g of m-chloroper-benzoic acid in 50 ml of methylene chloride b) 5-Cy~looctyl-2-methylenevaleric acid ethyl ester 5.5 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester, in the form of an oil, which is purified ~ 3 ~3644 by chromatography on silica gel (migrating agent:
95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 10.1 g of cyclooctylpropyl)-malonic acid ethyl ester, 1.28 g of paraformaldehyde, 10 ml of pyridine and 0.5 ml of piperidine.
c) (3-CYclooctvlProPyl)-malonic acid ethYl ester 10.2 g of (3-cyclooctylpropyl)-malonic acid ethyl ester are obtained in the form of a yellowish oil by the procedure described in Example lc) from 16 g of (3-cyclooctylpropyl)-malonic acid diethyl ester and 2.87 g of potassium hydroxide.
d) (3-CYclooctvlProPYl~-malonic acid dieth~l ester 16 g of (3-cyclooctylpropyl)-malonic acid di-ethyl ester are obtained in the form~of a yellowish oilby the procedure described in Example 4d) from 20.0 g of 3-cyclooctylpropyl bromide, 20.6 g of malonic acid diethyl ester and a solution of 2.37 g of sodium in 180 ml of ethanol.
e) 3-CvclooctYlProPYl bromide 19.7 g of 2-cyclooctyl-propan-1-ol are boiled under reflux for 3 hours with 35 ml of 48~ strength hydrobromic acid and 0.1 g of red phosphorus, 7 ml of concentrated sulphuric acid are added and the mixture is boiled for a further 3 hours It is poured into I00 ml of ice water and the mixture is extracted with twice 100 ml of diethyl ether and the combined organic phases are dried over sodium sulphate and concentrated.
20.0 g of 3-cyclooctylpropyl bromide are left as .
.
; -~ 1 63~4~1 residue in the form of a brown oil.
Exam~le 1~
2-(3-CycloundecYlpro~vl)-oxirane-2-carboxylic acid ethvl ester S a) 2-(3-CvcloundecYlPropyl)-oxirane-2-carboxylic acid ethyl ester 2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 9O:10 petroleum ether/
ethyl aceta ; ~ n layer ~hx~bx~e~hy cn s;lica gel with pe~roleum e~x~/ethyl acetate 9:1: Rf = O.S), are obt~d by the pro~h~e descr~ in E~ple la) from 4.4 g of S-cyclo~y1-2-methy1ene-valeric acid ethyl ester and 5.15 g of m-chloroperbenzoic acid in 40 ml of methylene chloride.
b) 5-CycloundecYl-2-methvlenevaleric acid ethYl ester 4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica~gel (migrating agent. 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 7.6 g of (3-cycloundecylpropyl)-malonic acid ethyl ester, 0.84 g of paraformaldehyde, 7 ml of pyridine and 0.3 ml of piperidine.
c) (3-CYcloundec~lPropyl)-malonic acid ethYl ester
b) 5-Cvclopentyl-2-methYlenevaleric acid ethyl ester 20,2 g of 5-cyclopentyl-2-methylenevaleric acid ethyl ester, bp, 63 - 65C at 0,01 mm Hg (1,3 Pa), are : ~ .
' ' .
`~ 1 636~4 obtained by the procedure described in Example lb) from 43.8 g of (3-cyclopentylpropyl)-malonic acid ethyl ester, 5 7 g of paraformaldehyde, 45 ml of pyridine and 1.55 g of piperidine.
c) (~-CyclopentYlpropyl)-malonic acid ethyl ester 43.8 g of (3-cyclopentylpropyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 72.8 g of t3-cYolopentylpropyl)-malonic acid diethyl ester (pre-pared analogously to Example 4d) and 17.7 g of potassium hydroxide in 580 ml of ethanol, Example 9 2-(4-CyclopentYlbutYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-14-Cvclo~entvlbutyl)-oxirane-2-carboxYlic acid ethvl ester 4 0 g of the title compound are obtained in the form of a colourless oil, bp 100 - 107C at 0.03 mm Hg (4 Pa), by the procedure described in Example la) from 8.5 g of 6-cyclopentyl-2-methylenehexanoic acid ethyl ester and 13.1 g of m-chloroperbenzoic acid in 120 ml of methylene chloride.
b) 6-Cvclopentyl-2~methylenehexanoic acid ethYl ester 8.5 g of 6-cyclopentyl-2-methylenehexanoic acid ethyl ester, bp 80 - 87C at 0.01 mm Hg (1.3 Pa), are obtained by the procedure described in Example lb) from 18,3-g of (4-cyclopentylbutyl)-malonic acid ethyl ester, 2.6 g of paraformaldehyde, 20 ml of pyridine and 0.9 ml of piperidine.
~ ~ 636~4 c) (4-Cyclopentylbutyl)-malonic acid ethyl ester 18.3 g of (4-cyclopentylbutyl)-malonic acid ethyl ester are obtained in the form of a viscous oil by the procedure described in Example lc) from 29.9 g of (4-cyclopentylbutyl)-malonic acid diethyl ester (prepared analogoùsly to Example 4d) and 5 9 g of potassium hydroxide in 200 ml of ethanol.
Example 10 2-(6-CYclopentylhexvl)-oxirane-2-carboxylic acid ethyl ester a) 2-(6-CYcloPentYlhexvl)-oxirane-2-carboxYlic acid ethvl ester 5,33 g of the title compound, in the form of a nearly colourless oil, which is purified by chromato-graphy on silica gel (migrating agent: 90:10 petroleumet~er/ethyl acetate), are obtained by the procedure des-cribed in Example la) from 11.4 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester and 15.6 g of m-chloroperbenzoic acid in 120 ml of methylene chloride.
b) 8-CYclopentvl-2-methvleneoctanoic acid ethvl ester 11 5 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 22.1 g of (6-cyclopentylhexyl)-malonic acid ethyl ester, 2 8 g of paraformaldehyde, 22 ml of pyridine and 1 ml of piperidine.
~ ~ 63644 c) (6-Cyclopentylhexyl)-malonic acid ethyl ester 22.l g of (6-cyclopentylhexyl)-malonic acid ethyl ester are obtained in the form of a yellow oil by the procedure described in Example lc) from 37,9 g of (6-cyclopentylhexy~)-malonic acid diethyl ester and 6,8 g of potassium hydroxide in 200 ml of ethanol, d) (6-Cyclopentylhexvl)-malonic acid diethyl ester 38 g of (6-cyclopentylhexyl)-malonic acid diethyl ester are obtained in the form of an oil by the procedure described in Example 4d) from 48,9 g of 6-cyclopentylhexyl bromide, 50,3 g of malonic acid diethyl ester and a solution of 5,8 g of sodium in 300 ml of ethanol, Example ll .
2-(3-Cvclohe~tylproPYl)-oxirane-2-carboxYlic acid ethYl ester a) 2-(3-CYclohePtYlPropyl)-oxirane-2-carboxylic acid ethyl ester 9,3 g of the title compound, bp 107-110C at 0,08 ~m:Hg.. ~10,6 Pa), are obtained by the procedure des-cribed in Example la) from 18,2 g of 5-cycloheptyl-2-methylenevaleric acid ethyl ester and 26,3 g of m-`
chloroperbenzoic acid in 200 ml of methylene chloride, b) 5-CYclohePtYl-2-methvlenevaleric acid ethYl ester 18,2 g of 5-cycloheptyl-2-methylene~aleric acid ethyl ester, bp 89 - 98C at O,Ol mm Hg (l,3 Pa), are obtained by the procedure described in Example lb) from 33,3 g of (3-cycloheptylpropyl)-malonic acid ethyl ester, 4,43 g of paraformaldehyde, 35 ml of pyridine and l,6 ml ` 1 3636~4 of piperidine.
c) (~-CvcloheptYlpropvl)-malonic acid ethyl ester 33.3 g of (3-cycloheptylpropyl)-m~lonic acid ethyl ester are obtained in the form of a yellow o-il by the procedure described in Example lc) from 49.7 g of (3-cycloheptylpropyl)-malonic acid diethyl ester and 9.33 g of potassium hydroxide in 300 ml of ethanol~
d) (3-CYclohePtylproPYl)-m-lonic acid diethYl ester 49.8 g of (3-cycloheptylpropyl)-malonic acid diethyl ester, bp"12Q-122C at OrO8 mm Hg ~1:0.6 P~), are obtained by the procedure described in Example 4d) from 63 g of 3-cycloheptylpropyl bromide, 69 g of malonic acid diethyl ester anda solution of 7.9 g of sodium in 400 ml of ethanol.
EX~mple 12 2-(3-CYclooctylpro~Y1)-oxirane-2-carboxylic~ acid ethYl ester a) 2-(3-Cyclooct~lpropYl)-oxirane-2-carboxylic acid ethyl ester 2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel ~migrating agent: 90:lO petroleum ether/
ethyl acetate), are obtained by the pro~edure described in Example la) from 5.42 g of 5-cyclooctyl-2-methylene-~5 valeric acid ethyl ester and 5.55 g of m-chloroper-benzoic acid in 50 ml of methylene chloride b) 5-Cy~looctyl-2-methylenevaleric acid ethyl ester 5.5 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester, in the form of an oil, which is purified ~ 3 ~3644 by chromatography on silica gel (migrating agent:
95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 10.1 g of cyclooctylpropyl)-malonic acid ethyl ester, 1.28 g of paraformaldehyde, 10 ml of pyridine and 0.5 ml of piperidine.
c) (3-CYclooctvlProPyl)-malonic acid ethYl ester 10.2 g of (3-cyclooctylpropyl)-malonic acid ethyl ester are obtained in the form of a yellowish oil by the procedure described in Example lc) from 16 g of (3-cyclooctylpropyl)-malonic acid diethyl ester and 2.87 g of potassium hydroxide.
d) (3-CYclooctvlProPYl~-malonic acid dieth~l ester 16 g of (3-cyclooctylpropyl)-malonic acid di-ethyl ester are obtained in the form~of a yellowish oilby the procedure described in Example 4d) from 20.0 g of 3-cyclooctylpropyl bromide, 20.6 g of malonic acid diethyl ester and a solution of 2.37 g of sodium in 180 ml of ethanol.
e) 3-CvclooctYlProPYl bromide 19.7 g of 2-cyclooctyl-propan-1-ol are boiled under reflux for 3 hours with 35 ml of 48~ strength hydrobromic acid and 0.1 g of red phosphorus, 7 ml of concentrated sulphuric acid are added and the mixture is boiled for a further 3 hours It is poured into I00 ml of ice water and the mixture is extracted with twice 100 ml of diethyl ether and the combined organic phases are dried over sodium sulphate and concentrated.
20.0 g of 3-cyclooctylpropyl bromide are left as .
.
; -~ 1 63~4~1 residue in the form of a brown oil.
Exam~le 1~
2-(3-CycloundecYlpro~vl)-oxirane-2-carboxylic acid ethvl ester S a) 2-(3-CvcloundecYlPropyl)-oxirane-2-carboxylic acid ethyl ester 2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 9O:10 petroleum ether/
ethyl aceta ; ~ n layer ~hx~bx~e~hy cn s;lica gel with pe~roleum e~x~/ethyl acetate 9:1: Rf = O.S), are obt~d by the pro~h~e descr~ in E~ple la) from 4.4 g of S-cyclo~y1-2-methy1ene-valeric acid ethyl ester and 5.15 g of m-chloroperbenzoic acid in 40 ml of methylene chloride.
b) 5-CycloundecYl-2-methvlenevaleric acid ethYl ester 4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica~gel (migrating agent. 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example lb) from 7.6 g of (3-cycloundecylpropyl)-malonic acid ethyl ester, 0.84 g of paraformaldehyde, 7 ml of pyridine and 0.3 ml of piperidine.
c) (3-CYcloundec~lPropyl)-malonic acid ethYl ester
7.6 g of ~3-cycloundecylpropyl)-malonic acid ethyl ester are obtained in the form of a thick, yellow oil by the procedure described in Example lc) from 10.6 g of (3-cycloundecylpropyl)-malonic acid diethyl ester and 1.67 g of potassium hydroxide in 4O ml of ethanol.
- ~ , ,' '- ';
' ' ' ' ~ 1 636~4 d) (3-CycloundecYlpropYl)-malonic acid diethyl ester 10.6 g of (3-cycloundecylpropyl)-malonic acid diethyl ester are obtained in the form of an oil by the procedure described in Example 4d) from 15 g of 3-cycloundecylpropyl bromide, 13 g of malonic acid di-ethyl ester and a solution of 1.5 g of sodium in 80 ml of ethanol.
e) 3-CYcloundecvlproPYl bromide 15 g of 3-cycloundecylpropyl bromide are obtained in the form of an oil by the procedure des-cribed in Example 12e) from 16 g of 3-cycloundecylpropan-l-ol, 30 ml of 48% strength hydrobromic acid, 0.1 g of red phosphorus and 5 ml of concentrated sulphuric acid.
The star~ing material 3-cycloundecylpropan-1-ol is obtained as follows: hydroxymethylcycloundecane is reacted with thionyl chloride to give chloromethyl~
cycloundecane, which is reacted with malonic acid di-ethyl ester in the presence of sodium ethylate to give (cycloundecylmethyl~malonic acid diethyl ester, which, after saponifying the ester group and decarboxylating the corresponding malonic acid, gives 3-cycloundecyl-propionic acid. 3-Cycloundecylpropionic acid is reduced with lithium aluminium hydride in tetrahydro-furan to give 3-cycloundecylpropanol Example 14 -Sodium 2-(3-c~clohexYlPropyl)-oxirane-2-carboxylate 1 1 g of 2-(3-cyclohexylpropyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 4.58 ml of lN sodium hydroxide , ~ ~
i 1 ~38~4 solution and 5 ml of tetrahydrofuran. The mixture is concentrated to half its ~olume and the crystals of the title compound which have been precipitated are filtered off. Mp 105-110C.
Example 15 2-~2-(3-Cyclohexylpropyloxy~-ethyl~-oxirane-2-carboxylic acid ethyl ester a) 2-t2-(3-CyclohexYlpropyloxY)-ethYl]-oxirane-carboxylic acid ethyl ester 6.8.g of the title compound, in the form of a colour-less oil, which is purified by chromatography on silica.gel (migrating agent: 90:10 petroleum ether/ethyl acetate) are obtained by the procedure described in Example 1a) from 12.4.g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester and 18.7 g of. m-chloroperbenzoic acid in 250 ml of methylene chloride. Thin layer chromatography on silica.gel with petroleum ether/ethyl acetate:/glacial acetic acid 80:20:3: Rf = 0.65.
b) 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl .ester 82~3:g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica:gel (migrating agent:
chloroform), are obtained by the procedure described in Example lb) from 103.6:g of 2-(3-cyclohexylpropyloxy)-ethyl-malonlc acid ethyl ester,. 11 g of paraformaldehyde, 105 ml of pyridine and 2.9:g of piperidine.
~, . . . ~ , .
. ~ . ~ '' ' ' '' ', 1 ~ 636~4 c) 2-(3-Cyclohexylpropyloxy)-ethylmalonic acid ethyl ester 104.6 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid ethyl ester are obtained in the form of a yellowish oil by t~e procedure described in Example 1c) from 125.4;g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid diethyl ester and 24.5 g of potassium hydroxide in 750 ml of ethanol.
d) 2-(3-Cyclohexylpropylox~)-et~ylmalonic acid diethYl ester 125.9 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid diethyl ester, in the form of a colourless oil ~bp 13a-140C at 0.03 mm Hg (4.0 Pa~] are obtained by the procedure described in Example 4d) from 118.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride, 97.4;g of malonic acid diethyl ester and a solution of 13.3 g sodium and 0.5 g of potassium iodide in 420 ml of ethanol.
e) 2-(3-~yclohexylpropyloxy)-ethyl chloride 110.4 g of 2-(3-cyclohexylpropyloxy)-ethanol, 2 ml of pyridine and 112 ml of thionyl chloride are boiled under reflux for 30 minutes. The reaction mixture is allowed to cool and is then poured onto 500 g of ice. The mixture is extracted with twice 500 ml of methylene chloride. The combined organic phases are washed with water, with sodium hydrogen carbonate solution, with water again and are then concentrated. The residue is distilled. 119.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride are obtained ~bp 68-69C at 0.01 mm Hg (1.3 Pa)].
~ 3 636~4- 40 -f) 2-(3-C~clohexylpropyloxy)-ethanol 85 ml of xylene are added to a solution of 15.75 g of sodium in 182.2 g of ethylene glycol. The mixture is heated ta 100C, and a solution of 140.5 g of 3-cyclohexyl-propyl bromide in 70 ml of xylene is added dropwise within3 hours. When the addition has ended, the mixture is boiled for 4 hours~under reflux, cooled, and then 500 ml of water are added. The mixture is extracted with twice 500 ml of petroleum ether, the combined organic phases are d~ied over sodium sulphate and the remaining oil is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate). 105.3 g of 2-(3-cyclohexyl-propyloxy)-ethanol are obtained.
Example 16 2-(5-CycloheptylPentyl)-oxirane-2-carboxYlic acid ethyl ester a~ 2-(5-Cycloheptylpentyl)-oxirane-2-carboxylic acid ethyl ester 7.5 g of the title compound, in the form of a colour-less oil, which is purified by chromat~graphy on silica~gel(migrating agent: 90:10 petroleum ether/ethyl acetate;
thin layer chromatography on silica gel with petroleum ether/
ethyl acetate 8:2: Rf = 0.55), are obtained by the procedure described in Example la) from 13.1 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester and 12.0 g of m-chloro-perbenzoic acid in 200 ml of methylene chloride.
.
~ 3 S3644 b) 7-Cycloheptyl-2-methyleneheptanoic acid ethyl ester 23.7 g of 7-~ycloheptyl-2-methyleneheptanoic acid ethyl ester, in the form of a colourless oil, purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example 1b) from 35 g-of 5-cycloheptylpentyl-malonic acid ethyl ester, 3,& g of paraformaldehyde, 35 ml of pyridine and 1 g of piperidine.
c) 5-Cycloheptylpentylmalonic acid ethyl ester 35.8 g of 5-cycloheptylpentylmalonic acid ethyl ester are obtained in the form of a tough oil by the procedure described in Example 1c) from 55.7 g of 5-cycloheptylpentyl-malonic acid diethyl ester and 11.3 g of potassium hydroxide in 220 ml of ~thanol.
d) 5-CyclohePty-lpe-ntylmalonic acid diethyl ester 55.7 g of the title compound are obtained in the form of a nearly colourless oil by the procedure described in Example 4d) from 44.8 g of 5-cycloheptylpentyl bromide, 32: g of-~alonic acid diethyl ester and a solution of 4.2;g of sodium in 140 ml of ethanol.
e) 5-~vcloheptylpentyl bromide 44.9 g of 5-cycloheptylpentyl bromide are obtained in the form of a light yellow oil ~bp 135-138C at 12 mm Hg (t600 Pa)~ by the procedure described in Example 12 e) from 35.3 g of 5-cycloheptylpentan-1-ol, 57 ml of 48~ strength hydrobromic acid, 0,2:g of red phosphorus and 12 ml of con-centrated sulphuric acid.
? 3 636~4 The starting material 5-cycloheptylpentan-1-ol is obtained as follows: cycloheptylpropylmalonic acid ethyl ester is heated to 180C for one hour. The resulting 5-cycloheptyl-valeric acid ethyl ester ~bp 80-82C at 0.008 mm Hg S ~1.O Pa)] is reduced with lithium aluminium hydride in tetrahydrofuran to yield 5-cycloheptylpentan-1-ol ~bp 92-94C at 0.008 mm Hg (1.0 Pa)~.
Example 1i Sodium 2-(5-Cyc~ohexyipenty~j-ox;rane-2-carboxylate 1.5 g of 2-(5-cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 5,6 ml o~ 1 N sodium hydroxide solution and 5 ml of tetrahydrouran. The mix*ure is concentrated to half its volume a~d the atty g~eaming plates of the title compound 15 which have been precipitated are filtered off.
Galenical Examples Example 1 Mixture ~or ampoules 100 g of sodium 2-(5-cyclohexylpentyl)-oxirane-2-carboxylate are dissolved in approx. 8 litrès of twice-distilled water with the addition of an equivalent amount of sod~um hydroxide solution. The pH of the solution is adjusted to 7.0 + 0.5 and the solution is made up to 10 litres with twice-distilled water. It is then filtered under sterile conditions and filled into 2 ml ampoules under aseptic conditions.
, . . .
~ 1 636~4 Example 2 10,000 capsules each containing 30 mg of active compound are prepared from the following ingredients:
300 g of 2-t2-~3-~c~ 1prcey10x~)-etby1~ xne-2~cLffx~y1ic acid ethyl es~ are mixed with 500 g of neutral oil and the mixture is filled into soft gelatine capsules.
Example ~
Tablets containing 25 mg of active compound are prepared as follows: 1.0 kg of sodium 2-(3-cyclohexyl-propyl)-oxiriane-2-carboxylate, 4.5 kg of xylitol and 3.0kg of cialcium phosphate, are grianulated with 0.25 kg of polyvinylpyrrolidon~ (MW 25,000; MW = molecular weight) in approximately 0,5 1 of water. The granules are sieved through a screen wi~h a mesh width of 1.25 mm and, after drying, 0.9 kg of carboxymethylcellulose, 0.25 kg of talc and 0.1 kg of magnesium stearate are added.
The dry grianules are compressed to give tablets with a diameter of 8 mm, a weight of 250 mg and a hardness of 5-6 kg.
1 ~ 636~4 PharmacoL~
The epoxycycloalkylalkanecarboxylic acids of formul~ 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 Phenformin) having an extra-pancreatic action.
In the following Table the investigàted compounds are characterized by a serial number, which is allocated as follows:
Serial No. Name of Compound 1 Buformin 2 Phenformin 3 2-(3-Cyclohexylpropyl)-oxirane-2-carboxylic acid ethyl ester 4 2-(5-Cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester 2-(3-~yclopentylpropyl)-oxirane-2-carboxylic acid ethyl ester 6 2-(4-Cyclopentylbutyl)-oxirane-2-carboxylic - 25 acid ethyl ester 7 2-~2-(3-Cyclohexylpropyloxy)-ethyl]-oxirane-2-car~oxylic acid ethyl ester ~ 1 636~4 Serial No. Name of Compaund
- ~ , ,' '- ';
' ' ' ' ~ 1 636~4 d) (3-CycloundecYlpropYl)-malonic acid diethyl ester 10.6 g of (3-cycloundecylpropyl)-malonic acid diethyl ester are obtained in the form of an oil by the procedure described in Example 4d) from 15 g of 3-cycloundecylpropyl bromide, 13 g of malonic acid di-ethyl ester and a solution of 1.5 g of sodium in 80 ml of ethanol.
e) 3-CYcloundecvlproPYl bromide 15 g of 3-cycloundecylpropyl bromide are obtained in the form of an oil by the procedure des-cribed in Example 12e) from 16 g of 3-cycloundecylpropan-l-ol, 30 ml of 48% strength hydrobromic acid, 0.1 g of red phosphorus and 5 ml of concentrated sulphuric acid.
The star~ing material 3-cycloundecylpropan-1-ol is obtained as follows: hydroxymethylcycloundecane is reacted with thionyl chloride to give chloromethyl~
cycloundecane, which is reacted with malonic acid di-ethyl ester in the presence of sodium ethylate to give (cycloundecylmethyl~malonic acid diethyl ester, which, after saponifying the ester group and decarboxylating the corresponding malonic acid, gives 3-cycloundecyl-propionic acid. 3-Cycloundecylpropionic acid is reduced with lithium aluminium hydride in tetrahydro-furan to give 3-cycloundecylpropanol Example 14 -Sodium 2-(3-c~clohexYlPropyl)-oxirane-2-carboxylate 1 1 g of 2-(3-cyclohexylpropyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 4.58 ml of lN sodium hydroxide , ~ ~
i 1 ~38~4 solution and 5 ml of tetrahydrofuran. The mixture is concentrated to half its ~olume and the crystals of the title compound which have been precipitated are filtered off. Mp 105-110C.
Example 15 2-~2-(3-Cyclohexylpropyloxy~-ethyl~-oxirane-2-carboxylic acid ethyl ester a) 2-t2-(3-CyclohexYlpropyloxY)-ethYl]-oxirane-carboxylic acid ethyl ester 6.8.g of the title compound, in the form of a colour-less oil, which is purified by chromatography on silica.gel (migrating agent: 90:10 petroleum ether/ethyl acetate) are obtained by the procedure described in Example 1a) from 12.4.g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester and 18.7 g of. m-chloroperbenzoic acid in 250 ml of methylene chloride. Thin layer chromatography on silica.gel with petroleum ether/ethyl acetate:/glacial acetic acid 80:20:3: Rf = 0.65.
b) 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl .ester 82~3:g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica:gel (migrating agent:
chloroform), are obtained by the procedure described in Example lb) from 103.6:g of 2-(3-cyclohexylpropyloxy)-ethyl-malonlc acid ethyl ester,. 11 g of paraformaldehyde, 105 ml of pyridine and 2.9:g of piperidine.
~, . . . ~ , .
. ~ . ~ '' ' ' '' ', 1 ~ 636~4 c) 2-(3-Cyclohexylpropyloxy)-ethylmalonic acid ethyl ester 104.6 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid ethyl ester are obtained in the form of a yellowish oil by t~e procedure described in Example 1c) from 125.4;g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid diethyl ester and 24.5 g of potassium hydroxide in 750 ml of ethanol.
d) 2-(3-Cyclohexylpropylox~)-et~ylmalonic acid diethYl ester 125.9 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid diethyl ester, in the form of a colourless oil ~bp 13a-140C at 0.03 mm Hg (4.0 Pa~] are obtained by the procedure described in Example 4d) from 118.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride, 97.4;g of malonic acid diethyl ester and a solution of 13.3 g sodium and 0.5 g of potassium iodide in 420 ml of ethanol.
e) 2-(3-~yclohexylpropyloxy)-ethyl chloride 110.4 g of 2-(3-cyclohexylpropyloxy)-ethanol, 2 ml of pyridine and 112 ml of thionyl chloride are boiled under reflux for 30 minutes. The reaction mixture is allowed to cool and is then poured onto 500 g of ice. The mixture is extracted with twice 500 ml of methylene chloride. The combined organic phases are washed with water, with sodium hydrogen carbonate solution, with water again and are then concentrated. The residue is distilled. 119.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride are obtained ~bp 68-69C at 0.01 mm Hg (1.3 Pa)].
~ 3 636~4- 40 -f) 2-(3-C~clohexylpropyloxy)-ethanol 85 ml of xylene are added to a solution of 15.75 g of sodium in 182.2 g of ethylene glycol. The mixture is heated ta 100C, and a solution of 140.5 g of 3-cyclohexyl-propyl bromide in 70 ml of xylene is added dropwise within3 hours. When the addition has ended, the mixture is boiled for 4 hours~under reflux, cooled, and then 500 ml of water are added. The mixture is extracted with twice 500 ml of petroleum ether, the combined organic phases are d~ied over sodium sulphate and the remaining oil is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate). 105.3 g of 2-(3-cyclohexyl-propyloxy)-ethanol are obtained.
Example 16 2-(5-CycloheptylPentyl)-oxirane-2-carboxYlic acid ethyl ester a~ 2-(5-Cycloheptylpentyl)-oxirane-2-carboxylic acid ethyl ester 7.5 g of the title compound, in the form of a colour-less oil, which is purified by chromat~graphy on silica~gel(migrating agent: 90:10 petroleum ether/ethyl acetate;
thin layer chromatography on silica gel with petroleum ether/
ethyl acetate 8:2: Rf = 0.55), are obtained by the procedure described in Example la) from 13.1 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester and 12.0 g of m-chloro-perbenzoic acid in 200 ml of methylene chloride.
.
~ 3 S3644 b) 7-Cycloheptyl-2-methyleneheptanoic acid ethyl ester 23.7 g of 7-~ycloheptyl-2-methyleneheptanoic acid ethyl ester, in the form of a colourless oil, purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example 1b) from 35 g-of 5-cycloheptylpentyl-malonic acid ethyl ester, 3,& g of paraformaldehyde, 35 ml of pyridine and 1 g of piperidine.
c) 5-Cycloheptylpentylmalonic acid ethyl ester 35.8 g of 5-cycloheptylpentylmalonic acid ethyl ester are obtained in the form of a tough oil by the procedure described in Example 1c) from 55.7 g of 5-cycloheptylpentyl-malonic acid diethyl ester and 11.3 g of potassium hydroxide in 220 ml of ~thanol.
d) 5-CyclohePty-lpe-ntylmalonic acid diethyl ester 55.7 g of the title compound are obtained in the form of a nearly colourless oil by the procedure described in Example 4d) from 44.8 g of 5-cycloheptylpentyl bromide, 32: g of-~alonic acid diethyl ester and a solution of 4.2;g of sodium in 140 ml of ethanol.
e) 5-~vcloheptylpentyl bromide 44.9 g of 5-cycloheptylpentyl bromide are obtained in the form of a light yellow oil ~bp 135-138C at 12 mm Hg (t600 Pa)~ by the procedure described in Example 12 e) from 35.3 g of 5-cycloheptylpentan-1-ol, 57 ml of 48~ strength hydrobromic acid, 0,2:g of red phosphorus and 12 ml of con-centrated sulphuric acid.
? 3 636~4 The starting material 5-cycloheptylpentan-1-ol is obtained as follows: cycloheptylpropylmalonic acid ethyl ester is heated to 180C for one hour. The resulting 5-cycloheptyl-valeric acid ethyl ester ~bp 80-82C at 0.008 mm Hg S ~1.O Pa)] is reduced with lithium aluminium hydride in tetrahydrofuran to yield 5-cycloheptylpentan-1-ol ~bp 92-94C at 0.008 mm Hg (1.0 Pa)~.
Example 1i Sodium 2-(5-Cyc~ohexyipenty~j-ox;rane-2-carboxylate 1.5 g of 2-(5-cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 5,6 ml o~ 1 N sodium hydroxide solution and 5 ml of tetrahydrouran. The mix*ure is concentrated to half its volume a~d the atty g~eaming plates of the title compound 15 which have been precipitated are filtered off.
Galenical Examples Example 1 Mixture ~or ampoules 100 g of sodium 2-(5-cyclohexylpentyl)-oxirane-2-carboxylate are dissolved in approx. 8 litrès of twice-distilled water with the addition of an equivalent amount of sod~um hydroxide solution. The pH of the solution is adjusted to 7.0 + 0.5 and the solution is made up to 10 litres with twice-distilled water. It is then filtered under sterile conditions and filled into 2 ml ampoules under aseptic conditions.
, . . .
~ 1 636~4 Example 2 10,000 capsules each containing 30 mg of active compound are prepared from the following ingredients:
300 g of 2-t2-~3-~c~ 1prcey10x~)-etby1~ xne-2~cLffx~y1ic acid ethyl es~ are mixed with 500 g of neutral oil and the mixture is filled into soft gelatine capsules.
Example ~
Tablets containing 25 mg of active compound are prepared as follows: 1.0 kg of sodium 2-(3-cyclohexyl-propyl)-oxiriane-2-carboxylate, 4.5 kg of xylitol and 3.0kg of cialcium phosphate, are grianulated with 0.25 kg of polyvinylpyrrolidon~ (MW 25,000; MW = molecular weight) in approximately 0,5 1 of water. The granules are sieved through a screen wi~h a mesh width of 1.25 mm and, after drying, 0.9 kg of carboxymethylcellulose, 0.25 kg of talc and 0.1 kg of magnesium stearate are added.
The dry grianules are compressed to give tablets with a diameter of 8 mm, a weight of 250 mg and a hardness of 5-6 kg.
1 ~ 636~4 PharmacoL~
The epoxycycloalkylalkanecarboxylic acids of formul~ 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 Phenformin) having an extra-pancreatic action.
In the following Table the investigàted compounds are characterized by a serial number, which is allocated as follows:
Serial No. Name of Compound 1 Buformin 2 Phenformin 3 2-(3-Cyclohexylpropyl)-oxirane-2-carboxylic acid ethyl ester 4 2-(5-Cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester 2-(3-~yclopentylpropyl)-oxirane-2-carboxylic acid ethyl ester 6 2-(4-Cyclopentylbutyl)-oxirane-2-carboxylic - 25 acid ethyl ester 7 2-~2-(3-Cyclohexylpropyloxy)-ethyl]-oxirane-2-car~oxylic acid ethyl ester ~ 1 636~4 Serial No. Name of Compaund
8 2-(3-Cycloheptylpropyl)-oxirane-2-carboxylic acid ethyl ester
9 2-~5-Cy loheptylpentyl)-oxirane-2-carboxylic acid ethyl ester .
_ Table I reflects- investigations of the effect of representa-tive compounds according to.the invention on the blood
_ Table I reflects- investigations of the effect of representa-tive compounds according to.the invention on the blood
10 :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) whi~h is observed in.the course of 6 hours after single oral administration of 0.6 mmoleof substance/kg of body weight.
Column B provides data relating.to acute toxicity ILD50;
mice, peroral administration).
Tàble I
Serial A B
No.Change in the bloodAcute toxicity .glucose concentration LD50(mg/kg) lin %) in.vivo .mice p.o.
.1 - 8 475 2 - 6 410*
' '' .' ~, 1 ~ 6364~
Serial A B
No. Change in the bl~odAcute toxicity glucose concentration LD50 (mg/kg (in %) in vivomice p.o.
. 10 Re Table I:
* Cited according to Blickens, D.A.; Riggi, S.J.: Toxicol.
Appl.Pharmacol., 14 (1969)~93-400 Column A~= maximum change in the blood glucose concentration 15 (in %, relative to the control animals) in vivo in rats which have been fasted at a dose of 0.6 mmole/kg Column B = Acute toxicity (LD50 in mg/kg); mice, p.o.) The pharmacological properties were determined by the follo-wing methods:
1. Determination of glucose in the blood after a single oral administration.
Young male Sprague-Dawley rats (body weight: 150 to 20-0g) are used. The animals (6 animals per dose) are kept in Makrolon cages with up to 4 animals per cage (ambient temperature: 23C, relative atmosperic humidity: 55%, .
, . . : , 1 1 6364d fixed day~night rhythm ~12/12 hours], standard diet:
Altromin~ . The rats are deprived of the feed 18 hours before the first sample of 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.
After deproteinization with perchloric acid, the glucose in the blood is determined by means of the enzymatic HK/G-6-PDH method of R. Richterich ~Klinische Chemie, Theorie und Praxis, (Clinical Chemistry, Theory and Practice), 3rd edition, 1971, S. Karger Verlag, Zurich-Basle, page 275].
A control group (tO animals,treated with pure solvent)is also investigated in each case for comparison.
2. Determination of the toxicity.
The toxicity investiga*ions are carried out on female NMRI mice (body weight: 22 to 26 g). 18 hours before the treatment, the feed (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 of a stomach tube. The observation time is 7 days. The LD50, that is to say the dose at which 50 % of the animals die, is determined graphically from the dose/response curve.
Column B provides data relating.to acute toxicity ILD50;
mice, peroral administration).
Tàble I
Serial A B
No.Change in the bloodAcute toxicity .glucose concentration LD50(mg/kg) lin %) in.vivo .mice p.o.
.1 - 8 475 2 - 6 410*
' '' .' ~, 1 ~ 6364~
Serial A B
No. Change in the bl~odAcute toxicity glucose concentration LD50 (mg/kg (in %) in vivomice p.o.
. 10 Re Table I:
* Cited according to Blickens, D.A.; Riggi, S.J.: Toxicol.
Appl.Pharmacol., 14 (1969)~93-400 Column A~= maximum change in the blood glucose concentration 15 (in %, relative to the control animals) in vivo in rats which have been fasted at a dose of 0.6 mmole/kg Column B = Acute toxicity (LD50 in mg/kg); mice, p.o.) The pharmacological properties were determined by the follo-wing methods:
1. Determination of glucose in the blood after a single oral administration.
Young male Sprague-Dawley rats (body weight: 150 to 20-0g) are used. The animals (6 animals per dose) are kept in Makrolon cages with up to 4 animals per cage (ambient temperature: 23C, relative atmosperic humidity: 55%, .
, . . : , 1 1 6364d fixed day~night rhythm ~12/12 hours], standard diet:
Altromin~ . The rats are deprived of the feed 18 hours before the first sample of 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.
After deproteinization with perchloric acid, the glucose in the blood is determined by means of the enzymatic HK/G-6-PDH method of R. Richterich ~Klinische Chemie, Theorie und Praxis, (Clinical Chemistry, Theory and Practice), 3rd edition, 1971, S. Karger Verlag, Zurich-Basle, page 275].
A control group (tO animals,treated with pure solvent)is also investigated in each case for comparison.
2. Determination of the toxicity.
The toxicity investiga*ions are carried out on female NMRI mice (body weight: 22 to 26 g). 18 hours before the treatment, the feed (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 of a stomach tube. The observation time is 7 days. The LD50, that is to say the dose at which 50 % of the animals die, is determined graphically from the dose/response curve.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of epoxycycloalkylalkane-carboxylic acids of the general formula I
(I) wherein R denotes a hydrogen atom or a lower alkyl groupl Y denotes an oxygen atom (-O-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y is an oxygen atom, and the sum of the numbers m, n and p is an integer from 6 to 15), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylene-carboxylic acid of the general formula II
(II) wherein 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 pharmacologically compatible salts or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
(I) wherein R denotes a hydrogen atom or a lower alkyl groupl Y denotes an oxygen atom (-O-) or a methylene group (-CH2-), m denotes an integer from 0 to 6, n denotes an integer from 0 to 6 and p denotes an integer from 2 to 11 (and m cannot be 0 or 1 if Y is an oxygen atom, and the sum of the numbers m, n and p is an integer from 6 to 15), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylene-carboxylic acid of the general formula II
(II) wherein 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 pharmacologically compatible salts or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
2. Process for the preparation of epoxycycloalkylalkane-carboxylic acids of the general formula I*
(I*) wherein R* denotes a hydrogen atom or a lower alkyl group, Y*
denotes a methylene group (-CH2-), m* denotes an integer from 1 to 6, n* denotes the number 1 and 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), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylene-carboxylic acid of the general formula II*
(II*) wherein 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, are then converted into the pharmacologically compatible salts, or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
(I*) wherein R* denotes a hydrogen atom or a lower alkyl group, Y*
denotes a methylene group (-CH2-), m* denotes an integer from 1 to 6, n* denotes the number 1 and 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), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylene-carboxylic acid of the general formula II*
(II*) wherein 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, are then converted into the pharmacologically compatible salts, or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
3. Process according to Claim 2, in which R* denotes hydrogen, methyl or ethyl, Y* denotes methylene (-CH2-), m* denotes 2, 3 or 4, n* denotes 1 and p* denotes 5.
4. Process for the preparation of epoxycycloalkylalkene-carboxylic acids of the general formula I**
(I**) wherein 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 and 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), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylenecarboxylic acid of the general formula II**
(II**) wherein 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, then converted into the pharmacologically compatible salts, or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
(I**) wherein 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 and 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), and also the pharmacologically compatible salts of the carboxylic acids, characterised in that a substituted .alpha. -methylenecarboxylic acid of the general formula II**
(II**) wherein 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, then converted into the pharmacologically compatible salts, or the resulting acids are converted into the pharmacologically compatible salts or lower alkyl esters.
5. Process according to Claim 4 in which R** denotes hydrogen, methyl or ethyl, Y** denotes oxygen (-O-), m** denotes an integer from 2 to 5, n** denotes an integer from 0 to 3 and p** denotes 5 (and the sum of the numbers m** and n** is an integer from 3 to 5).
6. A process for the preparation of 2-(5-cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester which comprises oxidising 7-cyclohexyl-2-methyleneheptanoic acid ethyl ester with an oxidising agent.
7. An epoxycycloalkylalkanecarboxylic acid of the formula I
given in claim 1, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
given in claim 1, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
8. An epoxycycloalkylalkanecarboxylic acid of the formula I* given in claim 2, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
9. An epoxycycloalkylalkanecarboxylic acid of the formula I* given in claim 2 wherein R*, Y*, m*, n* and p* are as defined in claim 3, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
10. An epoxycycloalkylalkanecarboxylic acid of the formula I** given in claim 4, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
11. An epoxycycloalkylalkanecarboxylic acid of the formula I** given in claim 4 wherein R**, Y**, m**, n** and p**
are as defined in claim 5, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
are as defined in claim 5, or a pharmacologically compatible salt thereof with an inorganic or organic base, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
12. 2-(5-Cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000397723A CA1163644A (en) | 1982-03-05 | 1982-03-05 | Process for the preparation of epoxycycloalkylalkanecarboxylic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000397723A CA1163644A (en) | 1982-03-05 | 1982-03-05 | Process for the preparation of epoxycycloalkylalkanecarboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1163644A true CA1163644A (en) | 1984-03-13 |
Family
ID=4122231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000397723A Expired CA1163644A (en) | 1982-03-05 | 1982-03-05 | Process for the preparation of epoxycycloalkylalkanecarboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1163644A (en) |
-
1982
- 1982-03-05 CA CA000397723A patent/CA1163644A/en not_active Expired
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