DE2605399A1 - MEDICINAL PREPARATIONS, CONTAINED IN THESE NEW COMPOUNDS AND PROCEDURES FOR THEIR MANUFACTURING - Google Patents

Description

Brentford, Middlesex, UK

"Medicinal products, new compounds contained in them and processes for their production"

Priority: February 19, 1975, Great Britain, No. 6909/75

The invention relates to medicinal preparations which are able to lower the fat content of the blood.

Vascular occlusive diseases are caused by an accumulation of lipids, especially cholesterol triglycerides and phospholipids, marked inside the great arteries. These accumulations clog the vessel and cause a Ischemia of the organ supplied by the artery. Prolonged or sudden ischemia caused in this way is the leading cause of death in many countries.

It has been found that increased levels of lipids in the blood, e.g.

609836/1017

of cholesterol, are associated with an increased propensity for coronary artery disease and heart attacks. It there is therefore a great need for medicinal preparations that effectively lower the serum lipid level.

In DT-OS 2 439 458 medicaments are described which by a content of at least one pharmacologically acceptable carrier material and / or diluent and at least one Compound of general formula I are characterized

in which R is the carboxyl group or one in the living body in this is convertible radical, R_ is a hydrogen atom or a lower one Alkyl or alkoxy means R, a hydrogen or halogen atom, the nitro group or a lower alkyl, alkoxy or Is haloalkyl radical, R ^. a hydrogen or halogen atom, the Nitro, phenyl or an esterified carboxyl group or a lower alkyl, alkoxy or haloalkyl radical, where R, and R ^ together can form the remainder of a benzene ring, Z a Oxygen or sulfur atom, X is a straight or branched chain lower alkylene, alkyleneoxy, alkylenethio or alkylene

b 0 P 8 3 6/1 C) 1 7

• y _

carbonyl radical means q has the value O or an integer of Represents 1 to 12 and one of m and η is O, while the other means 1.

It has now been found that from a class of substituted Phenoxy (or phenylthio) - allyl compounds, some compounds are able to lower the fat content of the blood.

Although some benzene derivatives, which are substituted with alkenyloxy or alkenylthio radicals, among other things, are considered pharmacological are known to be active, especially as anti-inflammatory or analgesic agents (see e.g. BE-PS 621 225 and 718,573, PR-PS 1,580,970, 2,054,532 and 2 108 9 ^ 3 and US-PS 3,586,713 and 3 824 277) there is still no reference to the new class of allyloxy and allylthiobenzene compounds to be found in the literature that these compounds have hypolipidemic activity.

The invention thus relates to medicinal preparations, characterized by a content of at least one pharmacologically acceptable carrier and / or diluent and at least one compound of the formula II as an active ingredient

(II)

= <■■ <■ '■ - <i> I i (ι 1 7

2 3 4 in which one of the radicals R, R and R is a radical of the formula

- (CHp) R. and the other radicals are V / assers t off atoms, where R is a carboxyl group or its pharms.ko logically acceptable Salts, esters, amides or hydrazides, optionally with at least one

at least one of a hydroxyl group or / or lower alkoxy radical substituted

Alkyl radical, cyano radical, pormyl radical, an acyl radical optionally substituted by a carboxyl group or a tetrazole radical and q is 0 or an integer from 1 to 12, Z is an oxygen or sulfur atom and B? , R and R 'are each a hydrogen atom or a lower alkyl radical.

The term "lower" means that the remainder has 1 to 6 carbon atoms Has.

5 6 7 Suitable lower alkyl radicals for R, R and R in formula II are the methyl or 'ethyl radical and straight-chain and branched propyl and butyl radicals.

The hydrogen atom is preferred for R.

used r "

According to the invention / compounds of the formula H ^ in which R and R

are different can occur as geometric isomers. The invention therefore relates to both the cis and the trans isomers and mixtures of these compounds.

If R in formula II is a salt of a carboxylic acid, suitable salts are metal salts, such as aluminum, alkali metal salts, e.g. sodium or Potassium salts, alkaline earth metal salts, e.g. calcium or

1 0 1 7

Magnesium salts and optionally substituted ammonium salts, for example with lower alkylamines such as triethylamine, lower hydroxyalkylamines such as 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, cycloalkylamines such as bicyclohexylamine, procaine, Dibenzylamine, Ν, Ν-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-ß-phenethylamine, dehydroabietylamine, N, N ^f -bis-dehydroabietylethylenediamine or bases of the pyridine type, such as pyridine, collidine or quinoline.

Preferred salts are sodium and potassium salts.

Suitable ester radicals for R in formula II are alkyl, aryl and arylalkyl esters, e.g. straight-chain or branched alkyl esters with 1 to 20 carbon atoms. Lower alkyl and aryl alkyl esters are preferred, e.g., the methyl or ethyl esters, or straight chain and branched propyl, butyl, pentyl, hexyl and benzyl esters.

Alkyl radicals can optionally be substituted with a hydroxyl group or a lower alkoxy radical. Preferred substituted The hydroxyethyl, methoxymethyl or ethoxymethyl radicals are alkyl radicals.

Suitable acyl radicals for R in formula II are alkanoyl radicals, preferably lower alkanoyl radicals, such as the acetyl radical.

Particularly suitable for the medicinal products according to the invention

B 0 q B 3 R / 1 Q 1 7

are compounds of formula III

R ¹

(CH ₂ ) _q

(III)

O-CH-, -CH = C

1 fi 7

in which R ₃ R ₃ R and q are as defined in formula II.

A compound with maximum activity as a blood lipid lowering agent must lower the serum lipid level significantly but not or only marginally affect growth, liver weight and liver lipids. These conditions are best met by compounds of the formula III in which R is a carboxylic acid group, the salt or ester thereof and q is O or in R is the methyl, hydroxymethyl or a carboxylic acid group or their salt or ester and q is an integer from 1 to means.

Another group of connections

for the medicinal preparations according to the invention with good Hypolipxdamic properties are compounds of the formula IV

(CH ₂ )

(IV)

O - CH ₂ - CH = C

609836/1017

1 f \ 7

in which R, R, R and q are as defined in formula II.

Preferred compounds are compounds of the formula II in which R is a carboxyl group or its salt or ester and q means.

Other suitable compounds of the formula V.

Connections are the

(V)

Z-CH ₅ -CH = C
²

in which R, Z and R are as defined in formula II, R is a lower alkyl radical and r is an integer from 1 to 12.

An integer from 2 to 6 is suitable for r in formula V. Preferably, r is 2 when R is a carboxylic acid group, its salt or alkyl ester.

The medicinal preparations according to the invention can be administered in any way but oral administration is preferred.

i: Π '\ : ■: Ί R / 1 C) 1 7

The medicinal preparations can be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations such as oral and sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration, can come in single doses and conventional auxiliaries such as binders, e.g. syrup, gum arabic, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone, fillers, 2.B. Lactose, sugar, corn starch, Calcium phosphate, sorbitol or glycine, tabletting auxiliaries, e.g. magnesium stearate, talc, polyethylene glycol or Contains silicon dioxide, disintegrants, e.g. potato starch, or humectants, such as sodium lauryl sulfate. The tablets can also be coated in a conventional manner.

Liquid preparations for oral administration can be in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir or also as a dry preparation which is diluted with water or another suitable diluent before use. These liquid preparations may contain conventional excipients, i _e suspending agents, for example sorbitol, syrup, methyl cellulose, ^Glvkosesiru P> gelatin, hydroxyethylcellulose, carboxymethylcellulose _w, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia, non-aqueous vehicle

(including edible oils), e.g. almond oil, fractionated coconut oil and other products

oil,. / like glycerine, / propylene glycol or ethyl alcohol,

l 0 Ί H Ϊ B / 1 Q 1 7

Preservatives, e.g. methyl p-hydroxybenzoate or propyl ester or sorbic acid, and optionally flavor and Dyes.

Suppositories contain the conventional bases, like cocoa butter or other glycerides.

With medicinal preparations according to the invention for parenteral administration the compounds of formula II, depending on the carrier and concentration used, in the sterile carrier, preferably water, either suspended or dissolved. The solution, which is suitable for injections, is prepared before filling into a suitable ampoule or bottle is sterile filtered, then the bottle or ampoule is sealed. In the carrier means can also other aids, such as a local anesthetic, preservatives and buffering substances, can be 'dissolved'. About stability To increase, you can freeze the preparation after filling into the ampoule and remove the water under reduced pressure. The dry lyophilized powder is then sealed in the ampoule and accompanied by an ampoule with water for injections, to dilute this dry preparation before use. Suspensions for parenteral administration are made accordingly produced, with the difference that the connection in the carrier means is not dissolved but suspended, and sterilization cannot be carried out by filtration. The active ingredient is before Suspending in the sterile vehicle treated with ethylene oxide. Advantageously, the suspension is placed in a network or Moisturizer too, in order to ensure the uniform distribution of the

B Π H B 3 6/1 0 1 7

To facilitate the active ingredient.

Medicinal preparations according to the invention can, depending on the type of administration 0.1 to 99 percent by weight, preferably 10 to 60 percent by weight Contain active ingredient. The medicinal preparations according to the invention preferably contain 50 to 1000 mg in a single dose Active ingredient. The dosage for adults is preferably 100 to 5000 mg per day, in particular 1500 mg per day, depending on the type and Frequency of administration.

Some of the compounds of formula II are new. The invention therefore also relates to compounds of the formula II

(ID

Z-CH ₉ -C = "C

2 3 4

in which one of the radicals R, R or R is a radical of the formula - (CH ₂ ) R and the other radicals are hydrogen atoms, Z is an oxygen

S 6 is 7 or hydrogen atom, R ₉ R and R are each a hydrogen atom or a lower alkyl radical and either q is 0, 1 or 2. and R is the cyano group or q is an integer from 2 to

12 and R denotes the carboxyl group or its pharmacological group compatible salts, esters, amides or hydrazides, one optionally with at least one hydroxyl group or "at least one

F. Π 9 8 3 6/1 Q 1 7

lower alkoxy radical substituted alkyl radical, a cyano group, Formyl group, one optionally substituted with a carboxyl group Is acyl radical, with the proviso that when Z is an oxygen atom and q is 2, R cannot be the carboxyl group.

Particularly suitable compounds of the formula II are compounds of the formula VI

(VI)

O - CH ₂ - CH = C

in which R is a lower alkyl radical or an ester radical, s one

6 7 denotes an integer from 2 to 6 and R and R as in formula II are defined.

Examples of compounds according to the invention are:

3- / ^I T- (3-methyl-but-2-enyloxy) -phenyl-7-propionic acid ethyl ester; k- (But-2-enyl-1-oxy) benzyl ethyl ether; 3- / J '- (But-2-enyl-1-oxy) -phenyl-7-propionic acid ethyl ester; Ethyl 2- (but-2-enyl-1-oxy) benzoate; Ethyl 4- (but-2-enyl-1-oxy) phenyiacetic acid; 4- (but-2-enyl-1-oxy) benzonitrile;

r f.

ά ¹ U; / 1 o 1 7

2- (but-2-eny1-1-oxy) acetophenone; 3 ~ (but-2-enyl-1-oxy) acetophenone; * 1- (but-2-enyl-1-oxy) ethylbenzene; 3- / TT ^t - (3ut-2-enyl-1-oxy) -nheny.17-pricpic acid isopropyl ester; 4- / 7 '- (3ut-2-enyl-1-oxy) -phenyl / -butan-2-one; 2- (But-2-enyl-1-thio) -benzoic acid ethyl cerium; 3 - ^ '- (But-2-enyl-1-oxy) -phenyl / -propionic acid benzyl ester; 3- ^ ^f - (But-2-enyi-1-oxy) -phenyl / -propionic acid-n-hexyl ester; 3- / 5 " ^f - (But-2-enyl-l-oxy) -phenyl / ^r -propionic acid; 4 ^f - (3ut-2-enyl-l-oxy) -benzoic acid; 3 - ^" Jr ^f - ( 3ut-2-enyl-l-oxy) -phenyl7 ~ P ^ro Pi ^ons äure sodium salt; H '- (But-2-enyl-1-oxy) -benzoic acid-sodium: salt;

Jj ~ (but-2-enyl-1-oxy) acetophenone; ^ - (But-2-enyl-1-thio) -benzoic acid ethyl ester; 3 ~ / Ji ^r - (But-2-enyl-l-oxy) -phenyl ^ -propionic acid ethy lest er · 3 - // T '- (Kept-2-enyl-l-oxy) -phynyl / -propionic acid ethyl ester.

The invention further relates to a process for the preparation of the compounds of Pornel II, which is characterized in that that a compound of the formula VII

(VII)

BOHR3fi / iOi7

with a compound of the formula VIII

(viii)

Q - CH ₀ - C = C ²

in which R ² , R ³ , r \ R ⁵ , R ⁶ and R ⁷ as defined in formula II

one of the leftovers
and / P or Q is a radical of the formula -ZH or its reactive derivative in which Z is as defined in formula II and the other radical is an easily displaceable radical, and optionally

1
a radical R, as defined in formula II, into another radical

R converts.

The compounds of the formula II prepared in the process according to the invention are then combined with a pharmacologically acceptable one Carriers and / or diluents combined to form the preparation according to the invention.

Reactive derivatives of the radical of the formula -ZH are salts and other derivatives that increase the nucleophilicity of the Z atom.

The term "easily displaceable radical" means an atom or a radical which can be easily displaced by a nucleophilic center, such as the single electron pair of a hydroxyl oxygen atom or an alkoxide ion, for example halides such as iodine, bromine or chlorine atoms, pseudohalides such as the azido radical Np-, active esters such as radicals of the formula O.SO ₂ CH ₂ .O.CO.OC ₂ H, or compounds that are formed in situ by

ti Ii η Pi 3 K / 1 0 1 7

Watering agents, such as carbodiimides or carbonyldiimidazoles, phosphorus pentachloride, phosphoryl chloride, thionyl chloride, Phosphorus pentoxide or sulfuric acid, can be produced.

In the preparation of compounds of the formula II in which Z is an oxygen atom, the radical of the formula -ZH is one Hydroxyl group. If this hydroxyl group is in the inventive Process as a salt, it is generally a sodium or potassium salt.

If a salt is used as one of the reagents in the process according to the invention, this is preferably prepared by means of a strong base, for example sodium hydride, sodium amide, a sodium alkoxide or sodium methoxide. Suitable solvents for this reaction are dimethylformamide or dimethyl sulfoxide, especially if sodium hydride, sodium amide or a base is used, methanol if sodium methoxide is used ₅ and ethanol if sodium ethoxide is used.

If, however, P or Q in the compounds of the formula VII or VIII is the free hydroxyl group, then that is according to the invention Process in the presence of an acid acceptor, e.g. a tertiary organic base such as pyridine, triethylamine or N-methylpyrrolidine, or of potassium carbonate, carried out in acetone as a solvent.

For the preparation of compounds of the formula II in which Z

609836/1017

is a sulfur atom, the radical of the formula -ZH means a thiol radical, which is either as a free thiol or as its salt is used.

Occasionally it is more beneficial to place the remainder R within the To modify substituents R, R ^ and / or R after the condensation reaction than before. Therefore is preferred in the preparation of compounds of the formula II in which R is a carbamoyl or carboxyl radical, the corresponding first Compound of formula II, in which R is the ester radical, prepared and then converted into a compound of formula II in a conventional manner converted, in which R is the carboxyl or carbamoyl group. For some compounds of the formula II in which R is an alkyl ester residue, hydrolysis to the corresponding carboxylic acid group is difficult, so it is often appropriate to use the To produce benzyl ester that is more easily hydrolyzable.

If the radical R contains a hydroxyl group, it is often favorable _; to protect these first by the formation of an easily hydrolyzable ester, which can easily be split off again after the condensation.

For the preparation of compounds of the formula II in which R is a

is an ester radical, one can use the free acid, its salt or / other esterifying reactive derivative or transesterifying a compound with another ester residue. The esterification takes place in a conventional way Way, e.g. by reacting the free acid with

i; rs ' / ■ - ρ? κ / 1 o 1 7

a) a corresponding alcohol in the presence of a catalyst, such as a strong acid, dry hydrogen chloride or p-toluenesulfonic acid,

b) with the corresponding alcohol halide or sulfate in the presence of dimethyl sulfoxide and calcium carbonate or the halide in the presence of hexamethylphosphoramide,

c) by phase transfer catalysis with the alcohol halide and / or sulfate in an aqueous and / or organic solution in the presence of a quaternary ammonium salt such as tetrabutylammonium bisulfate or halide or benzyltrimethylammonium halide.

The transesterification can be carried out in a conventional manner, e.g. by reacting an ester with the corresponding second Alkonol in Presence of a catalyst such as the sodium salt of alcohol, dry hydrogen chloride, p-toluenesulfonic acid or potassium cyanide.

Compounds of the formula II in which R is an ester radical can also be prepared by alkanolysis of the corresponding nitrile (R = C = N) or by hydrolysis of an Inimo ether compound of the formula II in which R is a radical of the formula below

R _x O - C -

NH

in which R is the hydrocarbon radical of an alcohol or phenol is.

κ ο μ 8 3 6/1 0 1 7

Compounds of the formula II in which R is a carboxylic acid residue can also be obtained by acidic or base-catalyzed hydrolysis the corresponding compound of the formula II in which R is the carbamoyl group, the nitrile group (C = N) or ester group, getting produced.

The hydrolysis of an amide can be done with a mineral acid as Catalyst, e.g. hydrochloric acid or sulfuric acid. The hydrolysis catalyzed by a base takes place with an alkali metal or alkaline earth metal hydroxide, e.g., sodium or potassium hydroxide. The hydrolysis is suitably carried out in an aqueous solvent and preferably under rather severe conditions, e.g. heating for several hours at the reflux. The desired compound can be obtained as a free acid by neutralizing the resulting reaction mixture or as the corresponding base addition salt, e.g. as sodium salt, when using sodium hydroxide ^ or as acid addition salt, e.g. as hydrochloride when using hydrochloric acid. On the other hand, you can use the free acid in conventional Way to convert into any other desired salt.

During the hydrolysis of a compound of the formula II in which R is a nitrile radical, ammonia is released. That's why the preferred catalyst is an acid that binds the ammonia, e.g., a hydrogen halide such as hydrogen chloride or hydrogen bromide. If the hydrolysis is catalyzed with a base, ammonia is released and the acid is obtained as an alkali metal salt

B 0 9 3 3 B / 1 0 1 7

or after neutralization as a free acid.

Used for the hydrolysis of an esterified carbic acid group- one in the inventive method is preferably one strong base such as sodium hydroxide. Suitable carboxylic acid radicals R are, for example, lower alkoxycarbonyl radicals, such as methoxycarbonyl or tert-butoxycarbonyl radicals. With regard to the salts of the free acid formed, those mentioned above also apply here Remarks.

Another process for the preparation of compounds of the formula II in which R is the carboxyl group is characterized in that that a compound of the formula II in which R is a radical of the formula -MX, in which M is a magnesium, Calcium or lithium atom and X is a chlorine, bromine or iodine atom, carboxylated and then hydrolyzed. These Reactions are known per se and. can be carried out in a conventional manner. Carboxylation is preferred carried out with carbon dioxide gas, solid carbon dioxide may also occasionally be used. The hydrolysis of the after the intermediate product formed by the carboxylation occurs through simple addition of water.

Compounds of the formula II in which R is the hydroxymethyl radical, can be prepared by reducing a compound of formula II in which R is formyl or ester, e.g. with sodium borohydride.

R 0 9 a 3 6/1 0 1 7

Compounds of the formula II in which R is a carboxyl radical _s can be prepared by oxidation of the corresponding compound of the formula II in which R

a) the formyl radical,

b) the methyl radical,

c) the hydroxymethyl radical,

d) is an acyl radical.

of examples / reagents suitable for this oxidation

a) basic silver oxide or concentrated nitric acid,

b) acidic sodium or potassium dichromate,

c) Manganese dioxide and then basic silver oxide,

d) a hypohalite.

The acyl radical can be an acetyl group (CH CO). The hypohalite is then preferably a sodium hypohalite which is in situ in aqueous solution by reacting sodium hydroxide with a mixture of iodine and potassium iodide.

The free acid can be isolated and converted to any desired salt in a conventional manner.

5 6 compounds of the formula II in which -R and R are hydrogen atoms each are in the cis configuration can by hydrogenation of the corresponding Acetylenes of the formula IX are prepared

Π Π 9 fl 3 R / 1 Q 1 7

(IX)

Z-CH - C ξ CR '2

in which R, R, R, R ^ and Z are as defined in formula II.

This hydrogenation can be carried out in the presence of palladium on barium sulfate take place.

Another method according to the invention is characterized in that that a compound of the formula X or XI with a compound of the formula XII or a compound of the formula XIII with a compound of the formula XIV or XV

(X)

R-

Z-CHo-CH-P - 0R _£ ² \

(XU)

B09836 / 1017

(XI)

Z - CH ₀ -

ι ^R

C = P -

ΕΙ

Z - Ch ₂ - C

(XIII)

JCOEt-P -OR \ ^a

S / «a

R.

(XV)

2 ₇ and P as in formula VII

in which R to R and Z are as defined in formula II / and R_, R, and R are identical or different and are each one

et D C

mean lower alkyl, aryl or arylalkyl radical.

This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature of about ⁰ to about 10O C. Under these conditions the reaction proceeds within several minutes to several hours smoothly. That

60 9 836/1017

Product can be isolated in a conventional manner, e.g. by evaporation of the solvent or by precipitation and then Filter. In some cases the reaction takes place in a solvent in which the product is insoluble, the Product then precipitates out as a solid and can be filtered. The product is cleaned in a conventional manner Chromatography or recrystallization.

During the preparation of the starting compounds of the formula X,. XI, XII, XIII, XIV or XV and also the end product of the formula II, it may be desirable to add reactive groups that are present protection. A free carboxylic acid group is preferably used by esterification, free amino groups in the for peptide synthesis known way protected.

The examples illustrate the invention. The products can occur both as geometric isomers and as a mixture of cis and trans isomers.

For example

3- / T- (3-methyl-but-2-enyloxy) -phenylJ [7 ~ P ^ro Pi ^ons äure ethyl ester

1.6 g (0.07 mol) of sodium are added to 50 ml of absolute ethanol Exclusion of moisture and dissolved with a solution of 9j7 g (0.05 mol) ethyl 3- (4-hydroxyphenyl) propionate in 25 ml added absolute ethanol. The mixture is stirred at room temperature for 30 minutes, then 6.7 g (0.05 mol) of l-bromo-3-diethyl

609836/1017

but-2-ene in 25 ml of absolute ethanol is added dropwise with stirring. The mixture is refluxed with stirring for 6 hours and then cooled. The inorganic salts are filtered off and washed with 30 ml of cold ethanol. The filtrate is evaporated. The residue is dissolved in 150 ml of dichloromethane, washed twice with 100 ml of 5% sodium hydroxide solution each time and once with 100 ml of water and dried over anhydrous magnesium sulfate. 8.01 g of crude product are obtained, which is distilled. This gives 5.0 g (38%) of the desired product, Kp./3 mm 178-182 ⁰ C.

B09836 / 1 01 7

'co co co

CM I

Examples 2 to 15

The following compounds are prepared according to the procedure of Example 1:
Example Yield (^) m.p./kp. (° C)

2 3 - ^ - (3-Methylbut-2-enyl-1-oxyJ> 7-benzoic acid ethyl ester

3 4- (but-2-enyl-1-oxy) benzyl ethyl ether

4 4- (but-2-enyl-1-oxy) toluene

5 2- (but-2-enyl-1-oxy) toluene

6 Ethyl 4- (prop-2-enyl-1-oxy) benzoate

7 Ethyl 4- (prop-2-enyl-1-oxy) phenylacetate

8 3 "/! 4 ~ '- (But-2-enyl-1-oxy) -phenyl-7-propionic acid ethyl ester

9 Ethyl 4- (but-2-enyl-1-oxy) benzoate

10 ethyl 2- (but-2-enyl-1-oxy) benzoate

11 Ethyl 3- (but-2-enyl-1-oxy) benzoate

12 Ethyl 2- (prop-2-enyl-1-oxy) benzoate

13 Ethyl 4- (prop-2-enyl-1-oxy) benzoate

14 ethyl 4- (but-2-enyl-1-oxy) phenylacetate

15 3- / TT '- (prop-2-enyl-1-oxy) -phenyl-7-propionic acid ethyl ester

'15 148 / 0.7 mm 39 125-128 / 1.0 mm 38 90-93 / 1.5 mm 29 71-74 / 0.2 mm 43 156/10 mm 32 126-127 / 0.5mm r 52 I68-I72 / 2 mm 36 M.p. 51-52 39 - 42 - 35 153/13 mm 46 88 / 0.1 mm 37 _

cn ο cn

example • ■ * 7.98 ^ 6.81 B (ppm) 10. • ■ · 5/81 (AH, aromatic, 'complex) - 11 4/54 (2H, = CK, zn) ' • '- 4.37 (2H, -OCH ₂ , m) 1.76 (2H, -OCH ₂ , ester, q) * ■ 1.39 (3H, -CH ,, d)
/ * 7.84-6.96 I.
(3H, -CH ₃ ester, Ό 5.80 (AH, aromatic, complex) 14th 4.50 (2H, = CH-, m) 4.38 (2H, -OCH ₂ , d) 1.83 (2H, -OCH ₂₎ ester, q) 1.39. (2H, -CH ₅ , d) 7.20)
6.68) (3H, -CH ₃ , t) 5'78 (AH, aroma-table, aa-bb) 4.41 4.13 (2H, = CH, m) 3/52 (2H, -OCH ₂ , m) 1.78 (2H, OCH ^ ester, q) (2H, -CH ₂ -, s) (3H, - CH ₃ , d).

(3H, -CH ₃ , ester, *) 15 7/12) (AH, aromatic, _aa , _bbf)

7/12) 6 _f 80)

5 * 98 (1Hi «CH, / m)

f. η ύ η 3 B / 1 α 1 7

(2H, = CH ₂ , t) 2605399 5.29 (2H, -OCH ₂ , d) 4.49 (2H, -OCH ₂ , Ester. 4.12 (4H, -CH ₂ , m) , q) 2.72 (3H, -CH ,, Ester, 1.21 t)

Example l6 A ^trans-3-f - (but-2-enyl-l-oxy) -propionic acid ethyl ester -phenyl7-

10 g (0.07 mol) of anhydrous potassium carbonate are dissolved in 80 ml

and
Suspended acetone / treated with 9.2 g (0.05 mol) of ^{ethyl 3 ~ (4 f} -hydroxyphenyl) propionate. The mixture is stirred at room temperature and 6.65 g (0.05 mol) of trans-1-bromobut-2-ene dissolved in 40 ml of acetone are added dropwise. The mixture is refluxed with stirring for 4 hours, then cooled to room temperature and filtered off with suction. The solvent is removed under reduced pressure. The residue is dissolved in 100 ml of ether, washed twice with 100 ml of 5% sodium hydroxide solution each time and once with 100 ml of water and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, 8.37 g of crude product are obtained, which is distilled under reduced pressure. 6.19 g (50 %) of the desired product are obtained, boiling point / 0.5 mm 153 to 155 ° C

6 0 9 B 3 R / 1 01 7

ι
t—
CM
I. 17 ■ 18th 19th 20th CD
O 21 9.8 3 6 / 22nd
23 σ 24 25th 26th 27 28 29 30th

Examples 17 to

The following compounds are prepared according to the procedure of Example 16: Example Yields) Mp./Kp. ( ⁰ C)

4- (but-2-enyl-1-oxy) benzonitrile

2- (but-2-enyl-1-oxy) benzaldehyde

3- (But-2-enyl-1-oxy) -benzaldehyde

2- (but-2-enyl-1-oxy) acetophenone

3- (But-2-eny1-1-oxy) acetophenone

4- (but-2-enyl-1-thio) toluene

4- (but-2-enyl-1-oxy) ethylbenzene

trans-3 -_ /? '- (But-2-enyl-1-oxy) -pheny 1,7-propionic acid isopror

trans-4- / Ti ^l - (but-2-enyl-1-oxy) -butan-2-one trans-2- (but-2-enyl-1-thio) -benzoic acid ethyl ester

trans-3 -_ /? ^l - (But-2 - <=> nyl-l-oxy) -pheny ^ .7-propionic acid- 2} 0

benzyl ester

3- ^ T} '' - (but-2-enyl-1-oxy) -phenylj7 "-P ^r opio ^NGE acid-n-43200-205 / 2.5 mm

hexyl ester 4- / 3-methyl-but-2-enyl-1-ox ^ 7-benzaldehyde 63 133 - I36 / I mm

ethyl trans-4- (hex-2-enyl-1-oxy) benzoate 73 159 - 160 / 0.4 mm

72 Pp 65-67 - 133 / 0.7 mm 40 115 - 117 / 0.7 mm 27 118 - 120 / 0.8 mm 52 129 - 132 / 2.5 mm 58 126 - 130 / 0.6 mm 47 100 - 106 / l mm 42 97 - 98 / 0.9 mm 40
ester ■ 150 - 151 / 0.2 mm 53 144-147 / 0.6 mm 73 132

Example 31

_ (But-2-enyl-1-oxy) -phenyl-7-propionic acid

48 g (0.194 mol) of 3- / J ^f - (but-2-enyl-l-oxy) -phenyl7-propionic acid ethyl ester are dissolved in 100 ml of absolute alcohol and with a solution of 10 g (0.25 mol) of sodium hydroxide in 100 ml of water are added. The mixture is refluxed for 18 hours, cooled and extracted twice with 100 ml of dichloromethane each time. The aqueous phase is acidified with 10 percent hydrochloric acid, the product is filtered and dried at 65 ° C. under reduced pressure. Crystallization from 20 percent aqueous ethanol gives 27.36 g (64 %) of the desired product, pp. 107-108 ° C.

Example- 32

4 '- (But-2-enyl-1-oxy) -benzoic acid is prepared according to the procedure of Example 31. After crystallization from 30 percent aqueous ethanol, the desired product is obtained in 81 percent yield, melting point 173 to 175 C.

Example 33 3- / 4 ~ '~ (But-2-enyl-1-oxy) -phenyl-7'-propionic acid, sodium salt

4.40 g (0.02 mole) of 3- / TT ^f - (but-2-enyl-l-oxy) -phenyl7-propionic acid are suspended in 20 ml of water, and I ₉ 68 g (0.02 mol)

ΠΠΠΠ36 / 1017

Sodium bicarbonate is added to 10 ml of water. The mixture is heated in a water bath for 1 hour. The water is removed under reduced pressure, the last traces of water become
azeotropically distilled off with ethanol. The residue is with
Treated acetone. The suspension is filtered, the product
is dried under reduced pressure at 60 ° C. 4.26 g (88 %) of analytically pure sodium salt, pp. 284 to 285 ° C., are obtained

Example 34

4 ^t - (But-2-enyl-1-oxy) -benzoic acid sodium salt is prepared according to the procedure of Example 33 in 88 percent yield. Pp> 300 ⁰ C.

Example 35 3- / Ji ¹ - (But-2-enyl-1-oxy) -phenylZ-propionoylhydrazide

5 g (0.02 mole) of 3- / 4 ~ ^l - (but-2-enyl-l-oxy) phenyl / -propionsäureäthylester are dissolved in absolute ethanol, 20 ml of a 40 per cent solution of hydrazine and the mixture heated for 6 hours at reflux . The mixture is left to stand overnight at room temperature, then diluted with 100 ml of water. The pesticide is filtered off, dried at 60 ° C. under reduced pressure and recrystallized from ethanol. 4.3 g (93 %) of the desired product, pp. 125 to 127 ° C., are obtained.

3 836/1017

Example 36 5 ~ / ^ r ^f - (But-2-enyl-1-oxy) -phenyl-7-tetrazole

8.65 g (0.05 mol) 4- (but-2-enyl-1-oxy) -benzonitrile, 3.75 g (0.051 mol) sodium azide and 7.5 g (0.15 mol) ammonium chloride are in dry Dimethylformamide mixed and heated to 115 ° C with stirring for 36 hours. The mixture is cooled to room temperature, the solvent is removed under reduced pressure, the residue is suspended in 100 ml of water and acidified to pH 2 with concentrated hydrochloric acid. The product is filtered off, dried and recirculated from absolute ethanol. 8.32 g (77 %) of the desired product, melting point 214 to 26 ° C., are obtained.

Example 37 3- / J '- (But-2-enyl-1-oxy) -phenyl-7-propionic acid, methyl ester

5.0 g (0.02 moles) 3- /? ^f - (But-2-enyl-1-oxy) -phenyl7-propionic acid ethyester are dissolved in a solution of 0.5 g of sodium in 150 ml of methanol. The mixture is refluxed for 5 hours and then cooled. The solvent is removed under reduced pressure. The residue is mixed with 50 ml of water and extracted twice with 50 ml of dichloromethane each time. The organic extracts are dried over magnesium sulfate and evaporated. 4.94 g of the crude methyl ester are obtained, which is distilled. Yield: 4.48 g (96 %) of the desired

60 9 836/1017

Product, bp / 0.3 ram 142-145 ° C

Example 38 4- (But-2-enyl-1-oxy) acetophenone

In a three-necked flask equipped with a stirrer, dropping funnel and a reflux condenser fitted with calcium chloride tubes, 13.6 g (0.1 mol) of 4-hydroxyacetophenone are dissolved in 50 ml of dry dimethylformamide and mixed in portions with an 80 percent suspension of 3 , 0 g (0.1 mol) of sodium hydride in paraffin were added. The mixture is ^{stirred at 50 °} C. for complete reaction, then cooled to room temperature and a solution of 13.5 g (0.1 mol) of 1-bromo-2-butene in 20 ml of dimethylformamide is added dropwise with stirring. The mixture is stirred for 2 hours at room temperature and 1 hour in a water bath, then cooled to room temperature and poured into 100 ml of ice water. The product is extracted twice with 100 ml ether, washed twice with 100 ml of 5 per cent sodium hydroxide solution and washed once with 100 ml water, dried over magnesium sulfate and evaporated. The product is des.tilliert, 10.43 g (55 %) of the desired product are obtained, boiling point / 1.5 mm 149 to 152 ° C.

Example 39

4- (But-2-enyl-1-oxy) -benzaldehyde is prepared according to the procedure of Example 38. Yield ": Sl% _t bp / 0.9 now 12 ** ^bis

6 0 P. 8 3 6/1 0 1 7

126 ⁰ C.

Example 40 ethyl trans- ^ l- (But-2-enyl-l-th.io) benzoate

8.30 g (0.023 mol) of 4,4'-dithio-bis-benzoic acid diethyl ester are dissolved in 275 ml of absolute ethanol at room temperature, and 1.83 g (0.048 mol) of sodium borohydride are added while stirring. The mixture is stirred for 90 minutes at room temperature, the solution turning yellow, then treated with a solution of 6.21 g (0.046 mol) of trans-1-bromo-but-2-ene in 20 ml of ethanol. The mixture is stirred at room temperature for 3 hours, then the solvent is removed under reduced pressure. The residue is dissolved in ether, washed with 50 ml of 10 percent aqueous sodium bicarbonate solution, 100 ml of water and 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated. A pale yellow oil is obtained which crystallizes on standing. After recrystallization from ligroin (boiling range 40 to 60.degree. C.), 4.60 g (43 %) of the desired product are obtained as colorless flakes, pp. 41 to 42.degree.

Example 41

a) 3- / 4 "'- (But-2-ynyl-1-oxy) -phenyl-7-propionic acid ethyl ester

absolute 2j4 g (0.104 mol) sodium v / earth in 8Ό ml / ethanol

Exclusion of moisture dissolved and with a solution of 20.6 g

609836/1017

- ^ - 26Ü5399

(0.106 mol) 3 - (^ - Hydroxyphenyl) propionic acid ethyl ester in 20 ml of ethanol are added. The mixture is 30 minutes at room temperature stirred, then dropwise with a solution of 12.5 g (0.08 mol) of but-2-ynyl methanesulfonate in 20 ml of ethanol offset. The mixture is refluxed with stirring for 3 hours, cooled and filtered. The solvent is under removed under reduced pressure. The product is diluted with 100 ml of water, extracted into ether, twice with 100 ml each time 5 percent sodium hydroxide solution and washed once with 100 ml of water, dried over magnesium sulfate and evaporated. 19 g of the crude product are obtained, which is distilled. Yield: 8.66 g (44 SSJ, b.p./2 mm 162-166 ° C.

b) cis-3- / 4 "'- (But-2-enyl-l-oxy) -phenyl7-propionic acid ethyl ester 4.1 g (0.0167 mol) 3- / 4"' - (But-2- Inyl-l-oxy) -phenyl7-propionic acid ethyl ester in 30 ml of methanol are hydrogenated in the presence of °> 15 g of 5-Prosentigem palladium on barium sulfate and 0.35 ml of quinoline at atmospheric pressure until exactly 1 equivalent of hydrogen (375 ml) is absorbed. The catalyst is filtered off under reduced pressure, the solvent is evaporated, the product is dissolved in 50 ml of ether. The ether solution is washed twice with 50 ml of 5 percent hydrochloric acid each time, once with 50 ml of saturated sodium bicarbonate solution and once with 50 ml of water, dried over magnesium sulfate and evaporated. After distillation of the crude product 3.43 g (83%) is obtained of the desired product, Kp./1,5 mm 146-150 ⁰ C.

609836/10 17

Example 42

According to the procedure of Example 41, a) 3-

in oil percent yield, b.p./1.6 mm 176 C and

t>) cis-3- / Tr ⁱ - (Hept-2-enyl-l-oxy) -phenyl7 ~ P ^ro Pi ^{oic acid "th} 2- y ^lester in 94prozentiger yield Kp./2,5 mm 182 to l84 ° C.

manufactured.

Example 43 4- / 3 ~ methyl-but-2-enyl-1-oxy7-benzyl alcohol

7.6 g (0.04 mol) 4- (3-methyl-but-2-enyl-1-oxy) -benzaldehyde are dissolved in 100 ml ethanol and mixed with 0.4 g (0.012 mol) sodium borohydride. The mixture is refluxed for one hour and then cooled. The solvent is removed under reduced pressure, the product is dissolved in 100 ml of dichloromethane, washed with 100 ml of water and dried over magnesium sulfate. After evaporation, 5.92 g of the crude product are obtained, which is chromatographed over silica gel in dichloromethane. 2.3 g (31 %) of pure 4- _J / 5-methyl-but-2-enyl-1-oxy_ / ^r -benzyl alcohol, melting point 42 ° C., are obtained.

6 0 3 8 3 6/1017

Biological experiments

The cholesterol and / or triglyceride lowering effects of some Compounds of the formula II according to the invention are determined on the basis of the following experiment:

Groups of 8 male albino rats (strain CPY) weighing about 150 g are fed a commercially available powdered diet (Oxoid) which contains up to 0.25 % compounds according to the invention. The rats are fed these diets for 7 days, then they are sacrificed. Total serum cholesterol and triglyceride levels are measured using a Technicon autoanalyzer.

The results are summarized in the following table, the lowering of cho] esterol and triglyceride in the blood is in Percent indicated.

B 0 P ft 3 6/1 0 1 7

Table (N.S. = insignificant)

26Ü5399

link % Reduction "- Triglyceridesc '- of the example Cholesterol. 48.9 1 14.8 53.4 2 20.0 43.0 3 21.4 N.S. 4th 19.3 32.6 .6 21.3 N.S. 7th 21.8 54.0 8th 13.0 59.4 9 32.2 27.0 10 19.0 28.4 12th , 14.1 40.5 14th 13.1 47.0 15th 23.0 26.5 16 N.S. 31.3 18th 19.3 29.9 19th 19.3 23.3 20th N.S. 22.1 21 N.S. 19.8 22nd N.S. 25.6 23 N.S. 56 27 9 N.S. 29 4th 51 30th N.S. * '43.3 31 20.7 ^: 48.0 32 25.0 46.0 34 28.2 40 37 7th - N.S. 39 30.9 13th 41 12th 35.8 42 N.S.

RO ^! H '-5 B / 1 0 1 7

Claims (9)

Claims 1. Medicinal preparations, characterized by a content of at least a pharmacologically acceptable carrier and / or diluent and at least one compound of the formula II as an active ingredient R- (ID R- Z - CHrj -C = R ^v r ' 2 3 4
in which one of the radicals R, R or R is a radical of the formula - (CH ₂ ) R and the other radicals are hydrogen atoms, where R is a carboxyl group or its pharmacologically acceptable salts, esters, amides or hydrazides, optionally with at least one hydroxyl group or at least one lower alkoxy radical substituted alkyl radical, a cyano group, formyl group, an acyl radical optionally substituted by a carboxyl group or a tetrazole radical and q is O or an integer from 1 to 12, Z is an oxygen or sulfur atom and R, R and R ' each is a hydrogen atom or a lower alkyl radical 2. Medicinal preparations according to claim 1, characterized by a Content of a compound of the formula II. in which R is a carboxyl group or their salts, esters, amides or hydrazides, a ge 6 0 9 H 3 G / 1 0 1 7 an alkyl radical optionally substituted by at least one hydroxyl group, a cyano group, a formyl group or an optionally substituted is acyl radical substituted with a carboxyl group. 3. Medicinal preparations according to claim 1 and 2, characterized by a Content of a compound of the formula II in which R is a hydrogen? atom is. k. Medicinal preparations according to Claims 1 to 3 _a, characterized by a content of a compound of the formula H ₃ in which Z is an oxygen atom. 5. Medicinal preparations according to claim 1, characterized by a content of a compound of the formula III as an active ingredient R ¹ (CH ₂ ) _q (III) R ⁶ O-CH ₉ -CH = C 1 f \ 7th in which R ₁ R ₁ R and q are defined according to claim 1. 6. Medicinal preparations according to claim 1 and 5, characterized by a content of a compound of the formula III in which R is a 60; j 836/1017 Carboxyl group or their pharmacologically acceptable salts or Is ester and q is O. 7. Medicinal preparations according to claim 1 and 5> characterized by a content of a compound of the formula III in which R is the Methyl, hydroxymethyl or carboxyl group or their pharmacologically acceptable salts or esters and q is an integer means from 1 to 12. 8. Medicinal preparations according to claim 1, characterized by a Content of a compound of the formula IV as active ingredient O - CH ₂ - CH = C in which R, R, R and q are defined according to claim 1. 9. Medicinal preparations according to claim 1, characterized by a content of a compound of the formula V as an active ingredient (V) / R ⁶ Z -CHo • CH ⁼ C "r ⁸ ' r. fr ^; '-äB / 1 η 1 7 in which R, Z and R are defined according to claim 1, R is a lower alkyl radical and r is an integer from 1 to 12. 10. Medicinal preparations according to claim 1 and 9, characterized by a content of a compound of the formula V in which r is a whole Number from 2 to 6 means. 11. Medicinal preparations according to claim 1, 9 and 10, characterized by a content of a compound of the formula V in which r is 2 and R is a carboxyl group or a pharmacologically acceptable group thereof Salts or alkyl esters. 12. Medicinal preparations according to claim 1, 9 to 11, characterized by a content of 3- / 7f '- (but-2-enyl-1-oxy) -phenyl7'-propionic acid ethyl ester. 13. Compounds of the formula II (ID R ⁵ Z - CH ₂ - C = C ; .n-: ■ 3 R / 1 η 1 7 2 3 4 in which one of the radicals R, R or R is a radical of the formula - (CHp) R is and the other radicals are hydrogen, Z is a ■ ί 6 7 means oxygen or sulfur atom, R, R and R ¹ each Are hydrogen atoms or lower alkyl radicals _; either q O, 1 is or 2 and R denotes the cyano group / or q exne is an integer of to 12 and R denotes the carboxyl group, its pharmacologically acceptable salts, esters, amides or hydrazides, optionally alkyl group substituted with at least one hydroxyl group or at least one lower alkoxy group, the cyano group, Formyl group, an acyl radical optionally substituted by a carboxyl group, with the proviso that when Z is the Is oxygen atom and q means 2, R cannot be the carboxyl group. 14. Compounds according to claim 13 of the formula II, in which Z is the oxygen atom. 15. Compounds according to claim 13 and 14 of the formula II, in which R is the hydrogen atom. 16. Compounds according to claim 13 of the formula VI 0-CH ₉ -CH = C ² 60 9836/1017 in which R is a lower alkyl radical or an ester radical, s is an integer from 2 to 6 and R and R 'according to claim 13 are defined. 17.3 - /? - (3-Methyl-but-2-enyloxy) -phenyl-7-propionic acid ethyl ester 18.4- (But-2-enyl-1-oxy) benzyl ethyl ether. 19.3 - /? '-_ (But-2-enyl-l-oxy) -phenyl-7-propionic acid ethyl ester Ethyl 2O.2- (But-2-enyl-1-oxy) -benzoate. 22.4- (But-2-enyl-1-oxy) -benzonitrile. 23.2- (But-2-enyl-1-oxy) acetophenone. 24. 3- (But-2-enyl-l-oxy) acetophenone .. 25.4- (But-2-enyl-1-oxy) ethybenzene. 26.3 - /? '- (But-2-eny1-1-oxy) -phenyl-7-propionic acid isopropyl ester. 27. l \ -ß * - (But-2-enyl-1-oxy) -phenyl / -butan-2-one .. 28.2- (But-2-enyl-1-thio) benzoic acid ethyester. 29.3- / 1P- (But-2-eny1-1-oxy) -phenyl / -propionic acid benzyl ester. 30. 3- / Ji ¹ - (But-2-eny 1- 1-oxy) -phenyl ^ -propionic acid-n-hexy les ter. 31.3- / 7 ¹ - (But-2-eny1-1-oxy) -pheny! / - propionic acid. 32.4 ^f - (But-2-eny 1- 1-oxy) -benzoic acid,. 33. 3-ß ¹ - (But-2-eny1-1-oxy) -phenyl / -propionic acid, sodium salt.-34.4 ^t - (But-2-enyl-1-oxy) -benzo-3-acid --- sodium salt3. 35.3- / ¹ P - (But-2-enyl-1-oxy) -phenylj-propionoyl hydrazide. 36.4- (But-2-enyl-1-oxy ^ acetophenone ,.
37.4- (But-2-enyl-1-thio) -benzoic acid ethyl ester. 38.3- ^ ¹ P- (But-2-eny1-1-oxy) -phenyl-7-propionic acid ethyl ester. 39.3- /? ¹ - (Hept-2-eny1-1-oxy) -phenylj-propionic acid ethyl ester. 609836/1017 _2,3- 26Ü5399 ^ iO. Process for the preparation of the compounds according to claim 13, characterized in that one
a) a compound of the formula VII (VII) with a compound of the formula VIII IT Q - CH ₉ - C = C \ 7 (VIII) ρ τζ! ι c ^ * 7 in which R, R, R, R, 'R and R according to claim 13 are defined and one of the radicals P or Q is a radical of the formula -ZH or its reactive derivative in which Z is defined according to claim 13, and the other radical is an easily displaceable radical, b) a compound of the formula X or XI with a compound of Formula XII or a compound of the formula XIII · with a compound of the formula XIV or XV J-: "■? H / 1 0 1 7 26U5 399 (X) Z - CHo - CH - P - OR, OR ₁ (XI) I / a Z - CH ₂ - C = P ~ R _b (XIII) Z - R ^ C = O R * rf . ^R c (XV) 6 f 1 μ a 3 6/1 O 1 7 2 7
in which R to R and Z according to claim 13 and P are as defined in formula VII and R, R. and R are identical or different and each represent a lower alkyl, aryl or arylalkyl radical, 1 1 and optionally converting the R group into another R group. 41. The method according to claim 40, step a) for the production of Compounds of formula II in which Z is the oxygen atom. 42. The method according to claim 40 and 4l, characterized in that to react compounds of the formula VII and VIII in which one or
the radicals P / Q a salt of the hydroxyl group and the other one Is halide. 43. Process for the preparation of compounds of the formula II, in the R is an ester radical, characterized in that one a) a corresponding compound of the formula II in which R is the carboxyl group, esterified, or b) transesterifying a corresponding compound of the formula II in which R is another ester radical, or c) a compound of the formula II in which R is the nitrile group, subject to alkanolysis, or d) a compound of the formula II in which R is an imino ether radical of the formula R _x OC- NH is, in which R is the hydrocarbon radical of an alcohol or Phenol is hydrolyzed. 609 8 36/1017 44. Process for the preparation of compounds of the formula II, in which R is the carboxyl group, characterized in that one a) a corresponding compound of the formula II in which R is the formyl, methyl or hydroxymethyl group or an acyl radical, oxidized, or b) a corresponding compound of the formula II in which R is the carbamoyl, nitrile or ester radical, acidic or alkaline hydrolyzed, or c) a compound of the formula II in which R is a radical of the formula -MX, in which M is a magnesium, calcium or lithium atom and X is a chlorine, bromine or iodine atom, carboxylated and then hydrolyzed. 45. Process for the preparation of compounds of the formula II in which R is the hydroxymethyl group, characterized in that that a compound of the formula II in which R is a formyl or carboxyl ester group is reduced. 46. Process for the preparation of compounds of the formula II in which R and R ^{0 are} hydrogen atoms in the cis configuration, characterized in that a compound of the formula IX is hydrogenated (IX) Z-CH -C = CR ⁷ Β0ύ336 / 1 01 7 - I ₁₇ . 2 3 1} γ in which R, R, R, R 'and Z are defined according to claim 13. 47 · Compounds of the formula IX 3. (IX) Z - CH ₂ - C ξ C - R ' 2 3 4 7 in which R, R, R, R 'and Z are defined according to claim 13. 9 8 3 6/1017