IE42948B1 - Pharmaceutically acceptable salts of alkanoic acid derivatives and compositions containing the same - Google Patents

Description

This invention relates to pharmaceutically acceptable salts of alkanoic acid derivatives and is concerned with the use of such salts in the treatment of pathological conditions due to disturbances of the central nervous system.

In British Specification No. 760,114, it is disclosed that the cholesterol level in the blood serum of a man or animal can be lowered by the administration of chemical compounds represented by the general formula: in which R represents an alkyl or aryl radical, R^ represents hydrogen or an alkyl radical, R2 represents an alkyl or alkylene radical, m is an integer equal to 0 or 1, and X is an -OH group, an —OM^ group, M being an alkali metal, an alkaline earth metal (including magnesium) or aluminium, and n being a fractional index such that the product of n multiplied by the valency of M is equal to 1, or X is an NH2 group or an -OB group, B being the cation of an organic base.

It has now been found tha£\the pharmaceutically acceptable salts of four particular alkanoic acid derivatives which are specified below and which fall within the very broad class of compounds defined by thk, foregoing general formula.but not specifically disclosed in the said U.K. Specification present valuable biochemical a.nd pharmacological _ 2 _ properties likely to render them particularly useful in the treatment of pathological conditions due to disturbances of the central nervous system.

As a result of biochemical and pharmacological tests, the pharmaceutically acceptable salts of the four alkanoic acid derivatives in question namely alkali metal salts of 3-methyl-butanoie acid, 3-ethyl-pentanoic acid, 3-n-propyl-hexanoic acid and 3-n-butyl-heptanoic acid were found to act as competitive inhibitors with respect to the action of γ-aminobutyric α-ketoglutaric transaminase and also as anticonvulsant and antianoxic agents.

Further investigations have shown that pharmaceutically acceptable salts of alkanoic acid derivatives having a chemical structure similar to that of 3-methyl-butanoic acid, 3-ethylpentanoic acid, 3-n-propyl-hexanoic acid and 3-n-butylheptanoic acid but falling outside the scope of British Specification No. 760,114 are also effective in the treatment of pathological conditions due to disturbances of the central nervous system in that they also present valuable competitive inhibitory activity with respect to the action of γ-aminobutyric α-ketoglutaric transaminase and also anticonvulsant and antianoxic activities.

The pharmaceutically acceptable salts of the four alkanoic acid derivatives specified above as well as the pharmaceutically acceptable salts of the other related acetic acid derivatives referred to are defined by the general formula I given hereinafter. $29 43 Consequently, the compounds with which the present invention is concerned are the salts of alkanoic acid derivatives represented by the general formula: R-C-DMe wherein Me represents a pharmaceutically acceptable alkali metal atom, for example lithium, sodium or potassium, and R represents the radical: Bo Re CH-(CH2)n-CH2- or CH-CH-- or C=CHz z r; r R, 4 4 in which R^ and R2, which'may be the same or different, each represent an alkyl radical having, from 1 to 4 carbon atoms, n is an integer from 1 to 3 inclusive and R^ and Rd, whieh are identical, each represent a straight-chain alkyl radical having from 1 to 4 carbon atoms.

In accordance with one aspect of the invention there are provided novel alkanoic acid derivatives correspon ding to the general formula: R= 0 \ II cH-(CH2)m-cH2-C-0Me la wherein Rg and Rg, which are identical, each represent npropyl or n-butyl, m represents 0, 1 or,2 and Me has the same meaning„ as in Formula I.

A preferred class of compounds falling within the scope of formula Ia can be represented by the general formul n-C„H_ Ο 3< II CH-(CH„) -CH„-C-0Me Zz m £t wherein Me and m have the same meaning as in formula I.

The invention also relates to the process for preparing the said novel alkanoic acid derivatives of formula la.

In accordance with another aspect of the invention there is provided a pharmaceutical or veterinary composition comprising, as essential active principle, at least one compound of formula I in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.

The invention also relates to a pharmaceutical or veterinary composition comprising, as essential active principle, at least one novel compound of formula la in association with a pharmaceutical carrier or excipient therefor.

Another aspect of the present invention is to provide a method of treating central neurological disorders including, in particular convulsive states and seizures, in a non-human subject in need of such treatment, such method comprising the administration to said subject of an effective dose of at least one alkanoic acid derivative of formula I.

For human therapy, daily dosage will preferably be between 400 and 2000mg of active principle by any route for a human being weighing 60kg, for example about lOOOmg _ 5 _ by oral or rectal route.

Amongst the compounds of formula I certain are known products. In this connection may be cited: Sodium 3-methyl-butanoate which is cited in C A, 76, 33629j (1971).

Alkali metal salts of 4-ethyl-hexanoic acid and 3-methylbutanoic acid which are disclosed in French Patent of Addition No. 76.585 on Specification No. 1,218,577.

Sodium 3-methyl-pentanoate which is cited in British Patent No. 414,485.

Potassium 3-methyl-2-butenoate which is disclosed in Australian Journal of Chemistry 19, 317 (1966).

The compounds of the invention can be obtained by various procedures in accordance with their chemical structure Thus, the compounds of formula I wherein R represents RgR^CH-CHg- may be prepared by hydrogenating in a solvent such as, for example, absolute ethanol in the presence of a catalyst such as, for example, Raney's nickel, a mixture of ethylenic acids obtained by dehydrating, for example with acetic anhydride, a S-hydroxy acid of the general formula: C-CH„-C-OH II wherein Rg and R4 have the same meaning as in formula I, which provides a β-dehydrated acid which is then treated with an alkali metal hydroxide, for example lithium, sodium _ 6 _ 48948 or potassium hydroxide, to obtain the corresponding pharmaceutically acceptable alkali metal salt of formula I.

The hydrogenation is carried out under pressure and by heating the mixture of ethylene acids in question and the dehydration is preferably effected by heating the reagents.

The compoundsof formula I wherein R represents R,R„CH-(CH„) -CH„- can be obtained by oxidizing, for example i Zj Zj Q ύ by means of chromic anhydride, in a solvent such as for example acetic acid , an alcohol of the general formula: R1 XCH-(CHO) -CEo-CH„-0H III / z n z z R2 wherein R^, Rg and n have the same meaning as in formula I, to obtain an alkanoic acid derivative in free acid form which is further treated by means of an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to form the corresponding pharmaceutically acceptable alkali metal salt of formula I.

The compounds of formula I wherein R represents RgR^C=CH- can be obtained by dehydrating, for example by means of acetic anhydride, a β -hydroxy acid derivative of the general formula II hereabove to form a S-dehydroxylated acid which is further treated by means of an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to obtain the corresponding pharmaceutically acceptable alkali metal salt of formula I.

The dehydration may be effected by heating the reagents, for example under reflux.

The compounds of formula II can be prepared by reacting a dianion obtained from acetic acid^ an aromatic hydrocarbon such as naphthalene or anthracene and an alkali metal such as lithium, sodium or potassium with a ketone of the general formula: H IV R3-C-R4 wherein Rg and R^ have the same meaning as in formula I in an anhydrous ether such as ethyl ether, hydrolysing the alkali metal salt so obtained and subsequently acidifying the salt to form the required β-hydroxy acid derivative.

All the ketones of formula IV are known and commercial compounds.

The compounds of formula III are either known compounds or can be prepared by the method described in Ann. Chem. 1966, 693, 90-98.

As already mentioned, the compounds of the invention have been found to possess valuable biochemical properties, and in particular a marked competitive inhibitory effect with respect to the action of γ-aminobutyric a-ketoglutaric transaminase. The compounds of the invention also possess powerful pharmacological activity and more particularly marked antianoxic and anticonvulsant properties.

These properties, when taken as a whole, are likely to render the compounds of the invention useful for _ 8 _ treating various kinds of central neurological disturbances.

As an example of such central neurological disturbances or of disorders induced by central neurological dysfunction, the following may be cited : convulsive states and seizures such as, for example, epilepsy, choreic states such as Huntington's chorea, difficulties with respect to memory, balance and fixing the attention, as well as dizziness, decrease of arterial pressure, cephalalgia and comatose states. γ-Aminobutyric acid or GABA is an important constituent of the brain of the vertebrates. At present, it represents the only known physiological inhibitor of the pre- and postsynaptic discharges which it has been possible to isolate in the brain. Furthermore, this acid plays an all important role in the case of choreic patients in whom cerebral depletion in GABA has been observed.

The normal oxidative metabolism of the carbohydrates leads in particular to the production of a-ketoglutaric acid through the medium of the tricarboxylic cycle of KREBS.

From this point a deviation occurs which results in the formation of GABA.

Various enzymes regulate by natural processes the production and destruction of α-ketoglutaric acid and of GABA itself which is re-transformed into α-ketoglutaric acid, this latter acid being taken up again in the KREBS' cycle.

The activity of these enzymes can itself be either accelerated or inhibited by several substances. _ 9 _ 4^048 It has been discovered, in accordance with the invention, that the pharmaceutically acceptable salts of alkanoic acid derivatives of formula I are capable of producing a competitive inhibitory effect with respect to the action of γ-aminobutyric α-ketoglutaric transaminase or GABA T which destroys GABA. Such an inhibitory effect consequently produces an increase in the GABA level in the organism.

These biochemical properties are likely to produce more particularly a-n anticonvulsant action in pharmacology and in clinical use to exert antiepileptic and antichoreic effects.

Furthermore, the compounds of formula I have been found to be strong antianoxic agents capable in particular of delaying the onset of cerebral pain due to oxygen deficiency, i.e. originating from cerebral ischemia.

Cerebral ischemia can be provoked by numerous factors such as, for example, cerebral vascular deficiency due to senescence, thrombosis or tumours. At present cerebral vasodilators are commonly used in order to delay the onset of cerebral pain due to oxygen deficiency or to treat cerebral vascular deficiency and its resulting disorders for example central neurological disturbances such as those cited hereabove.

However, such drugs must be employed in accordance with the vascular state of the patient. Since these compounds act by mechanical means, namely by dilating the arterioles to increase the blood flow and consequently the amount of _ 10 _ oxygen in the brain, they will be ineffective, for example in cases involving arteriosclerosis.

Furthermore, certain agents can provoke a marked cerebral vasodilation of the healthy parts which upsets the circulatory equilibrium. As a consequence of this, a decrease of irrigation in the ischemic parts can occur.

The compounds of formula I on the other hand do not present these disadvantages as they do not act by mechanical means but exert their effect driectly on the metabolism of the nervous cells without affecting the conditions of irrigation. They do, in fact, act by bringing about an ecomony and a better use of oxygen in the nervous cells. These antianoxic properties will also be useful for preventing convulsive seizures as it is well known that anoxia can induce such seizures.

In the light of these different properties, the compounds of formula I will be likely to constitute valuable antianoxic agents, for example, for treating central neurological disturbances due to cerebral ischemia, particularly in cases where the classic drugs are ineffective.

In the field of diseases requiring anticonvulsant therapy and, in particular, epilepsy, there are numerous drugs of undeniable efficacy. However, these classic medicaments, such as the barbiturates and molecules of similar structure cause an overall depression of the central nervous system, which moreover, explains their anticonvulsant effect. - 11 42948 For this reason, such drugs frequently cause undesirable side-effects such as difficulty in fixing the attention, reduction in intellectual efficiency and somnolence as well as biological disorders of which the most serious are hematological.

The compounds of formula 1 do not present these disadvantages since they do not act by provoking a general depression of the central nervous system, but on the contrary, they function by means of an enzymatic mechanism involving the metabolism of a neurotransmitter which is a physiological inhibitor namely γ-aminobutyric acid. Furthermore, certain well-known anticonvulsant agents are toxic at relatively low doses while others are only useful for the treatment of one single type of epilepsy.

The compounds of formula I do not present thebe disadvantages since they are relatively non-toxic and at the same time posses a very wide range of properties which are likely to render them useful in the treatment of an extremely broad variety of convulsive states.

Compounds of a similar chemical structure to that of the compounds of formula I, namely dialkylacetic acid derivatives which possess anticonvulsant properties have been published in British Specification No. 980,279 . A detailed study has been carried out with sodium di-n-propylacetate which is the preferred compound of the above-cited British specification.

This study, which is reported in J. of Neurochemistry, _ 1969, Vol. 16, pp. 869-873, showed that sodium di-n-propylaeetate is capable of increasing the level of intracerebral GABA by inhibiting GABA T. Up to present, no other therapeutic substance is known which possesses this property.

This property endows sodium di-n-propylacetate with powerful anticonvulsant activity and a completely original mechanism of action.

Similarly, it has been demonstrated, as reported Sci z in Bull. Sac/ Vet. et Med. comparee, Lyon, 1970, 72, PP· 303-325, that sodium di-n-propylacetate possesses very marked antianoxic properties.

At present, sodium di-n-propylacetate is widely available as an antiepileptic agent.

However, it has been discovered in accordance with the present invention that the pharmaceutically acceptable salts of alkanoic acid derivatives of formula I possess the above-cited properties of sodium di-n-propylacetate but to different degrees which confer on them an originality of action'as compared with this latter product.

Thus, pharmacological tests have shown that at least one of the three biochemical and pharmacological activities cited hereabove is more intense in the case of the compounds of formula I than in that of sodium di-npropylacetate.

In therapeutic use this essential difference between sodium di-n-propylacetate and the compounds of formula I will be likely to render the latter more _ 13 S48 selective for the treatment of certain kinds of central neurogolical disorders. For example, the compounds of formula I which have been found to be more active then sodium di-npropylacetate as competitive inhibitors of GABA T will be likely to be more effective, for example, in the treatment of choreic states. On the other hand, the compounds of formula I which have shown better antianoxic properties than sodium di-n-propylacetate will be inore active in the treatment of central neurological disorders due to cerebral ischemia.

Disturbances and dysfunction of the central nervous system are numerous and constitute one of the most widespread disorders at the present time.

For this reason, it is very difficult for the doctor to choose amongst the various drugs at his disposal, that which will be effective for the particular case under treatment. When faced with a case of chorea, epilepsy or other affection, the neurologist is often obliged to feel his way by trying several drugs one after the other until he discovers the most suitable medication.

From this point of view, the compounds of formula I will constitute valuable additions to the therapeutic arsenal at the disposal of the doctor and, if necessary, will provide useful replacement medication for a drug which has become ineffective for any reason such as, for example, a change in the state of the patient or habituation.

The compounds of formula I which have been found to be particularly useful for the treatment of central 14neurological disturbances and in particular epilepsy are: Sodium 3-n-propyl-hexanoate and Sodium 5-n-propyl-octanoate.

Pharmacological trials have been undertaken with a view to determining the presence of a competitive inhibitory effect with respect to the action of γ-aminobutyric o-ketoglutaric transaminase, as well as antianoxic and anticonvulsant properties which, taken together, are capable of rendering the compounds of formula I useful for treating central neurological disturbances.

I· Inhibition of GABA T This test was undertaken in vitro in the absorption cell of a double-beam D.V. spectrophotometer.

The activity of GABA T was determined by coupling this enzyme with an excess of succinosemialdehyde dehydrogenase (NADP ) so that the rate of formation of the succinosemialdehyde dehydrogenase coenzyme (NADPH) was limited by the activity of the GABA T. The coupling of the two reactions was as follows: GABA T GABA + sodium a-ketoglutarate _r sodium glutamate + succinosemialdehyde In the presence of succinosemialdehyde dehydrogenase of which the active element is NADP+ the reaction became: succinosemialdehyde + NADP + HgO —> sodium succinate + NADPH + H+.

The overall reaction can be represented by the following equation : _ GABA + Sodium α-ketoglutarate + NADP’’ -:- HgO => sodium succinate + sodium glutamate + NADPE + H+.

The activity of GABA T was measured by following the reduction rate (v) of NADP* by measuring the optical density at 340 mu. speetrophotometrically.

Determination of the activity rate of GABA T by the principle hereabove described can be effected by measuring the reduction rate of NADP+ when different concentrations of one of the substrates, in the present case GABA, are used but always in the presence of a saturating concentration of the second substrate namely sodium eketoglutarate. As concentrations of GABA, a saturating concentration thereof is used in one case and different limiting concentrations are used in the other cases. A saturating concentration means a concentration of the substrate at which the enzyme, in the present case GABA T, can catalyze the above cited reaction at a maximum rate. On the other hand, a limiting concentration means a concentration of the substrate at which GABA T cannot catalize the reaction in question at a maximum rate, the activity rate of GABA T being limited by the concentration of the substrate.

Thus, it is possible to discover the activity rate of GABA T in relation to the concentration of GABA and, in this way, to determine the affinity of GABA T for GABA.

Similar measurements of the activity of GABA T were then carried out in the presence of different con-sentrations (I) of an inhibitor, namely a compound of - 16. 42848 formula I, so as to evaluate the effectiveness of the latter. The effectiveness was represented by the constant or constant of inhibition which determines the affinity of the enzyme (GABA T) for the inhibitor.

This constant is expressed in units of concentration, in the present case, in m mol per ml and can be determined by plotting all the curves corresponding to | = ί (I) for a saturating concentration of GABA and for different limiting concentrationsof GABA.

The point of coincidence of these curves determines the in question or the necessary concentration of inhibitor to arrest completely the activity of the GABA T.

The lower the value is, the greater is the effectiveness of the inhibition of GABA T by the compound of formula I.

The following experimental procedure was used: In the absorption cell (optical passage : 1 cm, volume : about 1 ml) the following solutions were introduced. 0.5 ml of a 1.5 molar solution of sodium sulphate 0.05 ml of a molar buffer solution of pH = 7.9 0.05 ml of a 0.1 molar solution of mercapto-ethanol 0.05 ml of a 20 mg/ml solution of NADP+ 0.125 ml of a solution of GABA 0.03 ml of a 40 mg/ml solution of GABASE (namely a bacterial enzyme i&olated from Pseudomonas fluorescens containing a mixture of γ-aminobutyric α-ketoglutaric transaminase and succinosemialdehyd®· dehydrogenase). 0.125 ml of a solution of the compound to be studied. _ 17- _ 48 Different measurements of optical density were effected by varying the concentration of GABA and the concentration of the compound under study. Control, assays were also effected by replacing the solution of the compound to be studied by 0.125 ml of water.

The content of the absorption cell was allowed to incubate for 10 minutes at 306C and then the enzymatic reaction was started by adding 0.1 ml of a 0.02 molar solution of sodium α-ketoglutarate to the absorption cell.

The final volume was 1.03 ml. The reaction was then followed by spectrophotometric recording of the reduction rate of the NADP+ at 340 mp and at 30°C. The optical density was automatically registered every 30 seconds.

In accordance with the process hereabove described, the following compounds of the invention were studied.

The pharmaceutically acceptable alkali metal salts of formula I such as the sodium salt, are in fact more advantageous that the acids themselves. These salts have a much milder irritant effect upon the upper part of the digestive tract than the acids.

Thus, the pharmaceutically acceptable alkali metal salts of formula I present an undeniable superiority over the corresponding acids.

This will serve to reduce considerably the undesirable side-effect, namely the i'riitant effect upon the upper part of the digestive tract, when the salts are used in therapeutics.

- IS 42948 Sodium 3-n-propyl-hexanoate (Compound A) Sodium 5-n-propyl-octanoate (Compound B) Sodium-* 3-methyl-butanoate (Compound C) The following IC were registered with these different compounds of the formula I: TABLE I Compound K^(in m mol/ml) A 0.63 ί 0.15 B 1.18 ± 0.50 C 0.51 - 0.14 A comparative test carried out, under the same conditions with sodium di-n-propylacetate gave a of 0.8 m mol/ml. This result shows that Compounds A and C are more active than sodium di-n-propylacetate in this test.

II Antianoxic activity Action on the antianoxic seizure induced by gallamine triiodoethylate The injection of a sufficient dose of a synthetic curariform substance such as gallamine triiodeoethylate 2o provokes paralysis of the diaphragm in mice. The animal then dies through asphyxia.

An intraperitoneal dose of the compound to be studied was administered to batches of 20 mice five minutes before the administration of 16 mg/kg of gallamine triiodo25 ethylate, by intraperitoneal route. The dose of the compound to be tested was calculated so that each batch received a 348 higher dose then the preceding batch.

The period of survival of the treated animals was noted in comparison with that of the controls which had not received the compound under Study. The period of time of survival was registered by measuring cardiac arrest by means of an electrocardiogram.

Under these conditions, an antianoxic effect produces an increase in the period of survival of the animal.

The following results were recorded with compounds of the invention.

TABLE li: Dose administered Compound in mg/kg % of increase in the period of survival in comparison with the controls A 360 60 C 250 73 A comparative trial undertaken with sodium di-npropylacetate, under the same conditions, showed that a dose of 330'mg/kg of this product increases by 40% the period of survival of the animals in comparison with the controls.

Table II hereabove shows that Compound C is appreciably more active than sodium di-n-propylacetate as antianoxic agent while at the doses studied Compound A appears to be slightly more active than sodium di-n-propylacetate. 111. Anticonvulsant activity This test is carried out on mice with a view to determining whether the compounds of formula I, when given preventively by intraperitoneal route, are capable at certain doses of protecting some of the animals against the epileptic seizure produced by a predetermined dose of pentylenetetrazole which would be 100% fatal in the absence of the compound.

The test was carried out on batches of 10 mice.

Each batch of animals received an intraperitoneal dose of the compound to be studied so that each batch received a higher dose then the preceding batch. Fifteen minutes after administration of the compound to be tested, the animals were each given 125 mg/kg of pentylenetetrazol by intraperitoneal route. The percentage of deaths was noted 3 hours after injection of this latter compound and the result was expressed as a percentage of protection.

The results obtained with compounds of formula I are given in the following Table: TABLE III Dose administered Compound in mg/kg A 160 B 185 of protection 100 A comparative trial performed with sodium di-npropylacetate under the same conditions showed that a dose of 250 mg/kg of this product protects 100% of the animals against the pentylenetetrazole^-induced seizure. 12948 These results indicate that Compound A is more active, in this test, than sodium di-n-propylacetate.

It was observed that Compound B exerts its action over a longer period of time than sodium di-n-propylacetate. Thus, 210 mg/kg of Compound B which offers about 100% protection against the pentylenetetrazole-indueed seizure, still protects 70% of the animals one hour after administration As against this, a dose of 250 mg/kg of sodium di-n-propylacetate only offers, in this test,' 20% protection of the animals, one hour after administration.

Furthermore, additional trials performed with compounds of formula I in accordance with the process described hereabove have shown that a dose of Compound A as low as 105 mg/kg administered by intraperitoneal route, offers 85% protection against the pentylenetetrazole-indueed seizure.

Similarly, it was found that a dose of 125 mg/kg of Compound B, also administered by intraperitoneal route, protects 65% of the mice against the pentylenetetrazoleindueed seizure.

IV. Acute toxicity Acute toxity was determined on mice. For this purpose, a dose of the compound to be tested was administered to batches of 5 mice, by intraperitoneal route, so that each batch received a higher dose than the preceding batch.

The following results were registered with the compounds of formula I. 4S948 Compound ΒΡ,-θ in mg/kg A 500 B 350 Furthermore, the LDQ of Compound A, namely the maximum tolerated dose (M.T.D.) or the highest dose which provokes no deaths amongst the trial animals was found to be greater than 400 mg/kg, by intraperitoneal route, in mice.

It will be appreciated that for therapuetic use the compounds of formula I will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the composition comprising as active ingredient at least one compound of the invention in association with a . pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hardor soft-gelatin capsule, a suspension or a syrup. The composition may alternatively take the form of a suppository for rectal administration, or of a solution or suspension for parenteral administration.

When in dosage unit form, the composition may contain from 200 to 500 mg of active ingredient per dosage unit for oral administration, from 400 to 1000 mg of active ingredient per dosage unit for rectal administration, or from 100 to 400 mg of active ingredient for parenteral adminstration.

The therapeutic compositions of the invention will _ 23 _ 4SS48 be prepared by associating at least one of the compounds of formula I with at least one appropriate carrier or excipient therefor. Examples of suitable carriers or excipients are talc, magnesium stearate, lactose, saccharose, colloidal silica, carboxymethylcellulose, starches, kaolin, levilite, mannitol, cocoa butter.

The following Examples illustrate the preparation Of the compounds of formula X together with a suitable therapeutic composition.

EXAMPLE 1 Preparation of sodium 3-n-propyl-hexanoate (a) 3-nc*-propyl-3-hydroxy-hexanoie acid In a 3-necked flask, an anion radical solution was prepared by mixing 128 g (1 mol) of naphthalene, 6.9 g. (1 mol) of lithium and 600 ml of tetrahydrofuran for 3 to 4 hours. The mixture was then cooled to between -10 and -15°C and 30 g (0.5 mol) of acetic acid for metalation dissolved in the same volume of tetrahydrofhran were added drop by drop. The reaction medium was heated to 50-60°C for 90 minutes. The dianion so formed was brownish-coloured. This mixture was then quickly added to 57 g (0.5 mol) of 4heptanone dissolved in 250 ml of anhydrous ether. The mixture so formed was refluxed for 90 minutes and then hydrolysed with a minimum of water. The alkaline layer was decanted and acidified. It was then extracted with diethyl ether, dried over anhydrous sodium sulphate and filtered.

The ether was evaporated out and the residue was distilled. -24. _ 4294S In this manner, 49.6 g of 3-n-propyl-3-hydroxyhexanoic acid were obtained in the form of a viscous liquid. Yield : 59% B.P. 108-110°C under 0.25 mmHg.

By following the same procedure as that described above but using the appropriate starting-products, the compounds listed hereunder were prepared: Compound 3-ethyl-3-hydroxy-pentanoic acid used in crude form (yield : 52%) 3-n-buryl-3-hydroxy-heptanoic acid used in crude form (yield : 35%) (b) 3-n-propyl-hexanoic acid The 3-n- propyl-3-hydroxy-hexanoic acid, obtained above, was refluxed in a flask with 248 g of acetic anhydride (1 g of acid for 5 g of anhydride) for 120 to 150 minutes. After this period of time, the excess anhydride was removed by means of a rotary evaporator. The mixture of ethylenic acids so obtained was mixed with 100 ml of distilled water for 30 to 60 minutes by heating under reflux. The mixture was then extracted with diethyl ether. The ethereal phases were dried over anhydrous sodium sulphate and the filtrate was evaporated. The residue so obtained, which was composed of the mixture of the isomeric acids was distilled and the higher fraction was discarded. The new residue so obtained comprised a mixture of 3-n-propyl-2-hexenoic and 3-a-propyl3-hexenoic acids. Then 15.6 g (0.1 mol) of the mixture of 3® isomeric ethylenic acids dissolved in 150 ml of absolute ethanol were placed in a bomb-apparatus maintained at a temperature of 100°C for 10 hours, under a pressure of 100 kg/cm and in the presence of about 10 g of Raney's nickel (i.e. a finely divided nickel catalyst obtained by dissolving out with alkali the aluminium from a nickelaluminium alloy). After cooling, the reaction mixture was filtered, the alcohol evaporated off and the residue was distilled.

In this manner, 3.6 g of 3-n-propyl-hexanoic acid were obtained in the form of a colourless, slightly viscous liquid, insoluble in water and soluble in the organic solvents.

Yield : 55% calculated from the mixture of ethylenic acids.

B.P. 131 °C under 15 mmHg By following the same procedure as that described hereabove, but with hydrogenation periods up to 20 hours and using the appropriate starting-products, the following compounds were prepared : Boiling point in °C 176 (760 mmHg) S5-87 (1 mmHg) . 130 (4 mmHg) Compound 3-methyl-butanoic acid 3-ethyl-pentanoic acid 3-n-buty 1-h eptanoi c acid (c) Sodium 3-n-propyl-hexanoate In a sufficient volume Of water, 0.1 mol of 3-npropyl-hexanoic acid was reacted with 0.1 mol of a sodium hydroxide solution in water. In this manner sodium 3-n26 2348 propyl-hexanoate was obtained.

EXAMPLE 2 Preparation of sodium 5-n-propyl-octanoate (a) 5-n-propyl-oetanol In. a flask, 150.4 g (0.8 mol) of 5-n-propyl-l,5octanediol (B.P. 142-144°C under 3 mmHg) were refluxed with 400 ml of acetic anhydride for 3 hours. The acetic acid so formed and the acetic anhydride in excess were distilled off and the residue so formed was refluxed for a further 30 minutes. The acetyl derivative so obtained was then hydrogenated at room temperature and in glacial acetic acid to which palladium/barium sulphate had been added. The reaction mixture was then filtered. The 5-n-propyl-l-octyl acetate (B.P. 108-110°C under 3 mmHg) contained in the filtrate was then saponified by adding a methanolic solution of potassium hydroxide.

In this manner, 5-n-propyl-oetanol was obtained boiling at 105°C under 0.1 mmHg. (b) 5-n-propyl-octanoic acid In a flask, 86 g (0.5 mol) of the 5-n-propyloctanol obtained above, were added drop by drop to a previously cooled solution of 191 g of chromic anhydride in 1.7 1 of glacial acetic acid containing 195 ml of water, care being taken to maintain the mixture at a temperature of 10 °C maximum. The reaction medium was then allowed to stand for about 2 hours at 0°C and 24 hours at room temperature. After this time, 8.5 1 of water were added 4294§ and the mixture was extracted with chloroform.

In this manner, 5-n-propyl-oetanoic acid was obtained boiling at 136°C under 3 mmHg.

By following the same procedure as that described above but using the appropriate starting-products, the compounds hereunder were prepared: Compound Boiling point °C 4-methyl-pentanoic acid 197 (750 mmHg) 4-n-propyl-heptanoic acid 106-107 (1 mmHg) (c) Sodium 5-n-propyl-octanoate In a sufficient volume of water, 0.1 mol of 5-npropyl-octanoic acid was reacted with 0.1 mol of a sodium hydroxide solution in water. In this manner, sodium 5-npropyl-octanoate was obtained.

EXAMPLE 3 Preparation of sodium 4-n-propyl-heptanoate In a flask, 17.2 g (0.1 mol) of 4-n-propylheptanoic acid, prepared as described in the above Example 2, were dissolved in a sufficient volume of water. After that 4 g (0.1 mol) of a sodium hydroxide solution in water were added and the mixture was evaporated to dryness.

The residue so obtained was rinsed with ethyl ether and maintained in a desiccator under vacuum.

In this manner, sodium 4-n-propyl-heptanoate was obtained. This product does not melt but decomposes when heated. 42348 EXAMPLE 4 Tablets containing the following ingredients were prepared in accordance with known pharmaceutical techniques: Ingredients mg per tablet Sodium 4-n-propyl-hexanoate 200 Mannitol 138 Corn starch. 120 Colloidal silica 24 Magnesium stearate 18 500

Claims (32)

1. A pharmaceutical or veterinary composition comprising as essential active principle at least one compound corresponding to the general formula : R-S-OMe wherein Me represents a pharmaceutically acceptable alkali metal atom and R represents the radical : CH-CH 2 - or C=CHin which R^ and Rg, which may be the same or different, each 10 represent an alkyl radical having from 1 to 4 carbon atoms, n is an integer of from 1 to 3 inclusive and Rg and R 4 , which are identical, each represent a straight-chain alkyl radical having from 1 to 4 carbon atoms, in association with a pharmaceutical carrier or excipient therefor other than 15 ordinary tap water or a common organic solvent.

2. A -pharmaceutical or veterinary composition comprising as essential active principle sodium

3. -methylbutanoate, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common 20 organic solvent. - 30 3. A phntonaceutical or veterinary composition comprising as essential active principle sodium 3-ethylpentanoate, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common 5 organic solvent.

4. A .pharmaceutical or veterinary composition comprising as essential active principle at least one compound corresponding to the general formula: R- 0 5 \ H CH-(CH„) -CH„-C-OMe ✓ 2 ΣΠ Z 10 wherein Rg and Rg, which are identical, each represent npropyl or n-butyl, m is 0, 1 or 2 and Me represents a pharmaceutically acceptable alkali metal atom, in association with, a pharmaceutical carrier or excipient therefor.

5. A pharmaceutical or veterinary composition comprising as essential active principle at least one compound corresponding to the general formula: n- c 3H 7 II n- c 3H^ CH(CH > m -CH 2 -C-0Me wherein Me represents a pharmaceutically acceptable alkali metal atom and m represnts 0, 1 or 2, in association with a pharmaceutical carrier or excipient therefor. - 31

6. A pharmaceutical or veterinary composition as claimed in claim 1, 4 or 5, wherein the salt is a lithium, sodium or potassium salt.

7. A pharmaceutical or veterinary composition comprising as essential active principle sodium 3-n-propylhexanoate, in association with a pharmaceutical carrier or excipient therefor.

8. A pharmaceutical or veterinary composition comprising as essential active principle sodium 3-n-bueyl heptanoate, in association with a pharmaceutical carrier or excipient therefor.

9. A pharmaceutical or veterinary composition comprising, as essential active principle sodium 4-n-propylheptanoate, in association with a pharmaceutical carrier or excipient therefor.

10. A pharmaceutical or veterinary composition comprising as essential active principle sodium S-n-prOpyloctanoate, in association with a pharmaceutical carrier or excipient therefor.

11. A composition as claimed in any preceding claim, wherein,the composition is in a dosage unit form. 3243948

12. A composition as claimed in claim 11, wherein the dosage unit is in a form intended for oral administration.

13. A composition as claimed in claim 11, wherein the dosage unit is in a form intended for rectal administration. 5

14. A composition as claimed in claim 11, wherein the dosage unit is in a form intended for parenteral administration.

15. A ph^Jhiaceutical composition substantially as described in the foregoing Example 4. 10

16. A method of treating central neurological disorders in a non-human subject in need of such treatment, comprising the administration to said non-human subject of an effective dose of at least one compound corresponding to the general formula: 15 R-C-OMe as defined in claim 1.

17. Alkanoic acid derivatives corresponding to the general formula: R_ 0 \ u CH-(CH 2 ) m -CH 2 -C-OMe 2o as defined in claim 4. 33 59 48

18. Alkanoic acid derivatives corresponding to the general formula : II CH-(CHg) m -CH 2 -C-OMe as defined in claim 5.

19. Alkanoic acid derivatives as claimed in claim 17 or 18, wherein the alkali metal is lithium, sodium or •potassium.

20.

21.

22.

23.

24. having Sodium 3-n-propyl-hexanoate. Sodium 3-n-bUty1-hept ano at e. Sodium 4-n-propy]rhep£anota.__, Sodium 5-n-propyl-octanoate. Process for preparing an alkanoic acid derivative the general formula: x · u CH -CH o -C-0Me / 2 R 6 in which R g , R g and Me are as defined in claim 4, wherein a mixture of ethylenic acids obtained by dehydrating a 0-hydroxy acid of the general formula: 34 48948 C-CH--C-OH /1 2 Rg OH wherein Rg and Rg have the same meaning as defined above, is hydrogenated under pressure in a solvent and in the presence of a catalyst, to obtain the acetic acid derivative 5 in free acid form which is then treated with an alkali metal hydroxide.

25. Process according to claim 24, wherein the solvent is ethanol.

26. Process according to claim 24 or 25, wherein the 10 catalyst is Raney's nickel.

27. Process according to claim 24, 25 or 26, wherein the dehydration is carried out by heating the β-hydroxy acid in the presence of acetic anhydride.

28. Process for preparing an alkanoic acid derivative having the general formula: '5 / R 6 a CH-(CHg) p -CH 2 -C-OMe wherein Rg and Rg, which are identical, each represent n propyl or n-butyl, £ represents 1 or 2 and Me represent a pharmaceutically acceptable alkali metal atom, which process comprises oxidizing an alcohol of the general formula 1 _3 5_ $

29. 48 \ CH-(CH 2 ) p -CH 2 -CH 2 0H wherein Rg, R g and £ have the meaning hereabove defined, in a solvent to obtain an acetic acid derivative in free acid form v.'hich is then treated with an alkali metal hydroxide. > 29. Process according to claim 28, wherein the oxidation is effected with chromic anhydride.

30. Process according to claim 28 or 29, wherein the solvent is acetic acid.

31. Process according to any one of claims 24 to 30, 0 wherein the alkali metal hydroxide is sodium hydroxide.

32. Process’ for preparing an alkanoic acetic acid derivative as claimed in claim 17 substantially as described in any of the foregoing Examples1, 2 or 3. 15 Applicants' 47 Merrion Square