SE500710C2 - Optically active oxo-isoindoline derivatives - Google Patents

Abstract

Optically active oxo-isoindolinyl compounds of formula (I> wherein R is C1-C4 alkyl; and R1 is hydrogen, C1-C4 alkyl or wherein n is 1 or 2 and each of R2 and R3, which may be the same or different, is hydrogen or C1-C4 alkyl, or physiologically acceptable salts thereof, are prepared by resolving a racemic compound of formula (II): into its optical isomers, to give an optically active compound of formula (II) as such or as a salt; reacting the said compound or salt with o-phthalic anhydride to give the corresponding optically active phthalimido compound; and reducing the optically active phthalimido compound. The product obtained can be esterified or salified as desired. The resultant optically active compounds, in particular that in which R is ethyl, exhibit platelet aggregation inhibiting activity.

Description

(Il CD \ Äl C._1 2 <5 -.

N CH-COOR \ G l / å 1 ~ (c) O in which R and RL have the meanings given above.

Thus, according to the prior art, an optically active compound of formula (A) can be prepared by: (i) reacting a racemic compound of formula (B) with o-phthalic anhydride to give the corresponding racemic phthalimido compound of formula (C), (ii ) reducing the resulting racemic phthalimido compound of formula (C) to give the corresponding racemic 1-oxo-Z-isoindoline compound of formula (A), and (iii) dividing the resulting racemic 1-oxo-2-isoindoline compound into the individual optical isomers with the formula (A).

It has now been found that said optically active 1-oxo-Z-isoindoline compounds of formula (A) can be prepared in a more advantageous manner according to a new process, characterized in that the optical division is carried out at an earlier stage in the synthesis of instead of at the end of the process, ie. on the end products. Thus, a first embodiment of the invention is a novel process for the preparation of an optically active compound of formula (i) wherein R represents a C 1 -C 5 alkyl group, and R 1 represents hydrogen, a C 1 -C 4 alkyl. alkyl group or - (CH 2) n N <- where n is 1 or 2 and each of R 2 and R 3, which may be the same or different, represents hydrogen or a C 1 -C 8 alkyl group, including salts of the compounds of formula (I) wherein RI denotes hydrogen with physiologically acceptable bases.

A second object of the invention is the optically active right-turning isomers of the above formula (I), in which R represents an ethyl group, which, as already mentioned, are not specifically identified in German patent application 22 58 088. 500 'HU 3 According to the new process , which is the first object of the invention, the optically active compounds of formula (I) are prepared by (a) dividing a racemic compound of formula (II) CH-COOR R where R and RI have the meaning given above, in its optical isomers to give an optically active compound of formula (II) as such or in the form of a salt, (b) reacting a thus obtained optically active compound of formula (II) as such or in the form of a salt of o phthalic anhydride to give an optically active phthalimido compound of formula (III) 0 \ (N fH-COORI an) 0 z. f R where R and RI are as defined above, and (c) reducing the optically active compound of formula (III) and if desired an optically active compound thus obtained with formula (I), in which R 1 represents hydrogen, to give a corresponding optically active compound of formula (I), in which R 1 represents a C 1 -C 4 alkyl group or the group defined above - (CH 2) n N or forming a salt of the same with a physiologically acceptable base to give a physiologically acceptable salt thereof.

In the above formula (I), the C 1 -C 6 alkyl group is preferably a methyl or ethyl group.

When R 1 is a group defined above - (CH 2) n -N 2, R 2 and R 3 are preferably both hydrogen or both of methyl groups. In formula (I), R preferably represents a methyl or an ethyl group and R 1 represents hydrogen, a methyl or ethyl group, in particular hydrogen. The salts of the compounds of formula (I) in which R 1 represents hydrogen with physiologically acceptable bases include, for example, salts with either physiologically acceptable inorganic bases such as, for example, alkali metal hydroxides, for example sodium or potassium hydroxide, alkaline earth metal hydroxides, for example calcium or magnesium hydroxide, physiologically acceptable organic m 4 bases, such as, for example, aliphatic, aromatic or heterocyclic amines, for example triethylamine, benzylamine or pyridine, or also dimethylethanol or amino acids such as, for example, lysine, arginine or betaine.

The term "right-turning" or "(*)" refers to a compound whose dilute solution (containing 0.1 to 1% of this compound) in dimethylformamide (DMF) or methanol (MeOH) or ethanol (EtO1-1) is clockwise at room temperature at a light wavelength of about 589 lum.

Correspondingly, the term "left-handed" or "(-)" means a compound whose diluted solution exhibits a negative twist under the same conditions.

Preferred optically active compounds of formula (I) are the "right-turning" or "(+)" isomers, since they exhibit greater biological activity than the "left-turning" or "(-)" isomers, in particular analgesic and anti-inflammatory activity. , as well as platelet aggregation inhibitory activity.

The new process according to the invention for the preparation of optically active 1-oxo-2-isoindoline compounds of formula (I), in which the optical division is carried out at an early stage of the synthesis, offers, as mentioned above, remarkable advantages especially from an economic point of view compared to the known method according to the prior art, where the optical division is carried out at the end of the synthesis, i.e. of the compounds of formula (II. J ') The step of resolving the final 1-oxo-2-isoindoline compounds of formula (I) is in fact fraught with at least the following considerable disadvantages.

First of all, the undesired isomer obtained by said optical division of racemic formula (U-compounds, i.e. the left-handed isomer can not be suitably returned to the process. Its recovery by racemization takes place in low yields, especially due to instability of oxo-2-isoindoline molecule with concomitant formation of decomposition products which are difficult to remove.Every racemic product that can be recycled lacks the required purity.Experimental division experiments have given unsatisfactory results in terms of yields and optical purity.

The consequence of this is that the undesired optical isomer, which comes from the partition carried out on the racemic formula (I) compound, is lost for the most part if not completely. This is a major cost disadvantage, considering the high proportion of desired, right-turning isomer lost along with the undesired isomer at the end of the decomposition process: see for example the decomposition yields reported in the working examples of the German patent application 22 58 088.

Furthermore, since the division is carried out on a compound of formula (I), in which RI represents hydrogen, it is further necessary to use an optically active base, and optically active bases are generally known to be very expensive, in particular bases of the kind indicated in the above-mentioned German patent application, ie alpha-methylbenzylamine, quinine, kinedine, quinchonine, cinchonidine, ephedrine, bruzine, morphine, yohimbine, benzedrine, mentylamine, alpha- (1-naphthyD-ethylarnin and 2-aminobutane.

In addition, a quantitative recovery of these expensive bases is generally impossible and this also has a significant effect on the cost of the final process.

The new process according to the invention is an advance over the known method, in that it allows most, if not all, of the above disadvantages to be overcome, thereby providing a much cheaper and industrially satisfactory process for the production of optically active 1-oxo-2-isoindoline compounds of formula (I).

The main advantage of the new method according to the invention is that the optical! the decomposition, which is carried out at a very early stage of the synthesis of the compounds of formula (II), allows almost quantitative recovery of the undesired isomer, which can be completely reversed: its racimization takes place in very high yields, since the compounds of formula (II) are completely stable under the conditions of racimization and no decomposition products are therefore formed.

According to the process of the invention, the undesired isomer is completely returned to the production cycle together with mother liquors from the production of the desired isomer, without lowering the yields and without the need for further purification.

The almost complete recovery of the undesired isomer largely allows for improved yields and reduced costs. A comparison between the respective yields indicates, taking into account the recovery of the undesired isomer, that the yield at the completion of the partition of the compounds of formula (II) will be at least twice as high as the yield at the partition carried out on the final compounds of formula (II). IN).

(YI Cl: I) 6 Furthermore, due to the almost complete recovery of the undesired isomer, it is obvious that the amount of formula (ID compound required for the process is significantly reduced and this leads to a considerable saving of formula (IU intermediate). as well as of starting materials and reagents used earlier in the synthesis for their preparation.

In addition, the optical partitioning of the compounds of formula (II) according to the process of the invention is preferably carried out by means of an optically active acid, such as, for example, optically active tartaric acid, mandelic acid, dibenzoyl tartrate or camphorsulfonic acid. Optically active acids are generally much cheaper than optically active bases - as a single example we can point to the case of (+) - tartaric acid, which costs at least ten times less than (+) - alpha-methylbenzylamine - and vice versa to the optically active bases, they can be recycled quantitatively and this makes an additional contribution to reducing costs.

According to the process of the invention, the optically active compounds of formula (II) are obtained in a very high optical purity and no loss of optical activity is observed in the subsequent synthesis steps.

From the above it is clear that the new process according to the invention is considerably more advantageous than the process closest to the prior art for the preparation of optically active compounds of formula (I), since it offers better yields and lower costs and at the same time constitutes an industrially satisfactory method. .

It provides a more economical and industrially advantageous way of synthesizing optically active 1-oxo-Z-isoindoline compounds of formula (I).

The partitioning step (a) in the process according to the invention is preferably carried out as previously mentioned by means of an optically active acid, selected for example from optically active tartaric acid, mandelic acid, dibenzoyl tartrate and camphorsulfonic acid.

The racemic compound of formula (II) is reacted with the optically active acid, for example one of the above, in a suitable solvent such as, for example, water, an aliphatic alcohol, for example methanol, ethanol or isopropanol, acetone, acetonitrile or methyl ethyl ketone at a temperature which can vary between room temperature and around 100 ° C during reaction times ranging from, for example, a few minutes up to 21+ hours.

L (+) - tartaric acid is a particularly preferred acid and water is a particularly preferred solvent. The resulting optically active salts are separated from their mixtures by conventional means, for example by filtration or centrifugation or by fractional crystallization, and the isolated, desired, optically active salt is despaired either to liberate the corresponding optically active amino compound of formula (II). ) or used as such for the subsequent reaction with g-phthalic anhydride according to step (b).

The saponification can be carried out, for example, with an alkali metal hydroxide, for example sodium or potassium hydroxide, operating in aqueous medium at a temperature from about room temperature to about 30-40 ° C. Although the optical division of the compounds (II) as mentioned above is preferably carried out by using an optically active acid, in the case of compounds which RI represents hydrogen, nevertheless, if desired, said division can also be carried out with an optically active base, for example a of those previously mentioned in this specification, although this is less advantageous. In this case, the release of the formula (II) compound from the corresponding optically active salt is effected by acid treatment, for example by reaction with hydrochloric acid in aqueous medium according to customary procedures.

All parent liquors from the preparation of the desired isomer are pooled and subjected to racimization to recover and recycle the unwanted isomer together with any undivided product present. The racimization is preferably carried out by alkali treatment, the alkali metal hydroxide being preferably used as the base, such as, for example, concentrated sodium or potassium hydroxide, the aqueous medium being operated at elevated temperature, for example at the boiling point of the solvent. The recycled racemic formula (ID compound) is then returned to the production cycle.

When a salt of the optical isomer of formula (II) is used for reaction with o-phthalic anhydride, the salt already mentioned is the same salt which comes from the partitioning step (a), i.e. according to a preferred process, the salt of the acid, for example L (+) - tartaric acid, which is used to divide the racemic formula (ID compound).

The reaction between the desired optical isomer of formula (II), which comes from step (a) and β-phthalic anhydride, according to process step (b), can be carried out in a polar, preferably aqueous, solvent such as, for example, water or acetic acid, by heating to a temperature that can vary between, for example, about 50 ° C and about 160 ° C.

The reduction of an optically active compound of formula (II) according to process step (c) may be carried out with a suitable reducing agent, which may for example be preferably zinc and formic acid or zinc and acetic acid, preferably operating under a nitrogen atmosphere at a temperature between about 60 ° C and about 160 ° C, preferably at reflux, following the known procedures described in organic chemistry for this type of reduction.

The optically active compound of formula (I) obtained can be purified in a customary manner, for example by crystallization from a suitable solvent, which may be, for example, an aliphatic alcohol such as ethanol.

Conventional procedures can also be followed for the possible esterification of an optically active compound of formula (I), in which R 1 represents hydrogen, to give the corresponding compound, wherein R 1 represents a C 1 -C 4 alkyl group or a group defined above - ( CH2) nN <â2 as for the salt formation with an optically active compound of formula (I). The starting racemic compounds of formula (II) are known compounds or can be prepared according to known methods from known compounds. For example, they can be prepared by reduction of the corresponding nitro derivative according to known methods, for example by hydrogenation at about room temperature of 5% palladium / carbon to give an inert solvent such as, for example, a C1-C8 aliphatic alcohol, for example methanol, ethanol, water or glacial acetic acid.

Said nitro compounds consist of known compounds or can be prepared according to known methods from known compounds.

As already mentioned, a second object of the present invention is the optically active right-turning isomers of the above-mentioned formula (I), in which R represents an ethyl group, including physiologically acceptable salts thereof.

A preferred compound within the scope of this class is the compound (+) 2- (1 + - (1-oxo-2-isoindolinyl) phenyl) butyric acid (right-turning isomer) and physiologically acceptable salts thereof.

An object of the invention is also the optically active phthalimido compounds, in particular the right-turning isomers, of the above-mentioned formula (III).

The optically active compounds of formula (I) obtained according to the novel process of the invention show, in addition to good analgesic and anti-inflammatory activity, also high platelet aggregation inhibitory activity, in particular the class of compounds of formula (I ), in which R represents an ethyl group. The platelet aggregating activity of these compounds is obtained in extremely low doses compared not only with compounds with different chemical structure but also compared with the racemic compounds with the same structure.

Platelet aggregation inhibition data, shown in the following table, clearly show, for example, the biological superiority of the optically active compound of the invention, namely (+) 2- (4- (1-0xo-2-isoindolinyl) -phenyl) butyric acid compared to the corresponding racemic compound, which for example, is described in U.S. Patent No. 1,010,274. Tabulated data have been obtained by evaluating the inhibitory effect of tested compounds on platelet aggregation induced by 2 mcg / ml collagen on guinea pigs and human platelet-rich plasma (PRP), respectively.

The platelet aggregation inhibitory effect is expressed as ED30 values, i.e. the dose that produces a 30% inhibition of the induced aggregation compared to the control group.

TABLE, Inhibition of collagen-induced platelet aggregation on guinea pigs and human PRP Compounds ED30 (mcg / ml) Guinea pig PRP Human PRP (+) 2- (4- (1-oxo-2-isoindolinyl) phenyl) butyric acid 1.68 1.29 (i) 2 - (# - (1-oxo-2-isoindolinyl) phenyl) butyric acid 3.37 2.43 In view of their antiaggregating activity, the optically active compounds of the invention, in particular the compounds of formula (I ), in which R represents an ethyl group, may be useful for the prevention and treatment of occlusive ischemic arterial diseases of the cerebral circulation, coronary circulation or the peripheral circulation, in particular they may be used, for example, in the treatment of intermittent claudication.

They may also be useful for maintaining openness after shunt transplantation, endoarterectomy, percutaneous transluminal angioplasty, (51 (I) 10 for prophylaxis in venous thromboembolism and for antithrombotic activity in extracorporeal circulation.

The compounds of the invention may be administered by the use of conventional therapeutic preparations including sustained release formulations. They are preferably administered orally. Preferred pharmaceutical compositions therefore consist of tablets, capsules, pills and the like, in which the active component is mixed with common solid excipients, such as, for example, talc, starch stearic acid, magnesium stearate, cellulose and the like.

Daily doses suitable for oral administration to humans may vary for adults between about 25 mg and about 200 mg. The compounds are preferably taken twice daily.

The toxicity of the compounds of the invention at the therapeutic doses is very low, so that they can be used safely in therapy.

The following exemplary embodiments illustrate but do not limit the invention in any way.

The abbreviation DMF denotes dimethylformamide.

Example 1 A mixture of (I) 2- (4-aminophenyspropionic acid (1ß, 34 g) and L (+) - tartaric acid (3.9l + g) in deionized water (26.0l + g) was heated for ten minutes with stirring at 80 g. After complete dissolution of the solid, the solution was allowed to cool on its own to room temperature with stirring and then stirred for a further 21+ hours, the temperature was brought to 20 ° C, the precipitated left-handed tartrate (A) was separated by centrifugation and added The solution containing the right-turning tartrate was concentrated in vacuo at 40-45 ° C. After bringing the temperature to 30-32 ° C, sodium hydroxide of 35 Be (1.01 + g) was added over ten minutes. The mixture is stirred at 30 ° C for 30 minutes and centrifuged to collect the precipitate, which is washed with cold water and dried to give (+) 2- (4-aminophenyl) propionic acid (1.36 g), melting point: 17z-i74 ° c, (onåo + 73, a ° (c = o, 1%, ston).

The mother liquors from the centrifugation and washing of the right-turning acid are combined with the left-turning tartrate (A) and water (13 g). Raised lime (3.8 g) is added to the mixture and the suspension is heated to 50 ° C and kept at this temperature for 4.5 hours. The hot suspension is centrifuged to remove the precipitated calcium tartrate, which is washed with 500 [mu] l of water at room temperature. The mother liquors from centrifugation and washing are combined and sodium hydroxide of 35 Be (10.0 g) is added. The reaction mixture is brought to reflux and after some water (214 g) has been removed by distillation, it is kept at reflux for 22 hours.

After cooling to a temperature between 0 and 5 ° C, 32% hydrochloric acid is added to reach a pH of 14.3. The suspension is brought to 15-20 ° C and centrifuged. The precipitate is washed with water and dried to give 2.52 g of recovered racemic (in 2- (4-aminophenylpropionic acid, m.p. 146-148 ° C).

Example 2 Phthalic anhydride (3.56 g) and (+) 2- (4-aminophenyl) propionic acid (3.78 g) are added in this order to glacial acetic acid (17 g) with stirring.

After refluxing for eight hours at 18 DEG C. with stirring, the reaction mixture is allowed to cool on its own to room temperature and is then stirred for a further 2 hours at 20 DEG C. The suspension is centrifuged and the precipitate is thoroughly washed with water and dried at 70 ° C in vacuo to give (+) 2- (4- (1,3-dioxo-2-isoindolinyl) phenyl) propionic acid (5.8l + g), m.p. 234 - 236 ° C, (GUD + 68 ° (c = 1%, DMF).

Example 3 To 99% formic acid (37.5 g) are added in the following order 85% zinc powder (3.25 g) and (+) 2- (1 + - (1,3 dioxo-2-isoindolinyl) phenyl) propionic acid (2.5 g) with stirring and nitrogen atmosphere. After refluxing for eight hours, the reaction mixture is cooled to 60 ° C and formic acid is removed by distillation. The residue is taken up in a sulfuric acid solution, prepared from water (25 g) and 96% sulfuric acid (5.6 g), and the resulting suspension is heated to 50 ° C for 30 minutes with stirring and a nitrogen atmosphere. After cooling, the mixture was centrifuged. The precipitate was washed repeatedly with water, slurried in deionized water (30 g) and dissolved by treatment with sodium hydroxide of 35 Bè with stirring to pH 12. After heating to 50 ° C, 20% (NH 4) 2 S (1 ml) is added. ) and the precipitate is filtered in vacuo. To the filtered solution is added 99% formic acid with stirring until a pH of 3.5-4 is reached. The resulting suspension is centrifuged, the precipitate is washed repeatedly with deionized water and dried in vacuo at 70 ° C to give 2.2 g of crude product, which after crystallization in 9596 g of ethanol gives pure (+) 2- (4- (1 -oxo-2-isoindolinyl) phenyl) -propionic acid (2 g), m.p. 207-208 ° C, b + 507.410 (c = 1%, DMF). Example 4 A suspension of (i) Z- (aminophenylbutyric acid (100 g) and L (+) - tartaric acid (83.7 g) is heated to reflux in anhydrous ethanol (2000 ml) until complete dissolution and the resulting salt is allowed to crystallize under one day at room temperature The precipitate is filtered and recrystallized from anhydrous ethanol The salt obtained is dried in vacuo at 50 ° C to give 70 g of right-turning tartrate, (o:) É0 + 57 ° (c = 1%, DMF). release the optically active acid, the salt is slurried in water and then sodium hydroxide is added to a pH of about 4-5 The resulting suspension is filtered and the precipitate is washed with water and dried in vacuo at 60 ° C to give (+) Z- (1β-aminophenyl). ) butyric acid (35 g), m.p. 175-185 ° C, (Gda + 75 ° (c = 0.1%, MeOH).

All the mother liquors from the original filtration and recrystallizations of the tartrate are combined and evaporated to dryness in vacuo.

The resulting solid residue is dissolved in water (600 ml, 5 vol.) And calcium hydroxide (# 0 g) is added. The suspension is heated with stirring to 50 ° C. After 5 hours, precipitated calcium tartrate is filtered off and L (+) - tartaric acid is recovered by acidification and recycled. The filtered aqueous solution is treated with 35% sodium hydroxide (200 g), evaporated at atmospheric pressure to half volume and then heated under reflux.

After 214 hours, the solution is acidified and the precipitate is collected by filtration, washing with water and dried in vacuo at 60 ° C to give 50 g of recovered racemic (I) Z- (11-aminophenyl) butyric acid, melting point 143-iuwc, ° (c = 0.196, MeoH).

Example 5 A mixture of phthalic anhydride (8.5 g) and (+) 2- (4-aminophenyl) - butyric acid (9 g) in glacial acetic acid (140 ml) is heated under reflux for 8 hours and then cooled to about 20 ° C. The resulting precipitate is filtered, washed with water (100 ml) and dried in vacuo at 50 ° C to obtain (+) 2- (4- (1,3-dioxo-Z-isoindolinyl) phenyl) butyric acid (13, # g ), mp 234-237 ° C, (ME + 710 (c = 1%, DMF).

Example 6 A mixture of o-phthalic anhydride (12.8 g), 35% sodium hydroxide (15 g) and (+) Z- (10-aminophenylbutyril tartrate (12.7 g) is heated to reflux for 6 hours and cooled then to about 50 ° C. The resulting 500 TH) 13 precipitate is filtered, washed with water of 50 ° C (100 ml) and dried in vacuo at 50 ° C to obtain (+) 2- (4- (1.3 (1.3))). -dioxo-2-isoindolinyl) phenyl) butyric acid (10 s), lubricating point: zaa-zawc, (onso + 710 (c = 1%, DMF).

Example 7 To a solution of (+) 2- (4- (1β-dioxo-Z-isoindolinyl) phenyl) butyric acid (11 g) in 99% formic acid (200 ml) is added zinc powder (18 g) with stirring.

The mixture is heated to reflux for 8 hours and then evaporated in vacuo to dryness. The residue is slurried in dilute sulfuric acid (125 ml) and stirred. The solid product obtained after filtration is slurried in water (150 ml) and dissolved by adding dilute sodium hydroxide to pH 12. After removal of the heavy metals by treatment with 20% (NH 4) 2 S, the solution is acidified to pH 4.5 with formic acid and the precipitate thus obtained is filtered, washed with water and dried in vacuo at 70 ° C.

The crude product is crystallized from ethanol (85 ml, 8 vol.) To give (+) 2- (1 + - (1-oxo-2-isoindolinyl) phenyl) butyric acid (8.2 g), m.p. 97-198 ° C, ( oaâo + s3 ° (c = 1%, DMF).

Example 8 Tablets, each weighing 0.150 g and containing 25 mg of active substance, can be conveniently prepared as follows: Composition for 10 000 tablets: (+) 2- (4- (1-oxo-Z-isoindolinyl) phenyl) butyric acid 250 g Lactose 800 g Corn starch # 15 g Talcum powder 30 g Magnesium stearate 5 g (+) Z- (Q- (1-oxo-Z-isoindolinyl) phenyl) butyric acid, lactose and half the amount of corn starch are mixed. The mixture is then forced through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is slurried in hot water (90 ml) and the resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve with a 1.4 mm mesh opening, after which the remaining amount of starch, talc and magnesium stearate is added, mixed thoroughly and processed into tablets.

Claims (20)

/ ï PATENT REQUIREMENTS 1. A process for the preparation of an optically active compound of the formula (I) CH-COOR: Car (I) f | 1 -_ 0 =. R in which R represents a C 1 -C 4 alkyl group, and R 1 represents hydrogen, a C 1 -C 4 alkyl group or a group - (CH 2) n N 10, in which II is 1 or 2 and each of R 9 and R 3, which may be the same or different, represents hydrogen or a C 1 -C 4 alkyl group, or a physiologically acceptable salt thereof, which process comprises: (a) that a racemic compound of formula (II) E NÜCH-coonl (II) 2 IR in which R and R 1 have the meaning given above, are divided into their optical isomers to give an optically active compound of formula (II) as such or in the form of a salt, (b) to give an optically active compound of formula (II) thus obtained II) is reacted as such or in the form of a salt with g-phthalic anhydride to give an optically active phthalimido compound of formula (III) O, m, / OR 500 710 .o / 3 where R and R 1 have the meaning given above, and (c) reducing the optically active compound of formula (III) and, if desired, obtaining an optically active compound of formula (I) in which R hydrogen, esterified to give a corresponding optically active compound of formula (I), in which R 1 represents a C 1 -C 4 alkyl group or a group defined above - (CH 2) n N or that it is converted into a salt by means of a physiologically acceptable base to give a physiologically acceptable salt thereof. A process according to claim 1, in which the racemic compound of formula (II) is resolved by means of an optically active acid in step (a). A process according to claim 2, wherein said acid is optically active tartaric acid, mandelic acid, dibenzoyl tartrate or camphorsulfonic acid. A process according to any one of the preceding claims, in which R represents a methyl or ethyl group and R 1 represents hydrogen in the racemic compound of formula (II) used in step (a). A process according to any one of the preceding claims, in which the right-turning isomer of formula (II) is separated in step (a) for use in step (b). A process according to any one of the preceding claims, in which the isomer of formula (II), which is separated in step (a) and not required for use in step (b), is racemized and recycled for use in step (a). A process for the preparation of an optically active compound of formula (I) according to claim 1, or a physiologically acceptable salt thereof, which process comprises reducing an optically active compound of the formula (III) defined in claim 1 and, if desired , an optically active compound of formula (I) thus obtained, in which R 1 represents hydrogen, is esterified to give a corresponding optically active compound of formula (I), in which R 1 represents a C 1 -C 4 alkyl group or a in group I (CI-I2) nN defined or that it is transferred to a salt by means of a physiologically acceptable base to give a physiologically acceptable salt thereof. _ A process according to claim 7, in which R represents a methyl or ethyl group and R 1 represents hydrogen in the compound of formula (III). A method according to any one of claims 1 to 8, further comprising preparing the product thus obtained with an inert carrier or excipient. (ri / b A process for the preparation of an optically active compound of the formula (III) defined in claim 1, which is an intermediate in the process, which comprises reacting an optically active isomer of the formula (II) defined in claim 1 with g- phthalic anhydride. An optically active right-turning isomer of the formula (I) according to claim 1, which can be prepared by the process according to any one of claims 1 to 9, in which R represents an ethyl group, and physiologically acceptable salts thereof. A right-turning isomer according to claim 11, which consists of the compound (+) 2- (4- (1-oxo-2-isoindolinyl) phenyl) butyric acid and physiologically acceptable salts thereof. A pharmaceutical composition comprising an inert carrier or excipient and, as active substance, a right-turn isomer of the formula (I) defined in claim 1, obtainable by the process according to any one of claims 1-9, in which R represents an ethyl group, or a physiologically acceptable salt thereof according to claim 11 or 12. A pharmaceutical composition according to claim 13 for use as a platelet aggregation inhibitor. A pharmaceutical composition according to claim 14 for use in the treatment of claudication intermittent. A right-turn isomer of the formula (I) defined in claim 1, which can be prepared by the process according to any one of claims 1-9, in which R represents an ethyl group, or a physiologically acceptable salt thereof according to claim 11 or 12 for use as a platelet aggregation inhibitor. A right-turning isomer of formula (I) according to claim 16 for use in the treatment of cladication intermittent. An optically active intermediate, produced by the process according to any one of claims 1-10 of the formula (III) defined in claim 1, in which R represents an ethyl group. Use of a right-turn isomer of the formula (I) defined in claim 1, in which R represents an ethyl group, or a physiologically acceptable salt thereof according to claim 11 or 12, for the preparation of a pharmaceutical composition for use as a platelet aggregation inhibitor . Use of a right-turning isomer of formula (I) according to claim 19 for the preparation of a pharmaceutical composition for use in the treatment of cladication intermittent.