NL8800575A - OPTICALLY ACTIVE OXO-ISOINDOLINYL DERIVATIVES. - Google Patents

Description

N.0. 35011 / "" "S.

*

Optically active oxo-isoindolinyl derivatives.

The invention relates to a method of preparing optically active oxo-isoindolinyl derivatives.

British Pat. No. 1,344,663 relates to 1-oxo-2-isoindolinyl compounds of formula 1, wherein R is hydrogen or C 5-5 Chalkyl 1, R 1 is hydrogen, C 1 -C 4 alkyl or a group - (CH 2) 1 5 where η is 1 or 2 and R2 and R3 are independently hydrogen or C1-4 alkyl.

In that patent, only racemic compounds are described and no optically active derivatives are indicated.

German patent application 2,258,088 generally discloses optically active isomers of the above formula. However, only optical isomers of formula 1, in which R is methyl and R 1 is hydrogen, are expressly mentioned and indicated. In this German patent application it is said that the optically active compounds are prepared as described for the racemic compounds in the Belgian patent 774,895 corresponding to the aforementioned British patent 1,344,663.

According to one of the synthetic routes mentioned in British Pat. No. 1,344,663, the racemic compounds of formula 1 can be prepared by reacting o-phthalic anhydride with the desired racemic p-aminophenylacetic acid derivative of formula 2, wherein R and Rj have the aforementioned meanings followed by reduction of the obtained racemic phthalimido compound of formula 3, wherein R and R 1 are as previously defined.

Thus, the prior art teaches that an optically active compounds of formula 1 can be prepared by: (i) reacting a racemic compound of formula 2 with o-phthalic anhydride to form a racemic phthalimido compound of formula 3; (Ii) reduction of the obtained racemic phthalimido compound of formula 3 to form the racemic 1-oxo-2-isoindolinyl compound of formula 1; and (iii) cleavage of the obtained racemic 1-oxo-2-isoindolinyl compound into the individual optical isomers of formula 1.

It has now been found that the same optically active 1-oxo-2-isoindolinyl compounds of formula 1 can be more advantageously prepared according to a new method characterized in that the splitting in optical antipodes occurs at an earlier stage of the synthesis and. 8 8 e C l 7 5 2 not at the end of the process, i.e. at the final products.

Accordingly, a first object of the invention is a new process for the preparation of an optically active compound of formula 1 wherein R is C 1 -alkyl and hydrogen, C 1 -C 2 -alkyl or "^ CH 2" n "NR 2 R 3 15> wherein η is 1 or 2 and R 2 and R 3 are independently hydrogen or C 1 -C 6 alkyl, as well as the salts of the compounds of formula 1 with R 2 equal to hydrogen with physiologically acceptable bases.

A second object of the invention is the optically active right-turning isomers of the formula 1, wherein R is ethyl, which, as already mentioned, are not disclosed as such in German patent application 2,258,088.

According to the method of the invention, the optically active compounds of formula 1 are prepared by (a) cleavage of a racemic compound of formula 2, wherein R and Rj have the above meanings, in the optical isomers to form an optically active compound of formula 2 as such or as a salt; (B) reaction of an optically active compound of formula 2 thus obtained, as such or as salt, with o-phthalic anhydride to form an optically active phthalimido compound of formula 3, wherein R and Rj have the above meanings; and (c) reduction of the optically active compound of formula 3, and, if desired, esterification of an optically active compound of formula 1 obtained thereby, wherein R 1 is hydrogen; to form an optically active compound of formula 1, wherein R 1 is C 1 -C 2 alkyl or - ((^ 2), - ^ 2 ^ 3 as described above or, if desired, salt formation with a physiologically acceptable base to form a physiologically acceptable salt.

In formula 1, the group R is preferably methyl or ethyl.

When R 1 is a group - (CH 2) n-NR 2 R 3, R 2 and R 3 are preferably both hydrogen atoms or both methyl groups. Preferably R 1 is hydrogen, methyl or ethyl and most preferably it is hydrogen.

Salts of compounds of formula 1 wherein R 1 is hydrogen with physiologically acceptable bases are, for example, the salts with physiologically acceptable inorganic bases, such as the hydroxides of alkaline. β ε? o ü η * 3 Limetals, such as sodium or potassium, of alkaline earth metals, such as calcium or magnesium, or physiologically acceptable organic bases, such as aliphatic, aromatic or heterocyclic amines, for example triethyl amine, benzylamine or pyridine or also dimethylaminoethanol 5 or amino acids, such as for example lysine, arginine or betaine.

The term "clockwise rotation" or "(+)" means a compound of which a dilute solution (containing 0.1 to 1% of that compound) in dimethylformamide (DMF), methanol (MeOH) or ethanol (EtOH) is at room temperature. shows positive rotation of light with a wavelength 10 of about 589 µm.

Likewise, the term "counterclockwise" or a compound which exhibits a negative rotation under the aforementioned conditions.

Preferred optically active compounds of formula 1 are the right-turning isomers because they exhibit a stronger biological activity than the left-turning isomers, especially in terms of analgesic and anti-inflammatory activity, and also the inhibitory action on platelet clotting.

The method according to the invention in which the cleavage in optical antipodes takes place at an early stage of the synthesis has, as already mentioned, important advantages, especially from an economic point of view, compared to the known method in which the separation at the end of the synthesis, i.e. with the products of formula 1, is carried out.

Cleavage in antipodes of the compounds of formula 1 has, inter alia, the following minor drawbacks.

First and foremost, the undesired isomer resulting from the separation of racemic compounds of the formula I, i.e. the right-turning antipode, cannot simply be recycled into the process; conversion to usable material by racemization proceeds only in low yield, mainly due to the instability of the Compound accompanied by the formation of decomposition products which are difficult to remove. What can be gained from racemic product is not clear. Attempts to separate again into optical antipodes do not have the desired result from the viewpoint of yield and optical purity.

As a result, the undesired optical isomer obtained in the separation of the racemic compounds of the formula I is largely or even completely lost. From a cost point of view, this is a major drawback given the high percentage of desired right-handed isomer 40 that at the end of the cleavage process with the unwanted isomer. β $ η · ϊί? 5 Λ 4 * is lost: see, for example, the separation yields mentioned in the examples of German patent application 2,258,088.

Furthermore, since the cleavage is performed on a compound of formula 1, wherein R 1 is hydrogen, the use of an optically active base and optically active bases are known to be generally very expensive, especially the kind of bases which the aforementioned German patent application mentions, namely a-methylbenzyl-amine, quinine, quinidine, cinchonine, cinchonidine, ephedrine, brucine, morphine, yohimbine, benzedrine, menthylamine, 1- (l-naphthyl) -ethylamine and sec- butyl amine.

In addition, complete recovery of those expensive bases is generally impossible, and this also adds up to significant process costs.

The process of the invention obviates most if not all of the above-mentioned drawbacks and provides a much cheaper and industrially satisfactory process for the preparation of optically active 1-oxo-2-isoindolinyl compounds of formula 1.

The main advantage of the method according to the invention is that by performing the separation of optical antipodes at a very early stage of the synthesis, on the compounds of formula 2, an almost complete recovery of the undesired isomer and therefore a complete reuse thereof it is possible: the racemization proceeds in very high yield because the compounds of formula 2 are otherwise stable under racemization conditions in other respects and thus no decomposition products are formed.

According to the method of the invention, the undesired isomer as a whole is re-introduced into the production cycle along with residual water from the work-up of the desired isomer, without reducing yield and without the need for further purification.

The virtually complete reuse of the undesired isomer greatly improves the yield and significantly reduces costs. It has been found that when the reuse of the undesired isomer is taken into account, the yield of the separation of the compounds of the formula II is ultimately at least twice the yield of the separation of the products of the formula 1.

Furthermore, it is clear that due to the almost complete recovery of the undesired isomer, the amount of the compound 40 of formula II required is considerably reduced, thereby saving proportionally. 8 6 0 00 5 * on starting materials and reagents used for the preparation of this compound of formula 2.

Furthermore, the enantiomeric separation of the compounds of formula II according to the invention is preferably carried out using an optically active acid, such as, for example, optically active tartaric acid, mandelic acid, dibenzoyl tartaric acid or camphor sulfonic acid. As is known, optically active acids are generally much cheaper than optically active bases - for example, (+) - tartaric acid is at least ten times cheaper than (+) - o-methylbenzyl amine - and in addition, these acids, in contrast to the optically active bases , be quantitatively recovered which is a further contribution to cost reduction.

According to the method of the invention, the optically active compounds of formula 2 are obtained in very high optical purity and no loss of optical activity is observed in the following preparation steps.

It will now be appreciated that the process of the invention offers significant advantages over the most related known process for preparing optically active compounds of formula 1 because of the better yields and lower costs, while at the same time, satisfactory from an industrial point of view.

In the separation step (a) of the process according to the invention, the racemate of formula 2 is, as mentioned, treated with an optically active acid, such as one of the aforementioned acids, in a suitable solvent such as, for example, water, an alkanol, such as methyl ethyl or isopropyl alcohol, acetone, acetonitrile or methyl ethyl ketone at a temperature, for example, between room temperature and 100 ° C, at reaction times ranging from a few minutes to 24 hours.

L (+) - Tartaric acid is particularly preferred, and the preferred solvent is water.

The resulting optically active salts are separated from the mixture in a known manner, for example, by filtration or centrifugation, or by fractional crystallization, and the desired isolated optically active salt is either saponified to form the optically active amino compound of formula 2 or as treated in step (b) with o-phthalic anhydride.

The saponification can take place in a known manner, for example with an alkali metal hydroxide in an aqueous medium at a temperature between about room temperature and 40 ° C.

Although the enantiomeric separation of the compounds of formula 75 6 2 preferably takes place by means of an optically active acid, if desired, compounds of formula 2 in which R 1 is hydrogen can also be separated, albeit with less advantage, by means of an optically active base like any of the aforementioned. In this case, the compound of formula II is released from the optically active salt by treatment with acid in a known manner.

All residual liquids obtained from working up the desired isomer are combined and racemized to recover and reuse the undesired isomer as well as any unseparated product still present.

The racemization is preferably carried out by treatment with base, preferably with an al potassium hydroxide such as concentrated sodium or potassium hydroxide, in an aqueous medium at an elevated temperature, for example at the boiling point of the solvent.

The recovered racemized compound of formula 2 is then recycled into the production cycle.

When a salt of the optical isomer of the formula II is used in the reaction with o-phthalic anhydride, this salt is, as said, the salt originating from the separation step (a), so according to the preferred embodiment, the salt with the racemate cleavage acid, such as L (+) - tartaric acid.

The reaction between the desired optical isomer of formula 2 from step (a) and o-phthalic anhydride in step (b) can take place in a polar, preferably aqueous, solvent such as water or acetic acid at an elevated temperature, for example between 50 and 160 ° C.

The reduction of the optically active compound of formula 3 in step (c) can be effected with a suitable reducing agent, preferably zinc and formic acid or zinc and acetic acid, preferably under nitrogen at a temperature between about 60 and 160 ° C, preferably at The boiling point of the solvent is operated according to the usual methods for this type of reduction.

The optically active compound of formula 1 obtained can be purified in the usual manner, for example by crystallization from a suitable solvent, for example an alkanol such as ethanol. Also for the optional esterification of an optically active compound of the formula 1 wherein hydrogen is, to form a compound wherein R | is a C 1 -C 2 alkyl group or a group - (CH 2) n -NR 2 R 3, with the meanings indicated above for R 2 and R 3, as well as for the salt formation of compounds of formula 40 1, the known procedures can be followed.

81 D- 7

The racemic compounds of the formula II used as starting materials are known compounds or can be prepared from known compounds by known methods. For example, they can be prepared by reduction of a corresponding nitro compound, for example, by hydrogenation at room temperature on 5% palladium / carbon in an inert solvent, such as methanol, ethanol, water or acetic acid.

These nitro compounds are also known compounds or can be prepared from known compounds by known methods.

The invention also relates to the optically active right-handed isomers of formula 1 wherein R is ethyl, as well as to its physiologically acceptable salts.

Within this group, a preferred compound is the (+) a- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (clockwise rotation) with its physiologically acceptable salts.

The invention also relates to the optically active phthalimido compounds, in particular the right-handed isomers, of the formula III.

The optical active compounds of the formula 1 obtained according to the method of the invention not only have a good analgesic and anti-inflammatory effect, but also, and this applies in particular to the group of compounds of the formula 1, in which R is ethyl, a strong inhibitory effect on platelet aggregation. This anti-clumping activity of the compounds is already obtained at very low dosages, not only compared to compounds of different chemical structure but also to racemic compounds of the same structure.

For example, the platelet aggregation inhibition data listed in the table below clearly demonstrates the superiority of the optically active compound of the invention 30 {+) a- [4- {1-oxo-2-isoindolinyl) phenyl] butyric acid of the corresponding racemic compound, which is described, for example, in U.S. Pat. No. 4,010,274. The data in the table was obtained by determining the inhibitory effect of the tested compounds on the platelet clot induced by 2 mcg / ml collagen in platelet rich plasma (PRP) from guinea pigs and human, respectively.

The inhibitory effect on clotting is expressed as EDgg value, i.e. the dose causing 30¾ inhibition of the induced clotting relative to the control.

. S C V V 7 L> b 8 v

TABLE

Inhibition of collagen-induced platelet clumping in guinea pig and human PRP Compounds ED30 (mcg / ml)

Guinea pig-PRP_Mensel i.ik PRP

(+) a- [4- (1-oxo-2-isolinolinyl) -phenylbutyric acid 1.68 1.29 (+) a- [4- (1-oxo-2-isoindolinyl) -phenyl] butyric acid 3, 37 2.43

In view of the anti-caking activity of the optically active compounds of the invention, these compounds, especially those of formula 1, wherein R is ethyl, are useful for the prevention and treatment of hidden ischemic arterial diseases of the cerebral, coronary and peripheral circulation. In particular, they can be used in the treatment of interrupted lameness (intermittent claudication).

They may also be useful for keeping vessels open after bypass grafting, endoarterectomy, percutaneous transminal an-gioplasty, for the preventive treatment of venous thromboembolism and for antithrombic action in extracorporeal circulation.

The compounds of the invention can be administered by conventional therapeutic compositions, including slow-release compositions. Preferably they are administered orally. Preferred pharmaceutical preparations are therefore tablets, capsules, pills and the like in which the active ingredient is mixed with conventional solid carriers such as talc, starch, stearic acid, magnesium stearate, cellulose and the like.

The daily doses suitable for oral administration to humans can range from about 25 mg to about 200 mg for adults. Preferably, the compounds are administered in two daily doses.

The toxicity of the compounds of the invention is very low at the therapeutic doses and therefore they can be safely used therapeutically.

The following examples illustrate the invention without disclosing it; : 9 limit.

The abbreviation DMF stands for dimethylformamide.

Example I

A mixture of (+) 2- (4-aminophenyl) propionic acid (4.34 g) and L (+) - tartaric acid (3.94 g) in 26.04 g of deionized water is stirred at 80 ° C for 10 minutes . After the solids have completely dissolved, heating is stopped and the mixture is stirred at room temperature for an additional 24 hours. Then, at 20 ° C, the precipitated counterclockwise tartrate (A) is separated by centrifugation and stored for recovery by racemization. The solution containing the right-handed tartrate is evaporated under reduced pressure at 40-45 ° C. 1.04 g of sodium hydroxide solution of 35 ° Be are added over ten minutes at 30-32 ° C. The mixture is stirred at 30 ° C for 30 minutes and centrifuged, after which the collected precipitate is washed with cold water and dried to obtain 1.36 g (+) - 2- (4-aminophenyl) propionic acid with a mp. of 172-174 ° C, Ca] § ° + 73.4 ° (c = 0.1% in EtOH).

The centrifugation mother liquor and the washing liquid of the clockwise acid are added to the clockwise tartrate (A) with 13 g of water. 3.8 g of slaked lime are added to the mixture and the suspension is kept at 50 ° C for 4.5 hours. The warm suspension is centrifuged to remove precipitated calcium tartrate which is washed with water at room temperature. The mother liquor from the centrifugation and the washing water are combined and 10.1 g of 35 ° B sodium hydroxide solution are added thereto. The mixture is brought to a boil and after 24 g of water is removed by distillation, it is refluxed for 22 hours. After cooling to 0-5 ° C, the pH is adjusted to 4.3 with 32% hydrochloric acid. The suspension is brought to 15-20 ° C and centrifuged. The solid is washed with water and dried to give 2.52 g of racemic (+) 2- (4-aminophenyl) propionic acid, m.p. 146-148 ° C.

Example II

3.56 g of phthalic anhydride and 3.78 g of (+) 2- (4-aminophenyl) propionic acid are successively added to 17 g glacial acetic acid: After refluxing for 8 hours and stirring at 118 ° C, the mixture slowly becomes cooled to room temperature and stirred for an additional 2 hours at 20 ° C.

The suspension is centrifuged and the solid washed thoroughly with water and dried at 70 ° C under reduced pressure to obtain 5.84 g (+) - 2- (4-phthalimidophenyl) propionic acid, m.p. 234-236 ° C, [<x] D + 68 ° (c = 0.1%, DMF).

. 8 ε o rr '5> 10%

Example III

3.25 g of 85% zinc powder and 2.5 g of (+) - 2- (4-phthalimidophenyl) propionic acid are successively added to 37.5 g of 99% formic acid under stirring and under a nitrogen atmosphere. After boiling under reflux for 8 hours, the mixture is cooled to 60 ° C and the formic acid is removed by distillation. The residue is taken up in dilute sulfuric acid, obtained from 25 g of water and 5.6 g of 96% sulfuric acid, and the resulting suspension is stirred at 50 ° C for 30 minutes under a nitrogen atmosphere. After cooling, the mixture is centrifuged, after which the solid is washed several times with water, suspended in 30 g of deionized water and dissolved by adding sodium hydroxide solution of 35 ° Be to a pH of 12 with stirring. After heating to 50 ° C, 1 ml of 20% ammonium sulfide is added and the precipitate is filtered off under reduced pressure. To the filtered solution, 99% formic acid is added with stirring until a pH of 3.5-4 is reached. The resulting suspension is centrifuged, the solid is washed several times with deionized water and dried at 70 ° C under reduced pressure to obtain 2.2 g of crude product which, after recrystallization from 95% ethanol, produces 2 g of pure (+) 2- [4 - (1-oxo-2-isoindolinyl) phenyl] propionic acid, m.p. 207-208 ° C, [a] § ° + 77.41 ° (c = 1%, DMF).

Example IV

A suspension of 100 g (+) - 2- (4-aminophenyl) butyric acid and 83.7 g L (+) - tartaric acid is refluxed in 2000 ml of anhydrous ethanol until the solid is dissolved and the mixture is then is put at room temperature for a day so that the resulting salt can crystallize. The precipitate is filtered off and recrystallized several times from anhydrous ethanol. The salt is dried under reduced pressure at 50 ° C, after which 70 g of right-turning tartrate are obtained [α] + + 57 ° (c = 1%, DMF). To release the optically active acid, the salt is suspended in water and caustic soda is added to a pH of about 4-5. The suspension is filtered and the solid is washed with water and dried under reduced pressure at 60 ° C to obtain 35 g of (+) - 2- (4-aminophenyl) butyric acid, m.p. 157-158 ° C, [α] 25D + 75 ° (c = 0.1%, MeOH).

All mother liquors from the first filtration and from the recrystallization of the tartrate are combined and distilled dry under reduced pressure. The solid residue is dissolved in 5 parts of water (600 ml) after which 40 g of calcium hydroxide are added. The suspension is stirred at 50 ° C and after 5 hours the precipitated calcium tartrate is filtered off and the L (+) tartaric acid is recovered by acidification and reused. The filtered aqueous solution is treated with 200 g of sodium hydroxide solution, evaporated at normal pressure to half the original volume and then heated to reflux. After 24 hours, the solution is acidified and the precipitate is collected by filtration, washed with water and dried under reduced pressure at 60 ° C, recovering 50 g of racemic 2- (4-aminophenylbutyric acid with a melting point of 143-144 ° C, [ct] 20 + o ° (c = 0.1%, MeOH).

Example V

A mixture of 8.5 g of phthalic anhydride and 9 g of (+) 2- (4-aminophenyl) butyric acid in 140 ml of glacial acetic acid is refluxed for 8 hours and then cooled to about 20 ° C. The precipitate is filtered off, washed with 100 ml of water and dried under reduced pressure at 50 ° C, whereby 13.4 g of (+) 2- (4-phthalimidophenyl) butyric acid are obtained, m.p. 234-237 ° C, [α] J ° + 71 ° (c = 1%, DMF).

Example VI

A mixture of 17.8 g of phthalic anhydride, 15 g of 35% sodium hydroxide and 12.7 g of (+) - 2- (4-aminophenyl) butyric acid tartrate is refluxed for 6 hours and then cooled to about 50 ° C.

The precipitate is filtered off, washed with 100 ml of water at 50 ° C and dried at 50 ° C under reduced pressure to obtain 10 g of (+) - 2- (phthalimidophenyl) butyric acid, m.p. 234-237 ° C, ω§ ° + 71 (C-K, DMF).

Example VII

To a solution of 11 g (+) - 2- (4-phthalimidophenyl) butyric acid in 200 ml of 99% formic acid, 18 g of zinc powder are added with stirring. The mixture is refluxed for 8 hours and then evaporated to dryness under reduced pressure; the residue is suspended in 125 ml of dilute sulfuric acid and stirred. The solid is filtered off and suspended in 150 ml of water and dissolved by adding dilute sodium hydroxide to pH 12. After removing the heavy metals by treatment with 20% ammonium sulfide, the solution is brought to pH 4.5 with formic acid. the solid formed is filtered off, washed with water and dried under reduced pressure at 70 ° C.

The crude product is recrystallized from 8 volumes of ethanol (85 ml) to give 8.2 g of (+) - 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid, m.p. 197-198 ° C, [α] D + 83 ° (c = 1%, DMF).

8 8 µ C7 t; * 12 *

Example VIII

150 mg tablets containing 25 mg of active substance are prepared as follows.

5 Composition for 10,000 tablets: (+) - 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid 250 g 1actose 800 g corn starch 415 g talcum powder 30 g 10 magnesium stearate 5 g

The oxoisoindolinylphenylbutyric acid, the lactose and half of the corn starch are mixed; the mixture is forced through a 0.5 mm mesh sieve. 10 g of corn starch is suspended in 90 ml of warm water and the resulting paste is used to granulate the powder. The granulate is dried, comminuted on a 1.4 mm mesh screen, then the rest of the starch, talc and magnesium stearate are added and the whole is carefully mixed and processed into tablets.

pent 'V r.

f V V: t * '

Claims (15)

A method for preparing an optically active compound of formula 1 according to the formula sheet, wherein R is a C2 -C4 alkyl group and Rj is a hydrogen atom, a C2 -C4 alkyl group or a group - (CH2) - - NR2R3, wherein n is 1 or 2 and R 2 and R 3 are independently hydrogen or C 1 -C 4 alkyl, or a physiologically acceptable salt thereof, characterized in that (a) a racemic compound of formula 2, wherein R and R 1 is Having the above meanings, splits into the optical isomers to yield an optically active compound of formula 2 as such or as a salt; (b) the optically active compound of formula 2, as such or as salt, reacts with phthalic anhydride to form an optically active phthalimido compound of formula 3, wherein R and R 2 have the above meanings; and (c) reducing the optically active phthalimido compound of formula 3 and, if desired, esterifying a resulting optically active compound of formula 1, wherein R 1 is hydrogen, to obtain a corresponding optically active compound of formula 1, wherein R 2 C 2 -C 4 alkyl or a group - (0 ^) ^^ 2¾ or converts into a physiologically acceptable salt with a physiologically acceptable base. 2. Process according to claim 1, characterized in that the racemic compound of formula 2 in step (a) is split with the aid of an optically active acid. A method according to claim 2, characterized in that the optically active acid is optically active tartaric, mandelic, dibenzoyl-tartaric or camposulfonic acid. Method according to any one of the preceding claims, characterized in that. that R is methyl or ethyl and Rj in the racemic compound of formula 2 in step (a) is hydrogen. 5. Process according to any one of the preceding claims, characterized in that the right-turning isomer of formula 2 is separated in step (a) and used in step (b). Process according to any one of the preceding claims, characterized in that the isomer of formula 2 separated in step (a) which is not required for use in step (b) is racemized and reused in step (a). A process for the preparation of an optically active compound .881 * of formula 1 according to claim 1 or a physiologically acceptable salt thereof, characterized in that an optically active compound of formula 3 as mentioned in claim 1 is reduced and if desired an optically active compound of the formula 1 in which R 5 is hydrogen esterified thereby to obtain a corresponding optically active compound of the formula 1 in which R 1 is C 1 -C 4 alkyl or a group - (CH 2) n -NR 2 R 3 as defined in claim 1 or with converts a physiologically acceptable base into a physiologically acceptable salt thereof. Process according to claim 7, characterized in that R is methyl or ethyl and R 1 in the compound of formula 3 is hydrogen. The right-handed isomer of the compound of formula 1 according to claim 1, wherein R is ethyl, or a physiologically acceptable salt thereof. A right-handed isomer according to claim 9, characterized in that it is the compound (+) - a- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid or a physiologically acceptable salt thereof. 11. Pharmaceutical composition comprising an active substance and an inert carrier, characterized in that the active substance is a compound according to claim 10 or 11. Pharmaceutical preparation according to claim 11, characterized in that it is suitable for inhibiting platelet aggregation. Pharmaceutical preparation according to claim 12, characterized in that it is suitable for treating interrupted lameness. Process for the preparation of an optically active compound of the formula 3 according to claim 1, characterized in that an optically active isomer of the formula 2 according to claim 1 is reacted with phthalic anhydride. The optically active compound of formula 3 according to claim 1, wherein R is ethyl. ++++++++++++. 86 0 fi; i:>