NZ223805A

NZ223805A - Preparation of optically active oxo-isoindolinyl derivatives, and pharmaceutical compositions containing them

Info

Publication number: NZ223805A
Application number: NZ223805A
Authority: NZ
Inventors: Giovanni Carniel; Fabrizio Orzi; Giorgio Ceroni; Bruno Miorini; Pierluigi Griggi
Original assignee: Erba Carlo Spa
Priority date: 1987-03-10
Filing date: 1988-03-09
Publication date: 1990-11-27
Also published as: IL85651A0; NO174666C; AU605253B2; DE3807595A1; DK128988A; CN1017527B; HUT47247A; SE8800846D0; PH26254A; CH675419A5; PT86933A; IL85651A; NL8800575A; YU46565B; GR880100137A; FI93725B; AT392068B; FI881075A; AU1267988A; IE880648L

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £23805 m a HO DRAWHIRg Priority Ds:e|s); ... i Q/.sv.sr?.-.... Corn^ioU Specification Filed: Clgfn: Sc?7? lJ=J , 1271«OV"«90' Publication Date: P.O. Journal, No: . ...V3^. 22 3 8 0 5 The inventors of this invention in the sense of being the actual deviser thereof within the meaning of Section 23 of the Patents Act 1953 are GIOVANNI CARNIEI. of via San Vito 5, Milan, Italy; FABRIZIO ORZI of via Angera 10, Milam, Italy; GIORGIO CERONI of via Cadorna 14, Bovisio (Milan), Italy; BRUNO MIORINI of via Ronchi 36, Milan, Italy; PIERLUIGI GRIGGI of via Gallarana 4, Monza (Milan), Italy all Italian citizens. a NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION OPTICALLY ACTIVE OXO-ISOINDOLINYL *" 9 MAR 1988 O RIVATIVES o We, FARMITALIA CARLO ERBA S.r.l., an Italian company of Via Carl Imbonati 24, 20159 Milan, Italy, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) I ..- w^.. :-&.< >•>'-• • -v f m 223805 n O - iQ- DESCRIPTION OPTICALLY ACTIVE OXO-ISOINDOLINYL DERIVATIVES The present invention relates to a process for the preparation of optically active oxo-isoindolinyl derivatives and to some, specific, optically active oxo-isoindolinyl compounds. Ff'.'Z.Patent No. 165293 relates to l-oxo-2-isoindoline compounds of the following formula (A) CH-COOR. (A) wherein R is hydrogen or C1~C4 alkyl and R^ is hydrogen, C1-C4 alkyl or a group -(CH2)n~N^^2 wherein n is 1 or 2 and 10 each of Rj an^ Rj/ which may be the same or different, is hydrogen or alkyl. Only racemic compounds are described in that patent as no mention or identification is given there of any optically active derivative. 15 According to one synthetic approach reported in N.Z. Patent No. 165293 above formula (A) the racemic compounds of the 20 • -..■•■K^;^., '.. , » ...... I * 22 3 8 0 5 o *>IWT' -ifr- Patent No. 774,895, which is the Belgian counterpart of U.K. Patent No. 1,344,663. According to one synthetic approach reported in U.K. Patent No. 1,344,663, the racemic compounds of the 5 above formula (A) Vj> © O ~au 22 3 8 0 5 may be obtained by reacting o-phthalic anhydride with the desired racemic £-aminophenylacetic acid derivative of formula (B) m-O- CH-COOR^ (B) R wherein R and R^ are as defined above, followed by reduction of the obtained, racemic, phthalimido compound of formula (C) 0 Si -/""Vch-coor, / V=/ I 1 (c) 1 R 0 wherein R and R^ are as defined above* Thus,the prior art teaches that an optically active compound of formula (A) can be prepared: (i) reacting a racemic compound of formula (B) with o-phthalic anhydride, to give a corresponding, racemic, phthalimido compound of formula (C); (ii) reducing the obtained, racemic, phthalimido compound of formula (C) to give the corresponding, racemic, l-oxo-2--isoindoline compound of formula (A); and (iii) resolving the obtained,racemic,l-oxo-2-isoindoline compound into the single optical isomers of formula (A). It has now been found that the same optically active 1-oxo--2-isoindoline compounds of formula (A) can be more advantageously prepared by a new process characterized in that the ■r s& i s Jsj ■I # w? ' _*}_ «J J o j i i o 22 3 8 0 5 optical resolution is carried out at an earlier stage of the synthesis, rather than at the end of the process, i.e. on the final compounds. I Accordingly, a first object of the invention is a new process 5 for the preparation of an optically active compound of (Q) formula (I) i^N ,—. L. !1 n—/' r:H-rnr>R (I) wherein R is C -C. alkyl; and R, is hydrogen, 0,-0,, alkyl or B 1 4 1 va 14 -(CH_) -N. _ wherein n is 1 or 2 and each of R smd R , 2 n R3 ^ j 10 which may be the same or different, is hydrogen or alkyl, including the salts of the compounds of formula (I) wherein R1 is hydrogen with physiologically acceptable bases. A second object of the invention are the optically active dextrorotatory isomers of the above formula (I) wherein 15 R is ethyl, which as already said, are not specifically identified in German patent application No. 22 58 088. According to the new process which is the first object of the invention, the optically active compounds of formula (I) 20 are prepared by (a) resolving a racemic compound of formula (II) v-fy-c^ (ID i - 4 - 22 3 8 0 wherein R and are as defined above, into its'optical isomers, to give an optically active compound of formula (II) as such or as a salt; % (b) reacting an optically active compound of formula (II) thus obtained, as such or as a salt, with o-phthalic anhydride to give an optically active phthalimido compound of formula (III) 0 0^/n~O~ih~coorI (in) wherein R and are as defined above; and (c) reducing foe optically active compound of formula (III);. and,if desired,esterifying an optically active compound of formula (I) thus-obtained wherein is hydrogen to give a corresponding optically active compound of formula (I) wherein R, is C,-C, alkyl or a group -(CH_) -N 114 2 n as defined above, or salifying it with a physiologically acceptable base to give a physiologically acceptable salt thereof. In the above formula (I) a alkyl group is, preferably, methyl or ethyl. ^•R2 When R, is a group -(CH_) -NSo as defined above, preferably 1 d n Kg R and R_ are both hydrogen or both methyl groups. & W Preferably in formula (I) R is methyl or ethyl and R^ is hydrogen, methyl or ethyl, most preferably hydrogen. The salts of the compounds of formula (I) wherein R^ is hydrogen with physiologically acceptable bases include, for instance, the salts with either physiologically acceptable . V ~ mm**™******. "''"""' 't'"> ,r 22 3 8 0 5 -5- inorganic bases such as, e.g., alkali metal, e.g. sodium or potassium, hydroxides, alkaline-earth metal, e.g. calcium or magnesium hydroxides, or physiologically acceptable organic bases such as, e.g., aliphatic, aromatic or heterocyclic 5 amines, e.g., triethylamine, benzylamine or pyridine, or also dimethylethanol or aminoacids such as, e.g., lysine, arginine or betaine. Under the term "dextrorotatory" or "(+)" we mean a compound whose diluted solution (containing 0.1 to 1% of such compound) 10 in dimethylformamide (DMF) or methanol (MeOH) or ethanol (EtOH) shows- a positive rotation at room temperature when using light of a wave-length of about 589 pm. Similarly, under the term "laevorotatory" or "(-)", we mean a compound, whose diluted solution shows a negative rotation 15 in the same conditions. Preferred optically active compounds of formula (I) are the "dextrorotatory" or "(+)" isomers because they show higher biological activity than the "laevorotatory" or "(-)" isomers, particularly analgesic and anti-inflammatory activity, as 20 well as platelet aggregation inhibiting activity. As already said, the new process of the invention for preparing optically active l-oxo-2-isoindoline compounds of formula (I), wherein the optical resolution is made at an early stage of the synthesis, offers remarkable advantages, 25 especially on the economical point of view, over the known « • 223805 % ■ - < - , t process of the prior art wherein the optical resolution is carried out at the end of the synthesis, i.e. on the formula (I)-compounds. The resolution step on the final 5 l-oxo-2-isoindoline compounds of formula (I) suffers, in fact, at least from the following considerable disadvantages. Most importantly, the undesired isomer coming from the said optical resolution of racemic formula (I)-10 compounds, i.e. the laevorotatory antipode, cannot be conveniently recycled through the process; its recovery by racemization proceeds with low yields especially due to instability of the l-oxo-2-isoindoline molecule and consequent formation of decomposition products which are 15 difficult to eliminate. What racemic product it is possible to recover lacks purity. Attempts at its optical resolution have proved to be unsatisfactory from the point of view of the yields and of the obtained optical purity. The consequence of this is that the unwanted 20 optical isomer coming from the resolution carried out on the racemic formula (I)-compounds is lost for the most part if not completely. This is a strong disadvantage from the costs' point of view if it is considered the high percentage of desired,dextrorotatory, isomer which is wasted/lost with 25 the undesired isomer at the end of the resolution process: see, e.g., the resolution yields reported in the working examples of German Patent application No. 22 58 088. O o ■fc»WiS£i rb*' •** "•'Wi 22 3 8 0 5 -7- Furthermore, since the resolution is carried out on a compound of formula (I) wherein is hydrogen, it necessitates the use of an optically active base and, as is known, optically active bases are generally highly expensives, especially bases of the kind indicated in the here above said German patent application, i.e. oi -methylbenzylamine, quinine, quinidine, cinchonine, cinchonidine, ephedrine, brucine, morphine, yohimbine, benzedrine, menthylanu.ne, d-(l-naphthyl)-ethylamine and 2-aminobutane. In addition,a quantitative recovery of thpse expensive bases is generally impossible and this has a considerable effect too on the final process's cost. The new process of the invention represents a progress over the known method in that it allows to overcome most if not all the disadvantages indicated above, providing a very much cheaper and industrially satisfactory method for the production of optically active l-oxo-2-isoindoline compounds of formula (I). The main advantage of the new process of the invention resides in that the optical resolution carried out at a very early stage of the synthesis on the compounds of formula (II) permits almost quantitative recovery of the undesired isomer which can be entirely recycled: its racemization proceeds with very high yields since <££ <-<.380 -8- the formula (II)-compounds are completely stable in the racemization conditions and so no decomposition products are formed. According to the process of the invention, the undesired isomer is wholly re-inserted into the production cycle together with the residual waters from the processing of the wanted isomer, without decrease in yields and without need of supplementary purification. The nearly complete recovery of the unwanted isomer allows to improve yields and reduce costs at a great extent. A comparison between the respective yields indicate?that, considering the recovery of the undesired isomer, the yield of the resolution carried out on the compounds of formula (II) ccmes to be at least two times higher than the yield of the resolution performed on the end-formula (I) compounds. Furthermore, it is evident that, due to the almost complete recovery of the undesired isomer, the amount of formula (ID-compound required for the process is considerably reduced and this results in a remarkable saving of the formula (II)-intermediate as well as of the starting materials and reagents used upstream in the synthesis for its preparation. In addition, the optical resolution of the compounds of formula (II) according to the process of the invention is, preferably, performed with the aid of an optically active I o ^JJ o m 22 3 8 0 5 -9- acid, such as, e.g., optically active tartaric, mandelic, dibenzoyl tartaric or camphorsulfonic acid. As is known, optically active acids are generally much less expensive than optically active bases - as a single example we may 5 point out the case of the (+) tartaric acid whose cost is at least ten times lower than that of ( + ) ol -methylbenzyl-R) amine - and, moreover, contrary to the optically active bases, they can be quantitatively recovered, and this is a further contribute to the lowering of the costs. 10 According to the process of the invention the optically active compounds of formula (II) are obtained with a very high optical purity degree and no lost of optical activity is observed in the subsequent synthetic steps. The above makes clearly evident that the new process of the 15 invention is considerably more advantageous that the closest prior art process for preparing optically active compounds of formula (I), because it offers better yields and lower costs being, at the same time, an industrially satisfactory method. 20 It provides a more economical and industrially advantageous route to the synthesis of optically active l-oxo-2-isoindo-line compounds of formula (I). The resolution step (a) of the new process of the invention is preferably carried out, as already said, by the aid of 25 an optically active acid chosen, e.g. from optically active I I §& i -*&• -10- o 22 3 8 0 5 tartaric, mandelic, dibenzoyl tartaric and camphorsulfonic acid. The racemic formula (II) compound is reacted with the optically active acid, e.g. one of those hereabove specified, 5 in a suitable solvent such as, for instance, water, an aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, O) acetcne, acetonitrile or nethylethy Ike tone, at a temperature which may vary between the roan temperature and about 100°C,for reaction times ranging,, e.g.,from few minutes to 24 hours. 10 L(+) tartaric acid is a particularly preferred acid and water is a particularly preferred solvent. The obtained optically active salts are separated from their mixture in a conventional way, for instance by filtration or centrifugation, or by fractional crystallization, and 15 the isolated, desired, optically active salt is either saponified to release the corresponding optically active amino-compound of formula (II), or used as such for the subsequent reaction with o-phthalic anhydride according to /T\ step (b). 20 The saponification may be performed, e.g., with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, operating in aqueous medium at a temperature from around the room temperature to around 30-40°C. Even if, as previously said, the optical resolution on the 25 compounds (II) is preferably performed by the use of an optically active acid, nevertheless, if desired, for compounds of formula (II) wherein R is hydrogen the same - 11 - 22 3 8 0 5 resolution may also be, even though less advantageously, carried out with em optically active base, e.g. one of those mentioned before in this specification. In this case the release of the formula (II) - compound from the corres- % ponding optically active salt is obtained by acidic treatment, e.g. by reaction with hydrochloric acid in aqueous medium according to conventional procedures. All the residual liquors coming from the processing of the wanted isomer are combined and submitted to racemization in order to recover and recycle the undesired isomer as well as any possibly present unresolved product. The racemization is preferably performed by basic treatment, preferably using, as a base, an alkali metal hydroxide such as, e.g.', concentrated sodium or potassium hydroxide, operating in aqueous medium at elevated temperature, e.g. at the boiling point of the solvent. The recovered racemic formula (II)-compound is then recirculated back into the productive cycle. When for the reaction with o-phthalic anhydride a salt of the optical isomer of formula (II) is used, the salt is, as already said, the same salt coming from the resolution step (a), i.e., according to a preferred procedure, the salt with the acid, e.g. L(+)tartaric acid, employed for the resolution of the racemic formula (II)-compound. The reaction between the desired optical isomer of formula (II) coming from step (a) and o-phthalic anhydride, according to process step (b), may be carried out in a polar, preferably aqueous, solvent, such as, for instance, water or acetic acid, by heating at a temperature which may vary, e.g., between about 50°C and about 160°C. I I 0. J - 12 - 22 3 8 0 The reduction of an optically active compound of formula (III) according to process step (c) may be carried out with a suitable reducing agent which may be, for example, | preferably, zinc and formic acid or zinc and acetic acid ! ^ 5 operating, preferably, under nitrogen atmosphere at a temperature between about 60°C and about 160°C, preferably at the reflux temperature, following the known procedures described in the organic chemistry for this kind of reductions. 10 The obtained optically active compound of formula (I) may be purified in a conventional way, e.g. by crystallization from a suitable solvent which may be, for example, an aliphatic alcohol, e.g. ethanol. Conventional procedures may be followed also for the 15 possible esterification of an optically active compound of formula (I) wherein is hydrogen to give a corresponding compound wherein R1 is alkyl or a group -(CH ) -N^ 2 as defined above, as well as for the 2 n Rg salification of an optically active compound of formula 20 (I) The starting racemic compounds of formula (II) are known compounds or may be prepared by known methods from 1 v ' known compounds. For example they may be prepared by reduction of the corresponding nitro-derivative according to known procedures, e.g. by hydrogenation at around the 25 room temperature on 5% palladium/carbon in an inert sol- vent such as, for instance, a C -C_ aliphatic alcohol, X o 22 3 8 0 5 - 13 - e.g. methanol, ethanol, water or glacial acetic acid. The said nitro-derivatives are known compounds too or may be prepared by known methods from known compounds. 5 As already said, a second object of the invention are the optically active dextrorotatory isomers of the above formula (I) wherein R is ethyl, including the physiologically acceptable salts thereof. A preferred compound in the ambit of this class 10 is the compound (+) 2-[4-(l-oxo-2-isoindolinyl) phenyl] butyric acid (dextrorotatory isomer) and the physiologically acceptable salts thereof. Object of the invention are also the optically active phthalimido compounds, especially the dextrorotatory 15 isomers, of the above formula (III) . The optically active compounds of formula (I) obtained by the new process of the invention, besides possessing good analgesic and anti-inflammatory activity, show also, particularly the class of the compounds of 20 formula (I) wherein R is ethyl, high platelet aggregation inhibiting activity. The platelet anti-aggregating activity of these compounds is obtained at extremely low dosages if compared not only with compounds of different chemical structure but also with the racemic compounds 25 having identical structure. The platelet aggregation inhibition data reported 22 3 8 0 5 - 14 - on the following Table provide, for instance, clear evidence of the biological superiority of the optically active compound of the invention ( + ) 2- [4- (l-oxo-2--isoindolinyl)-phenyl] butyric acid over the corresponding 5 racemic compound, which is described, for instance, in U.S. Patent No. 4,010,274. The tabulated data have been obtained by evaluating the inhibiting effect of the tested compounds on the platelet aggregation induced by 2 mcg/ml collagen in Guinea pig and, respectively, human platelet 10 rich plasma (PRP) . The platelet aggregation inhibiting effect is expressed as ED^q value, i.e. the dose producing the 30% inhibition of the induced aggregation in respect to controls. 1 c TABLE Inhibition of collagen induced platelet aggregation in Guinea pig and human PRP Compounds ED30 (mc9/ml) Guinea pig PRP human PRP <■+•)2— [4- (l-oxo-2-iso-indolinyl) phenyl]bu-tyric acid 1.68 1.29 (-) 2- [4- (l-oxo-2-iso-indolinyl) phenyl]butyric acid 3.37 2.43 - 15 - 22 3 8 0 5 In view of their anti-aggregating activity the optically active compounds of the invention, particularly the compounds of formula (I) wherein R is ethyl, can be useful for the prevention and the treatment of occlusive ischemic arterial diseases of the cerebral, coronary or peripheral circulation. In particular, for example, they can find application in the treatment of the intermittent claudication. They may be also useful for the maintenance of patency after by-pass graft, endoarterectomy, percutaneous transluminal angioplasty, for the prophylaxis of venous thromboembolism and for the antithrombotic activity in extracorporeal circulation. The compounds of the invention can be administered by using the conventional therapeutical formulations, including slow release formulations. They are preferably administered orally. Preferred pharmaceutical compositions are therefore tablets, capsules, pills, and the like, where the active principle is mixed with conventional solid excipients, such as, for instance, talc, starch, stearic acid, magnesium stearate, cellulose, and the like. Daily doses suitable for the oral administration to humans may range in adults between approximately 25 mg and approximately 200 mg. Preferably the compounds are administered in two daily doses. The toxicity of the compounds of the invention at the therapeutic doses is very low and so they can be safely used in therapy. The following examples illustrate but do not limit in any way the invention. The abbreviation DMF stands for dimethylformamide. 22 3 8 0 Example 1 A mixture of (-) 2-(4-aminophenyl)propionic acid (4.34 g) and L(+) tartaric acid (3.94 g) in deionized water (26.04 g) is heated for ten minutes under stirring at 80°C. After complete dissolution of the solid material the solution is left to spontaneously reach the room temperature under stirring and then stirred for further 24 hours. The temperature is brought to 20°C, the precipitated laevorotatory tartrate salt (A) is separated by centrifugation and set aside for recovery by racemization. The solution containing the dextrorotatory tartrate salt is concentrated under vacuum at 40-45°C. After bringing the temperature at 30-32°C# 35 Bd sodium hydroxide (1.04 g) is added in ten minutes. The mixture is stirred at 30°C for 30 minutes and centrifu-ged to collect the precipitate which is washed with cold water and dried to give (+) 2-(4-aminophenyl)propionic acid (1.36 g), m.p. 172-174+ 73.4* (c=0.1#t EtOH). The mother waters from the centrifugation and the washings of the dextrorotatory acid are combined with the laevorotatory tartrate salt (A) and water (13 g). To the mixture slaked lime (3.8 g) is added and the suspension is heated to 50°C and kept at this temperature for 4.5 hours. The hot suspension is centrifuged to eliminate the precipitated calcium tartrate which is washed with water at room temperature. The mother waters from centrifugation and washings M _.. ; . . 22 3 8 0 5 -17- are combined and 35 BS sodium hydroxide (10.1 g) is added. The reaction mixture is brought to reflux and, after eliminating some water (24 g) by distillation, it is maintained at reflux temperature for 22 hours. 5 After cooling at a temperature between 0°C and - 5°C, 32# aqueous hydrochloric acid is added to reach a pH of 4.3. The suspension is brought to 15-20°C and centrifugated. The solid is washed with water and dried to give 2.52 g of recovered racemic (-) 2-(4-aminophenyl)propionic acid, 10 m.p. 146-148°C. Example 2 Phthalic anhydride (3.56 g) and (+) 2-(4-aminophenylJpropio-nic acid (3.78 g) are added in the order to glacial acetic acid (17 g), under stirring. After refluxing 8 hours at 15 118°C under stirring, the reaction mixture is left to reach slowly the room temperature and then stirred for additional 2 hours at 20°C. The suspension is centrifuged and the solid is washed thoroughly with water and dried at 70°C under vacuum to give (+) 2-^4-(1,3-dioxo-2-isoindolinyl) 20 phenyl7propionic acid (5.84 g), m.p. 234-236°C, Z"d7D + 68* (c=l%, DMF). Example 3 Operating under stirring-and nitrogen atmosphere, 85# zinc powder (3.25 g) and ( +)2-/'4-( 1,3-dioxo-2-isoindolinyl) 25 phenyl^propionic acid (2.5 g) are added in the order to 99# •:•■ ■'.. 22 3 8 0 5 n -18- formic acid (37.5 g). After 8 hours boiling at the reflux temperature, the reaction mixture is cooled to 60°C and the formic acid is eliminated by distillation. The residue is taken up with a sulfuric mixture obtained from water (25 g) 5 and 96% sulfuric acid (5.6 g), and the resulting suspension /"""n is heated at 50°C for 30 minutes under stirring and nitrogen atmosphere. After cooling, the mixture is centrifuged; the solid is repeatedly washed with water, suspended in deionized water (30 g) and dissolved by treatment with 35 B6 sodium 10 hydroxide under stirring to pH 12. After heating to 50°C, 20# (NH^JgS (1 ml) is added and the precipitate is filtered under vacuum. To the filtered solution, 99# formic acid is added under stirring until to reach a pH of 3.5-4. The obtained suspension is centrifuged, the solid is 15 repeatedly washed with deionized water and dried under vacuum at 70°C to give 2.2 g of crude product which, after crystallization from 95# ethanol, leads to pure (+)2-/4-(l--oxo-2-isoindolinyl )phenyl7propionic acid (2 g), m.p. 207-208°C ^ + 77.41® (c = l#, DMF) . 20 Example 4 A suspension of (-)2-(4-aminophenyl)butyric acid (100 g) and L(+) tartaric acid (83.7 g) is heated at reflux tempe-rature in anhydrous ethanol (2000 ml) until complete dissolution and the resulting salt is allowed to crystallize 25 for a day at room temperature. The precipitate is filtered -19- 22 3 8 0 5 and repeatedly crystallized from anhydrous ethanol. The resulting salt is dried up under vacuum at 50°C to give 20 70 g of dextrorotatory tartrate salt, * 570 (c=l%, DMF). To release the optically active acid, the salt is 5 suspended in water and then sodium hydroxide is added until a pH of about 4-5. The resulting suspension is filtered and the solid is washed with water and dried under vacuum at 60°C to give (+)2-(4-aminophenyl)butyric acid, (35 g), m.p.l57-158°C, 20 £<U* + 75° (c=0.1%, MeOH). 10 All the mother liquors from the original filtration and the recrystallizations of the tartrate salt are combined and distilled to dryness under vacuum. The resulting solid residue is dissolved in water (600 ml, 5 vol.) and calcium hydroxide (40 g) is added. The suspension is heated under 15 stirring at 50°C. After 5 hours the precipitated calcium tartrate is filtered and the L(+)tartaric acid is recovered by acidification and recycled. The filtered aqueous solution is treated with 35% sodium hydroxide (200 g), evaporated at normal pressure to half of the original volume, and then 20 heated under reflux. After 24 hours the solution is acidified and the precipitate collected by filtration, washed with water, and dried under vacuum at 60°C, to give 50 g of recovered racemic (^)2-(4--aminophenyl)butyric acid, m.p. 143-144°C, 0° (c=0,l%, 25 MeOH). c ■ m \ '■ ''h-ve^ r) u - 20 - 22 3 8 0 5 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, then cooled at about 5 20°C. The resulting precipitate is filtered, washed with water (100 ml) and dried under vacuum at50°C to obtain (+)2-/4-(1,3-dioxo-2-isoindolinyl)phenyl7butyric acid (13.4 g), m.p. 234-237°C, + 71*(c=l%, DMF). Example 6 10 A mixture of o-phthalic anhydride (17.8 g), 35% sodium hydroxide (15 g) and (+) 2-(4-aminophenyl)butyric acid tartrate salt (12.7 g), is heated at reflux temperature for 6 hours and then cooled at about 50°C. The resulting precipitate is filtered, washed with water 15 at 50°C (100 ml) and dried under vacuum at 50°C to obtain ( + ) 2-[4-(l,3-dioxo-2-isoindolinyl)phenyl}butyric acid 20 (10 g), m.p. 234-237°C, [oC.] +71° (c=l%, DMF). it $ - 21 - 223805 Example 7 To a solution of (+)2-/4-(1,3-dioxo-2-isoindolinyl)pheny^J butyric acid (11 g) in 99% formic acid (200 ml), zinc powder (18 g) is added under stirring, the mixture is heated at reflux temperature for 8 hours, then evaporated under vacuum to dryness; the residue is suspended in diluted sulfuric acid (125 ml) and stirred. The solid obtained after filtration is suspended in water (150 ml) and dissolved by addition of diluted sodium hydroxide to pH 12. After removal of the heavy metals by treatment with 20% ^NH4^2S' solution is acidified to pH 4.5 with formic acid and the solid thus formed is filtered, washed with water and,dried under vacuum at 70°C. The raw product is crystallized from ethanol (85 ml, 8 vol.) to give (+)2-/4-(l-oxo-2-isoindolinyl)phenyl7butyric acid 20 (812 g), m.p. 197-198°C, fc(7p + 83° (c=l%, DMF). </div>

Claims

<div class="application article clearfix printTableText" id="claims"> „ v- <*■. ^-.■.■!i"'^'''^3V"-"^'' ' '- ).f''','%W?" Jvt^eui^ t ^ 1 , 22 3 8 - 22 - Example 8 Tablets, each weighing 0.150 g and containing 25 mg of active substance can be manufactured as follows. Composition for 10,000 tablets 5 (+)2-/4-(l-oxo-2-isoindolinyl)pheny\7 butyric acid 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g 10 Magnesium stearate 5 g The (+)2-/4-(l-oxo-2-isoindolinylJphenylJbutyric acid, the lactose and half the com starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water 15 (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets. ,o\ o 10 15 22380 - 23 - WHAT WE CLAIM IS:

1. A process for the preparation of an optically active compound of formula (I) CH-C00R, (I) wherein R is Cl-C< alkyl; and Rt is hydrogen, Cj-C4 alkyl or R_ wherein n is 1 or 2 and each of R, and R., R3 - (CHj )n -N which may be the same or different, is hydrogen or Cl-Ci alkyl; or a physiologically acceptable salt thereof comprising: (a) resolving a racemic compound of formula (II) V-O- CH-COOR, I ] R (II) wherein R and are as defined above, into its 'optical isomers, to give an optically active compound of formula (II) as such or as a salt; (b) reacting an optically active compound of formula (II) thus obtained, as such or as a salt, with o-phthalic anhydride to give an optically active phthalimido compound of formula (III) laUMKUK.EBiUVP m 22 3 8 0 5 - 24 - o o cX)o w» I ll N—( f— CH-COORj^ (III) wherein R and R1 are as defined above; and C^i (c) reducing the optically active compound of formula (III); '"«wr and, if desired, esterifying an optically active compound of 5 formula (I) thus-obtained wherein Rx is hydrogen to give a corresponding optically active compound of formula (I) wherein Rj is Cx -C4 alkyl or a group -(CHa )B-N as 3 defined above, or salifying it with a physiologically acceptable base to give a physiologically acceptable salt 10 thereof.

2. A process according to claim 1, wherein the racemic compound of formula (II) is resolved by means of an optically active acid in step (a).

3. A process according to claim 2, wherein the 15 said acid is optically active tartaric, mandelic, dibenzoyl tartaric or camphorsulfonic acid.

4. A process according to any one of the preceding claims, wherein R is methyl or ethyl and R1 is hydrogen in the racemic compound of formula (II) employed in 20 step (a).

5. A process according to any one of the preceding claims, wherein the dextrorotatory isomer of formula (II) is separated in step (a) for use in step (b). 22 3 8 0 5 - 25 -

6. A process according to any one of the » preceding claims, wherein the isomer of formula (II) separated in step (a) which is not required for use in step (b) is racemised and recycled for use in step (a). N 5

7. A process for the preparation of an optically v v,-' active compound of formula (I) according to claim 1, or a physiologically acceptable salt thereof, the process comprising reducing an optically active compound having the formula (III) reported in claim 1, and, if desired, 10 esterifying an optically active compound of formula (I) thus-obtained wherein Rx is hydrogen, to give a corresponding optically active compound of formula (I) wherein Rx is C1 -C4 alkyl or a group -(CHa)o-N^^ as defined in claim 1, or salifying it with a physiologically acceptable base to give a physiologically acceptable salt thereof.

8. A process according to claim 7, wherein R is methyl or ethyl and Rx is hydrogen in the compound of formula (III). I % O 20

9. A process according to any one of claims 1 to 8 further comprising formulating the product thus obtained with an inert carrier or excipient. 223805 -26-

10. An optically active dextrorotatory isomer having the formula (I) reported in claim 1 wherein R is ethyl, and the physiologically acceptable salts thereof.

11. A dextrorotatory isomer according to claim 10 which is the compound ( + ) 2-[4-( l-oxo-2-isoindolinyl JphenyQ butyric acid, and the physiologically acceptable salts thereof.

12. A pharmaceutical composition comprising an inert carrier or excipient and, as an active substance, a dextrorotatory isomer of formula (I) as defined in claim l wherein R is ethyl, or a physiologically acceptable salt thereof, as claimed in claim 10 or 11.

13. A pharmaceutical composition according to claim 12 suitable for use as a platelet aggregation inhibitor.

14. A pharmaceutical composition according to claim 13 suitable for use in the treatment of intermittent claudication.

15. A dextrorotatory isomer of formula (I) as defined in claim 1 wherein R is ethyl, or a physiologically acceptable salt thereof, as claimed in claim io or 11, suitable for use as a platelet aggregation inhibitor.

16. A dextrorotatory isomer of formula (I) according to claim 15 suitable for use in the treatment of intermittent claudication.

17. The use of a dextrorotatory isomer of formula (I) as defined in claim 1 wherein R is ethyl, or a physiologically acceptable salt thereof, as claimed in claim 10 or 11, in the preparation of a pharmaceutical composition suitable for use as a .platelet aggregation inhibitor. 223805 -27-

18. The use of a dextrorotatory isomer of formula (I) according to claim 17 in the preparation of a pharmaceutical composition suitable for use in the treatment of intermittent claudication.

19. A process for the preparation of an optically active compound having the formula (III) reported in claim 1, comprising reacting an optically active isomer having the formula (II) reported in claim 1, with o-phthalic anhydride.

20. An optically active compound having the formula (III) reported in claim 1 wherein R is ethyl.

21. A process according to claim 1 substantially as herein described or exemplified in Examples 1 to 7.

22. A composition according to claim 12 substantially as herein described or exemplified in Example 8. • O O FARMITALIA CARLO ERBA S.r.l. By Their Attorneys HENRY HUGHES LTD By: </div>