AU658662B2

AU658662B2 - Process for the preparation of a dextrogyral isomer of an isoindolinone derivative

Info

Publication number: AU658662B2
Application number: AU23606/92A
Authority: AU
Inventors: Marie-Therese David-Comte
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1991-07-12
Filing date: 1992-07-10
Publication date: 1995-04-27
Anticipated expiration: 2012-07-10
Also published as: FR2678934A1; EP0594775A1; IE72500B1; CA2112980A1; IL102446A0; KR100235373B1; CA2112980C; MA22589A1; WO1993001187A1; EP0522972A1; NZ243494A; AU2360692A; FR2678934B1; JPH06509083A; IE922238A1; MX9204054A; ZA925099B

Description

J PI DATE 11/02/93 APPLN. ID 23606/92 111~ N NI 111~I ll~llhlhlIII AOJP DATE 08/04/93 PCT NUMBER PCT/FR92/00666 11111111111111111111111 AU9223606 DEMANDE INTERNATIONALE PUBLIEE EN VERTU DU TRAITE DE COOPERATION EN MAI I hIh V fl~tVt I b CT) F(51) Classification Internationale des brevets 5 (11) Num~ro de publication internationale: WO 93/01187 C07D 221:00./ 22100)41/4A (43) Date de publication internationale: 21 janvier 1993 (21.01.93) (21) Numero de la demnande internationale: PCT/FR92/00666 (81) Etats d~sign~s: AU, CA, HU, JP, KR, NO, RU, US, brevet europ~en (AT, BE, CH, DE, DK, ES, FR, GB, (22) Date de dep6t international: 10 juillet 1992 (10.07.92) GR, IT, LU, MC, NL, SE), brevet OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD, TG).

Donnees relatives a ]a priorite: 91/08830 12 juillet 1991 (12.07.9 1) FR Publie Avec rapport de rechierche internationale.

(71) Diposant (pour tous les Etats d~sign&s sauf US): RHONE- POULENC RORER S.A. [FR/FR]; 20, avenue Raymond-Aron, F-92160 Antony 68 (72) Inventeur; et Inventeur/D~posant (US seulemnt) DAVID-COMTE, Marie-Th~r~se [FR/FR]; 1, all~e Costes-et-Bellonte, F- 94500 Chevilly-Larue (FR).

(74)Mandataire: PILARD, Jacques; Rh6ne-Poulenc Rorer 20, avenue Raymond-Aron, F-92 165 Antony C~dex

(FR).

(54) Title: PROCESS FOR THE PREPARATION OF A DEXTROGYRAL ISOMER OF AN ISOINDOLINONE DERI VA-

TIVE

(54)Titre: PROCEDE DE PREPARATON DE L'ISOMERE DEXTROGYRE D'UN DERIVE DE L'ISOINDOLINONE 0 CI COOH I-CI N NN

N

(57) Abstract Process for the preparation of the dextrogyral isomer of the product having the formula (II) by cyc,,ization of the dextrogyral isomer of the product having the formula (57) Abr~g6 Proc6d& de preparation de l'isom~re dextrogyre du produit de formule (11) par cyclisation de I'isom~re dextrogyre du produit de formule i i i i: WO 93/01187 1 PCT/FR92/00666 -PROCESS FOR THE PREPARATION OF THE DEXTROROTATORY ISOMER OF AN ISOINDOLINONE DERIVATIVE The present invention relates to a process for the preparation of the dextrorotatory isomer of the isoindolinone derivative of formula: 0 C1 (1)

ON

0 which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant properties.

According to American Patent US 4,960,779, the dextrorotatory product of formula may be obtained from the corresponding racemic product by chiral phase chromatography. However, the industrial application of this process is not always convenient to implement.

It has now been found, and this is the subject of the present invention, that the dextrorotatory isomer of the product of formula can be obtained by cyclisetion of the dextrorotatory isomer of the product of formula:

N

O

H C l 'c 2 Generally, the cyclisation is carried out by means of thionyl chloride while optionally working in the presence of a condensation agent such as imidazole or pyridine in an organic solvent such as methylene chloride.

The process according to the invention may also be used on the product of formula (II) prepared in situ.

The dextrorotatory isomer of the product of formula (II) may be obtained by resolution of the corresponding racemic product by means of a chiral base. To this end, it is particularly advantageous to carry out, in succession, the following operations: 1) formation of a salt with a chiral base or a chiral acid, 2) precipitation of one of the optical isomers and then 3) release of the dextrorotatory optical isomer of the product of formula either from the precipitated salt or from the filtration mother liquors of the precipitated salt after optional formation of another salt with an appropriate chiral base or appropriate chiral acid.

It is also possible to form a salt of the racemic product of formula (II) with (+)-ephedrine while operating in an appropriate organic solvent such as ethanol. The salt of the dextrorotatory product of formula (II) is displaced from its salt by means of a strong acid such as hydrochloric acid.

4' It is also possible to prepare a salt of the product of formula (II) with cinchonine in an appropriate solvent such as ethanol. The salt of the laevorotatory product of formula (II) with cinchonine precipitates. After being displaced from its cinchonine salt, the dextrorotatory isomer of the product of formula which is mainly found in the filtration mother liquors of the laevorotatory salt, is converted to an insoluble salt with cinchonidine. The dextrorotatory isomer of the product of formula (II) is displaced from its salt by means of a strong acid such as hydrochloric acid.

The product of formula (II) in the racemic form may be obtained by opening of the pyrrolinone ring of a racemic product of formula in basic medium.

Generally, the opening of the pyrrolinone ring is carried out by means of an inorganic base at a temperature of between 0 and 50 0 C and, preferably, of between 0 and 30 0

C.

Generally, the process is carried out by stirring an aqueous-organic solution of the product of formula in the presence of an excess of inorganic base chosen from the hydroxides and the carbonates or bicarbonates of alkali or alkaline-earth metals. It is particularly advantageous to use sodium hydroxide as inorganic base and to work in a water-pyridine mixture.

It is also possible to carry out the reaction by using a water-dioxane mixture as solvent.

i i-I The product of formula can also be obtained by action of an inorganic base on the product of formula: S[ |CI (111) N N

HOCO

0 Generally, at least two equivalents of the inorganic base chosen, preferably, from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate are used while working in water or in an aqueous-organic medium at a temperature of between 0 and 50°C, preferably, between 0 and 30 0 C. A dioxane-water mixture is preferably used as aqueousorganic medium.

The product of formula (III) can be obtained by hydrolysis in acid medium of a product of general formula: N C1I 0V) N N

ROCO

in which R represents an alkyl radical containing 1 to carbon atoms in a straight or branched chain.

Generally, the hydrolysis is carried out by means of a strong inorganic acid such as concentrated 1 1~ sulphuric acid while working at a temperature of between 0 and 50°C, preferably approximately 20 0

C.

The products of formula (III) and (IV) can be obtained under the conditions described in American Patent US 4,960,779.

The following examples illustrate the present invention.

EXAMPLE 1 g of the dextrorotatory isomer of 2-{1- [(7-chloro-l,8-naphthyridin-2-ylamino]-6-methyl-3oxoheptyl}benzoic acid and 21.8 g of imidazole in 400 cm 3 of methylene chloride are introduced into a 1 litre reactor. 7 cm3 of thionyl chloride are introduced, using a syringe, at a temperature of 20 0 C. The suspension is heated at reflux for 30 minutes, is subsequently cooled to 20 0 C and is then washed 2 times with 200 cm 3 of distilled water. The solution is concentrated, at atmospheric pressure, to half its volume and then 450 cm 3 of absolute ethanol are added.

The distillation of the methylene chloride is continued until the temperature of the vapour reaches 78 0 C. 1 g of decolorising charcoal is then added and the mixture is then left for one hour at 78 0 C. The suspension is filtered. The precipitate is washed with 50 cm 3 of absolute ethanol at 75 0 C. The filtrate and the washes are combined and then cooled to 15°C over 2 hours. The suspension is filtered. The precipitate is washed with 3 times 35 cm 3 of absolute ethanol at 15 0 C and then ilu 7 dried at 60 0 C for 16 hours under reduced pressure mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro- 1, 8-naphthyridinyl) (5-methyl-2-oxohexyl) 1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: optical rotation: [a]o +1320 (c 1; methylene chloride) enantiomeric purity 98.8%.

The dextrorotatory isomer of 2-{1-E(7-chloro- 1,8-naphthyridin-2-ylamino]-6-methyl-3oxoheptyl}benzoic acid can be prepared according to one of the following methods: 1) 1450 cm 3 of 95% ethanol, 100 g of of cinchonine and 145 g of (7-chloro- 1, 8-naphthyridin-2-yl) amino] -6-methyl-3oxoheptyl}benzoic acid are introduced into a stirred, 2 litre reactor. The suspension is heated to 40 0 C and then cooled, over 3 hours 30 minutes, to 10°C. The suspension obtained is filtered. The precipitate is washed with 2 times 50 cm 3 of ethanol at 10 0 C and then dried at 60 0 C for 16 hours under reduced pressure mm of mercury; 2.0 kPa). 99.3 g of the salt of cinchonine and 2-{1-[(7-chloro-1,8-naphthyridin- 2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: [a]J 0 +192.60 (c 1; methylene -chloride) enantiomeric purity: 98.5%.

1274.3 g of ethanolic liquors (corresponding to the filtrate of the cinchonine salt obtained previously with addition of the ethanol wash). 260 cm 3 of an N aqueous hydrochloric acid solution are added at 0 C. After stirring for 15 minutes, 650 cm 3 of distilled water are added. The solution is concentrated under reduced pressure (25 mm of mercury; 3.3 kPa) at a temperature below 30°C in order to remove the ethanol.

The suspension is then filtered. The precipitate is washed with 6 times 100 cm 3 of water and then dried at 0 C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa).

79.6 g of a white product mainly consisting of the dextrorotatory isomer of 2-{l-[(7-chloro- 1,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid are thus obtained, whose characteristics are the following: chloride) enantiomeric purity: 73.2%.

78.5 g of the product obtained previously, 54.3 g of cinchonidine and 700 cm 3 of 95% ethanol are introduced into a 1 litre reactor. The solution is heated to reflux and then cooled over 3 hours to a temperature of 10 0 C. A product crystallises. The suspension is filtered. The precipitate is washed with 8 2 -times 50 cm 3 of 95% ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; kPa).

92.8 g of the cinchonidine salt of [(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: -137.70 (c 1; methylene chloride) enantiomeric purity: 100%.

g of the cinchonidine salt obtained previously are dissolved in 250 cm 3 of N-methylpyrrolidone in a 1 litre reactor. 90 cm 3 of N hydrochloric acid are added over 30 minutes while holding the temperature below 20 0 C. After stirring for minutes at 20 0 C, 600 cm 3 of distilled water are added over 1 hour. The suspension obtained is filtered. The precipitate obtained is washed with 5 times 100 cm 3 of distilled water and then dried at 600C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa).

29.7 g of 1,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: [Ea] 0 222.80 (c 1; methylene chloride) i: C- ""llllll---C"I enantiomeric purity: 100%.

2) 250 g of 2-{1-[(7-chloro- 1,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid, 97 g of (+)-ephedrine and 875 cm 3 of 95% ethanol are introduced, at a temperature of approximately 20 0 C, into a 2 litre reactor. After dissolving the suspension at 40 0 C, the I reaction mixture is cooled to approximately 2 0 C. The precipitate obtained is separated off by filtration, washed with 2 times 125 cm 3 of 95% ethanol at 2 0

C

and then dried for 16 hours at 60 0 C under reduced Spressure (15 mm of mercury; 2.0 kPa). 156.6 g of the j salt of (+)-ephedrine and 2-{l-[(7-chloro- 1,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: -640 (c 1; methylene chloride) enantiomeric purity 100%.

2.75 g of the salt obtained previously and cm 3 of N-methylpyrrolidone are introduced into a i 50 cm 3 flask. 1.2 cm 3 of concentrated hydrochloric acid and then, over 10 minutes, 15 cm 3 of distilled water are added while maintaining the temperature at 20 0 C. The suspension obtained is filtered. The precipitate is washed with 5 times 10 cm 3 of distilled water and then dried for 16 hours at 60 0 C under reduced pressure mm of mercury; 2.0 kPa).

1.97 g of 2-{1-[(7-chloro-1,8-naphthyridin- 2-yl)amino] -6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: [a]0 +222.80 (c 1; methylene chloride) enantiomeric purity: 100%.

2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]- 6-methyl-3-oxoheptyl}benzoic acid can be prepared according to one of the following methods: A 1400 cm 3 of dioxane and 20 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl- 2-oxohexyl)-1-isoindolinone are introduced, at a temperature of approximately 20 0 C, into a stirred, 2 litre reactor. 244 cm 3 of an N aqueous solution of sodium hydroxide are added over 5 minutes. The mixture is left to react for 4 days at a temperature below 300C.

The dioxane is removed by distillation under reduced pressure (40 mm of mercury; 5.3 kPa) at a temperature below 30 0 C. 100 cm 3 of distilled water are Sadded during the distillation.

An insoluble product is removed by filtration at 20 0 C. This product is washed with 3 times 50 cm 3 of distilled water and is removed. The combined aqueous phases are acidified by addition, over 3 hours, of 48 cm 3 of 5N hydrochloric acid at a temperature of 20 0

C.

I

p,- ;-iL 11 The pH of the suspension is then approximately After filtering the suspension, the precipitate is washed with 6 times 100 cm 3 of distilled water and is then dried under reduced pressure (15 mm of mercury; 2.0 kPa) at 60 0 C for 16 hours.

14.3 g of 2-{1-[(7-chloro-1,8-naphthyridin- 2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time is 4.8 minutes by high performance liquid chromatography using a column 25 cm long and 0.46 cm in diameter with "Lichrospher O.D.S. 5 um" as the stationary phase and a mixture of 200 cm 3 of pH 3, 25 mM phosphate buffer, 560 cm 3 of acetonitrile and 240 cm 3 of methanol, at a flow rate of 0.8 cm 3 /minute, as the mobile phase.

2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5methyl-2-oxohexyl)-1-isoindolinone can be prepared according to the method described in American Patent US 4,960,779.

B 20 g of 2-(7-chloro-1,8-naphthyridin-2yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone, 400 cm 3 of pyridine and 60 cm 3 of a 2N aqueous sodium hydroxide solution are introduced, at a temperature of approximately 20 0 C, into a stirred, 1 litre reactor.

The mixture is left to react for 23 hours and the pyridine is then distilled under reduced pressure mm of mercury; 2.0 kPa) at a temperature below 500 cm 3 of distilled water are added. An insoluble 'i LI i- r 12 material is separated off by filtration. The aqueous phase is acidified to pH 3.8 by addition of 40 cm 3 of 4N hydrochloric acid. The suspension is filtered, the precipitate is washed with 5 times 140 cm 3 of distilled water and then dried for 16 hours at reduced pressure mm of mercury; 2.0 kPa) at 60 0

C.

19.2 g of 2-{1-[(7-chloro-l,8-naphthyridin- 2-yl) amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time by high performance liquid chromatography is 4.8 minutes under the conditions described previously.

C A suspension of 30 mg of 2-[2-(7-chloro- 1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl -6-methyl- 3-oxoheptanoic acid in 4.7 cm" of distilled water and 1.32 cm 3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 20 0 C for 72 hours. An insoluble product is removed by filtration and the filtrate is acidified to a pH 2 by addition of a 0.IN aqueous hydrochloric acid solution. The precipitate obtained is separated off by filtration, washed with water and dried in air. 10 mg of 2-{1- [(7-chloro-1,8-naphthyridin-2-yl) amino] -6-methyl- 3-oxoheptyl)benzoic acid are thus obtained whose characteristics are identical to those of the product obtained previously.

[2-(7-Chloro-, 8-naphthyridin-2-yl) 3-oxoheptanoic acid can be prepared in the following manner: 13 A solution of 23 g of ethyl 2-[2-(7-chloro- 1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl- 3-oxoheptanoate in 235 cm 3 of 98% sulphuric acid is stirred for 20 hours at a temperature of approximately 20 0 C and is then poured onto 1.5 kg of ice. The precipitate obtained is separated off by filtration, washed with water to a pH 6 and dried in air. The solid obtained is taken up in 3.8 litres of distilled water and 480 cm 3 of a 0.1N aqueous sodium hydroxide solution. The insoluble product is separated off by filtration and the filtrate is acidified to a pH 3 by addition of a 0.1N aqueous hydrochloric acid solution.

The precipitate obtained is separated off by filtration, washed with distilled water and then with isopropyl ether and dried at 20 0 C under reduced pressure (0.07 kPa). 9.2 g of 2-[2-(7-chloro- 1,8-naphthyridin-2-yl)-3-oxo-l-iscindolinyl]-6-methyl- 3-oxoheptanoic acid, melting at 176 0 C, are thus obtained.

Ethyl 2-[2-(7-chloro-l,8-naphthyridin-2-yl)- 3-oxo-l-isoindolinyl]-6-methyl-3-oxoheptanoate can be obtained by the method described in American Patent t j US 4,960,779.

EXAMPLE 2 118.3 g of the salt of (+)-ephedrine and 2-{l-[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl- 3-oxoheptyl}benzoic acid and 1700 cm 3 of methylene chloride are introduced into a 2.5 litre reactor. The 14 organic solution is washed, at 20 0 C, with 400 cm 3 of a aqueous hydrochloric acid solution and then with 400 cm 3 of distilled water. The organic phase is dehydrated by azeotropic distillation at 20 0 C under reduced pressure (250 mm of mercury; 33.3 kPa). The volume of the organic phase is adjusted to 1700 cm 3 by addition of dry methylene chloride, 95.2 g of imidazole are then added and then, over 10 minutes, 25 cm 3 of thionyl chloride. The suspension is heated to 40 0 C for 30 minutes, then cooled to 20 0 °C and washed with 2 times 700 cm 3 of distilled water. The methylene chloride is removed by distillation at atmospheric pressure while adding, to keep the volume constant, 2500 cm 3 of absolute ethanol. When the temperature of the vapour reaches 78 0 C, the distillation is halted and 4 g of decolorising charcoal in suspension in 20 cm 3 of absolute ethanol are then added. The mixture is left for 30 minutes at 78 0 C and then filtered while hot. The decolorising charcoal is rinsed with 200 cm 3 of ethanol at 77 0 C. The wash and the filtrate are combined and then cooled, at a rate of 20 0 C/hour, to a temperature of 10 0 C. The suspension is filtered. The precipitate is L washed with 3 times 140 cm 3 of absolute ethanol at and then dried at 60 0 C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). The slightly yellow product obtained (68.9 g) is recrystallised from 1400 cm 3 of ethanol at reflux. After cooling to 10 0

C,

the suspension is filtered. The precipitate is washed 4 -xi with 3 times 100 cm 3 of absolute ethanol at 10 0 C and then dried at 60°C for 16 hours under reduced pressure mm of mercury; 2.0 kPa). 65.1 g of (+)-2-(7-chloro- 1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)- 1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: optical rotation: [a] 0 +1320 (c 1; methylene chloride) enantiomeric purity 100%.

;s

P

C ii i' a 15a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

0 a 00 000 o a 4 *t o o 3i 6 9501 9,p:\operkdab,23606.spe,15

J_

Claims

16- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Process for the preparation of the dextrorotatory isomer of the product of formula: characterised in that the dextrorotatory isomer of the product of formula: t t e it.. itt' a I. a t a,4 a a GE I I t i i a I II« I I S( i a it+ tilts I t t tit t t L t t I t I i at' (1 L I 1 C t I t IaI (I 4 4 tai t l (II) is cyclised. 2. Process according to claim 1, characterised in that 25 the cyclisation is carried out by means of thionyl chloride in the presence of a condensation agent. 3. Process according to claim 2, characterised in that the condensation agent is imidazole or pyridine. 4. Process according to one of claims 1 to 3, characterised in that the cyclisation is carried out in an organic solvent such as methylene chloride. 5. The dextrorotatory isomer of the product of formula: IL 950109,popcr\db,2366.spe,16 I i- I I

17- when it is obtained according to the process of one of claims 1 to 4. 6. Processes for the preparation of dextrorotatory isomers of the product of formula substantially as hereinbefore described with reference to the Examples. I i .o 0 0 00 0 0o0 0 04 '0 0 0 Q 0 00 0 00 p a o e o a 0 ft Ot 0 00 06 00 0 0 0 0, Q 0 0 9 0 000 0«« 0f *r r o t t IL tat DATED this 9th day of January, 1995 Rhone-Poulenc Rorer S.A. By Its Patent Attorneys DAVIES COLLISON CAVE 950109,pAoperdab,236G6.sp, 17 vi INTERNATIONAL SEARCH REPORT International application No. PCT/FR 92/00666 A. CLASSIFCATION OF SUBJECT~ MATTER Int.Cl. 5 CO7D471/04; //'(co7D471/04,22J1:00,221:0O) According to International Patent Classification (IP'q or to bath national classification and IPC B F1ELDS SEARCHED Minimum docuimentatiorn searchtii (classification system followed by classification C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during thr international search (name of data base and, where practicable, Search terms used) C. DOCUMENTS CONSIDERED TO BE RELVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X US,A,4 960 779 BOtJRZAT ET AL.) 2 October 1990 cited in the application see column 1.1, lines 35-48; column 19, example 33 A FR,A,2 321 290 (RHOE-POULENC INDUSTRIES) 1 18 March 1977 see page 3, formnula (IX) A FR,A,2 313 060 (SOCcIT DES USINES CHIMIQUES 1 RHONE-POULENC) .31 Decemh-.-r 1976 see page 4, formula WX E Further documents are listed in the continuation of Box C. El See patent family annex. Special categories of cited documents: -T laterdoructinotpublisbedafterthelinternlationtal filitgdateorpriority ocuentdefnin th genralstae o th ar whih i no cosidred datemand Dot in conflict with tbe application but cited to understand tA ocmn h eiigtegarlsae of parhcle reevnc whc.sntcniee the principle or theory underlying the invention earlier document but published oo or after the international filing date "X"I document Of particular relevance; the claimed invention cannot be considered h~ovel or cannot be considered to Involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other Special reaso0 (aS Speetfied) docmnent of particular revance; the claimned invention cannot he document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with oneormoreothersuch documcots,such combination document published prior to the international filing date but later than being obvious to a prson akilled in the art the priority date claimed &"document memober of the smie patent family Date of the actual completion of the international search Date of mailing of the international search report 6 October 1992 (06.10.92) 26 October 1992 (26.10.92) Name and mailing address of the ISA/ Authorized officer7 European Patent Office Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. FR 9200666 SA 62541 ThIis limeX UMst the patent farally memnbers relating to the patent douets cited in the above-mentionedf intenironal search report. The menbs arc as contained in the European Patent Office EDP file on The European Patent Office is in no way Liable for these particalars which2 are merely given for the purpose of information. 06/ 10/92 Patent document Publication Patent family PubLicatiou crtcd in starch report date mber(s) -Tdaft US-A-4960779 02-10-90 FR-A- 2607503 03-06-88 AU-B- 600776 23-08-90 AU-A- 8191187 02-06-88 OE-A- 3772259 26-09-9 1 EP-A,B 0274930 20-07-88 JP-A- 63154681 27-06-88 SU-A- 1577698 07-07-90 SU-A- 1630612 23-02-91 ZA-A- 8709000 01-06-88 FR-A-232 1290 18-03-77 AT-B- 348528 26-02-79 AT-B- 348529 26-02-79 AT-B- 348524 26-02-79 AU-A- 1267476 13-10-77 BE-A- 840428 06-10-76 CA-A- 1072957 04-03-80 CH-A- 613453 28-09-79 CH-A- 614209 15-11-79 DE-A- 2615067 28-10-76 GB-A- 1483996 24-08-77 JP-A- 51122094 25-10-76 JP-B- 62000149 06-01-87 LU-A- 74703 02-02-77 NL-A- 7603307 11-10-76 OA-A- 5287 28-02-81 SE-B- 421793 01-02-82 SE-A- 7604044 08-10-76 jUS-A- 4086348 25-04-78 US-A- 4131674 26-12-78 FR-A-2313060 31-12-76 AT-B- 343666 12-06-78 AT-B- 343123 10-05-78 AU-B- 503200 30-08-79 -WlBE-A- 835325 06-05-76 detail ab~out this smx ste Offical Joamal of the European Patcat Office, No. 12/82 1. This an 'Zbcm The E FR I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. RR 9200666 SA 62541 nex lists the patent family memheaw relating to the patent documaets cited in the aboverneetiooed interational mnri repot bers arc as contained in the European Patent Office EDP file on ropean Patent Office is in no way iable for thece particulmr whidi ame merely given for the purpo of inlormation. 06/10/92 Q For wore dels abwUt this nex we OffiCil Journal of the EumPan Officep No. 12/82