AU657569B2 - Method for the preparation of optical isomers of a 2-amino naphthyridine derivative - Google Patents

Description

OPI DATE 11/02/93 AOJP DATE 08/04/93 APPLN. ID 23608/92 1111111I111IINi1111111ii PCT IUMBER PCT/FR92/00668li Ili!li iiiIliI iiliiIIii AU9223608 DEMAND E INTERNATIONALE PUBLIEE EN VERTU DU TRAITE DE COOPERATION EN MAXIERE DE UKVE Is (FL, (51) Classification internationale des brevets 5 (11) Num~ro de publication Internationale: WO 93/01189 C07D 221:0,/ 22100)41/4A (43) Date de publication internationale: 21 janvier 1993 (21.01.93) (21) Num~ro de la demande internationale: PCT/FR92/00668 (81) Etats disignis: AU, CA, Fl, RU, JP, KR, NO, RU, US, bruvet europ~en (AT, BE, CR, DE, DK, ES, FR, GB, (22) Date de d~p6t international: l0juillet 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).

Donnies relatives i la prioriti: 91/08828 12 juillet 1991 (12.07.9 1) FR Publi~e Avec rapport de recherchze internationale.

(71) D~posant (pour tous les Etats d~sigmns satif US): RHONE- POULENC RORER S.A. EFR/FRj; 20, avenue Ray- b 6 mond-Aron, F-92160 Antony (FR).

(72) Inventeur; et 1nventeur/D~posant (US seulernent) DAVID-CO MTE, Marie-Th~r~se [FR/FR]; 1, all~e Costes-et-Bellonte, F- 94500 Chevilly-Larue (FR).

(74)Mandataire: PILARD, Jacques; Rh6ne-Poulenc Rorer Direction Brevets, 20, avenu- Raymond-Aron, F- 92165 Antony C~dex (FR).

F_ O l> (54)Title: METHOD F0RAPREPARATW 4 OPTICAL ISOMERS OF A 2-AMINO NAPHTHYRIDINE DERIVATIVE (54)Titre: PROCEDE DE PREPARATION DES ISOMERES OPTIQUES D'UN DERIVE DE L'AMINO-2 NAPRTYRI-

DINE

COOM

NIH -i ZN CI N N

WI

0 (57) Abstract A method fr preparing the dextrorotatory isomer of the product or formula from the salt of the corresponding racemic product with )-ephedrine. The use or the resulting dextrorotatory isomer for preparing the dextrorotatory isomer or the product of rormula (11) is also described.

(57) Abrkg6 Proc&d& de preparation de 1'isom~re dextrogyre du produit de rormule -6 partir du set du produit rac~mique correspondant avec la (+)-6ph~drine, Utilisation de l'isom~re dextrogyre ainsi obtenu pour la preparation de l'isom~re dextrogyre du produit de formule (11).

WO 93/01189 1 PCT/FR92/00668 PROCESS FOR THE PREPARATION OF THE OPTICAL ISOMERS OF A 2-AMINONAPHTHYRIDINE DERIVATIVE The present invention relates to a process for the preparation of the optical isomers of the 2aminonaphthyridine derivative of formula:

COOH

NH C N N More particularly, the present invention relates to the preparation of the dextrorotatory isomer of the product of formula which is useful for the preparation of the dextrorotatory isomer of the product of formula: N Cl (11) N 0 which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic anc muscle-relaxant properties.

It has been shown that, in the case of the product of formula (II) which, with analogous products, is the subject of American Patent US 4,960,779, the active entity or eutomer is the dextrorotatory N isomer.

-2- According to one aspect of the present invention there is provided a process for the preparation of the dextrorotatory isomer of the product of formula

COOH

NH N Cl

(I)

O

characterised in that the salt of the corresponding racemic product with (+)-ephedrine is precipitated, separated by filtration and then the dextrorotatory isomer is released from its salt.

15 According to another aspect of the present invention there is provided a process for the preparation of the S: dextrorotatory isomer of the product of formula:

(II)

0O 25 which comprises preparing the dextrorotatory isomer of the product of formula: COOH I

(I)

O

by the process defined above and then converting this product into the dextrorotatory isomer of the product of formula 950 1O9,p;ocrWkb,23608.spc,2 2a NI

II)

O

According to the invention, the formation of the salt of the racemic product of formula with (+)-ephedrine is carried out in an appropriate organic solvent such as ethanol. The salt of the dextrorotatory product of formula and of (+)-ephedrine precipitates. The pure dextrorotatory isomer of the product of formula is 15 displaced from its salt by means of a strong acid such as hydrochloric acid.

The dextrorotatory isomer of the product of formula (I) is cyclised to the eutomer of the product of formula (II) by means of thionyl chloride, optionally in the presence of a condensing agent such as imidazole or pyridine in an organic solvent such as methylene chloride.

S...iq *o* 950109,p:\opctab.23608.spe,2 It is not necessary to separate the dextrorotatory isomer of the product of formula (I) prior to the cyclisation to the dextrorotatory product of formula (II).

The product of formula can be obtained by opening of the pyrrolinone ring of a racemic product of formula (II) 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 (II) 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.

The product of formula can also be obtained by action of an inorganic base on the product of formula: I d 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 0 C, preferably between 0 and 30°C. A dioxane-water mixture is preferably used as aqueous organic medium.

The product of formula (III) can be obtained by hydrolysis in acid medium of a product of general formula: 0 ON C (IV) 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 sulphuric acid while working at a temperature of between 0 and 50 0 C, preferably aproximately 20 0

C.

The products of fr.mula (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 1 250 g of 2-{l-[(7-chloro-1,8-naphthyridin- 2-yl)amino]-6-methyl-3-oxoheptyl}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 reaction mixture is cooled to approximately 2 0 C. The precipitate obtained is separated by filtration, washed with 2 times 125 cm 3 of 95% ethanol at 2°C and then dried for 16 hours at under reduced pressure (15 mm of mercury; kPa). 156.6 g of the salt of (+)-ephedrine and 2- {1-[(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: [a] 0 -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 cm 3 round bottom flask. 1.2 cm 3 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 under reduced pressure (15 mm of mercury; 2.0 kPa).

2 6 1.97 g of :''ro-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: +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: 1) 1400 cm 3 of dioxane and 20 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl- 2-oxohexyl)-l-isoindolinone are introduced, at a temperature of approximately 20°C, into a stirred, 2 litre reactor. 244 cm' of a N aqueous solution of sodium hydroxide are added over 5 minutes. The mixture is left to react for 4 days at a temperature below 0

C.

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

The pH of the suspension ip then approximately 'I t el S 7 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°C for 16 hours.

14.3 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 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 pm" 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 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.

2) 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) at a temperature below 20 0 C. 500 cma of distilled water are added. An insoluble material is separated 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 under reduced pressure (15 Km of mercury; 2.0 kPa) at 19.2 g of 2-{l-[(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 by high performance liquid chromatography is 4.8 minutes under the conditions described previously.

3) A suspension of 30 mg of 2-[2-(7-chloro- 1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl- 3-oxoheptanoic acid in 4.7 cm 3 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 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated 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-1,8-naphthyridin-2-yl)-3oxoheptanoic acid can be prepared in the following manner: A solution of 23 g of ethyl 2-[2-(7-chloro- 4- 9 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 and is then poured into 1.5 kg of ice. The precipitate obtained is separated 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 by filtration, the filtrate is acidified to a pH 3 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated 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-l,8-naphthyridin-2-yl)-3-oxolisoindolinyl]-6-methyl-3-oxoheptanoic acid, melting at 176 0 C, are thus obtained.

Ethyl 2-[L-(7-chloro-1,8-naphthyridin-2-yl)- 3-oxo-l-isoindolinyl]-6-methyl-3-oxoheptanoate can be obtained by the method described in American Patent US 4,960,779.

EXAMPLE 2 g of the dextrorotatory acid obtained under the conditions described previously and 21.8 g of imidazole are dissolved in 400 cm 3 of methylene chloride in a 1 litre reactor. 7 cm 3 of thionyl chloride are introduced, using a syringe, at a temperature of 20 0

C.

The suspension is heated at reflux for 30 minutes and v; is then cooled to 20°C and is then washed 2 times with 200 cm 3 of distilled water. Tte solution is concentrated, at atmospheric pressure, to half its volume and Chen 450 cm 3 of absolute ethanol are added.

The distillation of the iiethylene chloride is continued until the temperature of the vapours reaches 78 0 C. 1 g of decolorising charcoal is then added and the mixture is left for one hour at 78'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 0 C over 2 hours. The suspension is filtered. The precipitate is washed with 3 times 35 cm 3 of absolute ethanol at 156C and then dried at 60 0 C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro- 1,8-naphthyridinyl)-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: [ac]o +1320 (c 1; methylene chloride) enantiomeric purity: 98.8%.

EXAMPLE 3 118.3 g of the salt of (+)-ephedrine and 2- {1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3oxoheptyl}benzoic acid and 1700 cm 3 of methylene chloride are introduced into a 2.5 litre reactor. The organic solution is washed, at 20 0 C, with 400 cm 3 of a 11 aqueous hydrochloric acid solution and then 400 cm 3 of distilled water. The organic phase is dehydrated by azeotropic distillation at 20 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 at 40°C for 30 minutes, then cooled to 20°C and washed with 2 times 700 cm 3 of distilled water. Te 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 added.

The mixture is left' for 30 minutes at 78°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 fil' )red. The precipitate is washed with 3 times 140 cm 3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 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 with 3 times 100 cm 3 of absolute et+hanol at 10 0 C and then dried at 60°C for 16 hours Al 1 12 under reduced pressure (15 nmn of mercury; 2.0 kPa).

65.1 gj of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)- 3- (5-iethyl-2-oxohexyl )-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: optical rotation: [ac]2 0 +1320 (c methylene chloride) -enantiomeric purity: 100%.

12a 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.

**S

g 9o9 oo 9 9** oa.° .9 *o 950109,p\opcidab,23608speM 2

Claims (3)

1. Process for the preparation of the dextrorotatory isomer of the product of formula Goo* *0 ,00*0, s e S. 0 0 .0.9

009. 0 S S *SS characterised in that the salt of the corresponding racemic product with (+)-ephedrine is precipitated, separated by filtration and then the dextrorotatory isomer is released from its salt. 2. Process according to claim 1, characterised ir that the salt of the racemic product with (+)-ephedrine is precipitated from an organic solvent such as ethanol. 3. Process according to claim 1, characterised in that the release of the dextrorotatory isomer of the product according to claim 1 is carried out by means of a strong acid such as hydrochloric acid. 4. A process for the preparation of the dextrorotatory isomer of the product of formula: (II) which comprises preparing the dextrorotatory isomer of the product of formula: 950109,p:Nopcrdab,236.spc, 13 14 by the process of Claim 1, 2 or 3, and~ then converting this product into the dextrorotatory isomer of the product of formula 0* o S S S. S SS S S S S S. S S S S .5

55.. S S S S S. (I I) 5. Procoesses for the preparatiLon of dextrorotatory isomers of the products of the~ formulae and (II) substantially as hereinbefore described with reference to the Examples. DATED this 9th day of January, 1995 Rhone-Poulenc Rorer S.A. By Its Patent Attorneys DAVIES COLLISON CAVE 95NG9,p:aopcevkb,23608.spe, 14 RAPPORT DE RECHERCHE INTERNATIONALE Dentand. Internationale No PCT/FR 92/00668 1. Q.ASSENIENT DE L'INVENTION (si plusieurs sym boles de clssification soot applicabkes, Ies Lndlquer taus) 7 Salon la classification Internationale des brevets (CIB) on i l a fois selon la classification national* et la CIB CIB 5 C07D471/04; //(C07D471/04,221,-00,221:00) H3. DOMAINES SUR LESQUELS LA RECHERCI{E A FORTE Documentation minimale consultde 8 Systdse de classification Symboles de classification CIB 5 C07D Documecntation coasult~e ajitre que Ix documentation minimale dans la niesure oiA de tels documents foot partie des domaines stir lesquels la recherchte a portP 19I. DOCUMENTS CONSIDERIES COMME PERTINENTSI 0 Caftri Identification des documents cltis, avec indication, Ai n~cessaire02 No. des A FR,A,2 321 290 (RHONE-POULENC INDUSTRIES) 18 1,4 Mars 1-977 voir page 3, forinule (IX) A FR,A,2 313 060 (SOCIETE DES USINES CHIMIQUES 1,4 RHONE-POULENC) 31 Ddcembre 1976 voir page 4, formule (X) A US,A,4 960 779 BOUR.ZAT ET AL.) 2 Octobre 1990 cit6 dans la dernande voir colonne 11, lignes 35-48; colonne 19, exeinple 33 0 Catigories spdales de documents cltd. 11 document uhtideur publJ6 post~rieuremnent i la date de dip~t ocuentd~fnlsaatI'dat dndl d Iacliiqu, ~internatiomal ou di la date de prioritk at tk'a patenanant Wa '"dcun dkfiisan I'a gika de ltehiunni 1tat de la technique pertinent, mais dtk pour comprendre coasdir cowe artculiremnt ertnen Itprincipe oti la thboia constiuant la base do I'Invention document mnt~rieur, mnals publik A la date de dkpdt interna- -XI document partitld~irement pertinent; i'Inventioa revendi- tional ou api carte date q6a ne pott e consid&~e cmmc nouveile oti cmmc 'V document pouvant leter tno doute sur tine revendicatlon do INpliquant tine actlvitb Inventive priortk oti dth pour diterminer la date de pblication d'uoe document p aiuli ent petnet rivnt reven- autro citation ou pour t raison sp~dale (tlle qm'indiquhe) dlquke ne petit fte conzlddke cmmc Impllquant tine document se rkfkmat ;k tine divuigadon orabe, i an usage, i artivlt Inventive Iorsque It doctument est aszoc:6 i un on tine exposition on tous autres incyeas plusleurs atitres documents do m~me nature, carte combi- document publik avant la date de d&$t International, mals naison kint Evidente pour tine personae du mkder. postieurement d. la date de priorit6 revendiquke WA document qul Wat parie deI& memo famlle do brevets IV. CERTIFICATIN Date i laquelle la recherche Initernationale a Wt effectivement achevie Date d'expkdition dti prksent rapport de rechercheo Internationale 06 OCTOBRE 199? 26 OCT 1992 Administration cbargke de lI rechjerche Internationale Signature du fonctionnaire autorisA OFFICE EUROPEEN DES BREVETrS CHRISTIAN HASS VFsuuinkr P CTitSA/2I(dkuE feilal (Smntor 115) ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 9200668 SA 62543 La prisente annexe indiquc les membres de In famillec do brevets relatifs attx documents brevets citis dama le rapport de rechercbe internationale vise ci-deixus Lesdits zneibres sont contenus au fichier informatique de I'Officeceuropien des brevets i In date du Les renscigneinents fournis soot donnis i titre indicatif et Wengagent pasi]a respoosabiliti de I'Officoe uropieu des brevet. 06/ 10/92 Doemwet brevet citi Date do Mcrnbre(s) dc Ia Date de au rapport do recherche publication- 7 fami~le de brevetZ) publication FR-A-2321290 18-03-77 AT-B- 348528 26-02-79 AT-B- AT-B- AU-A- BE-A- CA-A- CH-A- CH-A- DE-A- GB-A- JP-A- JP-B- LU-A- NL-A- OA-A- SE-B- SE-A- U S-A- U S-A- 348529 348524 1267476 840428 1072957 613453 614209 2615067 1483996 51122094 62000149 74703 7603307 5287 421793 7604044 4086348 4131674 26-02-79 26-02-79 13-10-77 06-10-76 04-03-80 28-09-79 15-11-79 28-10-76 24-08-77 25-10-76 06-01-87 02-02-77 11-10-76 28-02-81 01-02-82 08-10-76 25-04-78 26-1~2-78 f FR-A-2313060 31-12-76 AT-B- AT-B- AU-B- BE-A- CA-A- C H-A- C GB-A,- JP-c- JP-B- LU-A- KI OX-A- SE-B- SE-A- U S-A- 343666 343123 503200 835325 1057755 609057 2550111 1468497 1018394 54098790 55008508 73738 7512732 5162 407063 7512477 4220646 12-06-78 10-05-78 30-08-79 06-05-76 03-07--79 15-02-79 13-05-76 30-03-77 28-10-80 03-08-79 04-03-80 06-09-76 11-05-76 31-01-81 12-03-79 10-05-76 02-09-80 US-A-4960779 02-10-90 FR-A- 2607503 03-06-88 AU-B- 600776 23-08-90 Pour tout reaseignement concernant cette annexe voir Journal Officiel do rOffice europn des brevets, No.12ISI2 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 9200668 SA 62543 This annex lists the patent family members relating to the patenmt documents cited in the above-mentioned international search report. The members ae as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. 06/10/92 Patent document Publication Patent family Publication cited in search report date member(s) date US-A-4960779 AU-A- DE-A- EP-A,B JP-A- SU-A- SU-A- ZA-A- 8191187 3772369 0274930 63154681 1577698 1630612 8709000 02-06-88 26-09-91 20-07-88 27-06-88 07-07-90 23-02-91 01-06-88 I 0 2 For more details about this annex: see Official Journal of the European Patent Offlice, No. 12/82 INTERNATIONAL SEARCH REPORT International application No. PCT/FR 92/00668 A. CLASSIFICATION OF SUBJECT MATTER Int. Cl. 5 CO7D 471/04; //(C07D 471/04, 221:00, 221:00) According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. Cl. 5 CO7D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A FR, A, 2 321 290 (RHONE-POULENC INDUSTRIES) 1,4 18 March 1977 see page 3, formula (IX) A FR A, 2 313 060 (SOCIETE DES USINES CHIMIQUES 1,4 RHONE-POULENC) 31 December 1976 see page 4, formula (X) A US, A, 4 960 779 BOURZAT ET AL.) 2 October 1990 cited in the application see column 11, lines 35-48; column 19, example 33 Further documents are listed in the continuation of Box C. See patent family annex S Special categories of cited documents: later documentpublished afterthe international filingdateor priority document defining the generai state of the art which is ot considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier document but published on or after the international filing date document of particular relevance: the claimed invention cannot be considered novel or ,annot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is aken aloneveiv cited to establish the publication date of another citation or otherep wen the dcume s aken special reason (as specified) document of particular relevance: the claimed invention cannot be document referring to an oral disclosure, us,, eMhibiteon or other considered to involve an inventive step when the document is means combined withoneor more othersuch documents,such combination document published prior to the interna;tnal filing date but lalvr than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 06 OCTOBER 1992 (06.10.92) 26 OCTOBER 1992 (26.10.92) Name and mailing address of the ISA/ Authorized officer 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. TR SA 9200668 62543 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international scarich report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars whih ra d ary given for the purpose of information. 06/10/92 Patent document Publication Patent family Publication cited in search report date member(s) date FR-A-2321290 18-03-77 AT-B- 348528 26-02-79 AT-B- AT-B- AU-A- BE-A- CA-A- CH-A- CH-A- DE-A- GB-A- JP-A- JP-B- LU-A- NL-A- OA-A- SE-B- SE-A- US-A- US-A- 348529 348524 1267476 840428 1072957 613453 614209 2615067 1483996 51122094 62000149 74703 7603307 5287 421793 7604044 4086348 4131674 26-02-79 26-02-79 13-10-77 06-10-76 04-03-80 28-09-79 15-11-79 28-10-76 24-08-77 25-10-76 06-01-87 02-02-77 11-10-76 28-02-81 01-02-82 08-10-76 25-04-78 26-12-78 FR-A-2313060 31-12-76 AT-B- AT-B- AU-B- BE-A- CA-A- CH-A- DE-A,C GB-A- JP-C- JP-A- JP-B- LU-A- NL-A- 0A-A- SE-B- SE-A- US-A- 343666 343123 503200 835325 1057755 609057 2550111 1468497 1018394 54098790 55008508 73738 7512732 5162 407063 7512477 4220646 12-06-78 10-05-78 30-08-79 06-05-76 03-07-79 15-02-79 13-05-76 30-03-77 28-10-80 03-08-79 04-03-80 06-09-76 11-05-76 31-01-81 12-03-79 10-05-76 02-09-80 US-A-4960779 02-10-90 FR-A- 2607503 03-06-88 AU-B- 600776 23-08-90 0 1 For mo-c details about this annex: see Official Journal of the European Patent Office, No. 12/82 ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 9200668 SA 62543 La pr~et amrLxe indique les membres de In famille de brevets redatift aux docuumets brevets cites dans le rapport de recherbeiterationale vise ci-dessus. Lesdits niembres soot contenus au fichier informatique de i'Officeceuropien des brevets a In date du Les resmgements fournis soot donnis i tite indicatif et n'eugagent pas In responsabiliti dri'Ofllce europene des brevems 06/10/92 Docwumt brevet citi Date de Menibre(s) de In Date de au rapport de recherche publication fainifle de brevet(s) publication US-A-4960779 AU-A- 8191187 02-06-88 DE-A- 3772369 26-09-91 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- 8,709000 01-06-88 Pour tout rcnpdgnemt concernant cot nn= voir Journal Ofliciel de l'Office eurp'An des breves, No.12/82