AU657568B2 - Method for preparing optical isomers of a 2-amino naphthyridine derivative - Google Patents

Description

A0PDATE 08/04/93 PCT NUMBER PCT/FR92/00667IIlIIIII" DATE11/0/93 PPLN tO 360792 II 11111 AU9223607 Ini DEMANDE IN I RNA I itNALU PUiLIUh h.N VbIIU DU I RAI I L Ul'LA I UN bN MAI I EKE UL Bt~Vt Ib (F) (51) Classification internationale des brevets 5 C07D 471/04, A61K 31/435 (CO7D 47 1/04, 221:00, 221:00) (11) Nurn~ro de, publication internationale: WO 93/01188 Al (43) Date de publication internationale: 21 janvier 1993 (21.01,93) (21) Num~ro de ]a demande internationale: PCT/FR92/00667 (22) Date de d~p6t international: l0juillet 1992 (10.07.92) Donn~es relatives i la priorit6: 91/08829 12juillet 1991 (12.07.91) FR (71) Diposant (pour wits les Etats d~sign&~ sauf US): RHONE- POULENC ROREFK S.A. [FR/FR]; 20, avenue Raymond-Aron, F-92 160 Antony (FR).

(72) Inventeur; et Inventeur/D~posant (US seulentent) DAVID-COMITE, Marie-Th~r~se [FR/FR]; 1, ale Costes-et-Bellonte, F- 94500 Chevilly-Larue (FR).

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

(81) Etats disign~s: AU, CA, Fl, H U, J P, KR, NO, RU, US, brevet europ~en (AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LU, MC, NL, SE), brevet OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD, TG).

Publi~e Avec rapport de recherche internationale.

57568 (54) Title: METHOD FOR PREPARING OPTICAL ISOMERS OF A 2-AMINO NAPHTRYRIDINE DERIVATIVE (54)Titre: PROCEDE DE PREPARATION DES ISOMERES OPTIQUES D'UN DERIVE DE L'AMINO-2 NAPHTYRI-

DINE

COOH

N. NH. Cl (1) N N (57) Abstract A method for preparing the dextrorotatory isomer of the product of formula from a salt of the corresponding racemic product with cinchonine then cinchonidine.

(57) Abrig6 Proc~c16 dc preparation de l'isom~re dextrogyre du produit de formule A partir d'un sel du prodult rac~mique correspondant avec la cinchonine puis avec ]a cinchonidine.

WO 93/01188 1 PCT/FR92/00667 PROCESS FOR THE PREPARATION OF THE OPTICAL ISOMERS OF A 2-AMINONAPHTHYRIDINE DERIVATIVE The present invention relates to a new process for the preparation of the optical isomers of the 2-aminonaphthyridine derivative of formula:

COOH

Q J NH 1^ (I) 0 More particularly, the present invention relates to the preparation of the dextrorotatory isomer of the product of the formula which is useful for the preparation of the dextrorotatory isomer of the product of formula: 0 N N (IcI which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant properties.

It has been shown that, in 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 isomer.

According to American Patent US 4,960,779, the separation of the optical isomers of the product of formula (II) was carried out by chiral phase chromatography. However, the industrial application of this process is not always convenient to implement.

According to the invention, the dextrorotatory isomer of the product of formula is obtained by first precipitating the cinchonine salt of the laevorotatory product of formula and then, after displacing the dextrorotatory isomer from its cinchonine salt in the filtration mother liquors of the cinchonine salt of the laevorotatory isomer, by precipitating the cinchonidine salt of the dextrorotatory isomer.

The dextrorotatory isomer of the product of formula after being displaced from its cinchonidine salt, is converted by cyclisation to the dextrorotatory isomer of the product of formula (II).

According to the invention, the formation of the cinchonine salt of the racemic product of formula is carried out by working in an organic solvent, such at ethanol, in which the salt is insoluble.

The product of formula enriched in the dextrorotatory isomer in the form of the soluble cinchonine salt, in the filtration mother liquors is displaced from its salt after acidification by means of a strong acid such as hydrochloric acid. The product which is enriched in the dextrorotatory isomer, whei treated with cinchonidine in an organic solvent such as ethanol, leads to the precipitation of the cinchonidine salt of the pure dextrorotatory isomer of the product of formula The rure dextrorotatory isomer of the 3Y) product of formula is displaced from its cinchonidine salt by means of a strong acid such as hydrochloric acid.

The dextrorotatory isomer of the product of formula 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.

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°C and, preferably, of between 0 and 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: o N N N

^HOCO

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: 0 N 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 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 invention.

X EXAMPLE 1 1450 cm 3 of 95% ethanol, 100 g of v^ l r f cinchonine and 145 g of 2-{1-[(7-chloro- 1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}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 0 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: []2 0 +192.60 (c 1; methylene chloride) enantiomeric purity: 98.5%.

250 cm 3 of N-methylpyrrolidone and 50 g of the salt obtained previously are introduced into a stirred, 2 litre reactor. 90 cm 3 of N hydrochloric acid are added over 30 minutes while maintaining the temperature at 200C. The mixture is left for 1 hour at this temperature and then 660 cm 3 of distilled water are added over 1 hour. The suspension obtained is filtered. The precipitate is washed with 5 times 103 cm 3 of water and then dried at 60°C for 16 hours under reduced pressure mm of mercury; 2.0 kPa).

28.6 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 characteristics are the following: optical rotation: []O2 -227.40 (c 1; methylene chloride) enantiomeric purity: 99.6%.

2-{l-[(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-[1- [(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2oxoheptyl)-l-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 0

C.

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 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 5 N hydrochloric acid at a temperature of 0 C. 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; S 2.0 kPa) at 60 0 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 wh, '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 p/m" 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-(5-methyl- 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-l,8-naphthyridin-2-yl)- 3-(5-methyl-2-oxohexyl)-l-isoindolinone, 400 cm 3 of pyridine and 60 cm 3 of a 2N aqueous sodium hydroxide solution Lre 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 cm 3 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 mm of mercury; 2.0 kPa) at 60 0

C.

19.2 g of 2-{1-[(7-chloro-1,8 naphthyridin- SO 2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus 8 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°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 hydrochlori. acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of 2-{l-[(7-chloro- 1,8-naphthyridin-2-yl) amino] -6-methyl-3-oxoheptyl}- 15 benzoic acid are thus obtained whose characteristics are identical to those of the product obtained previously.

2- [2-7-Chloro-1,8-naphthyrindin-2-yl)-3-oxo-lisoindolinyl] -6-methyl-3-oxoheptanoic acid can be prepared in 20: the following manner: 20 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 by filtration, washed with water to a pH 6 and dried in air. The solid obtained is taken up in 3.8 litras of distilled water

A

U and 480 cm 3 of a 0.1N aqueous sodium hydroxide solution.

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

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

EXAMPLE 2 400 cm 3 of methylene chloride, 20 g of the product obtained previously and 21.8 g of imidazole are introduced, at a temperature of 20°C, into a stirred, 1 litre reac o 7 cm 3 of thionyl chloride are added, using a syringe, over 10 minutes. The suspension is heated at reflux for 30 minutes, it is thexl cooled to 20°C and washed with 2 times 200 cm 3 of distilled water.

The washed solution is concentrated to half its volume and then 450 cm 3 of absolute ethanal are added.

Distillation at atmospheric pressure is continued until the temperature of the vapour is 78 0 C. 1 g of decolorising charcoal is added and the mixture is then held for 1 hour at 70*C. The suspension is filtered.

The precipitate is washed with 50 cm 3 of ethanol at 750C. The filtrate and the wash are combined. After cooling over 2 hours to 15 0 C, the suspension is filtered. The precipitate is washed with 3 times 35 cm 3 of ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa).

16.7 g of (-)-2-(7-chloro-1,8-naphthyridin-yl)methyl-2-oxohexyl)-1-isoindolinone are thus obtained in a form of a fluffy white product whose characteristics are the following: optical rotation: [a]O0 -1320 (c 1; methylene chloride) enantiomeric purity: 100%.

EXAMPLE 3 1274.3 g of ethanolic liquors (corresponding to the filtrate of the cinchonine salt obtained previously plus addition of the ethanol wash) are introduced into a 2 litre reactor. 260 cm 3 of an N aqueous hydrochloric acid solution are added at 20 0 C. After stirring for minutes, 6,'0 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 60 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-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are the following: optical rotation: +1600 (c 1; methylene chloride) enantiomeric purity: 73.2%.

I\ i'/ 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°C. A product crystallises. The suspension is filtered. The precipitate is washed with 2 times 50 cm 3 of 95% ethanol and then dried at 60 0 C for 16 hours under reduced pressure (15 mm of mercury; kPa).

92.8 g of the cinchonidine salt of [(7-chloro-, 8-naphthyridin-2-yl)amino] methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: optical rotation: [a]2 0 -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 maintaining the temperature below 20°C. After stirring for 15 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 (4-.)-2-{l-[(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 characteristics are the following: 12 optical rotatior. =222.80 (c 1; methylen chloride) enantiomeric purity: 100%.

EXAMPLE 4 20 g of the dextrorotatory acid obtained 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°C. Tha suspension is heated at reflux for 30 minutes, is subsequently cooled to 200C and is then washed 2 times with 200 cni of distilled water. The solut, on is concentrated, at atmospheric pressure, to half its volume and then 450 cm of absolute ethanol are added. The distillation of the methylene chloride is continued until the temperature of the vapour reaches 780C. 1 g of decolorising charcoal is then added and the mixture is then left for 1 hour at 78 0 C. The suspension is filtered. The precipitate is washed with 50 cm 3 of absolute ethanol at 75'C. The filtrate and the washes are combined and then cooled to 150C over 2 hours. The suspension is f4ltered. The precipitate is washed with 3 times 35 cm 3 of absolute ethanol at 15 0 C and then dried at 600C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro- 1,8-naphthyridin-yl) -3-(5-metblyl-2-oxohexyl)- 1-isoindolinone are thus obtained in the form of a fluffy white ptoduct whose characteristics are the following: optical rotation: +1320 (c 1; methylene chloride) i 30 erantiomeric strength: 98.8%.

ilp 12a Throughout this specification and the claims which follow, unless the context requires otherwise, the word 'comprise"l, 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 0 0 :0 '00:6S 0. 00 0. 0 0.0 10S,popa'Mk,236O0,s M. 12

Claims (9)

1. Process for the preparation of the dextrorotatory isomer of the product of formula: CO O H I Cl N (I) 0 characterised in that an insoluble salt of the corresponding racemic product is formed with cinchonine, it is separated by filtration, the product which is enriched in the dextrorotatory isoier is displaced from its cinchonine salt, the cinchonidine salt of the pure dextrorotatory isomer is precipitated and finally the dextrorotatory isomer is freed from its cinchonidine salt.

2. Process according to claim 1, charac- terised in that the cinchonine salt of the racemic Sproduct is precipitated in an organic solvent such as 15 ethanol.

3. Process according to claim 1, charac- terised in that the product which is enriched in the dextrorotatory isomer is separated from its cinchonine salt by means of a strong acid such as hydrochloric acid.

4. Process according to claim 1, charac- terised in that the cinchonidine salt of the product which is enriched in the dextrorotatory isomer is i' precipitated in an organic solvent such as ethanol. Process according to claim 1, characterised in that the pure dextrorotatory isomer is displaced from its cinchonidine salt by means of a strong acid such as hydrochloric acid.

6. The dextrorotatory isomer of the product of formula: N (I) 0 when it is obtained according to the process of one of claims 1 to too* ii 7. A process for the preparation of the 15 dextrorotatory isomer of the product of formula: O N .(II) S 20 0 which comprises preparing the dextrorotatory isomer of the product of formula: COOH n z H .Cl N N (I by the process of any one of claims 1 to 5 and tnen converting this product into the dextrorotatory isomez of the product of the formula:

8. Processes for preparing dextrorotatory isomers of the products of 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 S. S S.. S S S S S S. 55 e S S S. S S S .5 S .2 .2 I, INTERNATIONAL SEAkLCH REPORT International application No. POT/FR 92/00667 A. LLASSIFCATION OF SUB3ECT MATTER int. cl. C07D471/04; A61K3/435; //(c07D471/04,221:00,221:00) According to International Patent Ciassification (WPO1 or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) It. C CO 7 Documentation searched other than minimum documentation to the extent that such documents are incucted in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUhMNTS CONSIDERED TO BE RELEVANT Category' Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A US,A?4 960. 77. (RHMI-POULNC SANTE 2 Octtiber 1,6,7 1990 cited in the, app~lcation see claim 1; example 21 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: tater document publisbedafte the initiaaatial filing dateor priority document defining the general sutat of the art which is not considered date and not in conflict with the application but cited to understnd to be ot particular relevace the principle or tbeory underlying the invention earlier document but pubilahed on or after the international filing date document of particular relevance, the claimed Invention cannot be document which may throw doubts on priority claim(s) or which is consldered novel or cannot be considered to involve an tnIV01tlVC Clied to establishi the publication data of another citation or other step when the document is taken alone special reason (as specified) document of particular relervance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or otber considered to involve an inventive step when the document is means combinedwith oneor mortohersuch documsents, such combination 'P dcuet published prior to the international filing date but later than beoviutoapsnslldithar the priority date claimed document member of the sme patent family Date Of the actual completion of the international search Date of mailing of the international search report 27 August 1992 (27.08.92) 25 Septemiber 1992 (25.09.92) Name and mailing address of the ISAI Authorized officer EUROPEAN PATEN~T cO'FI(M Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) ANNEX TO THE INTERNAMiONAL SEARCH REPORT ON ITERNATIONAL PATENT APPLICATION No. FR 9200567 SA 62542 This annx Lsm the Puan family mecz.a rct~ to dt patent docameat; citd in tbe above-we*awred ntenadono march report- 7be meube ame as conizned in the Euaropean F~tent Office EMP file an Tbc Baropean Fatet Office ir in no way U&abl for chc~e pard~zdam wich x a re y given for the parpo of luflonrmdoo. 2 7/08/92 P-tn doasmenat Publicadon p tn fiamily I p ihodn cited in nuc rmport date I tocob(a) .I date US-A-4960779 02-10-90 FR-A- AU-B- AU-A- DE-A- EP-A,B8 JP-A- SU-A- S U-A- ZA-A- 2607503 600776 8191187 3772369 0274930 63154681 1577698 1630612 8709000 03-06-88

23-08-90 02-06-88

26-09-91 20-07-88

27-06-88 07-07-90 23-02-91 01-06-88 01 bi For mom~ detai about this am=. se Official Journal of the Europve. Patent Office, No. 121HBZ RAPPORT DE RECHERCHE INTERNATIONALE Dead. lateradooa No PCT/FR 92/00667 1. QASSEMENT DE LW4Nn0TIN (sl pluicurs syubdes do Adi tiI~cn soot aplcas, kes iziiique tutu) 7 Selch It dar~ficlcznwnzd0aLeI dos byryj (CI) 1, i I& fuis Won In diufmdzin =621 ctl to Iiua CIB 5 C070471/04; A61K31/435; //(C07D4.71/04,221: 00,221: 00) U. DONIAIES SUR LESQUELS LA RECI~aM- A FORMT Domcado tson m1nima coon, isl Doasmentacon conulti. aire qo. I& documenwon minIMal. dan; I& mnsure 0 g do ss dowinents fus pazdo des doailses sur IeeI& ita part# Ml. DOCUMENTS CONSIDEflS COMME PERTXNENTS Idanfmason des d*oens Lii, avoc irndolo, si nkos Nu No. des ,mcnladlus d5 puzzes paninmts1i jau 14 A US,A,4 960 779 (RHONE-POIJLENC .SANTE) 2 Octobre 1,6,7 1990 citd dans la dernande voir revendication 1; exempie 21 Cnigode spidalat do docommin dhks- T document chbiveur Vubil posulimuiemc i I& daie do dipit document dofinlmm Yin:t goal doI& tec~nlque, anti kntuORdAKI OU di late do pflOrftt At sk'"arsmem ps i r&w do In tod~n~que pordoost, innis dik pour crnaptoodre conslir CuU'AS poldtftlahiroflt wProc Is pdenipe ou In tb~uie cordumt In bAuz do f'lantdn Or' doazumt .Autkisr, main panih Al Is is d 0,4 htms- -z docmentm padckwiment pwftmtui rinvention mevei- tiouil gU l carto due qui a. pout Wue aonslditie =moo wuv*e cii mms deemact poaunzt jenmrun ductswtuneriwsecioisnd Ipl~unt Una intiviti Ifvtwood. pufotbt ou efti poor dkeruinor 13L dae do publlcusino drwu ey, docament pudit~ront p nt; Y'Lauittion -vn wuion 0 pmu noo unison i (alW~o qvLdjqU6o) dlqi no pouit *tm cousidk comms Iinpliquant us documet so rdfirant j no. dron mle, j tan -sall j acufyi aml Ant*Ique todocum*Qtwm asocli A o o =0 e mpcshihon oU kaut lwu inoyfums plusiouu aus dnanti do mnine num r canemii P1 document pubtli avnt J ogj j.148t Inamaol na nas. ifunt &irtni powr tan permso do abder. potweadvaseU t I& in dto do PrIodili j44j -e document qui talt pa"l~ ds In ie oa n =s do brtsei IV. CM~ZICATION Dii. i 1a4uollo I& roderchs Intarazziocale a WtI foedlvoment gaqeie Dane dexpiditlon dua priat rapport ds rscochs InWorudxlei 27 AOUT 1992 25. f9192 AtuInIadn chuig" do In newme Loterticlasle SIPauRe do tonutoanalro aunwdsi OFFCE EUROPEEN DES BEVETS HEY WOOD C.J'. fwa~ar rc*TIjZI AJ2u$w boualf1J,4w 150M1 ANNEXE AU RAPPORT DE RECHERCHE INTERNM1IONALE RELATIF A LA DEMANDE INTERATIONALE NO.Q FR 9200667 SA 62542 La ~Wscaft v indi"o hI mcmb de In faiih de bmveu rtliais wai io-aw kecyas cit~ is wnic ruppeit de rvdma wmmae vace Lart mcm mmit cew a ia idarwsxquce 1117 I'Ol £aia reets it In date dii Lts rwmitu,, mix noct douis i titro indaf ct jea. at pas In respoamWiti de i'Offlr twopica dme ktvcrz 27/08/92 D~cmmt hrm sci Datz do M~ev(s) 60In Date dc u arapport dcchwi T puhIlctioaIn~ I do bfevtgg) piiiaice US-A-4960779 02-10-90 FR-A- 2607503 03-06-88 AU-B- 600776 23-08-90 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- 15776PI 07-07-90 SU-A- 1630612 23-02-91 LA-A- 8709000 01-06-88 Four tout rezun'xt conwcuraustz azm voir Joumal omcw~ de oi mOffl; dca hrcvctU, Na.12132 INTERNATIONAL SEARCH REPORT International application No. PCT/FR 92/00667 A. CLASSIFICATION OF SUBJECT MATTER Int. Cl. C07D471/04; A61K31/435; //(C07D471/04,221:00,221:00) 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. C1l C07D 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 US,A,4 960 779 (RHONE-POULENC SANTE) 2 October 1,6,7 1990 cited in the application see claim 1; example 21 Further documents are listed in the continuation of Box C. 7 See patent family annex. Special categories of cited documents: laterdocument publishedaft'r theintemationi filing dateor priority document defining the general state of the art which is not considered date and not in conflic wth 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 internation l filing date document of particular relevance; the claimed Invention cannot be considered novel or cannot be considered to involve an inventive documrnt 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 ot%;er special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the documelt is means combined with oneor more othersuch documents,such combination document published prior to the international filing date but later 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 27 August 1992 (27.08.92) 25 Septembar 1992 (25.09.92) Name and mailing address of the ISA/ Authorized officer EUROPEAN PATENT OFFICE Facsimile No. Telephone No. Form PCI/ISA/210 (second sheet) (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. FR SA 9200667 62542 This annex fists the patent family members relating to the patent documents Lited in the above-mentioned international search report. Ile members are as contained in the European Patent Office EDP file on Ile European Patent Office is in no way liable for them particulars which are merely given for the purpose of information. 27/08/92 Patent document Publication Patent family Publication 1 cited in search report I date Imember(s) Tdate ]I US-A-49 60779 02-10-90 FR-A- AU-B- AU-A- DE-A- E.P-AB JP-A- SU-A- SU--A- ZA-A- 2607503 600776 8191187 3772369 0274930 63154681 1577698 1630612 8709000 03-06-88 23-08-90 02-06-88 26-09-91 20-07-88 27-06-88 07-07-90 23-02-91 01-06-88 hi For more details about this annex :see Official Journal of the European Patent Office, No. 12182 RAPPORT DE RECHERCHE INTERNATIONALE Poomad. Iftenai No PCT/FR 92/00667 1. Q.ASSEMEENT DE LINVENT]ION (i piusiaurs xymboles do Mlsifcation soat appicibles, las indIquer taus) I Seloo I& classlflcaton interaoale des bravets (CWB) ou A la fois sWon I& classification national, at I&a l CIB 5 C07D471/04; A61K31/435; //(C070471/04,221:00,221:00) U. DOMAINF.S SUR LESQUELS LA RECHERCHE A PORTE Documentation mioheale co-sstbe 1 l systaime do classificaion Symboles do clustflcatioo CIB 5 C07D Documeantation consultb. autra qua Ia documentation mInimal. dans lz meure cfl do tels documents fun: pard* des domalnes sur lusquels. la rachache a portif MI. D)OCUM1ENTS CONSMiDErS COMMqE pERTINENTSL 0 Catagrio Identiflcation des documents citis, avoc indication, Ai oicssalru, 2 No. des revandicatioos des paszps poets13~ vis6V 14 A US,A,4 910 779 (RHONE-POULENC SANTE) 2 Octabre 1,6,7 1990 cit6 dans la demr~aide voir revendication 1; exemple 21 Cattgorts spiciales do documnts clt~ll -r document ultkleour publib postidourement A la date do iot international on A la date do prdorii et napesartmat pas document diflalsssnt litat *nisa do la techique, no A i'tat doaI& techanique pertinent, miii ipour comprandra cons(46r6 comma particufliirtint pttzut is princips ou I& thia constituant I& based.o I'lavention 'E documan antitiqur, mats publb A I& date do dipot interne. -Z documan: partiwlikermant pcrat invantloo ravenil. I tional on apris ccme dito quit as peow atm coosid~r~a comma nouwelle on com~Aa 'V doctument porn'ant later n donte san* o riventication do Impllquunt na. mctinM Inventive prioriti on citi pour d~terminer I& date d. publication d'n 'Y document particuItkameat ptioat; Ilaoudton rreark autra chtno on pour no. ralson spiciaie (tle quinadiqula) dlqu** no pout dure considivis vomma implquant twou 00, documetnt so wit~ant i na diwigpilon oral*, A n usav, A lidvhieti v lovo rsque to document eat "ai i n Qn Una expositon am tons anue moyeas pluslenrs anta documents do madma nature, otta cntsbi. Ir Jocumerat publid avaut Is. data do dhp~t international, rals; nason kaunt autloi pour une parsonne du mier. pc.wvervmoan AI& date do pdocriti raveodiquda douMent qot filt partt do I& mama famlle do brevets IV. CERTIFICATION Data i laquatla I& redarclie lnternaional~,R it affecivetcent ache Data d'expdtion dn pritsent rapport do unhorch Internaionale 27 AO'JT 1992 2 5. G&92 Administration char0e dai1s rocbarcite Lnternitlonal Sipiature in fooctionakrtarsq OMFCE EUROPEEN DES BREVETS HEYWOOD C. J. 1umakoft PCi (SA/ZIO lee1~o tavillo 4Jeria LW ANNLX. AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR SA 9200667 62542 La preito anaeie idiqv ets maobres de I famille de bret rdlxils au doaimets brevet citis dam le rapport do reebarbe intmnatianal 'ria6d 2 demuz. Lad~ inembesn' c-ntnus mu ficiJer idonnatique de 1d'flice vuropiea des brevets i Is date du Lea renseim=e ,:ic mwt doni~s i dtre indatif et nngilent pas In reaponsahiliti dc IOffic europica des brevet 27/08/92 Douabet brerA zti Date de de In Dato-sd au rapport do rmcrmre publication fmmiile 6, bret publcaion US-A-4960779 02-10-90 FR-A- AU-B- AU-A- DE-A- EP-AB JP-A- SU-A- SU-A- ZA-A- 2607503 600776 8191187 3772369 0274930 63154681 1577698 1630612 8709000 03-06-88 23-08-90 02-06-88 26-09-91 20-07-88 27-06-88 07-07-90 23-02-91 01-06-88 Pour tout ucnsipmerErt coarnant cefte mntau: vole Journal Offidel do lOffee eizrop6en Ors brevetzi No.12192