AU641212B2 - Nonionic iodinated compounds, method for preparing them, and contrast products containing same - Google Patents

Abstract

Compounds having general formula (I), wherein R is selected among 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl groups. These compounds can be used as contrasting products for X-ray image formation.

Description

OPI DATE 24/07/91 APPLN. I D 70574 91 PCr AOJP DATE 05/09/91 PCT NUMBER PCT/FR9O/00969 DEMANDE INTERNATIONALE PUBLiEE EN VERTU DU TRAITE DE COOPERATION EN MATIERE DE BREVETS (PCT) (51) Classification internationale des brevets 5: (11) Nuiuro de publication internationale: WO 91/09836 C07C 237/46, A61K 49/04 Al (43) Date de publication internationale: I Ijuillet 1991,(11.07.91) (21) Num ero de la deniande internationale: PCT/FR90/00969 (74) Mandataire: LB GIJEN, Gerard; Cabinet Lavoix, 2, place I 'd'Estienne-d'Orves, F-75441 Paris Ci~dex 09 (FR).

(22) Date de d~p6t international: 28 d~cembre 1990 (28. f2.90) (81) Etats d~sign~s: AU, CA, FI, HU, KR, NO, RO.

Donnies relatives i la prioriti: 90/00106 5 janvier 1990 (05.01.90) FR Publie Avec rapport de rechierche intemnationgie.

(71) D~posant: GUERBET S.A. [FR/FR]; 15, rue des Vanesses, Avanzt l'expiration dui ddlai pr~vu pour la mnodification des F-93420 Villepinte revendications, sera republibe si de telles modifications sont refues.

(72) Inventeurs: SCHAEFER, Michel 4, rue Frangois-Girardon, F-91380 Chilly- Mazarin DUGAST-ZRIHEN, Maryse 107, rue Bobillot, F-75013 Paris GUIL- LEMOT, Michel 182 bis, boulevard P~reire, F-750174 Paris DOUCET, Didier 13, rue Am6d~e-Dunois,2 1 F-93 190 Livry-Gargan MEYER, Dominique 6, rue de Metz, F-94 100 S.-Maur (FR).

(54) Title, NONIONIC JODINATED COMPOUNDS, METHOD FOR PREPARING THEM, AND CONTRAST PRO- DUCTS CONTAINING SAME (54)Titre: COMPOSES NON IONIQUES IODES, LEUR PROCEDE DE PREPARATION ET PRODUITS DE CONTRASTE EN CONTENANT CON1 F ID_ CH

(P

0 (57) Abstract Comnpounds having general formula wherein R is selected among 2,3-dihydroxypropyl and groups. These compounds can be used as contrasting products for X-ray image formation.

1,3-dihydroxy-2-propyl (57) Abrigi L'invention a pour objet des composes r~pondant At la formule g~n~rale dans laquelle R est choisi parmi les groupes 2,3-dihydroxypropyle et 1,3-dihydroxy-2-propyle. Ces composits sont utilisables comme-produits de contraste en imagerie par rayons X.

The present invention relates to compounds which can be used as contrast media for radiography.

Iodobenzene compounds containing several iodine atoms in the benzene ring, usually 3 iodine atoms per benzene ring, and various other substituents have been used for a long time as contrast materials.

These other substituents are pharmacologically acceptable groups which enable the compounds to be administered to man and animals. Generally speaking, these substituents are chosen, on the one hand, in order to confer adequatef solubility in water on the compound so that they can be administered in aqueous solution and, on the other, in order to confer on these compounds a tolerance sufficient for their use in the human organism.

For this purpose, non-ionic structures have been suggested, i.e. iodobenzene derivatives possessing non-ionic substituents.

Thus, in the patent FR-A-2 053 037, carbamoyl iodobenzene compounds containing a total of at least one N-hydroxy alkyl group and at least two hydroxy groups were proposed.

A compound illustrative of this class is metrizamide which has, however, proved to be of limited stability.

4 352397gq In P ^ntCnt application 80 401 509.8, non-ionic compounds were suggested which are well tolerated by the human organism and which exhibit good stability in aqueous solution.

These compounds correspond to the formula:

R

13 CO-N-R2 R 4-N

IOI

1 1

CO

I -CH 2OH H'CH 2 0H in which Ris a group of formula

O-

R

6

R

5 being selected from C 1 -C 4 alkyl, C 1

-C

4 hydroxyalkyl or C 1

-C

4 Polyhydroxyalkyl, R 6 being selected from hydrogen, C 1 -C 4 alkyl, C 1

-C

4 hydroxyalkyl or C 1

-C

4 polyhydroxyalkyl, or a group of formula CO N -R7 R 7 being selected from C, -C 4 hydroxyalkyl or Cl-C 4 polyhydroxyalkyl, R 8 being selected from hydrogen or C 1 -C 4 alkyl, Ris selected from hydrogen, C 1

-C

4 hydroxyalkyl or C 1

-C

4 polyhydroxyalkyl, R 3 is selected from hydrogen or C,-C 4 alkyl, and Ris selected from-.hydrogen, Cl-C 4 alkyl, Cl-C 4 hydroxyalkyl or C 1 C 4 polyhydroxyalkyl.

The aim of the present invention is to provide novel compounds belonging to the family of the compounds of formula I, which are 6haracter'izeil by both good stability'and good szijubility 1i aqjUeous inedia.

The compounds according to the invention have to following general formula,

DE

Fro' R 0)(I) 0

DAB

in which.R is selected from 2,3-dihydroxypropyl or 1,3-dihydroxy-2propyl.

One of the compounds according to the invention is -3- [3-hydroxy-2- (hydroxymethyl )-propionamido] N'-dimethyl- N,N' -bis-(2, 3-dihydroxypropyl 6-triiodoisophthalamide, i.e. the compound of formula:

CM

CON OH OH- MO (A) HONM C ON OH OH HO0. 1

CHM

3 The other compound according to the invention is 5-[3hydroxy-2-(hydroxymethyl )-propionamido] -dimethyl-N,N' bis-(2,3-dihydroxypropyl)-2,4, 6-triiodoisophthalamide corresponding to the formula below: C

(B)

F-

HOD_

.H

I

*0

CH*(D

Ths fomlecvrntol .ercmtsbtas l nxetdy th copon Thes formulae coe not onyhheracemtsbtelsozal by a better solubility in aqueous medium than the compound of example 1 of AU 35235/89 mentioned above, namely the hydroxy-2- (hydroxymethyl 3-dihydroxypropyl )propionamido]-N',N"-bis-(2-hydroxy-ethyl)-2,4,6-triiodoisophthalamide.

The experimentally determined solubility values corresponding to these two compounds have been- reported in Table I. Each value is expressed as the maximum amount of the test compound which can be solubilized in 100 ml of water.

93OY709,p:\oper~dab,70574gue-spe, t I -4- TABLE I Compound A Compound of present Example 1 application AU 35235/89 Solubility value 71 32 (g 100 ml)

S

S

S

Furthermore, the compounds according to the invention possess the advantage, compared with the compound of example 1 of AU 35235/89 mentioned above, of being more easily accessible in that they do not require a final N-alkylation step which poses problems of purification at the industrial scale.

The compounds according to the invention may be obtained according to a procedure consisting of: a) reacting a diacyl chloride of formula: coC1

(II)

I

coci R' designating a -CH-(CH 2

OH)

2 group, the hydroxy groups of which are protected, with an amine selected from 1-(N-methylamino) propane-2,3-diol and 2-(N-methylamino) propane-1,3-diol, so as to produce a compound of formula:

CH

3

CO-N-R

o CH R'-C-HN

CO-N-R

0 I 0 I 0

(III)

93077,p:\oper\dab,70574gue.s 4 4a and b) removing the protecting groups from the R' group.

The compounds of formula II are described in FR-A-2 632304.

The present invention relates also to contrast media which contain at least one of the compounds according to the invention, together with a pharmaceutically acceptable carrier.

These contrast media are used in man and animals for radiological purposes.

The preferred pharmaceutical form of the contrast media according to the invention consists of aqueous solutions of the h *o oo* o 930707,p:\oper\dab,70574gue.spe,4 compounds.

The aqueous solutions usually contain a total of 5 to 100 g of compound according to the invention per 100 ml and the injectable volume of such solutions usually varies from 1 to 1000 ml.

The aqueous solutions of the compounds according to the invention may also contain certain additives such as: sodium chloride at concentrations between 0.1 and 10 mM disodium EDTA at concentrations between 0.1 and 2 mM 18 sodium citrate at concentrations between 0.1 and 10 mM heparin at doses between 10 and 100 units per 100 ml of solution.

These compounds may be administered by all routes conventionally used for iodinated non-ionic contrast materials. Thus they may be administered by the enteral or parenteral route (intravenous or intra-arterial route, opacification of the cavities) and in particular into the subarachnoid space.

An example of the composition according to the present invention will be given below.

Composition Compound A according to the invention 65 g Water for injectable preparation QS 100 ml The following examples illustrate the preparation of the compounds according to the invention.

EXAMPLE 1 Preparation of 5-f3-hydroxy-2-(hydroxymethyl)-propionamidol- NN'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

a) Preparation of Z2-isopropyl-l,3-dioxane-5-carboxamidQT-N,N'dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

74 g (98 mmoles) of 5-Z2-isopropyl-1,3-dioxane-5-carboxamidQ7- 2,4,6-triiodo-isophthaloyl dichloride are suspended in 300 ml of isopropanol containing 41 ml (294 mmoles) of triethylamine. 31 g (295 mmoles) of N-methyl-aminopropane-2,3-diol are added dropwise. Stirring is maintained for 12 h at room temperature. The triethylamine hydrochloride is removed by filtration.

The filtrate is evaporated to dryness, the residue is taken up in water and eluted from OH- resin IRA 67.

After evaporation, the product is purified by passage through silanized silica (Kieselgel 60 Merck) with water as eluant.

After evaporation to dryness, 60 g of a white powder are recovered in a yield of 68.5%.

Iodine determination: 96.4% HPLC purity 97% Hypersil CB 25 cm 5 am NaH 2

PO

4 0.01 M Methanol TLC SiO 2 Rf. 0.12 0.25 0.30 0.36 Eluant CHC1 3 55, MeOH 30, NH3H 2 0 NMR (DMSO) 1H 200 MHz 0.9 ppm (doublet) CH 3 2.8 ppm (singlet) N-CH 3 3 ppm (singlet) N-CH 3 3.3 ppm (multiplet) N-CH 2 and CH 3.5-3.9 ppm (multiplet) CH 2 and CH 4.3 ppm (quadruplet) CH 4.6 ppm (triplet) OH 4.7 ppm (doublet) OH 10.2 ppm (enlarged multiplet) NH (1H).

b) Preparation of 5-L3-hydroxy-2-(hydroxymethyl)propionamidQ7-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6triiodoisophthalamide.

g (50.6 mmole) of the compound described in a) are dissolved in 101 ml (10 eq.) of 5 N hydrochloric acid. Stirring is maintained for 12 h at room temperature. The solution is filtered and evaporated to dryness. The solid obtained is taken up in 100 ml of ethyl ether, then filtered off and eluted from silanized silica (Kieselgel 60 Merck) with water. After evaporation to dryness, 38 g of a white powder are recovered.

Yield Iodine determination: 98.3% HPLC purity 98% Hypersil C8 25 cm 5 a

I.

7 NaH 2 PO 4 0.01 M MeOl TLC SiO 2 Rf 0.56 0.63 0.67 Eluant CHUC1 3 55 9 MeOH 30, NH 3

H

2 O0 NR (DMSO) 1 H 200 MHz 2.7 pm (multiplet) CHI 2.85 ppm (enlarged singlet) N-CH 3 (3M); 3.08 (poorly resolved doublet) N-CH 3 3.10-3.35 ppm (multiplet) N-Cl! 2 3.45 ppm (quadruplet) CH 2 (4H1); 3.6-4 ppm (multiplet) OH (6H); 9.9 ppm (multiplet) Nil (III).

EXAMPLE 2 Pre~aration of 5-[3-hydroxy-2-( hydroxymethyl )-propionamido]- NN' -dimethyl-N.N' -bis-(1 ,3-dihydroxy-2-propyl)-2. 6-triiodoiso- Dthalamide).

a) Preparation of (2-isopropyl-1 ,3-dioxane-6-carboxamido)- N,N '-dimethyl-N,N' -bis-(1, 3-dihydroxy-2-propyl)-214 ,6-triiodoisophthalamide.

1.46 g (13.9 mmole) of N-methyl-aminopropane-l,3-diol (synthesized according to the European patent application EP-A-025 083 filed by EPROVA is dissolved in a mixtur e composed of ml of N,N-dimethylacetamide and 2 ml (114.4 mmole) of triethylamine.

g (4.65 mnole) of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4- 6-triiodoisophthaloyl dichloride are added in portions. Stirring is maintained for 3 hours at 30*C, then for 12 hours at room temperature.

The triethylamine hydrochloride is removed by filtration.

The filtrate is evaporated to dryness and the residue is crystallized in a mixture composed of 20 ml of isopropanol and 200 ml of ethyl ether.

After filtration and drying, 3.6 g of a white powder are recovered in a yield of 87%.

TLC SiO 2 Rf 0.16 0.28 Eluant toluene 60 methyl-ethyl-ketone 35 formic acid InM (DMS0) 1 H :200 MHz.

0.9 ppm (doublet) CH 3 1.7 ppm (multiplet) CH 2.7 ppm (singlet) N-CH 3 (3H) Z isomer; 2.99 ppm (singlet) N-CH 3 (MH) E isomer; 3.4-4 ppm (multiplet) CHT, CHT 2 (15H); 4.8 ppm (multiplet) CH 2 OH (QH); 10.2 ppm (muiltiplet) NH (M1).

b) Preparation of 5-1t3-hydroxy-2-(hydroxylmethyl-propionamido7N, N' -dimethyl-N -bis- (1 ,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.

3 (3.4 mmole) of the compound described in a) are dissolved in 10 ml (15 eq.) of 5N hydrochloric acid. Stirring is maintained for 3 hours at 45 0 C, then for 12 hours at room temperature. The solution is evaporated to dryness. The residue obtained is taken up in 50 ml of ethyl ether, filtered off, then dissolved in 50 ml of water before being eluted from a H1+ resin (IRN 77) and a OH- resin (IRA 68).

After evaporation to dryness, 1.7 g of a white powder are recovered in a yield of 60.7%.

Iodine purity: 98.4% TLrw o Rf 0.26 0.*33 0.45 Eluant butanol 50, water 25, acetic acid 11.

NMR (UMSO) 1 H 200 MHz.

2.7 ppm (enlarged singlet) N-CIT 3 Z isomer; 3 ppm (enlarged singlet) N-CH 3 E isomer; 3.3-4.05 ppm (poorly resolved multiplet) CHT, q.!20H (15H); 4.45 ppm (poorly resolved multiplet) CH 2 OCH 9.8 ppm (multiplet) NH (MH).

MI (DM53) 13 C 200 MHz.

170.6 ppm (2 172 ppm (1 149 ppm (CArli); 0 0 0 145 ppm (C Al-NT); 100-98-90 ppm (CAr-I) 61-57-52 ppm 59.1-59.9 ppm (CH 2 32.8-30.1 ppm (CH 3

Claims (13)

1. A compound of the formula: HO:) I I0 0\ i3~-H *5 S *SS. o S S in which R is selected from 2,3-dihydroxypropyl and 1,3- dihydroxy-2-propyl.

2. 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'- dimethyl-N,N'-bis-(2,3-dihydroxypropyl triiodoisophthalamide.

3. 5-[3-hydroxy-2-(hydroxymethyl) -propionamido] -N,N'-bis- (1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.

4. Contrast media, according to claim acceptable carrier. comprising 1, together at least one compound with a pharmaceutically Contrast media, comprising at least the compound of claim 2, together with a pharmaceutically acceptable carrier.

6. Contrast media, comprising at least the compound of claim 3, together with a pharmaceutically acceptable carrier.

7. Contrast media according to claim 5, which comprises an aqueous solution of the compound.

8. Contrast media according to claim 6, which comprises an aqueous solution of the compound. 93070,p:\oper\dab,70574gue.spe,9 10

9. Process for the preparation of a compound of the formula: CDN* R 54 HD- DD R 0 Q-L, in which R is selected from 2,3-dihydroxypropyl and 1,3- dilT.,,droxy-2-propyl, comprising: a) reacting an acyl dichloride of formula: C COC2. R -C-HN-1- coca RI designating a -CH-(CH 2 OH) 2 group, the hydroxy groups of which are proter. 4 -ed, with an amine selected from 1-(N-methylamino) propane- 2, 3-diol and 2-(N-methylamino) propane-1, 3-diol, so as to produce a compound of formula: CH3 CO-N-R 1(H 3 II R -C-HN CO-N-R 0 1 and b) removing the protecting groups from the R' group. 930707,p:\oper\dab,70574ge.sp,10 e #g i -11- Process for the preparation of contrast media in which a compound of the formula as defined in claim 1 is in an administrable form.

11. Process according to claim 10, in which the compound is in the form of an aqueous solution.

12. Compounds of formula or processes for their /preparation, substantially as hereinbefore described with reference to the Examples. :004 DATED this 9th day of July, 1993. 0** S 15 GUERBET S.A. By Its Patent Attorneys DAVIES COLLISON CAVE 00 *0 *ee 930709,p:\operdab,70574gue.spe,1I GUERBET S.A. Iodinated non-ionic compounds, pwooess for their preparation and contrast materiels containing then ABSTRACT OF THE TEMHICAL CONTFJI OF THE INVENTION The1 iinrentimx relates to~ oqxiwds of the general formula: CON~ R HOD- CNH ON -RP 0 C In which R is selected from 2, 3-dikydroxypropyl sand 1, 3-dlhydroxy-2- propyl. Theme compounds can be used as X ray oetav~t~ me Fig. None. INTERNATIONAL SEARCH REPORT Inlternational Application No PCT/FR9O/00969 1. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply. indicate all)I According to International Patent Classification (IPC) or t0 path National Classif'ication and IPC Int. Cl. 5:C07C 237/46, A61K 49/04 WI FIELDS SEARCHED Minimum Documentation Searched Classification System Clssilfication Symbols 51 Int. Cl. I C07C 237/00 Ooicumentation Searched other then Minimum Documentation to the Extent tha2 such Documents are included in the Fields Searched. Ill. DOCUMENTS CON311DERED TO 5E RELEVANTI Category Citation of Document. with indication, whiere saropriate, 01 the relevant pssage% I Relevant 10 Claim No. 1 A EP, A, 0015867 (SCHERING) 17 September 1980, 1 -11 see examples; claims A DE, A, 3429949 (SCH-ERING) 20 February 1986, 1-11 see examples; claims PX EP, A, 0357467 (GUERBET) 7 March 1990, 1-11 see the whole document (cited in the application) *Special categones at cited ccumnents 1 later document published altear tme international filing date 0t document defining the general State Of the art Which is hot Orionty date and not in conflict with the apoication but cited to conisidered to be ot Particular relevance untierstana the princtple or thioorY uhdoe"lYig the, invention arler dcumnt ut pblihedon or after the international document of particular relevance: the claimed invention cannot *'E"earier ocuent ut ub~ihedbe considered novel or cannot be considered to involve an tiling date inventive eteo document which may throw doubts on priority claim($) or document al particular relevance, the claimed invention cannot which is cited to *Plablish the publication date at another o osdrdt nov nivniese hnteocmn citation or other special reason tamsaceciliedl ecniee oivlea netv lo"ntedcmn is combined with one at mone other such documents, such document referning to an oral disclosure, use. exhibition or comoinalion oeing owvous to a person skilled in the, ant other means document membier of the same patent lemily document published onor to tme international filing daete but later than the ononty date claimed IV, CERTIFICATION Date of the Actual comoeion ot the international search i Date of Mailing of tis international Search Report 16 April 1991 (16.04.91) 22 May 1991 (22.05.91) International Searchinrg Authority Signature of Authorized Officer European Patent office Form PCT ISA 210 1 second sneot) lJanuatv 1965', ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 9000969 SA 43796 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 06/05/91 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date EP-A- 0015867 17-09-80 DE-A- AT-T- AU-B- AU-A- CA-A- JP-C- JP-A- JP-B- US-A- 2909439 1061 529565 5627280 1130316 1495122 55153755 63041898 4364921

18-09-80 15-06-82 09-06-83 11-09-80

24-08-82 16-05-89

29-11-80 19-08-88 21-12-82 DE-A- 3429949 20-02-86 None EP-A- 0357467 07-03-90 FR-A- 2632304 08-12-89 FR-A- 2643077 17-08-90 AU-A- 3523589 07-12-89 AU-A- 3833189 05-01-90 EP-A- 0345163 06-12-89 WO-A- 8912042 14-12-89 JP-A- 2025456 26-01-90 R For more details about this annex see Official Journal of the European Patent Office, No. 12/82 RAPPORT DE RECHERCHE INTERNATIONALE .Demands international. N PCT/FR 90/00969 1. CLASSEMENT DE L'INVENTION Isi plusleurs symboles do clsificmtion sont apiplicables, fee indiquer tout) Salon Is classification Internationale dolt brevots (CIS) ou k Is fois solon Is classification nationase at Is CIB CIB 5:C 07 C 237/46, A 61 K 49/0 4 11, DOMAINES SUR LESQUELS LA RECHERCHE A PORTE Documentation ininimale consulti. 0 Documentation consultile suts qua Is documentation minimal. dens Is meaure oci do togs documents font partlit des domalnos our losquols In recherche a pot6I Ill. DOCUMENTS CONSIDiRtS COMME PERTINENTS CtgreIdentification des documents citlia," avoc indication, si necossaire, N, des revenidicatlons goedes passages tiortinonit '2 v~s~es 1 A EP, A, 0015867 (SCHERING) 1-11 17 septembre 1980 voir exeinpies; revendications A DE, A, 3429949 (SCHERING) 1-11 f6vrier 1986 voir exemples; revendications P,X EP, A, 0357467 (GUERBET) 11 7 mars 1990 voir le document en entier (cit6 dans la demande) *Catilgories spiciales do documents citis: "aTs document ultiriour pubii6poatirleurementh ladate do di6t I A x document difinissant 16tat giiral do I& technique, non International Cu A Is date do prioritt It naPPArtonant paz consd~r coma prtiuiiromet prtientA I'Atat do Is technique pertinent, mrals citi pour comprondre conedir com prticliiomen petinetIs principeoCu Is thtoris constituxint Is bass do tinvontion wsw document antdriour, minis publi6 A Is date do ddq~t Intern.- aX a document partlcuilliroment pertinent: l'inventlon revendi- tio no[ ou apron COtt date quil. no pout Alto covnsld~r~o comma nouvelle ou comma a L document tiouvailt jeter un doute aur une revendicatlon do Impliqusnt une activitl Inventive prioritt ou cit* Pour ditorminer Is date ae publication dune s a document pa,-tlculibrermont pertinent: Pinvention rovem- suits citation ou pour uns raison spiclalo (lelle ou'lndiquie) dictuis no Pout Atre considlirte comma Impliouant une a 0 5 document so ritirant A une divulgatlon oral*, A un usage, A activiti Inventive loraque I* document oat asaoci A tn ou une exposition ou tous suttee moytna plusloura autren documents do milme naturo, cott* combi- a P is document Publid avant Is date do dip~t International, main naiman #tent Avidento pour uns personne du mitier. posbirisuroment A In date do pfioritt revonldillute ii 11 document qul falt partle di Is mimei tamlille do brevets IV. CERTIFICATION Date Ai laciusiie Is recherche Internationale a 6t6 offoctivement Date deapidltion du prisent rapport do recherche Internationale achavile 16 avriJ. 1991 22. 05. 91 Administration chargie do Is recherch Intrnatonale Signature du lonctionnalre autor OFFICE EUROPEEN DES BREVETSmssTMRES Formulaire PCTIISA/210 (dauxiime feullls) wm 1995) ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 9000969 SA 43796 Lai presente annexe indique :es membres de Is famille de brevets relatils aux documents brevets cites dans le rapport de recherche internationale vise ci-dessus. Lesdits membres sont contenus mu richier infortnatique de l'Office europien des brevets i [a date du 06/05/91 Les renseignements fournis soot donnes a titre indicatif et n'engagent pins In responsabiiiti de I'Offici europ~n des brevets. Document brevet citi Date dc Membre(s) de In I Date de mu rapport de roweberche publication lamille de brevet(s) publication EP-A- 0015867 17-09-80 DE-A- 2909439 18-09-80 AT-T- 1061 15-06-82 AU-B- 529565 09-06-83 AU-A- 5627280 11-09-80 CA-A- 1130316 24-08-82 JP-C- 1495122 16-05-89 JP-A- 55153755 29-11-80 JP-B- 63041898 19-08-88 US-A- 4364921 21-12-82 DE-A- 3429949 20-02-86 Aucun EP-A- 0357467 07-03-90 FR-A- 2632304 08-12-89 FR-A- 2643077 17-08-90 AU-A- 3523589 07-12-89 AU-A- 3833189 05-01-90 EP-A- 0345163 06-12-89 WO-A- 8912042 14-12-89 JP-A- 2025456 26-01-90 Pour tout renseignemcnt coocerant cette muncixe voir Journal Officiel de l'O~ffce europ~n des brevets, No.12/82