AU661299B2 - New thalidomide derivatives, method of manufacture and use thereof in medicaments - Google Patents

Abstract

New thalidomide derivatives of formula (I), medicaments containing those compounds, and a method for manufacturing them are disclosed.

Description

OPI DATE 17/11/92 A0JP DATE 214/121/92 APPLN. ID 14555/92 IIIIIIII I PTNUMBER PCT/EP92/00790 III11 1IIIEUI I AU92 14555 (51 InerntioalePatntkassfiktio 5(11) Internationale Veroffentlichungsnummer: WO 92/18496 C07D 401/04, A61 K 31/445 Al (43) Internationales Veroffentlichungsdatum: 29. Oktober 1992 (29.10.92) (21) Internationales Aktenzeichen: PCT/EP92/00790 (31) Bestimmungsstaaten: AT (europ~isches Patent), AU, BE (europdisches Patent), CA, CH (europaisc!)es Patent), (22) Iriternationales Anmeldedatum: 8. April 1992 (08.04.92) DE (europflisches Patent), DK (europitisches Patent), ES (europiiisches Patent), FR (europitisches Patent), GB (europaisches Patent), GR (europ~isches Patent), IT (eu- Priori tAtsdaten: ropdisches Patent), JP, LU (europ~isches Patent), MC P 41 12 566.5 17. April 1991 (!7.04.91) DE (europiiisches Patent), NL (europqiisches Patent), SE (europ~isches Patent), US.

(71) Anmelder (ffur alle Bestimmungsswten ausser US): GRCJN- ENTHAL GMBH [DE/DE]; Zieglerstralle 6, D-5100 Veriiffentliclit Aachen Mit internationalem Recherchenbericht.

(72) Erfinder; und Erlinder/Anmelder (nur flr US) EGER, Kurt [DE/DE]; Alte Landstrage 15/4, D-7400 Tfibingen EI-NIN- GER, Gerhard [DE/DE]; Sch6nbuchstrale 51, D-7405 Dettenhausen STUHLER, Alfred [DE/DE]: Wei- Ierstralle 18/1, D-7902 Blaubeuren (DE).

(54) Title: NEW THALIDOMIDE DERIVATIVES, METHOD OF MANUFACTURE AND USE THEREOF IN MEDICA-

MENTS

(54) Bezeichnung: NEUE THALIDOMIDDERIVATE, EIN VERFAIIREN ZU DEREN HERSTELLUNG SOWIE DIE VERWENDUNG DERSELB EN IN ARZNEIMITTELN 0 QR N 3I o 0 0 QH C2-- (57) Abstract New thalidomide derivatives of formula medicaments containing those compounds, and a method for manufacturing them are disclosed.

(57) Zusammenfassung Es werden neue Thalidomidderivate der Formel diese Verbindungen enthaltende Arzneimittel sowie emn Verfahren zu deren Herstellung offenbart.

I i New thalidomide derivatives, process of preparing them and use of these derivatives in medicaments (G 2105) The invention relates to new thalidomide derivatives of formula I 0

R

3

CH

2 1

CH

2

N

II R 2 0 R medicaments containing at least one of these compounds and a process for preparing these compounds and medicaments.

It is known that thalidomide (3-phthalimido-piperidine- 2,6-dione) has immunosuppressive and immunomodulating properties. The poor water solubility of this compound, however, is disadvantageous in respect to its therapeutic use. The result is that up to now thalidomide can only be orally administered which causes disturbances of resorption and considerable variations in plasma levels in case of disorders which are associated with mucosa defects in the gastrointestinal tract, e.g. the graft-versus-host disease.

It is therefore object of the invention to provide watersoluble derivatives of thalidomide being suitable for parenteral administration. Further the immunosuppressive and immunomodulating properties of these derivatives AI> re', AUSL.E.DOC02.6.93 4 1 1---11 II- l-rt 2 should be equal or better compared to the corresponding properties of thalidomide.

It now has been found that certain new thalidomide derivatives possess the required properties.

Accordingly the present invention relates to thalidomide derivatives of formula I 3 R 3 0 N

CH

1-2 -1 C CH- N II 2 R 2 0

R

in which the residues R 1 and R 2 independently represent a C1-6-alkyl group or R 1 and R 2 together represent

-CH

2

CH

2

-X-CH

2

CH

2

R

3 represents H or CH 3 and X represents O or NH, and/or the salts thereof in racemic or optically active form.

Derivatives of thalidomide in which the residue R 3 is H are preferred. Derivatives of thalidomide wherein the residues R 1 and R 2 together represent -CH 2

CH

2 0CH 2

CH

2 or

-CH

2

CH

2

NHCH

2

CH

2 especially -CH 2

CH

2 0CH 2

CH

2 are particularly preferred.

Due to their solubility in water and their stability in aqueous solutions or dispersions the compounds of the invention are especially suitable for parenteral administration.

rr -a" Accordingly the invention also relates to medicaments containing as active ingredient at least one thalidomide 3 derivative and/or at least one salt thereof in racemic or optically active form.

Compositions for parenteral administration may be solutions, suspensions, dry formulations suitable for easy reconstitution, ointments, pastes, gels, depots of an active ingredient in diluted form or plasters. All of the foregoing general types of pharmaceutical compositions to which the invention is applicable as well as the preparation of these compositions are known. The incorporation of the thalidomide derivatives according to the invention into these pharmaceutical compositions in the form and dosage desired poses no problems for an ordinarily skilled pharmacist. In the production of pharmaceutical compositions according to the invention the usual care must naturally be taken in the selection of carriers and inorganic or organic adjuvants such as diluents, solvents, stabilizers, dispersing agents, wetting agents, binders, coloring agents and flavorings. In particular care should be taken to achieve sterility and if the compositions are in liquid form, isotonicity.

The medicaments according to the invention are suitable in the treatment of immunological disorders such as leprosy, Becet's syndrome, lupus erythematosus, prurigo nodularis, mundaphtene in AIDS-patients, colitis ulcerosa and especially in the treatment of the graft-versus-host disease. The medicaments may be intravenously, intradermally, intramusculary, intranasally and locally administered. The local application is especially suitable in the treatment of infections of the skin, mucosae and eyes.

A further object of the invention is a process for preparing thalidomide derivatives of formula I i I VI i- 4 0

QN

S

3

R

2 1 in which the residues R 1 and R 2 independently represent a

C

1 -6-alkyl group or R 1 and R 2 together represent

-CH

2

CH

2

-X-CH

2

CH

2

R

3 represents H or CH 3 and X represents O or NH, and/or the salts thereof in racemic or optically active form, said process comprising the steps of reacting a compound of formula II 0

R

3 0

H

in racemic or optically active form with formaldehyde to form a N-hydroxymethyl compound of formula III 0

R

3 N 0 0

CH

2

OH

reacting the resulting N-hydroxymethyl compound with 4-chloromethylbenzoic acid in the presence of dicyclohexylcarbodiimide to form an ester of formula IV c I- I 0

R

3

N

0 N 0

CH

2

CL

0 transforming the resulting ester into a thalidomide derivative of formula I by reaction with a di(C 1 -6-alkyl)amine, morpholine or piperazine, and optionally converting the resulting thalidomide derivative with an acid into a corresponding salt.

To prepare thalidomide derivatives according to the invention the preferably used starting compound thalidomide is hydroxymethylated with formaldehyde at the glutarimide nitrogen atom. After reaction with 4-chloromethylbenzoic acid in the presence of dicyclohexylcarbodiimide in a solvent or solvent mixture, followed by reaction preferably with morpholine or piperazine, especially with morpholine in the presence of an alkali halide, e.g. sodium iodide, in an anhydrous solvent or solvent mixture a thalidomide derivative according to the invention is obtained which may be converted with an acid, e.g. hydrochloric acid, optionally in presence of a C1- 3 -alkyl alcohol into a corresponding salt.

L L 6 Example 1 Preparation of N-(4-morpholinomethyl-benzoyloxymethyl)thalidomide, hydrochloride salt 2.58 g of thalidomide in 30 ml of an aqueous solution containing 35 by weight of formaldehyde were heated under reflux. After formation of a clear solution the mixture was allowed to cool to 200 C. After 24 hours the mixture was filtered and the resulting residue washed with an aqueous solution containing 3 by weight of formaldehyde. The N-hydroxymethyl-thalidomide obtained (yield: melted at 1650 C.

1.1 g of N-hydroxymethyl-thalidomide, 0.68 g of 4-chloromethylbenzoic acid, 1.03 g of dicyclohexylcarbodiimide and 0.06 g of 4-pyrrolidinopyridin in 25 ml of dichloromethane were stirred at 200 C for 24 hours. After removal of cyclohexylurea by filtration and dichloromethane by destillation the resulting residue was recrystallized from ethanol to yield N-(4-chloromethyl-benzoyloxymethyl)thalidomide (yield: 60 melting at 215 to 2200 C.

880 mg of N-(4-chloromethyl-benzoyloxymethyl)thalidomide, 350 mg of morpholine and 20 mg of sodium iodide in anhydrous acetone were stirred at 200 C for 24 hours. After removal of acetone by destillation the resulting oily residue was purified by column chromatography ("Kieselgel 60" from E. Merck of Darmstadt, Germany) with ethyl acetate. The resulting oil was dissolved in ethanolic hydrochloric acid and precipitated by addition of diethyl ether. After recrystallization from ethanol N-(4-morpholinomethyl-benzoyloxymethyl)thalidomide, hydrochloride salt was obtained (yield: 40 melting at 236 C.

'N t 1 1 7 1 H-NMR (200 MHz, DMSO-d 6 2.08, 2.62 (in, m, 2H, C11 2

-CH);

2.84, 2.91 (in, m, 2H1, CH 2

CO);

3.10, 3.70 (in, m, 8H1, -CIi1 2 -C11 2 4.41 2H1, -CH 2 5.35, 5.43 (dd, 1H, CH-CH 2 5.92 2H1, N-CH 2 7.72, 7.92 (in, m, 811, aromat.); 11.20 111, H+) Example 2 N-(4-morpholinomethyl-benzoyloxymethyl)thalidomide, hydrochloride salt has a solubility in water of 1 lmg/mL corresponding to 5.4mg of thalidomide in linL of water, whereas the solubility in water of thalidomide is only 0.Ol2mg/inL (Arch. Pharm. 321, 371 (1988)). This means a 450 times higher water solubility of the thalidomide derivative of the present invention when compared to thalidomide per se.

C

cc' 4

C,,

'.4 v-.

44 [G:\WPUSER\LIBvVVIO433-:TCW

I

Claims (15)

1. Thalidomide derivatives of formula I 0 R 3 O N N 9H2 /CH2 R 1 in which R 1 and R 2 independently represent a Cl_ 6 -alkyl group or R 1 and R 2 together represent -CH 2 CH 2 -X-CH2CH 2 R 3 represents I-I or CH 3 and X represents O or NH and/or the salts thereof in racemic or optical active form.

2. Thalidomide derivatives according to claim 1, wherein R 3 is H.

3. Thalidomide derivatives according to claim 1 or claim 2, wherein R 1 and R 2 together represent -CH 2 CH 2 -X-CH 2 CH 2

4. Thalidomide derivatives according to claim 3, wherein R 1 and R 2 together are -CH 2 CH 2 -O-CH 2 CH 2 A pharmaceutical composition containing as active ingredient at least one thalidomide derivative and/or one salt thereof in racemic or optically active form according to any one of claims 1 to 4, together with a pharmaceutically acceptable carrier, S 15 diluent, excipient and/or adjuvant.

6. A pharmaceutical composition according to claim 5 for parenteral administration.

7. A process for preparing a pharmaceutical composition according to claim 5 or claim 6 comprising admixing at least one thalidomide derivative and/or at least one salt i 20 thereof in racemic or optically active form according to any one of claims 1 to 4 with t auxiliary agents and optionally pharmaceutically acceptable carriers, and preparing a dosage form from the resulting admixture.

8. A process for preparing thalidomide derivatives of formula I 0 O CH 2 O-0 CH 2 -N\ [G:\WPUSER\LIBVV]00433:TCW L~ H R 9 in which R 1 and R 2 independently represent a Cl_6-alkyl. group or R 1 and R 2 together represent -CH 2 CH 2 -X-CH 2 CH 2 R 3 represents H or CH 3 and X represents O or NH, and/or the salts thereof in racemic or optically active form, said process comprising reacting a compound of formula II O QN- 0 N 0 H in racemic or optically active form with formaldehyde to form a N-hydroxymethyl compound of formula III 0 jNQ o CH 2 0H reacting the resulting N-hydroxymethyl compound with 4-chloromethylbenzoic acid in the presence of dicyclohexylcarbodiimide to form an ester of formula IV 0 t 4 4 Sj R3 QN CH 2 O-C CH2-C 0 transforming the resulting ester into a thalidomide derivative of formula I by reaction with a di(C 1 l 6 -alkyl)amine, morpholine or piperazine and if desired converting the resulting thalidomide derivative with an acid into a corresponding salt.

9. A process according to claim 8, wherein said ester of formula IV is reacted with morpholine or piperazine. A process according to claim 9, wherein said ester of formula IV is reacted with morpholine.

11. A method of treating a patient suffering from an immunological disorder said method comprising administering to said patient an effective amount of at least one thalidomide derivative and/or at least one salt thereof in racemic or optically active form [G:\WPUSER\LIBVV]00433:TCW i according to any one of claims 1 to 4 or a pharmaceutical composition according to claim or 6.

12. A method of treating a patient suffering from a graft-versus-host disease comprising administering to said patient an effective amount of at least one thalidomide derivative and/or at least one salt thereof in racemic or optically active form according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 or 6.

13. A thalidomide derivative of formula I substantially as herein described with reference to Example 1.

14. A process of preparing a thalidomide derivative of formula I, substantially as herein described with reference to Example 1. A pharmaceutical composition comprising a thalidomide derivative of formula I as defined in claim 13, together with a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

16. A method of treating an immunological disorder in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one thalidomide derivative of formula I as defined in claim 13 or a pharmaceutical composition as defined in claim

17. A method of treating a graft-versus-host disease in a patient requiring such treatment, comprising administering to said patient an effective amount of at least one thalidomide derivative of formula I as defined in claim 13 or a pharmaceutical composition as defined in claim t f i t t Dated 10 May, 1995 I i t t en Grunenthal GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON iii C tC C l t t VIt 3 t: [G:\WPUSER\LIBvV]00433:TCW f t [G:\WUSERLIBV]0043:Ti Bl t r I, r i c c i -e )J A-L Abstract New thalidomide derivatives, pharmaceutical compositions containing those compounds and a process for preparing those compounds and compositions are disclosed. -1 T T ii -I tr I C1 1I1~- II1_11~-1 INTERNATIONAL SEARCH REPORT International application No. PCr/EP 92/00790 I-- I A. CLASSIFICATION OF SUBJECT iiATTER Int.C1 C 07 D 401/04 A 61 K 31/445 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) 5 Int.Cl.: C 07 D 401/00 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 DE, A, 1670391 (GRUNENTHAL) 5 November 1970, see examples 1,2 A DE, A, 1545706 (GRUNENTHAL) 9 October 1969, see claims 1-4 A DE, A, 1545672 (GRUNENTHAL) 5 August 1969, see the whole document A GB, A 768821 (GRUNENTHAL) 20 February 1957, see the whole document A Scientia Pharmaceutica, volume 49, No: 1, 30 March 1981, H. KOCH: "Die Arenoxid-Hypothese der Thalidomid-Wirkung. Uberlegungen zum molekularen Wirkungsmechanismus des "klassischen" Teratogens", pages 67-99, see the whole document 0 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: laterdocument published afterthe international filing dateorpriority document defining the general state of the art which is not 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 document which may throw doubts on priority claim(s) or which is s ie e when el or annt becosidered to involve an inventive cited to establish the publication date of another citation or other 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 document is means combinedwith oneormore 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 June 1992 (05.06.92) 30 July 1992 (30.07.92) Name and mailing address of the ISA/ Authorized officer European Patent Office Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992)- ,r I; -I- ~1 3 C~ ~1 C I. ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 9200790 SA 58337 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as co~tained in the European Patent Office EDP file on 10/07/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. M For more details about this annex see Official Journal of the European Patent Office, No. 12/82 m m- Lusammentassung Es werden neue Thalidomidderivate der Formel diese Verbindungen enthaltende Arzneimittel sowie ein Verfahren zu deren Herstellung offenbart. Ldrz- cs~TT7TaI ari Page ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 9200790 SA 58337 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 10/07/92 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 DE-A- 1545672 US-A- 3560495 02-02-71 GB-A- 768821 None ti A.fl^ c For more details about this annex see Official Journal of the European Patent Office, No. 12/82 ;Q For more details about this annex see Official Journal of the European Patent Office, No. 12/82 p L I 1~ AUSL-E.DOCO2.O9.93 I INTERNAl IONALER RECHERCHENBERICHT Internationales Aktenz#,.,en PCT/ EP 92/00790 KNade nentoae aetissifikation (PCsyiemc drnaina Klassifikationsmn er P C 07 0 401/00 Rechercitierte nicht zum Mindestpriifstoff gehorende Vcrbffentlichungen, soweilthdese unter die rechsmrchieflen Sachgebiete fallen III. EINSCEILAGIGE VEROFFENTLICHUNGEN 9 Art. 0 Kenazeichnung der Veroffewliichung 1 1 soweit erforderlich unter Angabe der mallgeblichen Telle 12 Betr. Anspruch Nr.13 A DE,A,1670391 (GRUNENTHAL) 5. November 1970, siehe Beispiele 1,2 A DE,A,1545706 (GRUNENTHAL) 9. Oktober 1969, siehe AnsprUche 1-4 A DE,A,1545672 (GRUNENTHAL) 5. August 1969, siehe Insgesamt A GB,A, 763821 (GRUNENTHAL) 20. Februar 1957, siehe Insgesamt A Scientia Pharmaceutica, 49. Jahrgang, Nr. 1, 30. Marz 1981, H. KOCH: "Die Arenoxid-Hypothese der Thalidomid-Wirkung. Uberlegungen zuni molekularen Wirkungsmechanismus des "klassischen" Teratogens", Seiten 67-99, siehe Insgesamt 0 Besondere Kategorien von angegebenen Veriiffentlichunget "A Veroffentlichung, die den allgerneinen Stand der Technik V Spbtere Veroiffentlichung, die nach dem internatiOnalen An- definiert, abet nicht als besonders bedeutsam anzusehen ist meldedatum oder dent Priorit~tsdaturn veroffentiicht worden dE lee Dkmncas jedoch ers1 am oder nach dent interna- ist und mit der Anmeldung nicit kollidiert, sondern our zuin tionalen Anmeldedatum veroffentlidst worden ist oerstnii e der lit!cun zugrundeliegenden Thoreanegb nps LV Veroffentlichung, die geeignet ist, einen Priorititsanspruch drdrirzgudlene hoi neee s zweifelhaft ersctteinen zu lassen, oder durch die das Verof- Veroffentlichung von besonderer Bedeutung- die beanspruch- fentlichungsdatum einer anderen mm Recherchenbericht ge. te Erfindlung kann nicht ais neu oder auf erfinderisciter Tktig- nannten Veroiffentlichung belegt werden soil oder lie aus elnen, keit beruhend betrachtet werden anderen besonderen Grund angegeben ist (wvie ausgefuhnt) Veroffentlichung von besonderer Bedeutung- die beanspruch- Veroffentlichung, die sich 21uf eine milodliche Offenbarung, te Erfmndung kann nicht a1S auf erfinderischer Thitigkeit be- ruhend betrachtet werden, wenn die Veroiffentlichung mit elne Benutzung, eine Aussteilung Ode! andere Maflnabmen ciner oder menreren anderen Verdffentlichungen dieser Kate- bezieht gone in "erbindlung gebracht wird und diese Verbindung fur Veroffentlichung, die vor dent internatlonalen Anmeldeda- elnen Fachmann naheliegend ist Surn, aber nach dent beansprucitten Prioritatsdatium veroiffent- W Veroiffentlichung, die Mitgiied derseiben Patentfamille ist IV, BESCHi. GUNG Datum des Abscblusses der internationalen Recherche Abseniedlatun des internationalen Recberchenberics 05-06-1992 0us Internationale Recherchenbehorde Unterschrift d EUROPAISCHES PATENTAM-f Furmblatt PCTIISA/210 JBlatt 21 IJanis 19951 I, ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT OBER DIE INTERNATIONALE PATENTANMELDUNG NR. EP 9200790 SA 58337 In diesem Anhang sind die Mlitglieder der Patentfamilien der im ohengcoannten internationaien Recherchenhericbt angefu-hrten Patenidokumente angegeben. Die Angaben Ober die Familienmitglieder entsprechen dem Stand der Datei des Europfiscben Patentamts am 10/07/92 Diese Angaben dienco our zur Untemrcbtung und erfolgen oboe GcwWir. Im Recberchenbericbt I Datum der Mlitglied(er) der Datum der angefuhrtes Patentdokument Verofentlichung Patentfamilie Ver~ffientlichung OE-A- 1670391 05-11-70 BE-A- 680696 07-11-66 CH-A- 478117 15-09-69 CH-A- 485707 15-02-70 FR-A- 1592059 11-05-70 FR-M- 5806 19-02-68 GB-A- 1075420 NL-A- 6606210 10-11-66 OA-A- 1951 04-02-70 US-A- 3560495 02-02-71 US-A- 3563986 16-02-71 OE-A,B 1545672 07-08-69 DE-A- 1545706 09-10-69 DE-A- 154b707 12-06-69 BE-A- 680696 07-11-66 CH-A- 478117 15-09-69 OH-A- 485707 15-02-70 DE-AB 1545672 07-08-69 OE-A- 1545707 12-06-69 DE-A- 1670391 05-11-70 FR-A- 1592059 11-05-70 FR-M- 5806 19-02-68 GB-A- 1075420 NL-A- 6606210 10-11-66 OA-A- 1951 04-02-70 US-A- 3560495 02-02-71 US-A- 3563986 16-02-71 DE-A- 1545706 09-10-69 I', 11 DE-A- 1545672 07-08-69 BE-A- CH-A- CH-A- DE-A- OE-A- OE-A- FR-A- FR-M- GB-A- OA-A- 680696 478117 485707 1545706 1545707 1670391 1592059 5806 1075420 6606210 1951 07-11-66 15-09-69 15-02-70 09-10-69 12-06-69 05-11-70 11-05-7

19-02-68 10-11-66 04-02-70 Ffir nihere Einueheiten zu diesem Anhang :siebe Amtsblatt des Europiiscben Patentamts6 Nr.12/82 I Seite 2 AM-lANG ZUM INTERNATIONALEN RECHERCHENBERICHT UBER DIE INTERNATIONALE PATENTANMELDUN NR. EP 9200790 SA 58337 In diesem Anhiang sind die Miitgjicder der Patentamilien der im obengenannten internationalen Rechercheohericbt angeftfuten Patentdokumente angegeben. Die Angaben fiber die Famiiienniitgiieder entsprechen dem Stand der Datei des Europiiscben Patentamnts am 10/07/92 Diese Angaben dienen nur zur Unterrichtung und erfolgen obnc Gewwb. In Recberchenbericht Datum der Mlitglied(er) der Datum der angeftibrtes Patentdokument Verdffeatfichung Patentfamilie Verdffentlichung OE-A- 1545672 US-A- 3560495 02-02-71 GB-A- 768821 Keine I Fdr nihere Einzelheiten zu diesem Anbang :siebe Amtrblatt des Europiiscben Patentamts, Nr.12/82 a