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EP0581793A1 - Phosphonates et phosphinates utilises comme agents anticancereux, anti-inflammatoires, antiallergiques et anti-myocardites - Google Patents

Phosphonates et phosphinates utilises comme agents anticancereux, anti-inflammatoires, antiallergiques et anti-myocardites

Info

Publication number
EP0581793A1
EP0581793A1 EP19920908170 EP92908170A EP0581793A1 EP 0581793 A1 EP0581793 A1 EP 0581793A1 EP 19920908170 EP19920908170 EP 19920908170 EP 92908170 A EP92908170 A EP 92908170A EP 0581793 A1 EP0581793 A1 EP 0581793A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
group
administered
phosphonate
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19920908170
Other languages
German (de)
English (en)
Inventor
Hassan Salari
Robert Bittman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of British Columbia
Original Assignee
University of British Columbia
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of British Columbia filed Critical University of British Columbia
Publication of EP0581793A1 publication Critical patent/EP0581793A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4081—Esters with cycloaliphatic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/303—Cycloaliphatic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds

Definitions

  • This invention pertains to the synthesis and use as therapeutic agents of a group of substances with a glycerol backbone or aliphatic chain structure linked to phosphonocholine, phosphinocholine, phosphonoinositol, phosphinoinositol, or other phosphorus-containing head groups.
  • the substance has anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease properties.
  • West German Patent No. P 0230575A2 dated April 12, 1986, discloses a group of glycerophosphohpids compounds having an alkyl chain of C2-C22 and a methoxy group at the sn-2 position and a phosphocholine at the sn-3 position. These compounds are stated to be useful as anticancer agents.
  • None of these patents discloses a substance with a glycerol backbone linked to a phosphorus atom with a polar head group used as an anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease treating agents.
  • the present invention provides anti-leukemic phospholipids of the general formula:
  • T is an oxygen atom
  • U is an oxygen atom
  • NH is an aliphatic chain such as hexadecyl or octadecyl
  • R 2 is a methyl group when U is oxygen or when U is NH
  • X is a methylene group
  • n is 0 to 14
  • R 3 is either an oxygen atom or a methylene group
  • m is 2, 3, 4, 5,
  • R 4 , R 5 and R 6 represent alkyl groups containing 1 to 3 carbon atoms.
  • Phosphonolipids of the general formula R-P(O)(O-)OR' wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
  • n 0 or 1
  • R 1 and R 2 are as defined in claim 1
  • R 4 is an alkyl group such as methyl, ethyl, n-propyl, or isopropyl.
  • the phosphonate or phosphinate compounds as claimed in described include either of the opposite stereochemical configurations [( R) or ( S)], or a mixture thereof.
  • a phosphinate for treatment of leukemic cells having the formula:
  • R 1 is a long-chain alkyl group
  • R 2 is a methyl group
  • n 0 or
  • R 3 is N + (CH 3 ) 3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
  • the compound as identified in the second paragraph of this summary can be used as an agent in inhibiting cancer cell growth when the compound is administered at a concentration in the range of 5 mg/l to 50 mg/l, and pharmaceutically acceptable acid or salts thereof; and a pharmaceutically acceptable carrier.
  • the compound as identified in the third paragraph of this summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
  • the compounds identithis summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
  • the phosphonates or phosphinates as identified in the second, third, fourth, fifth, and sixth paragraphs of this summary can be used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
  • a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula:
  • a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphonolipid of the general formula: R-P(O)(O-)(OR), wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
  • a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate of the general formula:
  • n 0 or 1
  • R 1 and R 2 are as defined in claim 1
  • R 4 is an alkyl group such as methyl, ethyl, n- propyl, or isopropyl.
  • the phosphonate or phosphinate compound can includes either of the opposite stereochemical configurations [(R ) or (S)], or a mixture thereof.
  • a method of treating leukemic cells in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate having the formula:
  • R 1 is a long-chain alkyl group
  • R 2 is a methyl group
  • n 0 or
  • R 3 is N + (CH 3 ) 3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
  • the present invention also provides phospholipids with the following structures:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above.
  • the present invention provides phospholipids with an inositol group for use as anti-inflammatory agents:
  • R 1 is as defined herein above.
  • phosphonates and phosphinates are useful as anti-cancer agents since they inhibit growth of leukemic and tumor cells, as anti-inflammatory and anti-allergic agents, and as anti-cardiovascular agents.
  • the invention also involves the use of one or several of the above-mentioned phosphonates and phosphinates for treatment of cardiovascular diseases, such as septic shock (cardiogenic shock, thrombosis and others) when given at 5-50 mg/l in a pharmaceutically acceptable acid or salt thereof, and carrier.
  • septic shock cardiac shock, thrombosis and others
  • the invention is also directed to the use of phosphonates and phosphinates in the treatment of malignant cells, solid tumors of any type, leukemia and in bone marrow transplantation.
  • the invention also pertains to the use of phosphonates in the treatment of inflammatory diseases of any form, for example, arthritis, inflammatory bowel diseases, colitis, and pulmonary inflammation.
  • the invention relates to the use of phosphonates in the treatment of allergic diseases of any form, such as asthma, allergic rhenitis, hay fever, skin rashes and seasonal allergies.
  • the phosphonocholines and phosphonoglycerols can be synthesized according to the following reaction sequence:
  • Diethyl phosphite is treated with hexadecyl (or octadecyl) bromide in a Michaelis-Becker reaction, giving the corresponding diethyl ester.
  • the alkyl phosphonic acid is formed in situ from the ester , then treated with 2.1 equivalents of pyridine at 0°C in tetrahydrofuran, followed by 2.1 equivalents of oxaloyl chloride at -78°C under nitrogen.
  • the phosphonic acid dichloride thus obtained is treated with either (R )-2-O -benzylglycerol (for conversion to phosphonoglycerol) or with ethylene glycerol to give the phospholane intermediate, which is reacted with triethylamine in acetonitrile at 75°C in a pressure bottle to give phosphonocholine.
  • the intermediates and products are purified by chromatography on silica gel G or by high-pressure liquid chromatography.
  • the structures are established by nuclear magnetic resonance spectroscopy, mass spectrometry, and by elemental analysis.
  • the phosphonoinositol is prepared by the following reaction sequence:
  • the phosphonoinositol is produced by reacting hexadecyl (or octadecyl) bromide with tris(trimethylsilyl)phosphite under argon at 135°C to form the alkyl phosphonic acid. After the excess phosphite is removed by distillation, the residue is purified and coupled to pentabenzylinositol in the presence of trichloroacetonitrile in pyridine at 60°C to form pentabenzylinositol phosphonate.
  • the phosphonoethanolamine is prepared by the following reaction sequence:
  • the phosphonoserine is prepared by the following reaction
  • N-tritylserine methyl ester is added to a solution of the alkyl phosphonic acid dichloride in tetrahydrofuran and diisopropylethylamine in tetrahydrofuran.
  • the intermediate N-tritylserine methyl ester is purified by silica gel chromatography, then subjected to detritylation with 0.1 M hydrochloric acid and alkaline hydrolysis of the methyl ester.
  • the product is purified by Dowex 50W-X8 (H + form) followed by silica gel chromatography.
  • Phosphonocholines are prepared by the following reaction sequence:
  • the r ⁇ c-phosphonic acid shown above is prepared by proceeding according to the following sequence of reactions.
  • a n-alkyl allyl ether is reacted with methanol in the presence of zinc oxide and iodine; alkyl groups other than methyl can be conveniently introduced by this method (reference: Rosenthal, A.F.; Kosolapoff, G.M.; Geyer, R.P. Recl. Trav. Chim. Pays-Bas 1964, 83, 1273).
  • the 1 - O-alkyl-2-O -methyliodopropane is treated with triethyl phosphite, affording the corresponding diethyl phosphonate ester, which is hydrolyzed to give the phosphonic acid.
  • Phosphonocholine is obtained by reaction with dry choline tosylate (9 equivalents) in the presence of trichloroacetonitrile in pyridine at 50°C for 2 days.
  • the corresponding glycerol-linked phosphonoethanolamine is prepared by reaction of the phosphonic acid with N-(tert-butoxycarbonyl)- ethanolamine (N-t-Boc-ethanolamine) in the presence of trichloroacetonitrile or 1H -tetrazole; after purification of the coupling product by silica gel chromatography, the Boc protecting group is removed under standard conditions (50% trifluoroacetic acid in dichloromethane at 0°C).
  • the corresponding glycerol-linked phosphonoserine is prepared in a similar fashion, using N-tritylserine methyl ester for coupling with the phosphonic acid.
  • the acid-labile trityl group is removed by treatment with 0.1 M hydrochloric acid in tetrahydrofuran-water (1:1), and then the methyl ester is hydrolyzed by using 0.2 M sodium hydroxide. Purification is by silica gel chromatography.
  • Isosteric phosphonates are prepared according to the following reaction sequences:
  • Isosteric phosphonocholine and isosteric phosphonoinositol are prepared from 1 ,2,5,6-diisopropylidene-D-mannitol as outlined above.
  • O-benzylation is carried out at the 3 and 4 positions, then the isopropylidene groups are removed and the primary alcohols are alkylated with long-chain alkyl groups via the mesylates or similar alkylati ⁇ g agents. Methylation is carried out at the 2 and 5 positions.
  • Phosphonoglycerols are available by a similar route.
  • octadecyl glycidol gives the enantiomeric phosphonolipid.
  • the nonisosteric phosphinocholines are prepared according to the following reaction sequence:
  • 1-O-alkyl-2-O-methyliodopropane gives isopropyl 2-methoxy-3- O-alkylpropyl(allyl)phosphinate, which is cleaved with osmate-periodate, and reduced with sodium borohydride in ethanol to the hydroxyethylphosphinate. The latter is converted to the mesylate and allowed to react with aqueous dimethylamine, followed by quaternization to give the phosphinate compound.
  • Isosteric phosphinocholines and phosphinoinositols are prepared according to the following reaction sequences:
  • Isosteric phosphinocholine is prepared as outlined by the reaction sequence shown above. Wittig reaction of the aldehyde followed by hydroboration gives the alcohol, which is then converted into the desired phosphinate. Hydroboration gives an alcohol (not shown) that can be coupled to a protected inositol to yield the corresponding phosphinoinositol. Mesylation of the alcohol gives the phosphinate compound, which is aminated, then treated with methyl iodide, and the phosphonate ester is hydrolyzed to give the isosteric phosphinocholine.
  • the distance between the phosphorus and nitrogen atoms in the phosphonolipids is varied by using procedures known in the corresponding phosphate-containing compounds (references: All, S.;
  • Table I shows the effect of various concentrations of the phosphonate of the following formula on the growth of WEHI-3B cells:
  • Table II shows results of thymidine uptake by WEHI-3B and HL-60 cells during 48 hours of incubation.
  • Thymidine uptake during 48 hours phosphonate thymidine uptake (% of control) concentration ( ⁇ M) WEHI-3B cells HL-60 cells
  • Table III shows the results of thymidine uptake by WEHI-3B and
  • Thymidine uptake during 72 hours phosphonate thymidine uptake (% of control)
  • Table V demonstrates the effect of phosphonate of the above structure on the incorporation of thymidine into DNA of the C-41 cell line (a human cervical tumor cell) Table V
  • Table VI shows the effect of the above phosphonate on tumor growth in mice.
  • BALB/C mice were injected with 3-Lewis lung carcinoma under the skin at the back. Three days after injection of tumor cells the treatment was initiated with 50 mg/day orally once a day. In the control group the mice received only the carrier mucilage of tragacanth. As seen in Table VI, in control animals the first sign of a detectable tumor was observed after the seventh day of post cell injection. In the phosphonate-treated animals, the tumor growth was retarded by approximately 6 days. The tumor size in the
  • Example 1 Effect of the phosphonate of the following formula on the activation of human neutrophils
  • Example 2 Effect of phosphonate on neutrophil degranulation and lysosomal enzyme release (elastase)
  • Petri dishes were coated with [ 3 H]elastin and were used to assess the release of elastase.
  • Neutrophils (10 6 ) in 500 ⁇ l of medium were added to each Petri dish well. Addition of 1 ⁇ M FMLP for 1 hour at 37°C
  • CPPD calcium pyrophosphate dihydrate
  • MSU monosodium urate
  • Asthma is an allergic disease caused by the contraction of airway
  • Thrombosis is the result of activation of platelets by agents such as
  • PAF platelet activating factor
  • Phosphonates also inhibited serotonin release from platelets activated with thrombin or PAF. As seen in Table XIII, phosphonate at 10 ⁇ M blocked serotonin release entirely.
  • Phosphonates were shown' to block PAF-induced hypotension in rats. When given at 5 mg/kg, phosphonates inhibited the hypotensive activity of PAF dramatically. As seen in Table XTV, normal rat blood pressure was about 150 mm Hg, and this dropped to about 40 mm Hg after administration of PAF (10 ⁇ g/kg). Animals given phosphonates (5 mg/kg) had only slightly reduced blood pressure after the injection of PAF, suggesting that phosphonates are anti-hypotensive agents.
  • An effective concentration of phosphonate (normally 5-50 mg/l) can be given orally, intravenously (i.v.), intramuscularly (i.m.) or subcutaneously (s.c.), in the form of tablets (orally), capsules (orally), or injection ampules (i.v., i.m., s.c).
  • the drug can be applied in the form of a rubbing cream.
  • Tablets can be prepared via compression of 50 mg of phosphonates, 200 mg of lactose, and 50 mg Avicel (TM) .
  • Capsules are made by making bilayers of liposomal phosphonates in the concentrations of 5-50 mg with lecithin.
  • Injection solutions are made either in water or propylene glycol with an upwardly adjusted pH in phosphate buffer.
  • the drag solution is sterilized through a filter of 0.22 mm.
  • Solutions can be made in 20% propylene glycol with about 0.5% of a preservative such as ascorbic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte à la synthèse et à l'utilisation, comme agents thérapeutiques, d'un groupe de substances présentant un squelette de glycérol ou une structure de chaîne aliphatique lié(e) à un atome de phosphore ou à un groupe de tête polaire. Selon le groupe de tête polaire, la substance présente des caractéristiques anticancéreuses, anti-inflammatoires, anti-allergiques ou agissant contre les maladies cardiovasculaires. On décrit aussi des composés de la formule (I) et (II), où n vaut de 0 à 14 et R1 représente un groupe alkyle C12-C20, R2 représente un groupe méthyle et R3 représente un groupe de tête d'analogue d'inositol, un groupe (CH2)mN+(CH3)3 où m vaut de 2 à 10, un groupe de tête de sérine ou un groupe de tête d'éthanolamine, ou de la formule (III) où R1 et R2 sont tels que décrits ci-dessus, n = 0 ou 1, et R3 représente (CH2)mN+(CH3)3 (m=2-10). L'invention se rapporte en outre à la synthèse et à l'utilisation, comme agents thérapeutiques, de substances ne possédant pas de squelette de glycérol, mais qui présentent une structure de chaîne aliphatique directement liée à un atome de phosphore de la formule générale R-P(0)(0-) OR', où R représente un groupe alkyle à chaîne longue tel que hexadécyle ou octadécyle et R' représente un groupe de tête tel que choline, glycérol, inositol, éthanolamine ou sérine.
EP19920908170 1991-04-25 1992-04-21 Phosphonates et phosphinates utilises comme agents anticancereux, anti-inflammatoires, antiallergiques et anti-myocardites Withdrawn EP0581793A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69245291A 1991-04-25 1991-04-25
US692452 1991-04-25

Publications (1)

Publication Number Publication Date
EP0581793A1 true EP0581793A1 (fr) 1994-02-09

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Country Link
EP (1) EP0581793A1 (fr)
WO (1) WO1992019627A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9600194D0 (sv) * 1996-01-19 1996-01-19 Perstorp Ab A new chemical compound
US7323601B2 (en) * 2001-02-21 2008-01-29 Research Foundation Of The City University Of New York Enanitomers of unsaturated alkyllysophosphonocholines and use as anti-neoplastics
WO2004062594A2 (fr) * 2003-01-09 2004-07-29 Zeneus Pharma Limited Composes d'ether lipidique antineoplasiques presentant des modifications au niveau du groupe carbone sn-3

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DE2619686C2 (de) * 1976-05-04 1986-08-07 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Verwendung eines Lysolecithins zur Tumorbehandlung
US4515722A (en) * 1982-03-30 1985-05-07 Merck & Co., Inc. Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents
US4562179A (en) * 1982-04-19 1985-12-31 Fujisawa Pharmaceutical Co., Ltd. Phospholipid derivatives, and pharmaceutical composition of the same
JPS5984824A (ja) * 1982-11-08 1984-05-16 Takeda Chem Ind Ltd 抗腫瘍剤
US4640913A (en) * 1983-01-10 1987-02-03 American Cyanamid Company Phosphocholine derivatives having antihypertensive action
DE58904595D1 (de) * 1988-04-19 1993-07-15 Hafslund Nycomed Pharma Neue alkylphosphonoserine, verfahren zu deren herstellung und diese enthaltende pharmazeutische mittel.
JPH0669088A (ja) * 1992-03-26 1994-03-11 Nec Kyushu Ltd 空調システム

Non-Patent Citations (1)

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Title
See references of WO9219627A2 *

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WO1992019627A2 (fr) 1992-11-12

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