Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

• R is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof are useful in reducing the symptons of parkinson disease such as rigor, 'akinesi'a and tremor, without causing peripheral adrenergic effects and other undesirable secondary effects.
• the L-antipode of formula I can be prepared by resolving a racemic mixture of the compound of formula I above into its optical antipodes and isolating the L-antipode of a compound of formula I above or a pharmaceutically acceptable salt thereof.
• the compound of formula I can be prepared from a compoundof formula:
• R is an amino group protected by aconventional amino protecting group convertible to an amino group;
• R is hydroxy or hydroxy protected by a conventional hydroxy protecting group convertible to a hydroxy group;
• R is carboxy or a conventional carboxy protecting group convertible to a carboxy group; or a pharmaceutically acceptable salt thereof, by simultaneously, or any sequence, converting the protected amino group into free amino groups, converting the protected hydroxy group into free hydroxy groups, and/or converting the protected carboxy group into the free acid.
• the free acid can, if desired be'converted into its salt form.
• lower alkyl designates both straight chain and branched chain alkyl groups containing from 1 to 7 carbon atoms such as methyl, ethyl, isopropyl, n-hexyl, etc.
• preferred alkyl groups are included methyl and ethyl.
• the compounds of formula I above are amphoteric in character. These compounds dissolve in water as well as in acids or in alkalies in which they form salts.
• Such acid addition salts are also within the scope of the invention.
• bases with which-the compounds of formula I form salts are the alkali metal bases such as sodium hydroxide, potassium hydroxide, etc., and ammonia.
• the resolution of the racemate of formula I to produce the L-antipode of formula I can be carried out by conventional methods of resolving racemic mixture.
• a racemic ester of formula I can be resolved using optically active acids such as camphorsulfonic acid, tartaric acid or tartaric acid-2,4-dichloro anilide.
• optically active acids such as camphorsulfonic acid, tartaric acid or tartaric acid-2,4-dichloro anilide.
• the resolution of a racemic free acid of formula I can be carried out using optically active bases such as ephedrine, dehydroabietylamine or the like, as well as optically active acids such as camphorsulfonic acid.
• the isolution of the desired L-antipodes can be carried out by conventional isolation methods such as crystallization of the salts and decomposition thereof.
• R in the compound of formula II can. be any conventionally protected amino group.
• conventional amino protecting groups are those which can beremoved by hydrogenolysis or hydrolysis.
• protected amino groups which are convertible into the free amino group (R, in the starting materials of formula II) are the following:
• Groups which are convertible into the free amino group by hydrolysis such as, for example, lower alkanoylamino groups, the formylamino group, the benzoylamino group and the tertbutoxycarbonylamino group.
• the formylamino group, the lower alkaoylamino groups, especially the acetoamino group, and the benzoylamino group are preferred.
• the hydrolysis of these groups can be carried out in a manner known per se with acids, especially with strong mineral acids such as with aqueous hydrochloric acid or sulfuric acid.
• the hydrolysis can be carried out at room temperature, but it is preferably carried out at an elevated temperature up to the boiling point of the mixture.
• hydrogenolysis can be carried out by hydrogenation in the presence of a hydrogenation catalyst.
• catalysts there can be used, for example, palladium/charcoal catalysts or platinum catalysts, in which case the hydrogenolysis is expediently carried out in a lower alkanecarboxylic acid such as glacial acetic acid or in a lower alkanol such as methanol or ethanol.
• Aqueous alkanols may also be used.
• R in the compound of formula II can be any conventional hydroxy protecting group.
• protecting groups are the protecting groups which can be removed by hydrogenolysis or hydrolysis.
• groups which are convertible into the hydroxy group are the following:
• the hydrolysis of these groups can be carried out by 7 conventional hydrolysis techniques such as with alkalies (e.g., with aqueous or aqueous-alcoholic sodium hydroxide or potassium hydroxide) or with acids (e.g., aqueous hydrochloric acid or sulfuric acid).
• alkalies e.g., with aqueous or aqueous-alcoholic sodium hydroxide or potassium hydroxide
• acids e.g., aqueous hydrochloric acid or sulfuric acid.
• the hydrolysis can be carried out at a temperature from about C. up to the boiling point of the mixture.
• R can represent an etherified hydroxy group such as a methoxy-methoxy group or a tetrahydropyranyloxy group which can be converted into the hydroxy group by hydrolysis with acids (e.g., with aqueous hydrochloric acid).
• R in the compound of formula ll can be any conventional carboxylic acid protecting group.
• protecting groups are the groups which can be removed by either hydrolysis or hydrogenolysis.
• groups which are convertible into the carboxyl group are the following:
• Groups which are convertible into the carboxyl group by hydrolysis such as, for example, lower alkoxycarbonyl groups (especially the methoxycarbonyl and ethoxycarbonyl groups) and amide groups; that is to say, amide groups derived from the free amino group and from primary or secondary amides such as the carbamoyl group and monoor di-alkylor arylsubstituted carbamoyl groups, in which case the alkyl groups can contain from 1 to 7 carbon atoms and the aryl group is especially the phenyl group.
• a further group which is convertible into the carboxyl group in a manner known per se is the cyano group.
• the conversion of aprotected amino group R, to the free amino group and the conversion of a group which may be present which is convertible into the hydroxy group or into the carboxyl group (R, and R into the hydroxy group or into the carboxyl group can be carried out in any desired sequence or simultaneously.
• a free acid obtained can be converted into a lower alkyl ester (R represents a lower alkyl group).
• R represents a lower alkyl group.
• This can be carried out by conventional esterification techniques such as using the usual esterification agents (e.g., an appropriate lower alkanol).
• bases obtained can be converted into salts if desired; the L-antipodes of the. free amino acid of formula I forming both acid addition salts and metal salts.
• acid addition salts are those with inorganic acids such as hydrochloric acid and those with organic acids such as oxalic acid.
• metal salts are, in particular, the alkali metal salts.
• the preferred starting materials of formula ll are those in which R represents a lower alkanoalamino group, especially the acetam'ino group, the formylamino group or the benzoylamino group.
• Another group of preferred starting materials of formula I! comprises those in which R represents the hydroxy group, the formyloxy group or a lower alkanoyloxy group, especially the acetoxy group.
• a further preferred group of starting materials of formula [I comprises those in which R represents the carboxyl group or a lower alkoxycarbonyl group, especially the methoxycarbonyl group or the ethoxycarbonyl group.
• the starting materials of formula ll are, in part, known and, in part, new.
• R and R are as above; and R is formyloxy or lower alkanoyloxy; and their salts, can be prepared by oxidizing the L- antipode of a compound of the general formula:
• R and R are as above;
• R is formyl or lower alkanoyl; with a peracid.
• peracids there can be used organic peracids, especially peralkanecarboxylic acids such as peracetic acid, performic acid, trifluoroperacetic acid and the like, the oxidation being preferably carried out in a lower alkanecarboxylic acid such as formic acid andacetic acid.
• Aromatic percarboxylic acids such as mchloroperbenzoic acid can also be used as the peracid, in which case the oxidation is expediently carried out in an organic solvent such as methylene chloride or chloroform.
• the oxidation with a peracid is expediently carried out at a temperature of about 0C. to about 50C.
• the L-antipode of a compound of formula ll-B obtained by the foregoing oxidation can subsequently be converted into corresponding compounds wherein R represents the hydroxy group by mild alkaline hydrolysis.
• This hydrolysis can be carried out, for example,
• an alkoxycarbonyl group R can be simultaneously hydrolyzed to the carboxyl group.
• hydrolysis of a compound of formula II-B with conversion of a formyloxy group R into a hydroxy group can also be carried out by mild acidic hydrolysis, for example, with aqueous hydrochloric acid at room temperature or by Kieselgel chromatography.
• the known starting materials of formula II can be prepared in an analogous manner (peracid oxidation and subsequent mild hydrolysis).
• Compounds of formula III where R is formyl can be obtained, for example, by reacting the compound of formula IV above with a formylation agent in the presence of a Lewis acid.
• a formylation agent in the presence of a Lewis acid.
• Any conventional method of formylating can be utilized to prepare the compound of formula III where R is formyl.
• the-formylation agents there can be used, for example, a formic acid ester, an orthoformic acid ester, formylchloride, a dihalomethyl lower alkyl ether, especially a dichloromethyl lower alkyl ether such as dichloromethyl methyl ether, hydrocyanic acid, dimethylformamide or other amides of formic acid. This reaction can take place in the presence of any conventional Lewis acid.
• a zinc halide such as zinc chloride, an aluminum halide such as aluminum chloride, a titanium halide such as titanium tetrachloride, an iron trihalide such as iron trichloride o a tin halide such as tin tetrachloride.
• the formylation reaction can be carried out in the absence of a further solvent if the formylation agent is used in excess.
• the formylation reaction can also be carried out in the presence of an inert organic solvent (e.g., nitrobenzene, carbon tetrachloride, methylene chloride or chloroform).
• the reaction temperature can vary within a very wide range. Generally, it is preferred to use a temperature of from about 50C. and the reflux temperature of the reaction mixture.
• R represents a lower alkanoyl group
• R represents a lower alkanoyl group
• R represents a lower alkanoyl group
• a functional derivative of a lower alkanecarboxylic acid e.g., acetic acid
• a Friedel-Crafts catalyst there can be used especially a strong Lewis acid
• any conventional reactive functional derivative of a lower alkane carboxylic acid can be used in this reaction.
• the functional derivatives of the lower alkane carboxylic acids there are especially used acid halides (e.g., acetyl chloride).
• the reaction is expediently carried out in an organic solvent (e.g., nitrobenzene) at a temperature between about 0and 200C.
• the present invention is also concerned with pharmaceutical preparations having anti-parkinsoon activity.
• the pharmaceutical preparations provided by the present invention contain as an essential active ingredient the L-antipode of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a compatible pharmaceutical carrier.
• the typical symptons of iodiopathic parkinsonism such as rigor, akinesia and tremor can be significantly improved or abolished without peripheral adrenergic effects and other undesirable secondary effects thereby occurring.
• the compounds of formula I and their salts can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier which can be an organic or inorganic inert carrier material suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
• a compatible pharmaceutical carrier which can be an organic or inorganic inert carrier material suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
• the pharmaceutical preparations can be made up in solid form (e.g., as tablets, dragees, suppositories or capsules) or in liquid form (e.g., as solutions, suspensions or emulsions).
• the preparations may be
• the active ingredients aforesaid i.e., the compounds of formula I or salts thereof
• the pharmaceutical preparations provided by the present invention possess a depot action (half-life 45 hours).
• the LD in the mouse amounts to more than 5,000 mg./kg. p.o. in the 24-hour test.
• the undesirable secondary effects which usually appear on administration ofL-dopa namely gastrointestinal complaints, involuntary movements and circulatory complaints, do not occur or only occur to a very slight extent.
• the pharmaceutical preparation provided by the present invention can be made up in solid or liquid form and, in addition to the essential active ingredient, can contain suitable pharmaceutical organic or inorganic carrier materials such as water, gelatin, lactose, magnesium stearate, talc or the like.
• suitable pharmaceutical organic or inorganic carrier materials such as water, gelatin, lactose, magnesium stearate, talc or the like.
• the pharmaceutical preparations can be made up in solid forms such as tablets, dragees or capsules or in liquid forms such as solutions, suspensions or emulsions. Tablets are preferred. u
• a pharmaceutical preparation in dosage unit form can expediently contain about 50 mg. to about 1,000 mg., preferably about 500 mg. to about 1,000 mg. of active ingredient.
• the pharmaceutical preparations can also contain one or more peripheral decarboxylase inhibitors,
• decarboxylase inhibitor there can be used any pharmaceutically
• the decarboxylase inhibitor a compound of the general formula:
• R-NH-NH-CHiQ wherein R is a hydrogen, amino-(lower alkanoyl), amino-(hydroxy lower alkanoyl; and n is-an integer from 2 to 3; or a pharmaceutically acceptable salt thereof.
• Q is hydrogen or lower alkyl; aswell as 3,4-dihydroxy-benzyloxyamine and salts thereof.
• the weight ratio of active ingredient to decarboxylase inhibitor expediently amounts to about 5:1 to 10:1.
• the pharmaceutical preparations provided by the present invention can be manufactured by mixing the L-antipode of a compound of formula 'I or a pharmaceutically acceptable salt thereof, if desired together with a peripheral decarboxylase inhibitor, with a compatible pharmaceutical carrier material suitable for medicinal administration.
• a compatible pharmaceutical carrier material suitable for medicinal administration there can be used the carrier materials which are usual in I pharmacy.
• rier materials or such a preparation can be manufactured by incorporating the active ingredient into a core, providing this with a coating which is resistant to gastric juice and applying thereover an external layer which contains the decarboxylase inhibitor.
• a pharmaceutical preparation from which the active ingredient is released with delay only after the decarboxylase inhibitor has been released preferably about 30 to 60 minutes after the decarboxylase inhibitor. This has been found to be especially expedient.
• the decarboxylase inhibitor is expediently administered first, expediently intravenously, andthe active ingredient is administered about 30 to 60 minutes later.
• the active ingredient in the treatment of Parkinsonism, can be administered either orally or parenterally, especially intravenously.
• the amount of active ingredient to be administered per day is governed by the particular case.
• an amount of active ingredient of about 1.5 to about 4 g. especially about 3 g. will be employed.
• the amount of active ingredient to be administered per day can lie between about 50 mg. and about 2 g., especially at about 1 g.
• the foregoing amounts relate to the active ingredient content calculated as 4-methoxy-L-m-tyrosine which represents a preferred active ingredient in accordance with the present invention.
• the amount of active ingredient administered can be reduced by the combined administration thereof with a peripheral decarboxylaseinhibitor.
• a combined administration there are expediently used amount of active ingredient which lies in the lower part of the foregoing ranges.
• 1 g. of active ingredient and mg. of a decarboxylase inhibitor ratio 10:1 parts by weight
• 500 mg. of active ingredient and 100 mg. of decarboxylase inhibitor ratio 5:1 parts by weight
• the administration is expediently effected in individual doses divided over the day.
• EXAMPLE 1 A mixture of 5.3 g. (19.9 mmol) of N-acetyl-4- methoxy-L-m-tyrosine methyl ester-and of 100 ml. of 3-N aqueous hydrochloric acid is heated at reflux in an argon atmosphere for 2 hours.
• the 4-methoxy-L-m- EXAMPLE 2 3.3 g. (13.3 mmol) of 4-methoxy-L-m-tyrosine hydrochloride are dissolved in ml. of ethanol and 12.5 ml. of propylene oxide are added to the solution in several portions in'the course of 3 hours. The mixture is then left to stand at 25C. for 20 hours and the precipitated crystals are filtered off.
• EXAMPLE 4 167 ml. of titanium tetrachloride are added with stirring in the course of 5 minutes to a solution of 95 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanine methyl ester in 1500 ml. of nitrobenzene, the temperature rising to 38C. The mixture is cooled to +23C., 69.4 ml. of dichloromethyl methyl ether are then added in the course of 3 minutes and the mixture is stirredat room temperature for 2 hours. The solution is cooled to +5C. and poured with stirring into 380 ml. of ice-cold 3-N aqueous hydrochloric acid. 4,000 ml.
• N-acetyl-3-( p-methoxyphenyl )-L-alanine methyl ester can be obtained by esterification with methanol of the corresponding free acid by the procedure given in Example 9 hereinafter.
• EXAMPLE 7 The Nacetyl-4-methoxy-L-m-tyrosine ethyl ester can be obtained by the procedure described in Example 3 (oxidation with peracetic acid in glacial acetic acid and hydrolysis) from N-acetyl-3-(3-formyl-4- methoxyphenyl)-L-alanine ethyl ester [melting point l-l0lC.; [041 25 +240 (0 1.0 percent in 95 percent ethanol)].
• N-acetyl-3-(3-formyl-4-methoxyphenyl)-L- alanine ethyl ester is obtained by the procedure de- 10 scribed in Example 4 by forrnylation of N-acetyl-3-(pmethoxyphenyl)-L-alanine ethyl ester [melting point 9394.5C.; [04],, 25 +23.3 (c 1.0 percent in 95 percent ethanol)].
• EXAMPLE 9 Dry hydrogen chloride gas is led into a solution of 160 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanine in 1,600 ml. of absolute ethanol until the solution is saturated, the temperature of the solution being held at 20-22C. by cooling (duration 2.5 hours). The solution is then evaporated under reduced pressure, the residue taken up in ethyl acetate, the solution obtained washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and then again evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and hexane. Pure N-acetyl-3-(p-methoxyphenyl)- L-alanine ethyl ester is thus obtained.
• EXAMPLE 11 EXAMPLE 12 47.4 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanine are added to a solution of g. of anhydrous aluminium chloride in 200 ml. of nitrobenzene. The solution thus obtained is cooled to +14C. and then, without further cooling, 45 ml. of acetyl chloride are added in one portion with stirring. The temperature rises immediately to 29C. After 20 minutes, the solution is poured onto a mixture of 10 ml. of concentrated aqueous hydrochloric acid and 400 g. of ice. The mixture is extracted twice with 400 ml. of ethyl acetate each time.
• EXAMPLE 14 4.38 ml. of titanium tetrachloride are rapidly added dropwise to a suspension of 2.37 g. of N-acetyl-3-(pmethoxyphenyl)-L-alanine in 40 ml. of nitrobenzene,
• EXAMPLE 16 A solution of 8.3 g. mmol) of N-acetyl-4- methoxy-L-m-tyrosine ethyl ester in 50 ml. of 3-N sodium hydroxide is left to stand at 25C. for 0.5 hour, then acidified to pH 2.0 with 6-N aqueous sulphuric acid and extracted with ethyl acetate. The extract is dried over sodium sulphate and evaporated. One recrystallization from ethyl acetate yields pure N-acetyl- 4-methoxy-L-m-tyrosine.
• EXAMPLE l7 4-Methoxy-L-m-tyrosine is obtained by the procedure described in Example 1 and Example 2, there being used, instead of N-acetyl -4-methoxy-L mtyrosine methyl ester or N-acetyl-4- methoxy-L-m-tyrosine ethyl ester, N,O-diacetyl-4- methoxy-L-m-tyrosine ethyl ester.
• EXAMPLE 18 A solution of 32.2 g. of N-acetyl-3-(3-acetyl-4- methoxyphenyl)-L-alanine ethyl ester in 40 g. of 40 percent peracetic acid in glacial acetic acid is held at a temperature of 30 for 2.5 hours by cooling at the beginning and warming somewhat towards the end. N,O- diacetyl-4-methoxy-L-m-tyrosine ethyl ester is obpressure.
• EXAMPLE 19 5.3 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanine ethyl ester are added to a solution of 10.7 g. of aluminium chloride in 80 ml. of nitrobenzene. The solution thus obtained is cooled to +19C. and then, without further cooling, 3 ml. of acetyl chloride are added in one portion with stirring. The temperature rises immediately to 26C. After 15 minutes, the solution is poured onto a mixture of 10 ml. of concentrated aqueous hydrochloric acid and 50 g. of ice. The mixture is extracted twice with 150 ml. of ethyl acetate each time.
• N-formyl-4-methoxy-L- m-tyrosine which can, in turn, be obtained by hydrolysis of the O-acetyl compound in accordance with the procedure described in Example 11.
• O-acetyl-N-formyl-4-methoxy-L-m-tyrosine can, in turn, be obtained by the procedure described in Example 15 by the peracid oxidation of 3-(3-acetyl-4- methoxyphenyl)-N-formyl-L-alanine which, in turn, can be obtained by the procedure described in Example 12 from N-formyl-4-methoxy-L-phenylalanine.
• EXAMPLE 21 The residue is dissolved in 500 ml. of water and, after I the addition of 10 g. of active charcoal, heated to C. for 10 minutes. The hot solution is filtered, washed with ml. of water and the filtrate evaporated under reduced pressure.
• EXAMPLE 23 Dry hydrogen chloride gas is introduced over a period of 1 hour into a suspension of 25 g. of 4-methoxy- L-m-tyrosine in 300 ml. of absolute methanol, the temperature rising to about 50C. and the 4-methoxy-L-mtyrosine gradually passing into solution. The solution is then left at room temperature for 72 hours and subsequently evaporated at 12 mm Hg. with the addition of 100 ml. of absolute toluene.
• the crystalline residue obtained is dissolved in 100- EXAMPLE 24
• 2.25 g. of 4-methoxy-D,L-m-tyrosine methyl ester (prepared from 4-methoxy-D,L-m-tyrosine by the procedure described in Example 8 melting point 6364C.) are heated on a steam-bath together with 3 g. of L-tartaric acid 2,4dichloroanilide in ml. of isopropanol.
• the clear solution obtained is cooledand an oily precipitate then separates out.
• the supernatant solution is decanted, digested with acetonitrile. Crystallization occurs and the crystals are recrystallized twice from acetonitrile/methanol.
• the crystals obtained (the salt of 4-methoxy-D,L-m-tyrosine methyl ester with L- tartaric acid 2,4-dichloroanilide) are suspended in 100 ml. of ethyl acetate. The suspension is shaken with 50 ml. of saturated aqueous sodium carbonate solution. The aqueous phase is separated and again washed with 50 ml. of ethyl acetate. The organic phases are combined, dried over sodium sulphate and evaporated.
• cellulose preparation AVlCEL 147.3 mg. maize starch 40 mg. methyl cellulose 10 mg. magnesium stearate 5 mg.
• a hard gelatin capsule, from which the active ingredient is released with delay after the release of a decarboxylase inhibitor, can be manufactured as follows:
• a core consisting of 50 mg. of 4-methoxy-L-mtyrosine, 8 mg. of maize starch, 15 mg. of lactose, 1.8 mg. of talc and 0.2 mg. of magnesium stearate is coated with a cellulose acetate phthalate varnish in order to make it resistant to gastric juice.
• a granulate is manufactured from 50 mg. of N-L serine-N 2,3 ,4-trihydroxybenzyl )-hydrazide hydrochloride, 5.8 mg. of mannitol and 2.4 mg. of polyvinylpyrrolidone in the usual manner.
• the coated core and the granulate are introduced into a hard gelatin capsule.
• R is hydrogen or lower alkyl group; or pharmaceutically acceptable salts thereof.
• R is loweralkanoylamino or formylamino; R is formyloxy or lower alkanoyloxy; R is carboxy or carbolower alkoxy.
• R is forrnylamino or loweralkanoylamino; R if formyl or lower alkanoyl; and R is carboxy or lower alkanoyloxy.

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Citations (3)

• 1971
  • 1971-10-01 ZA ZA716603A patent/ZA716603B/xx unknown
  • 1971-10-05 IL IL37846A patent/IL37846A0/xx unknown
  • 1971-10-11 AU AU34423/71A patent/AU3442371A/en not_active Expired
  • 1971-10-14 NL NL7114142A patent/NL7114142A/xx unknown
  • 1971-10-18 BR BR006909/71A patent/BR7106909D0/pt unknown
  • 1971-10-28 DE DE19712153803 patent/DE2153803A1/de active Pending
  • 1971-11-03 US US00195472A patent/US3853954A/en not_active Expired - Lifetime
  • 1971-11-09 BE BE775082A patent/BE775082A/fr unknown
  • 1971-11-09 ES ES396809A patent/ES396809A1/es not_active Expired
  • 1971-11-10 FR FR7140335A patent/FR2113902A1/fr not_active Withdrawn

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