US3853875A - Esters of 2-alkyl thiazole 5-carboxylic acid - Google Patents

Esters of 2-alkyl thiazole 5-carboxylic acid Download PDF

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Publication number
US3853875A
US3853875A US00262785A US26278572A US3853875A US 3853875 A US3853875 A US 3853875A US 00262785 A US00262785 A US 00262785A US 26278572 A US26278572 A US 26278572A US 3853875 A US3853875 A US 3853875A
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Prior art keywords
ethyl
carboxylate
thiazole
piperazino
phenyl
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US00262785A
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F Clemence
Martret O Le
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Sanofi Aventis France
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Roussel Uclaf SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms

Definitions

  • n represents the whole numbers 0, l, 2, 3, 4 or 5
  • n' represents the whole numbers 1, 2, 3, 4 or 5
  • m represents the whole numbers 0, l, 2, 3, 4 or 5
  • R represents a substituted or unsubstituted phenyl radical of general formula:
  • An object of the present invention is the preparation of new esters of 2-alkyl thiazole S-carboxylic acid of formula I:
  • n represents the whole numbers 0,1 ,2,3,4 or 5
  • n represents the whole numbers l,2,3,4 or 5
  • m represents the whole numbers 0,1,2,3,4 or 5
  • R represents a substituted or unsubstituted phenyl radical of general formula:
  • X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radical containing from l to 6 carbon atoms, an alkyloxy radical containing from I to 6 carbon atoms or a trihalogenomethyl group, or R represents a heterocycle containing a maximum of 6 links and capable of bearing 1 or more heteroatoms, and of salts of these compounds with a mineral or organic acid.
  • Another object of the present invention is the development of a process for the preparation of new esters of 2-alkyl thiazole S-carboxylic acid of formula I and of salts of these compounds with a mineral or organic acid.
  • a further object of the present invention is to provide therapeutic compositions and methods of combatting hypertension utilizing the compounds of formula I and salts thereof with a mineral or organic acid.
  • the present invention is directed to new esters of 2- alkyl thiazole S-carboxylic acid of formula I:
  • X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radi cal containing from l to 6 carbon atoms, an alkyloxy radical containing from 1 to 6 carbon atoms or a trihalogenomethyl group, or R represents a heterocycle containing a maximum of 6 links and capable of bearing 1 or more heteroatoms, as well as the salts of these compounds with a mineral or organic acid.
  • the X and X groupings represent more particularly an alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl radical, or an alkyloxy radical such as a methoxy, othoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, tert-butoxy, diethylaminoethoxy or trifluoroethoxy radical.
  • an alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl radical
  • an alkyloxy radical such as a methoxy, othoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, tert-butoxy, diethylaminoethoxy or trifluoroethoxy radical.
  • the heterocyclic radical R can be more particularly a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiapyranyl, oxazinyl or thiophene radical, the value of the m factor is preferably 0,] or 2.
  • the compounds of the invention are endowed with interesting physiological properties. They possess more particularly an adrenolytic and peripheral vasodilatory route, and between and 500 mg. using the buccal or rectal route.
  • the pharmaceutical forms such as injectable solutions or suspensions, plain or coated tablets, sublingual tablets and suppositories are prepared according to the usual methods.
  • the invention also includes a process for preparing compounds of formula I, as well as the salts of these compounds with a mineral or organic acid, characterized mainly in that one reacts the 2-alkyl thiazole 5- carboxylic acid of general formula 11:
  • n and R have the aforesaid meanings, then optionally salifies according to the usual methods, the resulting ester of general formula I;
  • 2-alkyl thiazole S-carboxylic acid ll To esterify alcohol 111, one can use 2-alkyl thiazole S-carboxylic acid ll. One operates in such a case in the presence of an acid catalyst, such as paratoluene sulphonic acid of hydrochloric acid and removes the water formed.
  • an acid catalyst such as paratoluene sulphonic acid of hydrochloric acid
  • a tertiary base such as triethylamine or pyridine.
  • the anhydride of 2-alkyl thiazole S-carboxylic acid [I can be conveniently obtained by reacting acid 11 with dicyclohexyl carbodiimido. To carry out esterification one can also use a mixed anhydride of acid 11. To prepare this anhydride, one reacts a tertiary base with acid 11, then subjects the resulting salt to the action of a lower alkyl chloroformate, to obtain the mixed anhyydride of general formula IV:
  • the tertiary base which one reacts with acid 11 is preferably triethylamine or pyridine.
  • Salification of acid 11 by the tertiary amine is carried out in an organic solvent such as acetone.
  • the lower alkyl chloroformate which one reacts with the salt is more particularly methyl or ethyl chloroformate. This condensation is carried out preferably in an acetonic medium. Condensation of the mixed anhydride of formula IV with alcohol of formula 111, is preferably carried out in an acetonic medium. Conjointly with the desired ester 1, it tends to form a lower alkyl hemicarbonate, which is immediately decomposed into carbon dioxide and the corresponding alcohol.
  • esterification can also be carried out by reacting the acid or one of its functional derivatives with an alcoholate of formula:
  • M represents an alkali-metal atom
  • Optional salification of the amino functions of the ester 1 piperazine ring can more particularly be realized by the action of a suitable acid with ester of for mula I.
  • This salification is carried out in an organic solvent such as methanol, ethanol, isopropanol. acetone or ether.
  • 4-benzyl piperazine ethanol can be obtained according to the process described in NATURWISSENSCHAFTEN 53 (16) 405 (1966).
  • 4-a-pyridyl piperazine ethanol can be obtained according to the process described in US. Pat. No. 2,562,036.
  • 4-o-to1yl piperazine ethanol is described by C. B. POLLARD and T. H. WICKER J. Am. Chem. Soc. 76 1853 (1954).
  • 4-(p-methoxy phenyl) piperazine ethanol is described in British Pat. No. 889,223.
  • 4-p-tolyl piperazine ethanol is described by C8. POLLARD and T.H. WlCKER J. Am. Chem. Sec. 76 1853 (1954), as well as 4-(0-ch1orophenyl) piperazine ethanol.
  • 4- (2',5-dimethyl pheny1)piperazine ethanol, and 4-(3- trifluoro methyl phenyl) piperazine ethanol can be prepared by the action of ethylene oxide on the corresponding substituted piperazines. The preparations for these 3compounds which are not described in the literature, are given in the experimental section.
  • Z-alkyl thiazole 5carboxylic acids are obtained by the process described in French Pat. No. 2,047.876.
  • Example I B-(4-phenyl 1-piperazine) ethyl 2-propy1 thiazole 5-carboxylate dihydrochloride
  • One taining the maleatel purifies the product by recrystallization from isopropa- T0 g-Df flleiC ac d n Solution in 150 0.6.
  • 10 g. of ,8-(4'-phenyl 1-piperazine) ether one adds 4 g. of B-[4(o-methoxy phenyl) 1'- ethyl 2-propyl thiazole S-carboxylate dihydrochloride, piperazino] ethyl 2-propyl thiazole S-carboxylate in soin the form of colourless crystals, soluble in chloro- 25 lution in 50 c.c.
  • the product takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether, melting at 145C.
  • Example 1V B-(4-p-tolyl l'-piperazine) ethyl 2-propyl thiazole S-carboxylate dihydrochloride:
  • the compound takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether and benzene, melting at 202C.
  • the 4-(o-tolyl) piperazine ethanol is obtained according to the process described by POLLARD et a1, .l.Am.Chem.Soc. 76, 1853-5, 1954.
  • the 4-(p-methoxy phenyl) piperazine ethanol is obtained according to the process described in British Pat. No. 889,223 (C.A., 1962,57,l3778a) By reacting 15 c.c. of a 3.15 N ethanolic solution of hydrochloric acid with 9.2 of base, one obtains 5.9 g. of B- ⁇ 4'-(p-methoxy phenyl) l'piperazino] ethyl 2- propyl thiazole S-carboxylate dihydrochloride, in the form of colourless crystals, soluble in water, methanol and chloroform, slightly soluble in ethanol, insoluble in ether and benzene, melting at 168C.
  • Example XIV B-[4'-(o-methoxy phenyl) l'- piperazino] ethyl 2-propyl thiazole S-carboxylate dihydrochloride: a. 2-propyl thiazole 5-carboxylic acid anhydride;
  • Example XV B-[4'-(o-methoxy phenyl) l'-piperazino] ethyl 2-butyl thiazole 5-carboxylate oxalate:
  • n represents the whole numbers 0, l, 2, 3, 4, 5, n represents the whole numbers 1, 2, 3, 4, 5, m represents the whole numbers 0, l, 2, 3, 4, 5, and R is a member of the group consisting of a phenyl of the formula wherein X and X identical or different, represent a member of the group consisting of a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl containing from 1 to 6 carbon atoms. an alkyloxy containing from 1 to 6 carbon atoms, trifluoro methyl and pyridyl; and their non-toxic, pharmaceutically ac ceptable acid addition salts.
  • the compound of claim 1 being B-(4'-phenyl 1'- piperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-[4-(ochlorophenyl) l'-piperazinp] ethyl Z-propyl thiazole S-carboxylate and its hydrochloride.
  • the compound of claim 1 being m[4-(o-methoxy phenyl)l-piperazino]butyl 2-propyl thiazole 5- carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-[4-(0, 0-- dimethyl phenyllllpiperazino ⁇ ethyl Z-propyl thiazole 5-ca r bo x late and its monohydrochloride.
  • the compound of claim 1 being B-(4'-benzyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B(4'-p-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-(4-o-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its hydrochloride.
  • the compound of claim 1 being B-[4'(pmethoxy phenyl) l-piperazino] ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-(4-a-pyridyl l-piperazino) ethyl Z-propyl thiazole i-carboxylate and its maleate.
  • the compound of claim 1 being B-[4-(mtrifluoro methyl phenyl) l-piperazino ⁇ ethyl 2-propyl thiazole S-carboxylate and its monohydrochloride.
  • the compound of claim 13 being B-[4-(o-ethoxy phenyl) l-piperazino ⁇ ethyl 2-propyl thiazole 5- carboxylate and its maleate.
  • the compound of claim 1 being B-[4'-(omethoxy phenyl) l-piperazino] ethyl 2-methyl thiazole S-carboxylate and its maleate.
  • the compound of claim 1 being ,8-[4-(omethoxy phenyl) piperazino ⁇ ethyl 2-butyl thiazole 5- carboxylate and its oxalate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US00262785A 1971-06-14 1972-06-14 Esters of 2-alkyl thiazole 5-carboxylic acid Expired - Lifetime US3853875A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7121466A FR2141526B1 (enrdf_load_stackoverflow) 1971-06-14 1971-06-14
FR7306847A FR2247243B2 (enrdf_load_stackoverflow) 1971-06-14 1973-02-27

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US (1) US3853875A (enrdf_load_stackoverflow)
JP (1) JPS5519251A (enrdf_load_stackoverflow)
AT (1) AT317895B (enrdf_load_stackoverflow)
BE (1) BE784777A (enrdf_load_stackoverflow)
CA (1) CA1001629A (enrdf_load_stackoverflow)
CH (1) CH555362A (enrdf_load_stackoverflow)
FR (2) FR2141526B1 (enrdf_load_stackoverflow)
GB (1) GB1382887A (enrdf_load_stackoverflow)
NL (2) NL176072C (enrdf_load_stackoverflow)
SE (1) SE389673B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4339617A1 (de) * 1993-11-20 1995-05-24 Vortex Gmbh Dt Rückschlagventil für ein Brauchwasser-Zirkulationssystem

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4411900A (en) * 1980-01-03 1983-10-25 Fujisawa Pharmaceutical Co., Ltd. Benzhydrylpiperozinyl thiazole derivatives and pharmaceutical composition comprising the same
DE3002989A1 (de) * 1980-01-29 1981-07-30 Hoechst Ag, 6000 Frankfurt Hydroxyphenyl-thiazol, -thiazolin und -thiazolidin-carbonsaeuren, verfahren zu ihrer herstellung und ihre verwendung zur beeinflussung des kollagenstoffwechsels
US6083966A (en) 1998-08-31 2000-07-04 University Of Florida Thiazoline acid derivatives
AU774956B2 (en) 1998-09-21 2004-07-15 Trustees Of Columbia University In The City Of New York, The Antimalarial agents
AU2003270473A1 (en) 2003-09-09 2005-04-27 University Of Florida Desferrithiocin derivatives and their use as iron chelators
JP5202299B2 (ja) 2005-04-04 2013-06-05 ユニバーシティ オブ フロリダ リサーチ ファウンデーション，インコーポレイティド デフェリチオシンポリエーテル類似体
CN104003955A (zh) 2007-03-15 2014-08-27 佛罗里达大学研究基金公司 去铁硫辛聚醚类似物
MX368275B (es) 2011-12-16 2019-09-26 Univ Florida Usos de análogos de 4'-desferritiocina.
AU2014352780A1 (en) 2013-11-22 2016-06-09 University Of Florida Research Foundation, Inc. Desferrithiocin analogs and uses thereof
HK1250216A1 (zh) 2015-04-27 2018-12-07 佛罗里达大学研究基金会 代谢程序化的金属螯合剂及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3238203A (en) * 1962-10-12 1966-03-01 Olin Mathieson Basic esters of n-alkenoylanthranilic acid
US3752819A (en) * 1969-12-23 1973-08-14 Ferlux 5-phenyl-isoxazole-3-carboxylic acids and their derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3238203A (en) * 1962-10-12 1966-03-01 Olin Mathieson Basic esters of n-alkenoylanthranilic acid
US3752819A (en) * 1969-12-23 1973-08-14 Ferlux 5-phenyl-isoxazole-3-carboxylic acids and their derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4339617A1 (de) * 1993-11-20 1995-05-24 Vortex Gmbh Dt Rückschlagventil für ein Brauchwasser-Zirkulationssystem

Also Published As

Publication number Publication date
CA1001629A (fr) 1976-12-14
DE2228805B2 (de) 1977-03-31
FR2247243A2 (enrdf_load_stackoverflow) 1975-05-09
NL7908300A (nl) 1980-03-31
FR2247243B2 (enrdf_load_stackoverflow) 1976-12-03
JPS5519251A (en) 1980-02-09
NL176072B (nl) 1984-09-17
NL7208138A (enrdf_load_stackoverflow) 1972-12-18
DE2228805A1 (de) 1972-12-21
BE784777A (fr) 1972-12-13
NL176072C (nl) 1985-02-18
FR2141526A1 (enrdf_load_stackoverflow) 1973-01-26
FR2141526B1 (enrdf_load_stackoverflow) 1975-05-30
SE389673B (sv) 1976-11-15
AT317895B (de) 1974-09-25
CH555362A (fr) 1974-10-31
GB1382887A (en) 1975-02-05

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