CN1015456B - Process for preparation of 3,5-diamino-1,2,4-triazole derivatives - Google Patents

Process for preparation of 3,5-diamino-1,2,4-triazole derivatives

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Publication number
CN1015456B
CN1015456B CN86100724A CN86100724A CN1015456B CN 1015456 B CN1015456 B CN 1015456B CN 86100724 A CN86100724 A CN 86100724A CN 86100724 A CN86100724 A CN 86100724A CN 1015456 B CN1015456 B CN 1015456B
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Prior art keywords
general formula
compound
defined above
triazole
methyl
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CN86100724A
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CN86100724A (en
Inventor
约瑟夫·里特
拉斯洛·普昂格
夫里格伊斯·格吉恩伊
彼得·克拉希
约瑟夫·巴科茨
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Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/14—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)

Abstract

The present invention relates to process for the preparation of 3, 5-diamino-1,2,4-triazole derivatives of formula I and the preparation of the pharmaceutically acceptable acid addition salt. The groups of the formula I are defined in the description.

Description

Process for preparation of 3,5-diamino-1,2,4-triazole derivatives
The present invention relates to a kind of new, improved 3,5-diaminostilbene, 2, the preparation method of 4-triazole derivative.
The invention provides 3 of formula I, the 5-diaminostilbene, 2, the preparation method of 4-triazole derivative and pharmaceutically-acceptable acid addition thereof,
Figure 86100724_IMG5
/Ⅰ/
Wherein
R 1And R 2Each represents hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; Or R 1And R 2Be connected with adjacent nitrogen-atoms together and generate heterocycle; R 3Represent hydrogen or alkyl.
The compound of formula I is known histamine H with persistency effects 2-encapsulant.These compounds can be treated the gastric acid secretion that causes owing to histamine, and can be used for ulcer treatment.
The known compound that has several methods to can be used to prepare formula I, according to belgian patent № 875846, the amine of general formula V
Figure 86100724_IMG6
(R wherein 1And R 2As defined above) the cyanogen imine derivative with the general formula VI reacts
(R wherein 4And R 5Be alkylthio or alkoxyl group).With the isourea or the isothiourea derivatives of the general formula VII that obtains, (R wherein 1And R 2Handle as defined above) with the replacement hydrazine of general formula VIII
(R wherein 3As defined above, Z represents 2 hydrogen atoms).In this reaction, obtain the mixture (R wherein of formula I and IX isometry compound 1, R 2And R 3As defined above).By
Figure 86100724_IMG9
Crystallization can be isolated the compound of formula I from this mixture.The weak point that this method is serious is, at R 3Replace the formula I that differs from one another of position and the isomer of IX and only just generate in the synthetic final step, then loss is very big to obtain the isomer of formula I.Because this loss occurs at this synthetic final step of being made up of several steps, so that make this method cost costliness.
The resultant of the general formula IX isomeric compound that generates in order to remove, according to the method that belgian patent № 875846 is introduced, the protected hydrazine derivative reaction of the isothiourea of general formula VII and general formula VIII (R wherein 3As mentioned above, Z represents a protecting group).From the protection of resulting general formula X cyanoguandine derivatives remove protecting group (R wherein 1, R 2, R 3With Z as mentioned above),
Figure 86100724_IMG10
The cyanoguandine derivatives of general formula XI automatically is cyclized into the compound (R wherein of formula I 1, R 2And R 3As defined above).
Figure 86100724_IMG11
According to this belgian patent, the protected hydrazine derivative of general formula VIII and the cyanogen imine derivative of general formula VI can be reacted the key intermediate species for preparing the general formula X.The protected cyanoguandine derivatives of general formula XII (R wherein 3And R 4As
The last definition, Z represents protecting group) be connected the required intermediate product that generates the general formula X with the amine of general formula V.
The common drawback of above-mentioned two kinds of methods is to need to use the protecting group Z that is used to remove general formula IX isomery triazole derivative in the closed loop procedure of triazole ring.The isomer this point that the reaction that is similar to dimethyl-N-cyanogen imido grpup-two thiocarbamate ester and N-methyl-hydrazine can cause generating the compound of formula I and IX type is known.(seeing organic chemistry magazine 39,1522,1974)] (J.org.Chem39,1522/1974).
Disclosed according to belgian patent № 875846, the isothiourea of the general formula VIII microorganism (R wherein that spreads out 1And R 2As defined above, R 8Be C 1-10Alkyl)
Can be further (wherein Y is-NH-, oxygen or sulphur, R with the thiosemicarbazide of aminoguanidine, Urea,amino-or general formula X IV 3Handle as defined above).
Figure 86100724_IMG14
The compound of resulting general formula X V can be converted to the triazole derivative of formula I then by ring-closure reaction
Figure 86100724_IMG15
(R wherein 1, R 2, R 3With Y as defined above, Q representative-NH-).
The further reaction process disclosed according to this belgian patent, the isocyanic ester of general formula X VI (R wherein 1And R 2As defined above, P is oxygen or sulphur)
Figure 86100724_IMG16
With the compound of general formula X IV (R wherein 3As defined above, Y representative-NH-) carry out addition reaction obtains the compound of general formula X V, obtains the triazole derivative of required formula I through crystallization.
The common weak point of above-mentioned two kinds of methods is the preparation complexity of agents useful for same, and the last condensation step time is long, and consumed energy, productive rate are not high.
The reaction process that this belgian patent further discloses is the isothiourea and the protected hydrazine reaction of general formula VIII of general formula X III, to remove protecting group.The aminoguanidine derivatives of general formula X VII (R wherein 1, R 2And R 3As defined above)
Figure 86100724_IMG17
Generate required generalformula with the urea chloride reaction.The shortcoming of this method is, for the isomer of the unwanted general formula IX of removing generation need use the protected hydrazine derivative (wherein Z is a protecting group) of general formula VIII, and the preparation complexity of agents useful for same, in the synthesis step sealing condensation time long, consumes energy.
The belgian patent № 875846 disclosed another kind of reactions that are different from above-mentioned reaction are to use the acid amides of general formula X VIII
(R wherein 1And R 2As defined above) or the acetal of general formula X IX or ring acetal (R wherein 6Represent alkyl or (R 6O) 2Group representative ring acetal.
The aminocompound that replaces the general formula V.This synthetic final step is to obtain the general formula R that generated from the intermediate product of the X XI of general formula XX 1, R 2, N-CH 2-group,
Figure 86100724_IMG20
(R wherein 1, R 2, R 3And R 6As defined above).Method therefor is the currently known methods of synthetic general formula V compound.
Disclosed according to belgian patent № 875846, another kind of method is with a kind of key intermediate species of general formula X XII (R wherein 3As defined above, X represents halogen)
Figure 86100724_IMG21
With general formula R 1, R 2NH(is R wherein 1, R 2Amine condensation as defined above).
According to european patent application № 29303, can be under reduced pressure, with the aldehyde (wherein R is as defined above) and the general formula R of general formula XX III 1, R 2The amine of NH (R wherein 1And R 2As defined above) carry out the compound that amination reaction prepares formula I.
Figure 86100724_IMG22
Disclosed according to this european patent application, its further reaction be secondary amine (R wherein with general formula XX IV 1And R 3As defined above)
Figure 86100724_IMG23
Be raw material and general formula R 7The aldehyde of CHO carries out reduction condensation (wherein by reduction R 7-CHO-group generates R 7-CH 2-group is the R group) or with general formula be R 7-CH 2The compound of-X (R wherein 7-CH 2-as defined above, X represents halogen) and carry out alkylated reaction, all can generate required generalformula.
In in the end described four reaction types, its reactions steps is identical with former disclosed reaction method, and just the precedence of reactions steps changes to some extent.Therefore these four methods have the identical weak point of discussing with the front of method.
The method disclosed, a group of generalformula according to belgian patent № 875846 can be by general formula XX V benzene oxyalkyl derivative (R wherein 3As defined above) with molecular formula be the ammonium chloride reaction of XX VI
Figure 86100724_IMG24
And make.The R of resulting generalformula 1And R 2Be methyl.
Figure 86100724_IMG25
The weak point of this method is, to carry out prepared classes of compounds limited although its preparation is suitable for.The reaction complexity for preparing the compound of general formula XX VI in addition, the cost height.
The another kind of method disclosed according to belgian patent № 875846, the aminoguanidine of general formula X IV (R wherein 3As defined above, Y represents imido grpup) with the urea chloride of general formula XX VII (R wherein 8And R 9Be suitable protecting group) reaction
Figure 86100724_IMG26
Can obtain 3 of general formula XX VIII, 5-diaminostilbene H-1,2,4-triazole derivative
Figure 86100724_IMG27
(R wherein 3, R 8And R 9As defined above), with the aldehyde reaction of gained compound and general formula XX IX (R wherein 1And R 2As defined above)
Figure 86100724_IMG28
Obtain the Schiff's base (R wherein of general formula XXX 1, R 2, R 3, R 8And R 9As defined above),
Figure 86100724_IMG29
With its reduction, slough protecting group at last.
A kind of improvement of aforesaid method is with the reaction of the active acid derivant of the aminotriazole of general formula XX VIII and general formula XX XI (wherein,
Figure 86100724_IMG30
A represents halogen, hydroxyl, alkoxyl group or acyloxy) obtain the acid amides (R wherein of general formula XX XII 1, R 2, R 3, R 8And R 9As defined above), its reduction is obtained the compound of required formula I.
Aforesaid method is further improved, be about to active ester reaction (wherein R and R as defined above, B is first sulphur acyloxy or adds Toxyloxy) the required generalformula of generation of aminotriazole with the general formula XXX III of general formula XX VIII.
Figure 86100724_IMG31
The shortcoming of aforesaid method is that the complicated approach of discussing with the front generates triazole ring, needs appropriate selection and removes protecting group R 6And R 9, this can cause other problem, and very inconvenient.
Target of the present invention is the shortcoming that overcomes above-mentioned known procedure, and a kind of economy is provided, the method for preparing generalformula of simple possible.
In the method for the compound of preparation formula I provided by the present invention and pharmaceutically-acceptable acid addition thereof, R 1And R 2Each represents hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; Or R 1And R 2Be connected with adjacent nitrogen-atoms together and generate heterocycle; R 3Represent hydrogen or alkyl;
This method comprises:
A) with the oxy-compound of general formula II (R wherein 3As defined above) change into the halogenated compound of general formula III, (R wherein 3
Figure 86100724_IMG32
As defined above, X represents halogen), with the basic metal of resulting compound and general formula IV phenol derivatives or the salt of alkaline-earth metal (R wherein 1And R 2Reaction as defined above), or
Figure 86100724_IMG33
(b) with the basic metal or the alkaline-earth metal reactant salt of the phenol derivatives of the halogenated compound of general formula III and general formula IV, the compound of resulting formula I can be converted into its pharmaceutically-acceptable acid addition if desired.
Can use known method the oxy-compound of general formula II to be converted into the halo derivatives of general formula III.
The embodiment of preferentially selecting for use is with the compound of general formula II and the halogenating agent, particularly thionyl halide that suits, preferably thionyl chloride reaction in inert solvent.The thionyl halide of preferentially selecting excess for use is as reaction medium.Aromatic hydrocarbon, for example benzene, toluene, dimethylbenzene also can be used as reaction medium.Reaction can be carried out for example 20-80 ℃ under room temperature or heating.
Then the halo derivatives of general formula III and an alkali metal salt (as calcium, magnesium) of general formula IV oxybenzene compound are reacted.Reaction can be carried out in the dipole aprotic solvent, as dimethyl formamide.
In dipole aprotic solvent (as dimethyl formamide), the phenol derivatives of general formula IV and the hydride or the ethylate (as sodium hydride, hydrolith or uncle's fourth potassium) of corresponding alkali metal or alkaline-earth metal are reacted, then can in its reaction mixture, obtain the basic metal of general formula IV compound or the salt of alkaline-earth metal.
The generalformula of available currently known methods resulting separation.With known method with resulting generalformula in organic solvent with corresponding inorganic or organic acid (example hydrochloric acid, Hydrogen bromide, sulfuric acid, toxilic acid, fumaric acid, lactic acid) reaction, can make its salt.
The raw material of general formula II and IV is known, the compound that obtains easily.
The compound of general formula III is new, does not introduce in prior art.
Noun " alkyl " refers to the saturated aliphatic hydrocarbon of straight or branched with 1-5 carbon atom, as methyl, ethyl, just-and propyl group, different-propyl group etc.Noun " alkenyl " refers to olefin group such as allyl group, the propenyl etc. of the straight or branched with 2-5 carbon atom.Noun " aralkyl " refers to by aryl substiuted alkyl group, as phenyl, β-styroyl etc.Noun " cycloalkyl " refers to the saturated cyclic aliphatic carbon hydrogen group with 3-8 carbon atom, as cyclobutyl, cyclopentyl, cyclohexyl etc.Noun " halogen " refers to oxygen, chlorine, bromine, iodine atom, preferentially selects chlorine, bromine for use, preferably the chlorine atom.
By R 1And R 2" heterocyclic radical " that generate with adjacent nitrogen-atoms can be 5 yuan of heterocycles or 6 yuan of heterocycles, can contain 1-2 nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can replace arbitrarily.The heterocyclic group of preferentially selecting for use is pyrrolidyl, piperidyl, morpholinyl, piperazinyl.
The R of preferential former usefulness 1And R 2Be methyl, or generate pyrroles's subbase or piperidino-(1-position only) with adjacent nitrogen-atoms.The R that preferentially selects for use 3Be methyl.
Method of the present invention is suitable for preparing 1-methyl-N especially 5-the 3-[3-(1-piperidyl)-methyl-]-phenoxy group-]-propyl group }-1H-1,2,4-triazole-3,5-diamines and salt thereof.
The major advantage of method of the present invention is as follows:
(a) this method is suitable for the production of commercial size.
(b) do not need special device and equipment.
(c) be easy to obtain in a large number raw material.
(d) owing to removed the isomer of general formula IV compound, and in synthetic required generalformula process, do not need progressively to carry out, two quantity are big to get final product to the intermediate product that equates and only need synthesize, so the overall yield of this synthetic method is far above the overall yield of currently known methods up to now.
Assign embodiment and be described in further detail the present invention, but these embodiment do not limit protection scope of the present invention.
Embodiment 1
N 5-(3-chloropropyl)-1H-1,2,4-triazole-3,5-diamine hydrochloride
5 gram (0.032 mole of N 5-(3-hydroxypropyl)-1H-1,2,4-triazole-3, the 5-diamines is dissolved in 15 milliliters of benzene.Be cooled to 10 ℃, under agitation condition, in this solution, add 4.2 gram (0.035 mole) thionyl chloride.The temperature of reaction mixture is gone up at leisure to room temperature.It is stirred half an hour, filter out the crystallization that has precipitated, wash with benzene.Obtain 6.3 gram required compounds, productive rate 92.8%.It dissolves in air, is the white crystals of the high suction temperature of tool, 130～132 ℃ of fusing points (in sealed tube).
Embodiment 2
N 5-(3-chloropropyl)-1H-1,2,4-triazole-3,5-diamines-hydrochloride
Its preparation process is similar to embodiment 1, and difference only is to add the thionyl chloride of 10.6 milliliters (0.15 moles), and it surpasses and adds part as reaction medium, does not use benzene.Obtain 6.8 gram required compounds, productive rate 94.4%.This product is identical with the compound that embodiment 1 method makes.
Embodiment 3
1-methyl-N 5-(3-chloropropyl)-1H-1,2,4-triazole-diamines-hydrochloride
Prepare title compound with the method similar in appearance to embodiment 2, its difference only is with 8.6 gram (0.05 mole) 1-methyl-N 5-(3-hydroxypropyl)-1H-1,2,4-triazole-3, the 5-diamines is as raw material, and compound of reaction is heated to 60 ℃, stirs 15 minutes.Obtain 10.7 gram required compounds.Productive rate 94.7%, 170～172 ℃ of fusing points (decomposition).
Embodiment 4
1-methyl-N 5-the 3-[3-[(1-piperidyl) methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines
The 3-(1-piperidino methyl that slowly adds 5.7 grams (0.03 mole) in the 1.0 gram oily suspension of (0.033 mole) 80% sodium hydrides at 20 milliliters of anhydrous dimethyl formamides) phenol at room temperature stirs this mixture half an hour.Under room temperature and agitation condition with 3.04 the gram (0.03 mole) triethylamines join in separating bottle 8.1 the gram (0.036 mole) 1-methyl-N 5-(3-chloropropyl)-1H-1,2,4-triazole-3,5-diamines-hydrochloride (in the solution of 15 milliliters of anhydrous dimethyl base acid amides) filters out sedimentary triethylamine hydrochloride, with some anhydrous dimethyl formamide washings.In room temperature and under stirring resulting solution is added in the dimethyl formamide solution of the phenolate that makes with aforesaid method.At room temperature reaction mixture was stirred 72 hours, add 30 ml waters then, use 20 milliliters chloroform extraction three times more at every turn.Merge organic phase, use water extraction three times, each 20 milliliters, with anhydrous magnesium sulfate drying chloroform phase, vacuum boils off chloroform then.Only put gained brown oily residuum (9.6 grams so that its slow crystallization, and then with this example be the mixture of 1: 4 ethyl acetate and hexanaphthene with its recrystallization, obtain 5.6 and restrain required product, productive rate 54.4%, 93～94 ℃ of fusing points.
Embodiment 5
1-methyl-N 5-the 3-[3-[(1-piperidyl)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines-fumarate
To be dissolved in the oily crude product that embodiment 4 methods make in 30 milliliters of ethanol, add 3.5 gram (0.03 mole) fumaric acid, and after the reaction mixture dissolving,, place in the refrigerator and spend the night, filter out sedimentary crystallization, use some washing with alcohol its cooling at 50 ℃.Obtain 7.8 gram required compounds, productive rate is 56.4%, 142～145 ℃ of fusing points.
Embodiment 6
1-methyl-N 5-the 3-[3-[(1-piperidyl)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines
Except using the 1-methyl-N-(3-chloropropyl of 10.2 grams (0.045 mole))-1H-1,2,4-triazole-3, outside 5-diamines-hydrochloride, other similar process obtains 5.3 gram required compounds, productive rate 51.4% in embodiment 4.Product is identical with the compound of example 4.
Embodiment 7
1-methyl-N 5-the 3-[3-[(1-piperidyl)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines
Except 1-methyl-N-(3-chloropropyl with 6.8 grams (0.03 mole))-1H-1,2,4-triazole-3,5-diamines-hydrochloride is outside the raw material, other process homogeneous phase is similar to embodiment 4.Obtain the required product of 4.9 grams.Productive rate 47.6%.Product is identical with the compound of embodiment 4.
Embodiment 8
1-methyl-N 5-3-[3-[1-piperidyl-methylphenoxy]-propyl group]-1H-1,2,4-triazole 3,5-diamines
Be prepared with the method similar in appearance to embodiment 4, difference is to represent sodium hydride with 1.4 gram (0.033 mole) hydroliths.Obtain 5.1 grams institute 4 and need product.Productive rate 49.5%.This product is identical with embodiment 4 prepared compounds.
Embodiment 9
1-methyl-N 5-the 3-[3-[1-pyrrolidyl)-methyl]-phenoxy group]-propyl group]-1H-1,2,4-triazole 3,5-diamines
Except with 5.3 the gram (0.03 mole) 3-(1-pyrrolidyl-methyl)-raw material of phenol as the general formula IV, other preparation process is all with embodiment 4.Obtain 4.9 gram required compounds.Productive rate 49.4%, 94～95 ℃ of fusing points.
Embodiment 10
1-methyl-N 5-the 3-[3-[1-pyrrolidyl)-methyl]-phenoxy group]-propyl group]-1H-1,2,4-triazole 3,5-diamines fumarate
Except the preparation of raw material with the embodiment 9, other process is all identical with embodiment 5.Obtain 7.2 gram required compounds.Productive rate 53.7%, 140～142 ℃ of fusing points.
Embodiment 11
1-methyl-N 5-the 3-[3-[(dimethylamino)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole 3,5-diamines
Except with 4.5 gram (0.03 mole) 3-dimethylaminomethyl-phenol as the raw material, other process is all with embodiment 4, obtains 4.1 gram required compounds.Productive rate 44.9%, fusing point 95-96 ℃.
Embodiment 12
N 5The 3-[-[(-piperidyl)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines
Except N-(3-chloropropyl with 7.6 grams (0.036 mole))-1H-1,2,4-triazole-3,5-diamines-hydrochloride is as outside the raw material, and other preparation process is all with embodiment 4.Obtain 4.7 gram required compounds, productive rate 47.9%, 100～101 ℃ of fusing points.
Embodiment 13
N 5-the 3-[3-[(dimethylamino)-methyl]-phenoxy group]-propyl group }-1H-1,2,4-triazole-3,5-diamines
Except restraining (0.036 mole) N with 4.5 gram (0.03 mole) 3-dimethylaminomethyl-phenol and 7.6 5-(3-chloropropyl)-1H-1,2,4-triazole-3,5-diamines-hydrochloride is as outside the raw material, and other preparation process is all with embodiment 4.Obtain 4.2 gram required compounds.Productive rate 48.2%, 91～93 ℃ of fusing points.

Claims (4)

1, shown in a kind of preparation formula I 3,5-diaminostilbene H-1,2, the method for 4-triazole derivative and medicinal acid addition salt thereof,
Figure 86100724_IMG2
(R wherein 1And R 2Each represents hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; Or R 1And R 2Be connected with adjacent nitrogen-atoms and form heterocycle, R 3Represent hydrogen or alkyl),
This method comprises makes the halogenated compound shown in the general formula III
Figure 86100724_IMG3
(Ⅲ)
With the basic metal of phenol derivatives shown in the general formula IV or alkaline earth salt (R wherein 1And R 2In the inertia aprotonic solvent, react as defined above),
(Ⅳ)
If desired, resulting generalformula can be converted into its medicinal acid addition salt.
2, in accordance with the method for claim 1, the basic metal or the alkaline earth salt that lead to the formula IV compound comprising preparation in described reaction mixture.
3, according to claim 1 or 2 described methods, comprising adopting dimethyl formamide as solvent.
4, in accordance with the method for claim 1, it is characterized in that with compound shown in general formula III and the general formula IV be raw material, wherein R 1And R 2Be connected with adjacent nitrogen-atoms and generate piperidino-(1-position only) ring, R 3Represent methylidene.
CN86100724A 1985-01-29 1986-01-29 Process for preparation of 3,5-diamino-1,2,4-triazole derivatives Expired CN1015456B (en)

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EP0029303B1 (en) * 1979-10-22 1985-01-30 Glaxo Group Limited 1,2,4-triazole derivatives, processes for their production and pharmaceutical compositions containing them
DK558181A (en) * 1981-01-30 1982-07-31 Smithkline Corp METHOD OF PREPARING 3,5-DIAMINO-1,2,4-TRIAZOLES
DE3336410A1 (en) * 1983-10-06 1985-04-18 Ludwig Heumann & Co GmbH, 8500 Nürnberg SULFEN AMIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
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NO167091C (en) 1991-10-02
NO167091B (en) 1991-06-24
DK42986D0 (en) 1986-01-29
FI860432A (en) 1986-07-30
GB8602136D0 (en) 1986-03-05
PT81935A (en) 1986-02-01
ES551388A0 (en) 1987-04-16
JPH0524906B2 (en) 1993-04-09
AR240046A1 (en) 1990-01-31

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