GB2146331A - Process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives - Google Patents

Process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives Download PDF

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GB2146331A
GB2146331A GB08422620A GB8422620A GB2146331A GB 2146331 A GB2146331 A GB 2146331A GB 08422620 A GB08422620 A GB 08422620A GB 8422620 A GB8422620 A GB 8422620A GB 2146331 A GB2146331 A GB 2146331A
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general formula
reacting
dihydroaryloxyalkylamino
pharmaceutically acceptable
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Jozsef Reiter
Peter Krajcsi
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Egyt Gyogyszervegyeszeti Gyar
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Egyt Gyogyszervegyeszeti Gyar
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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
    • C07D295/096—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

Compounds of general formula (I> <IMAGE> (wherein R1 and R2 are be the same or different and each represent hydrogen, C1-5 alkyl, C2-5 alkenyl, aralkyl or C3-7 cycloalkyl, or (together with the nitrogen atom to which they are attached) form a 5 to 10 membered ring, which may be saturated or contain at least one double bond; and R3 denotes C1-4 alkyl or C2-4 hydroxyalkyl) are prepared by a new process which comprises reducing an aryloxyalkylamine of general formula (II), <IMAGE> reacting the dihydroaryloxyalkylamine of general formula (III) thus obtained, <IMAGE> with N-cyanoiminodithiocarbamic acid dimethyl ester, reacting the isothiocarbamide of general formula (IV) thus obtained, <IMAGE> with a substituted hydrazine of general formula (V), R3-NH-NH2 (V> and, if desired, converting the dihydroaryloxyalkylamino-1,2,4-triazole of general formula (I) thus obtained into a pharmaceutically acceptable salt. The compounds of general formula (I) are potent H2-antagonists and inhibit the secretion of gastric acid when this is stimulated via histamine receptors.

Description

SPECIFICATION Process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives The invention relates to a new process for the preparation of dihydroaryloxyalkylamino-i 2,4- triazole derivatives of the general formula (I)
and pharmaceutically acceptable salts thereof, wherein R, and R2 may be the same or different and each represent hydrogen, C1 5 alkyl, C2 s alkenyl, aralkyl or C3 7 cycloalkyl, or they form, together with the nitrogen atom to which they are attached, a 5 to 10 membered ring, which may be saturated or may contain at least one double bond; and R3 denotes C, 4 alkyl or C24 hydroxyalkyl.
The compounds of the formula (I) possess valuable pharmaceutical properties. They have potent activity as H2-antagonists and show inhibition of the secretion of gastric acid when this is stimulated via histamine receptors. Owing to their histamine H2-blocking activity they can be used in the treatment of gastric ulceration.
The only known method for the preparation of the compounds having the general formula (1) is described in European patent specification No. 28483. According to this process the desired compounds are prepared by a Birch reduction of the aryloxyalkylamino-1,2,4-triazole derivatives of the general formula (VI),
wherein P1, R2 and R3 have the same meanings as above. The reduction is carried out with sodium in liquid ammonia in the presence of an alcohol.
The disadvantage of the known process is that beside the aimed 2,5-dihydrn-3-alkylaminome- thyl-aryloxyalkylamino derivative of the general formula (I) the isomeric 3-alkyl-aminomethyl-3,6 dihydro derivatives of the general formula (VII)
are also formed in the reaction. The isolation of the desired product in a form free of the other isomer requires cumbersome reaction steps causing a considerable loss of the end product.
The aim of the present invention was to provide a more economical process for the preparation of the compounds of the general formula (I), which is devoid of the above drawbacks.
According to the invention the dihydroaryloxyalkylamino-1,2,4-triazole derivatives of the general formula (I) and their pharmaceutically acceptable salts are prepared by reducing an aryloxyalkylamine of the general formula (II),
wherein R1 and R2 have the above defined meanings, reacting the dihydroaryloxyalkylamine of the general formula (Ill) thus obtained,
wherein R, and R2 are as defined above, with N-cyanoiminodithiocarbamic acid dimethyl ester, reacting the isothiocarbamide of the general formula (lV) thus obtained,
wherein R1 and R2 are as defined above, with a substituted hydrazine of the general formula (V), R3-NH-NH2 (V) wherein R3 is as defined above, and, if desired, converting the dihydroaryloxyalkylamino-1,2.4- triazole of the general formula (I) thus obtained into a pharmaceutically acceptable salt.
The aryloxyalkylamines of the general formula (II) used as starting substances are known compounds and can be produced by the methods described in Belgian patent specification No.
875846. Reduction thereof may be carried out with sodium metal in liquified ammonia at a temperature between - 85"C and - 33"C. The amount of the sodium used for the reaction is preferably 1.1-4.5 molar equivalent(s). It is particularly preferable to use 2.5 molar equivalents of sodium metal.
The dihydroaryloxyalkylamines of the general formula (III) obtained in the reaction have not so far been described in the literature. Under the conditions of the reduction formation of the compounds of the general formula (III) is accompanied by the formation of a small quantity of an isomeric dihydroaryloxyalkylamine derivative of the general formula (VIII),
wherein R, and R2 are as defined above. The isomers of the general formulae (III) and (VIII) may be separated if desired by conventional techniques (e.g. distillation), or they can be converted directly into a mixture of the isothiocarbamides of the general formulae (IV) and (IX),
wherein R, and R2 are as defined above.
The reaction of the compounds of the general formula (I II) with N-cyanoiminodithiocarbamic acid dimethyl ester may be carried out in the absence or presence of solvent. It is preferable to perform the reaction in a protic or aprotic solvent inert toward the reactants. For this purpose C1 4 alkanols, dimethylformamide, ethers, halogenated organic solvents, aromatic solvents or acetonitrile can be used. It is particularly preferable to use isopropanol as solvent. The reaction is preferably carried out at a temperature between 20"C and 120"C. The amount of the Ncyanoiminodithiocarbamic acid dimethyl ester used for the reaction is preferably 1.0 molar equivalent.
When an isomeric mixture of the compounds of the general formulae (III) and (Vlil) is reacted with N-cyanoiminodithiocarbamic acid dimethyl ester, a mixture of the isothiocarbamides of the general formula (IV) and (IX) are formed, and the isomer of the general formula (IV) is separated by crystallization.
The isothiocarbamides of the general formula (IV) are new compounds. The reaction thereof with a substituted hydrazine of the general formula (V) can be performed in a protic or aprotic organic solvent, preferably in a C14 alcohol, ether or in an aromatic solvent at a temperature between 20"C and 120"C. It is preferable to use n-butanol as solvent. The amount of the compound of the general formula (V) used for the reaction is preferably 1.0 to 1.5 molar equivalent.
The N-cyanoiminodithiocarbamic acid dimethyl ester, and the substituted hydrazines of the general formula (V) used as reagents for the synthesis according to the invention are commercial products.
The compounds of the formula (I) obtained in the reaction can be converted, if desired, into pharmaceutically acceptable salts. Particularly useful salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, tartarates, benzoates and fumarates. The salts may be formed in a conventional manner, e.g. by mixing appropriate quantities of the free base and the acid in an appropriate solvent.
The synthesis according to the invention provides the compounds of the general formula (I) in purer form than the known method, namely the separation of the intermediates of the general formulae (VIII) and (IX) resulting the undesired product of the general formula (VII) can be effected economically in the early phase of the synthesis.
The invention is illustrated but not limited by the following Examples: Example 1 Preparation of 3-E(5)1 -pyrrolidinylmethyl(- 1, 4-cyclohexadienyl)-oxy]- 1 -propaneamine a.) 19.8 g (0.425 mole) of ethanol are added to 19.9 g (0.085 mole) of 3-[3-(1pyrrolidinylmethyl)-phenoxy]-1-propaneamine, and 500 ml of ammonia gas is condensed onto the solution. The reaction mixture is cooled to - 85"C in an acetone-dry ice bath, and 10.00 g (0.425 mole) of crushed sodium metal are added portionwise to it so that the second and every further portion is introduced after the complete discolouration of the solution.When 1 g of sodium has already been added to the mixture, the cooling bath is removed and the reaction is allowed to run at - 33"C. When the last portion of sodium has been added the blue colour of the reaction mixture remains for 2.5 to 3 hours. After the final discolouration thereof it is refluxed for 30 minutes. Then 29.7 g (0.555 mole) of ammonium chloride are added to the mixture. When the ammonia has been evaporated, the residue is taken up in 400 ml of diethyl ether. The inorganic salt is filtered off and washed six times with 100 ml of diethyl ether each.
The ethereal solutions are combined and the solvent is removed in vacuo. The residue is distilled fractionally in vacuo. 18.6 g of product are obtained (b.p.: 162-168"C/1 Hgmm), which is a 4:1 mixture of the aimed compound and 3-[(3-)1-pyrrolidinylmethyl(-1 ,4-cyclohexadienyl)-oxy]- 1-propaneamine. The isomeric mixture is subjected to fractional distillation at 1 Hgmm. 16.5 g of product are obtained (b.p.: 166-168"C), which contains more than 90% of the aimed isomer.
Yield: 73.9% b.) One proceeds as described in Example 1) a, with the difference that instead of 10 g of sodium metal 4.4 g (0.19 mole) of sodium metal are used. After repeated distillation 15.1 g of product are obtained. B.p.: 165-167"C.
Yield 67.6%.
Example 2 Preparation of N-cyano-N'-3-(5-) 1 -pyrrolidin ylmeth yl(-l, 4-cyclohexadien yloxy]-propyl-carbamimi- dothioacid methyl ester a.) 9 g (0.038 mole) of 3-[(5-) 1 -pyrrolidinylmethyl(- 1 ,4-cyclohexadienyl)-oxy]- 1 -propaneamine obtained as specified in Example 1 are dissolved in 10 ml of isopropanol at room temperature.
To the thus-obtained solution 5.5 g (0.038 mole) of N-cyanoiminodithiocarbamic acid dimethyl ester are added. The reaction begins to run at room temperature while mercaptan is evolved.
After half an hour the reaction mixture is heated to boiling. It is boiled for 1.5 hour and evaporated in vacuo. The residual honey-like product is dissolved in 40 mi of acetonitrile under heating. Then the solution is cooled and the separated crystals are filtered and washed with acetonitrile. 1.1 g of N-cyano-N'-3-[(3-)1-pyrrolidinylmethyl(-1,4-cyclohexadienyl)-oxy]-propyl- carbamimidothioacid methyl ester is obtained. M.p.: 117 to 119"C. By evaporating the mother liquor 11.5 g of the aimed product is produced. P = 0.45(ethyl acetate:pyridine:water:acetic acid = 60:20:11:6) on a Kieselgel 60 silica plate.
b.) One proceeds as described in paragraph a.), with the difference that 40 ml of di-n-propyl ether are used as solvent, and the reaction mixture is boiled for 5 hours. In this way 11.4 g of honey-like product are obtained. Ref = 0.44 (The composition of the developing mixture is the same as described in paragraph a.). The product is identical to the compound obtained according to paragraph a.).
c.) One proceeds as described in paragraph a.). with the difference that 40 ml of chloroform are used as solvent, and the reaction mixture is boiled for 4.5 hours. In this way 11.5 g of honey-like product are obtained. R, = 0.45 in a developing mixture as specified in paragraph a.).
The product is identical to the compound obtained according to paragraph a.).
d.) One proceeds as described in paragraph a.), with the difference that 100 ml of benzene are used as solvent and the reaction mixture is boiled for 10 minutes. In this way 11.3 g of product, identical to the compound produced according to paragraph a.), are obtained.
Rf = 0.45. (The composition of the developing mixture is the same as specified in paragraph a.).
e.) One proceeds as described in paragraph a.), with the difference that 40 ml of acetonitrile are used as solvent and the reaction mixture is boiled for 4.5 hours. In this way 11.5 g of product, identical to the compound produced according to paragraph a.), are obtained.
R, = 0.44 in a developing mixture as specified in paragraph a.).
Yield: practically quantitative.
f.) 9 g (0.038 mole) of 3-[(5-)1-pyrrolidinylmethyl(-1,4-cyclohexadienyl)-oxy]-1-propaneamine are dissolved in 10 ml of dimethylformamide at room temperature. To the thus-obtained solution 5.5 g (0.038 mole) of N-cyanoiminodithiocarbamic acid dimethyl ester are added, and the reaction mixture is allowed to stand at 120"C for 5 hours. Then it is cooled and poured onto 100 ml of water and extracted 4 times with 30 ml of chloroform each. The chloroform phases are combined, dried over magnesium sulfate and filtered. The solvent is distilled off in vacuo.
The residue is dissolved in 35 ml of acetonitrile under heating. The solution thus-obtained is cooled, the separated crystals are filtered off and washed with acetonitrile. 0.8 g of N-cyano-N' 3-[(3-) 1 -pyrrolidinylmethyl(-1 ,4-cyclohexadienyI)-oxyprnpyIcarbamiminothioacid methyl ester is obtained. M.p.: 116 to 118"C. By evaporating the mother liquor 9.2 g of honey-like product are obtained. Rf = 0.46 (The composition of the developing mixture is the same as described in paragraph a.). The product is identical to the compound prepared according to Example 2/a.
Example 3 Preparation of 1-methyl-N5- (3-(5-) 1-pyrrolidinylmethyl(- 1,4-cyclohexadienyl)-oxy]-propyl,} - 1 H I ,2,44riazole-3, 5-diamine a.) 9 g (0.027 mole) of N-cyano-N'-3-[(5-) 1 pyrrolidinylmethyl( 1 -,4-cyclohexadienyl)-oxy]-pro- pyl-carbamiminothioacid methyl ester prepared as described in any of Examples 2/a-2/f are dissolved in 200 ml of n-butanol at room temperature. To this solution 1.24 9 (0.027 mole) of methyl hydrazine is added. The reaction starts at once, while mercaptan is evolved. After 20 minutes the reaction mixture is heated to boiling and kept at the same temperature for 20 hours. Then the solvent is distilled off in vacuo.To the thus-obtained honey-like product 20 ml of cyclohexane and 5 ml of acetonitrile are poured and the mixture is cooled. The separated crystals are filtered off and washed with acetonitrile. 7.5 g (83.8%) of the aimed compound melting at 81 to 84"C are obtained. The crude product is recrystallized from 60 ml of a 1:4 mixture of ethyl acetate and cyclohexane. 6.8 g (76%) of the aimed product melting at 86 to 87"C are obtained.
b.) One proceeds as specified in paragraph a.), with the difference that di-n-propyl ether is used as solvent. After recrystallization 5.4 9(60.3%) of product, identical to the compound prepared according to paragraph a.), are obtained. M.p.: 85 to 87"C.
c.) One proceeds as described in paragraph a.), with the difference that benzene is used as solvent. After recrystallization 5.1 9 (57%) of product melting at 85 to 88"C are obtained. The compound is identical to the product prepared according to paragraph a.).
d.) One proceeds as described in paragraph a.), with the difference that 1.86 g (0.041 mole) of methyl hydrazine is used. After recrystallization 6.6 g (73.9%) of product, identical to the compound prepared according to paragraph a.), are obtained. M.p.: 85 to 87"C.
Example 4 Preparation of 3-[(5-) 1-piperidinylmethyl(- 1, 4-cyclohexadienyl)-oxy]- 1-propaneamine 4.62 g (0.1 mole) of ethanol are added to 5.97 g (0.02 mole) of 3-[3-(1-piperidinylmethyl)phenoxy]-1-propaneamine, and 200 ml of ammonia is condensed to the thus-obtained solution.
The mixture is cooled to - 75"C with an acetone-dry ice bath, and 2.41 g (0.105 mole) of crushed sodium metal are added portionwise to it so that the second and every further portion is introduced after the complete discolouration of the solution. After about 0.5 g of sodium has been added the blue colour of the reaction mixture remains for 2.5 to 3 hours. After.the final discolouration the mixture is refluxed for 30 minutes and 6.89 9(0.13 mole) of ammonium chloride are added to it. When the ammonia has been evaporated, the residue is taken up in 200 ml of diethyl ether, the inorganic salt is filtered off and washed six times with 50 ml of ether each. The ethereal solutions are combined and the solvent is removed in vacuo.The residual oily product is subjected to fractional distillation in vacuo. 4.85 9 of product (b.p.: 1 30 to 135"C/0.3 Hgmm) are obtained, which is a 4:1 mixture of the aimed compound and 3-L(3-) 1 -piperidinylmethyl( 1-, 4-cyclohexadienyl)-oxy]- 1 -propaneamine. The isomeric mixture is subjected to repeated fractional distillation at 0.3 Hgmm. The fraction boiling at 1 33 to 135"C contains more than 90% of the aimed compound.
Yield: 78.0% Example 5 Preparation of N-cyano-N '-3-f(5-) 1 -piperidin ylmethyl(- 1, 4-cyclohexadienyl)-oxyj-propyl-carbami- dothioacid methyl ester 3.0 g (0.012 mole) of pure 3-[(5-)1-piperidinylmethyl(-1 ,4-cyclohexadienyl)-oxy3-1-propa- neamine prepared according to Example 4 are dissolved in 30 ml of diethyl ether, and 1.75 g (0.012 mole) of N-cyanoiminodithiocarbamic acid dimethyl ester is added while methyl mercaptan is evolved. The reaction mixture is boiled for 2 hours and evaporated. The residual white solid product is suspended in a slight amount of ether and filtered. In this way 3.9 9 (93.3%) of the aimed compound are obtained. M.p.: 90 to 95"C. After recrystallization from isopropanol it melts at 95 to 97"C.
Example 6 Preparation of 1-methyl-N5- (3-U5-)1 -piperidinylmeth 1, 4-cyclohexadienyl)-oxy]-propyl) -1 H- 1,2, 4-triazole-3, 5-diamine 1.74 g (0.005 mole) of N-cyano-N'-3-[(5-)1-piperidinylmethyl(.1 ,4-cyclohexadienyl)-oxy]-pro- pyl-carbamidothioacid methyl ester prepared according to Example 5 is dissolved in 5 ml of butanol, and 0.62 g (0.054 mole) of methyl hydrazine is added to the solution. The reaction starts at once, while mercaptan is evolved. After 20 minutes the reaction mixture is heated to boiling and kept at the same temperature for 20 minutes. Then it is cooled, the solvent is distilled off in vacuo, to the residue a slight amount of a 4:1 cyclohexane-ethyl acetate mixture is added and the solution is cooled. The separated crystals are filtered off. 1.5 9 (86.2%) of the aimed product is obtained. M.p.: 100 to 103"C.
After recrystallization from a 4:1 cyclohexane-ethyl acetate mixture the product melts at 105 to 106"C.

Claims (11)

1. A process for the preparation of dihydroaryloxyalkylamino-1 ,2,4-triazole derivatives of the general formula (1)
and pharmaceutically acceptable salts thereof, wherein R, and R2 may be the same or different and each represent hydrogen, C15 alkyl, C25 alkenyl, aralkyl or C3 7 cycloalkyl, or they form, together with the nitrogen atom to which they are attached, a 5 to 10 membered ring, which may be saturated or may contain at least one double bond; and R3 denotes C14 alkyl or C2 hydroxyalkyl, characterized by reducing an aryloxyalkylamine of the general formula (Il),
wherein R1 and R2 have the above defined meanings, reacting the dihydroaryloxyalkylamine of the general formula (III) thus obtained,
wherein R1 and R2 are as defined above, with N-cyanoiminodithiocarbamic acid dimethyl ester, reacting the isothiocarbamide of the general formula (IV) thus obtained,
wherein R, and R2 are as defined above, with a substituted hydrazine of the general formula (V), R3-NH-NH2 (V) wherein R3 is as defined above, and, if desired, converting the dihyd roaryloxyalkylamino-1 ,2.4- triazole of the general formula (I) thus obtained into a pharmaceutically acceptable salt.
2 A process as claimed in claim 1, characterized by reducing the aryloxyalkylamines of the general formula (II) with sodium metal in liquid ammonia.
3. A process as claimed in claim 2, characterized by using 1.1 to 1.5 molar equivalent(s), preferably 2.5 molar equivalents of sodium metal.
4. A process as claimed in any one of claims 1 to 3, characterized by carrying out the reduction at a temperature between - 85"C and - 33"C.
5. A process as claimed in any one of claims 1 to 4 characterized by reacting the dihydroaryloxyalkylamines of the general formula (I II) with N-cyanoiminodithiocarbamic acid dimethyl ester in a protic or aprotic solvent, preferably isopropanol.
6. A process as claimed in any one of claims 1 to 5 characterized by reacting the isothiocarbamides of the general formula (IV) with 1.0 to 1.5 molar equivalent of hydrazine derivative of the general formula (V).
7. A process as claimed in claim 6, characterized by carrying out the reaction in a protic or aprotic organic solvent, preferably n-butanol.
8. Dihydroaryloxyalkylamines of the general formula incorporate (III), wherein R, and R2 are as defined in claim 1.
9. Isothiocarbamides of the general formula (IV), wherein R, and R2 are as defined in claim 1.
10. A process substantially as hereinbefore described in Examples 1 to 3 or in Examples 4 to 6.
11. Dihydroaryloxyalkylamino-1, 2, 4 triazole derivatives and pharmaceutically acceptable salts thereof made by a process as claimed in any one of claims 1 to 10.
GB08422620A 1983-09-09 1984-09-07 Process for the preparation of dihydroaryloxy-alkylamino-1,2,4-triazole derivatives Expired GB2146331B (en)

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HU833145A HU191095B (en) 1983-09-09 1983-09-09 Process for the production of 3,5 diamino-1,2,4-triazole-derivatives

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GB2063874B (en) * 1979-10-22 1983-09-28 Glaxo Group Ltd Triazole derivatives processes for the preparation thereof 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

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YU45654B (en) 1992-07-20
CS244830B2 (en) 1986-08-14
FR2551752B1 (en) 1987-04-24
HU191095B (en) 1987-01-28
FI843527L (en) 1985-03-10
ATA287084A (en) 1989-03-15
FI80685B (en) 1990-03-30
AT389109B (en) 1989-10-25
DD219767A5 (en) 1985-03-13
ES8600258A1 (en) 1985-10-16
FI80685C (en) 1990-07-10
SU1480767A3 (en) 1989-05-15
FR2551752A1 (en) 1985-03-15
HUT34963A (en) 1985-05-28
GB8422620D0 (en) 1984-10-10
IT1180224B (en) 1987-09-23
IT8422568A0 (en) 1984-09-07
GB2146331B (en) 1987-05-13
DE3433143A1 (en) 1985-03-28
YU154784A (en) 1986-12-31

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