CA2028557A1 - Triazolyl hydrazide derivatives and process for their preparation - Google Patents

Abstract

NOVEL TRIAZOLYL HYDRAZIDE DERIVATIVES AND PROCESS FOR
THEIR PREPARATION

A b s t r a c t This invention relates to novel triazolyl hydrazide derivatives and a process for the preparation thereof.
The new triazolyl hydrazide derivatives of the general formula (I), (I) wherein Q represents hydrogen or a heterocyclic group optionally substituted by a C1-4 alkyl group; or a group of the formula SR1, wherein R1 stands for C1-4 alkyl or phenyl-(C1-4 alkyl), or a group of the formula NR2R3, wherein R2 and R3 each represent hydrogen, straight or branched chained C1-6 alkyl or C2-6 alkenyl;
Z represents hydrogen or a group of the formula (C=X)-(N-R4)-NR5R6, wherein X stands for oxygen or sulfur, R4, R5 and R6 each stand for hydrogen or C1-4 alkyl;
R7 denotes hydrogen, C1-4 alkyl or phenyl-(C1-4 alkyl) optionally substituted by one or more halogen atom(s), R8 stands for hydrogen or a group of the formula -(C=X)-(N-R4)-NR5R6, wherein X, R4, R5 and R6 are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R4)-NR5R6, R8 stands for hydrogen, and if Z represents hydrogen, R8 stands for a group of the formula (C=X)-(N-R4)-NR5R6, and pharmaceutically acceptable acid addition salts thereof exert valuable antianginal and/or gastric ulcer inhibiting properties and are useful in therapy.

Description

Ji ~J

NOVEL TRIAZOLYL HYDRAZIDE DERIVATIVES AND PROCESS FOR
THEIR PREPARATION

This invention relates to novel triazolyl hydrazide deriva-tives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of then for the treatment of diseases and also for the preparation of pharmaceutical compositions sui-table for the treatment of said diseases.
According to an aspect of the present invention there are provided new -triazolyl hydrazide derivatives of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, R7 z /N~-~N
R8 1 ~
N Q

wherein ~ Q represents hydrogen or a heterocyclic group optionally : substituted by a Cl 4 `alkyl group; or a group of the ; formula SRl, wherein Rl stands for Cl_4 alkyl or phenyl-(Cl 4 alkyl), or a group of the formula NR R , wherein R2 and R3 each represent hydrogen, straight or branched chained C1~6 alkyl or C2_6 alkenyl;

A 4696-62-PT-nz ;

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Z represents hydrogen or a group of the ~ormula (C=X)-(N-R )-NR R , wherein X stands for oxygen or sulfur, R4, R5 and R6 each stand for hydrogen or Cl ~ alkyl;
R7 denotes hydrogen, Cl 4 alkyl or phenyl-(Cl 4 alkyl) optionally substituted by one or more halogen atom(s), R8 stands for hydrogen or a group of the formula -(C=X)-(N-R4)-NR5R6, wherein X, R4, R5 and R6 are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R4)-NR5R6, R8 stands for hydrogen, and if Z represents hydrogen, R8 stands for a group of the formula (C=X)-(N-R4)-NR5R6.
The invention encompasses all the isomers or tautomeric fnrms of the compounds of the general formula ` (I).
The new compounds according to the present invention exhibit excellent biological activity and low toxicity, e.g. they possess antianginal, tranquillant-sedative, ` 20 cardiovascular, acid secretion inhibiting, gastric ulcer ,i~ inhibiting and antimicrobial properties and -they can be used as startiny materials of other pharmaceutically ;` ~ active derivatives as well.
; The term "heterocyclic group" used throughout the specification relates -to 4 to B membered he-terocyclic groups which can be formed from compounds comprising in-dependen-tly one or more nitrogen and/or oxygen atom(s) or a group which can be obtained by condensing the same compounds with each other or with benzene. Such groups may ~ ~ 30 be aromatic or partially or completely saturated and may `~ ~ carry one or more substituent(s).
As examples for such groups e.g. the piperidyl, morpholinyl, piperazinyl, furyl, imidazolyl, pyridyl, py-rimidinyl, pyrrolyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, ~ `~
,, .
`

pyrazolidinyl, pyrazolinyl, pyranyl or del-ta-3-piperidin-l-yl groups are mentioned.
The term "alkyl group" relates to straight or branched chained saturated aliphatic hydrocarbon groups comprising 1 to 4 or 1 to 6 carbon atom(s), e.g. methyl, ethyl, i-butyl, t-butyl, n-hexyl, octyl, etc.
As C2_6 alkenyl" groups straight or branched chained alkenyl groups are mentioned (e.g. vinyl, allyl, 2-methyl-allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-bu-tenyl, 2-pentenyl, 2-hexenyl etc.).
The -term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms.
Compounds of the general formula (I), wherein Q
represents morpholino, me-thylthio, dimethylamino or N-me-thyl-piperazinyl and R7 and R8 each stand for hydrogen, and pharmaceutically acceptable acid addition salts there-of possess particularly valuable pharmaceutical proper-ties.
Particularly preferred representatives of the com-pounds of the general formula (I) are the following deri-vatives:
1-(5-amino-3-morpholino-lH-1,2,4-triazol-1-yl)-N-me-thyl-carbo-thiohydrazide, 1-(5-amino-3-methylthio-lH-1,2,4-triazol-1-yl)carbo-thiohydrazide, 1-(5-amino-3-N-methylpiperazinyl-lH-1,2,4--triazol-1-yl)-carbothiohydrazide, 1-(5-amino-3-morpholino-lH-1,2,4--triazol-1-yl)-N,N'-di-methyl-carbothiohydrazide 3 and pharmaceutically acceptable acid addition salts thereof.
The compounds of the general formula (I) are or-ganic bases, so they can be transformed into acid addition salts. The pharmaceutically acceptable acid addition salts of the compounds of the general formula (I) can be formed .

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with inorganic or organic acids. As examples for the phar-maceutically acceptable acid addition sal-ts the hydroha-lides (such as hydrochlorides or hydrobromides), carbo-nates, sufates, acetates, fumarates, maleates, citrates, ascorbinates and -tartrates can be mentioned.
According to a further aspec-t of the present in-vention there is provided a process for -the prepara-tion of compounds of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, with comprises a) reacting a triazolyl ester of the general formula (II), R7 y lO~ N
N
( 11 ) wherein Y represents hydrogen or a group of the formula ~ (C=X)-XR9, wherein X is as stated above, R9 is -~ C1 4 alkyl or phenyl optionally substi-tuted by one or more halogen atom(s), R and Q are as defined above, RlO represents hydrogen or a group of the formula (C=X)-XR9, with the proviso that if Y stands for hydrogen, RlO represents a group of the formula (C=X)-XR9, wherein X and R9 are as stated above, and if Y stands for a group of the formula (C=X)-XR9, R10 represents hydrogen, with a hydrazine derivative of the general formula (III), .
- ~ -. '-i HN - N - R6 ( 111 ) :.
10wherein R4, R5 and R6 are as stated above, or b) for the preparation of isomeric compounds of the gen-eral formulae (Ib), (Ic) and (Id) representing subyroups of the compounds of the general formula (I), R7- N ~ R7-N ~ N~N,C~N ~ N - R6 R6-N - N-C ~ N Q N ~ Q

(Ib) (Ic) R6--N--~ N~H
` N
~ 30 (Id) ,:
' :
~: 35 ', , -. , . ~

.
.

2 ~ 2 ~

reacting a triazolyl ester of the general formula (IIa), X
Il R7-H ~ N~

Q
. ~
( lla) wherein R7, R9, X and Q are as stated above, with a hydrazine derivative of the general formula : (III), heating the thus-obtained compound of the general for-mula (Ia), , C--N--N--R6 ` N
~, ( 1~1 ` 25 and separating the isomers from each other by methods known per se; or ~ c) for the preparation of isomeric compounds of the gen-: eral formulae (Ib), (Ic) and (Id) representing subgroups `~ of the compounds of the general formula (I), heating a compound of the general formula (Ia) and separating the ~; isomers from the ~thus-obtained product by methods known per se; or . d) for the preparation of compounds of the general formula (Ia) representing a subgroup of the compounds of the general formula (I), wherein R4, R5, R6 and R7 repre-.
:

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sent hydrogen and Q stands for a group of -the formula SR11, wherein R11 deno-tes C1 ~ alkyl or phenyl-(Cl ~
alkyl) optionally bearing one or more halogen, C1 4 al-kyl or nitro substituent (s), reacting a compound of the general formula (IV), (IV) wherein X is as stated above, wi-th a compound of -the general formula (V), NC- N-C~ SRll, SRll (V ) wherein Rll is as s-ta-ted above;
and, if desired, converting the compound of the general formula (I) thus-obtained into a pharmaceutically acceptable acid addition salt thereof or setting free a base of -the general formula (I) from an acid addi-tion salt thereof, or converting an acid addition salt of a : base of the general formula (I) in-to ano-ther acid addi-tion salt.
The reac-tion of the compounds of the general for-mulae (II) and (IIa), respectively, with hydra7ine ~ ~ 1! 6'~ 3 ~ ~ ~ J

derivatives of the general formula (III) is carried ou-t in a solvent inert toward the reactants. For this purpose pre-ferably methanol, 2-propanol, benzene or dimethyl sulfo~id are used. The reaction is performed at a temperature of 0 to 190 C, preferably between 20 and 110 C. The reaction is op-tionally carried ou-t in the presence of a base, pre-ferably an organic base.
The isomerisation of the compounds of the general formula (Ia) into compounds of the general formulae (Ib), (Ic) and (Id) can be carried out in melt or by thermic rearrangenent in a polar or dipolar aprotic solvent, pre-ferably in acetic acid or dime-thylformamide, a-t a temperature between 50 C and 250 C, preferably a-t a temperature of lOO to 190 C. During the reaction a mixture of the compounds of the general formulae (Ib)~
(Ic) and (Id) is produced, which can be separated into the individual isomers by methods known per se, e.g. by chro-; matography or fractional crystallization.
The reaction of the compounds of the general for-mulae (IV) and (V) can be performed in a polar solvent,preferably in an aqueous methanol solution, dimethylform-amide or dimethyl sulfoxide, at a -temperature between 0 and 190 C, preferably at a temperature of 50 to 160 C.
The compounds of the general formula (I) obtained in form of a base can be converted into acid addition salts by methods known per se. For this purpose the free bases are reacted with the corresponding acid in an inert solvent.
The triazolyl esters of the general formula (II) used as starting ma-terials are known compounds or can be produced on the analogy of known compounds (US patent specification No. 3,686,301, DD pa-tent specification No.
105,~97).
The hydrazine derivatives of the general formula (III) are also known compounds (Belsteins Handbuch der Or-~ J~
_9_ ganischen Chemie 4, 546, Verlag Springer, Berlin, 1922;Ullmann: Encyklopadie dEr Technischen ~hemie 13, p. 95, Verlag Chemie Weinheim, 1977).
The carbohydrazide and thiocarbohydrazide of the general formula (IV) are commercially available products.
The compounds o~ the general formula (V) are also commercial products or can be prepared as described in Hungarian patent specification No. 184,743.
The compounds of the general formula (I) are only very slightly toxic and show excellent biological proper-ties. They exert antianginal, tranquillant-sedative, car-diovascular, acid secretion inhibiting, gastric ulcer in-hibiting and antimicrobial ef~ec-ts.
The ac-tivity of the compounds of the general for-mula (I) has been examined by the following tests.

1. ~ntianginal effect Method: Nieschulz, E., Popendiker, K. and Hoffmann, I., Arzneimittel-Forschung, 5, 680 (1955) The -test was carried ou-t on rats weighing 180 to 220 9. The animals were narcotised with chloralese-ure-thane (70 - 700 mg/kg ip.). The ECG was registered with needle electrodes in standard II leading. The experimen-tal coro-naria insufficiency was induced with vasopressin (1 NE/kg ; 25 i.v.). The height of wave T was measured before and after the administration of vasopressin in both the control and treated groups. Test compounds were administered intra-venously 2 minutes prior to the trea-tmen-t with vasopressin The results are summarized in Table I.
Table I
Antianginal e~fect Test compound ED50 mg/kg (Example No.) (iv.) :
..

' ` ' AJ

-17 0.84 Prenylamine 6.5 2. Motility inhibiting activity Method: Borsy, J., Csanyi, E., Lfizar, I.: Arch. Int.
Pharmacodyn. 124, 1-2 (1960) The tests were performed on mice. Groups consisting of 3 mice each were trated perorally with different doses of the compounds to be tested. One hour after -the admi-nistration the test animals were placed in a Dews equip-ment. In this equipment the number of interruptions of ~; 15 infrared beam within 30 minutes was counted. The results :~i obtained are shown in Table II.
:, ` Table II
Mo-tility inhibiting ef~ect Compound LD50 Therapeutical ~ (Example No.) mg/kg p.o. index - 1 100 ~ 10 17 70 ~ 5 - Meprobamate270 4.1 3. Acute toxicity on mice Method: Litchfield, J.T., Wilcoxon, ~.W.: Pharmacol. Exp.
Ther., 96, 99 (1949) White mice belonging -to the CFLP strain (body weight 18 to 22 9, both male and female) were used, 6 animals for each dose. The test compounds were administered orally in a volume of 20 ml/kg. After treatment the animals ' ' , ~ jJ ,~ ~? I , ; 1 were observed for a period of 14 days. The mice ~ere kep-t in a plastic cage at room temperature. The animals get tap wa-ter and s-tandard mouse fodder ad libi-tum. The toxicity data were determined with the aid of the method of Litchfield and Wilcoxon. The results are summarized in Table III.

Table III
Acute toxicity on mice Example No. Ld50 mg/kg p.O.

16 lO00 l ~ lO00 9 lO00 The above data show that certain representatives of the compounds according to the invention are 8 or 10 times as effective on the antianginal test as the re-ference substance Prenylamine and are superior as motility inhibi-tors to the reference compound Meprobamate. At the sametime they are only very slightly toxic.
In addition, the compounds according to the in-vention possess valuable antimicrobial effect, especially against nonfermenting Gram-negative bacteria strains. So the compound of Example 9 inhibits, determined by agar diffusion method in a concentration of 500 /ug/hole, the bacteria strains listed in Table IV.
:
` Table IV
An~timicrobial e~ffect of the compound according -to Ex. 9 .

~ J~ 5 Microbe strain HNCMB+ Inhibition (%) deposition number Salmonella enteritidis 10091 17 Shigella sonnei 20046 19 Acinetobacter calcoaceticus 150001 20 Pseudomonas aeruginosa 170006 14 Pseudomonas stutzeri 173008 25 Alcaligenea faecalis 140001 23 HNCMB = Hungarian National Collection of Medical Bacteria 4. Stomach-secretion and ulcus tes-ts on mice Method: 5hay, H., Komarov, S.A., ~els. 5.5., Meranze, O., Gruenstein, M., Siplet, H.: Gas-troenterology 5, 45 (1945); Adami, E., Marazzi-Ubertti, E., Tirba, C.: Arch. Int. Pharmacodyn. 147, 113 (1964).
Starved wistar mice of 150-250 9 body weight were used, 4 male and 4 female animals for each dose. On the day of the experiment the pylorus of the animals was ligatured under ether narcosis. The doses of the test compounds were administered per os, 3 hours before the operation. The control groups were treated with the carrier in identical way. 4 hours after -the operation the 'animals were over-narcotized wi-th ether, their stomach was removed, the stomach contents were separa-ted and after centrifugation the volume of -the gas-tric juices was - measured, then their free-acid content and to-tal acidity, resp., were determined by titra-tion wi-th 0.1 N NaDH sol-ution. The changes of the gastric mucous membrane were investigated macroscopically and characteri~ed by an ulcus `;

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index determined with -the aid of the punctuation method of Adami and coworkers.
The results obtained are shown in Table V.

Table V
Gastric-secretion- and ulcus-inhibiting effects on mice Example Dose Inhibition related to the cnntrol in %
No. mglkg Gastric Free Total Ulcus po. juice acid acidity index :

Cimetidine50 22 24 15 18 :
The above data unambiguously show that the effect of the compounds according to the invention reach or even surpasse that of Cimetidine but their toxicity is slight and due to the differing structures they are exempt from the very unfavcurable side-effect of causing impotency of Cimetidine.
According to a ~urther aspect of the present in-vention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of the general formula (I) or a pharmaceutically acceptable -: acid addition salt thereof in admixture with suitable : 30 inert solid or liquid pharmaceutical carriers.
The pharmaceutical compositions of the present in-vention can be prepared by methods.known ~ se by ad-mixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
The pharmaceutical compositions of the presen-t in-.- ~ .

vention may be suitable for oral (e.g. tablet, pill, coated pill, dragée, solid or soft gelatine capsule, solution, emulsion or suspension), parenteral (e.g.
injection solution) or rectal (e.g. suppository) admi-nistration.
As carrier for the preparation of tablets, coa-ted tablets, dragées and solid gelatine capsules e.g. lactose, corn starch, potatoe starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or the salts thereof, etc. can be used. As carrier for the soft gelatine capsules e.g. vegetable oils, :Eats, waxes or po-lyols of suitable consistency can be used. As carriers for the solutions and syrups e.g. water polyols (polye-thy].ene glycol),saccharose or glucose can be used. The injection solutions can comprise e~g. water alcohols, polyols, glycerol or vegetable oils as carrier. The suppositories can be prepared with the aid of e.g. oils, waxes, fats or polyols of suitable consistency.
In addition, the pharmaceutical formulations may comprise auxiliaries usually applied in pharmaceutical industry, e.g. wetting, sweetening agents, aroma substances, salts causing the change of osmotic pressure, buffers, etc.
The compounds of the general formula (I) can prefer-ably be used in -therapy orally in the form of tablets or capsules. Especially preferred are the capsules or tablets comprising 0.5 to 500 mg of active ingredient The daily dose of the compounds of the general for-mula (I) can vary within wide ranges depending on several factors, e.g. on the activity of the active ingredient, the patient`s condition and age, the severity of the disease, etc. The oral dose is generally 2 to 5000 mg/day, preferably 5 to 1000 mg/day. It has to be stressed tha-t the above dose is only of informative character and the administered dose must always be determined by the , . . . ' ,'. . ' .

physician thera~eutist.
AccQrding to a further aspect of the present in-vention there is provided the use of the compounds of the general formula (I) or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions having par-ticularly antianginal and/or gas-tric ulcer in-hibiting effects.
According to a still fur-ther aspect of the present invention there is provided a method for antianginal and/or gastric ulcer inhibiting treatment, which comprises ad-ministering to the patient an effective amount of a com-pound of the general formula tI) OL' a pharmaceutically acceptable salt thereof.
The invention is fur-ther il-lustra-ted by the aid of the following Examples of non-limiting character.

Example 1 1-(5-Amino-3-morpholino-lH-1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 25.7 9 (0.1 mole) of methyl (5-amino-3-morpholino-lH-1,2,4--triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. Then the separated crys-tals are filtered off and recrystallized from benzene.
Yield: 15.0 q (59 %) M.p.: 144 to 146 C.

E~ample 2 1-(5-Amino-3-morpholino-lH-1,2,4-triazol-1-yl)-N'-methyl-carbothiohydrazide One proceeds as described in Example 1, with the difference that the mother liquor obtained after filtering the reaction mixture is allowed to stand for 2 days. The separated crystals are then filtered off and recrystallized . .
, . . -~. . . j . .

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from 2-propanol.
Yield: 3.8 9 (15 %) M.p.: 125 to 126 C.

Example 3 1-(5-Amino-3-morpholino-lH-192,4-triazol-l-yl)-N-methyl-carbothiohydrazide 25.7 9 (0.1 mole) of methyl (5-amino-3-morpholino-lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 100 ml 10 of dimethyl sulfoxide, in the presence of 5.7 ml (0.11 mole) of methylhydrazine for 8 hours at room temperature.
The reaction rnixture is poured onto 100 ml of water, the separated crystals are filtered off and recrystallized from benzene.
15 Yield: 8.3 9 (38 %) M.p.: 144 to 146 C.

Example 4 - 1-(5-Amino-3-methylthio-lH-1,2,4-triazol-1-yl3-N-me-thyl-carbothiohydrazide 22.0 9 (0.1 mole) of methyl (5-amino-3-methylthio~
lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separa-ted crystals are filtered off and recrystallized from benzene.
Yield: 11.8 g (54 %) M.p.: 164 to 166 C.
:
Example 5 1-(5-Amino-3-methylthio-lH-1,2,4-triaznl-1-yl)-N-methyl-oarbothiohydrazide 22.0 g (0.1 mole) of methyl (5-amino-3-methyl-thio-1_-1,2,4-triazol-1-yl)carbodithioate are stirred in 400 ml of 2-propanol, in the presence of 6.9 ml (0.13 mole) of ~ - -, . .
.

.

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$ æY

methylhydrazine for 8 hours at room -temperature. The separated crystals are filtered off and recrys-tallized from benzene.
Yield: 10.5 9 (4B %) M.p.: 164 to 166 C.

Example 6 1-~5-Amino-3-me-thylthio-lH-1,2~4-triazol-1-yl)-N-me-thyl-carbothiohydrazide 22.0 9 (0.1 mole) of me-thyl (5-amino-3-me-thylthio-lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 200 ml of benzene, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 8 hours a-t room temperature. The separated crystals are fil-tered off and recrystallized from benzene.
Yield: 8.9 9 (41 ~) M.p.: 164 to 166 C.
.
Example 7 1-(5-Amino-3-methylthio-lH-1,2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 22.0 9 (0.1 mole) of methyl (5-amino-3-methylthio-lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene.
Yield: 11.8 9 (54 %) M.p.: 164 to 166 C.
Example 8 1-(5-Amino-3-methylthio-lH-1,2,4-triazol-1-yl~-N-methyl-carbothiohydrazide 22.0 9 (0.1 mole) of methyl (5-amino-3-methylthio-lH-1~2,4-triazol-1-yl)carbodithioate are boiled in 140 ml . .

. . .

:, .

~ ~; 2 ~

of methanol, in the presence of 5.7 ml (0.11 mole) of methylhydrazine for 1 hour. The reac-tion mixture is then evaporated to 70 ml, the separated crystals are filtered off and recrystallized from benzene.
Yield: 8.3 9 (3a %) M.p.: 164 to 166 C.

Example 9 1-~5-Amino-3-N-methylpiperazinyl)-lH-1,2 9 4-triazol-l-yl~-N-methyl-carbothiohydrazide 27.2 g (0.1 mole) of methyl (5-amino-3-N-methylpi-perazinyl-lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours. The reac-tion mix-ture is evaporated to dryness in vacuo. The oily product thus obtained crystallises upon adding of 2-propanol. The se-para-ted crystals are filtered off and recrystallized from acetonitrile.
Yield: 13 9 (48 %) M.p.: 150 to 152 C.

Example 10 1-(5-Amino-3-dimethylamino-lH-1,2,4-triazol-1-yl)-N-me~hyl-carbothiohydrazide 21.7 g (0.1 mole) of methyl. (5-amino-3-dimethyl-amino-1~1-1,2,4-triazol-1-yl)carbodithioate are stirred in 100 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at roorn temperature. The separated crystals are filtered off and recrystallized from benzene.
Yield: 12.2 9 (51 %) M.p.: 165 ta 167 C.

Example 11 1-(5-Ami~o-3-mo~pholirlo-4H-1,2,~ riazol-4-yl)-N-. ~

, ', ~, ' ' ' ~- , . ' ~

r methyl-carbothiohydrazide 25.5 9 (0.1 mole) of 1-(5-amino-3-morpholino-lH-`- 1,2,4-triazol-1-yl)~N-methyl-carbodithiohydrazide areboiled in 75 ml af acetic acid for 30 minutes, under stirring. The reaction mixture is cooled, the separated crystals are filtered off and recrystallized from ; methanol.
Yield: 10.5 9 (41 %) M.p.: 239 to 240 C.
Example 12 1-(5-Amino-3-morpholino-2H-1,2,4-triazol-2-yl)-N-methyl-carbothiohydrazide On proceeding as described in Example 11 the mother liquor ob-tained after filtering the reaction mixture is evaporated to dryness and the residue is recrys-tallized first from an aqueous ethanol solution then from aceto-nitrile.
Yield: 6.12 9 (24 %) M.p.: 258 to 259 C.
.
Example 13 2-Methyl-4-(3-morpholino-lH-1,2,4--triazol-5-yl) thiosemicarbazide 25.7 9 (0.1 mole) of methyl (3-morpholino-2H-1,2,4-~ triazol-5-yl)dithiocarbaminate are boiled in 250 ml of ;~ methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 2 hours, under s-tirring. The separated crystals are filtered off and recrystallized from methanol.
Yield: 17.34 9 (68 %) M.p.: 211 to 212 C.

Exa~ple 14 (5-Benzylamino-3-morpholino-lH-1,2,4-triazol-1-~5 yl)-N-me-thyl-carbothiohydrazide 34.9 9 (0.1 mole) o~ methyl (5-benzylamino-3-, ~, , ', 2 ~ 2 ~ 'J

morpholino-lH-1,2,4-triazol-1-yl)carbodithioate are stirred in 150 ml of methanol, in the presence of 6.9 ml (0.13 mole) of methylhydrazine for 4 hours at room temperature. The separated crystals are filtered off and recrystallized from benzene.
Yield: 22.5 9 (63 %) M.p.: 133 to 134 C.

Example 15 1-~5-Benzylamino-3-morpholino-lH-1,2,4-triazol 1-yl)-N'-methyl-carbothiohydrazide One proceeds as described in Example 14, wlth the difference that the mother liquor obtained after filtra-tion is allowed to stand for 2 days. Then the separated crystals are filtered off and recrystallized from a mixture of n-hexane and ether.
Yield: 5.6 9 (16 %) M.p.: 86 to 87 C.

Example 16 1-(5-Amino-3-morpholino-lH-1,2,4-triazol-1-yl) carbothiohydrazide A mixture of 25.7 g (0.1 mole) of methyl (5-amino-3-morpholino-lH-1,2,4-triazol-1-yl)carbodithioate, 2ûO ml of methanol and 6 ml (0.12 mole) o~ a 99 % hydrazine hydrate solution is stirred for 4 hours at room temperature. Then it is filtered and the ~thus-obtained crystals are recrystallized from a mixture of dime-thyl-formamide and acetonitrile.
Yield: 20.9 9 (86 %) M.p.: 180 to 18Z C.

Example 17 1-~5-Amino-3-me-thylthio-lH-1,2,4-triazol-1-yl) carbothioh~drazide . ;
.

` . ~

':

~ ~ ~ C,,~ ~; ?'~ rJ

A mixture of 22.0 9 (0.1 mole) of methyl (5-amino-3-methylthio-lH-1,2,4-triazol-1-yl)carbodithioate, 200 ml of methanol and 6 ml (0.12 mole) of a 99 % hydrazine hydrate solution is stirred for 4 hours at room J
temperature. Then it is filtered and the precipitated crystals are recrystallized from dimethyl~ormamide.
Yield: 17.3 9 (85 %) M.p.: 185 to 186 C.

Example 18 1-(5-Amino-~-methylthio-lH-1,2,4-triaznl-1-yl) carbo-thiohydrazide To a mixture of 10.6 9 (0.1 mole) of thiocarbohydrazide and 130 ml of water a solution of 15 9 (0.102 mole) of dimethyl (N-cyanocarbonimidodithioate) in 65 ml of methanol is added, and the reaction mixture is m boiled for 2 hours. Then it is cooled, the precipitated crystals are filtered off and recrystallized from dime-thylformamide.
Yield: 17.8 9 (86 %) M.p.: 185 to 186 C.

Example 19 1-~5-Amino-~-(N-methylpiperazinyl~-lH-1,2,4-triazol-l-yl~carbothiohydrazide 27.2 9 (0.1 mole) of methyl ~5-amino-3-(N-methyl-~ piperazinyl)-lH-1,2,4-triazol-1-yl)carbodithioate are -~ stirred in 150 ml of methanol, in the presence of 6.9 ml ~0.13 mole) of hydrazine hydrate for 4 hours at room temperature. Then the reaction mixture is cooled and the -thus-obtained crystals are recrystallized from dimethyl-formamide.
Yield: 24.5 9 (94 %) M.p.: 194 to 196 C.

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Preparation of the trihydrochloride salt:
1 9 of base ob-tained as described above is dissolved in 5 ml of hot dimethylformamide, and the solution is acidified to pH=2 with a 15 % (v/v) solution o~ hydrogen chloride in isopropanol. The separated product is filtered off and washed with isopropanol.
Yield: 0.9 9 M.p.: 158 to 160 C.

Example 20 1-(5-Amino-3-morphnlino-lH-1,2,4-triazol-1-yl)-N,N'-dimethyl-carbothiohydrazide 25.7 9 (0.1 mole) of methyl (5-amino-3-morpholino-lH-1,2,4-triazol-1-yl)carbodithioate are boiled in 1~0 ml of methanol, in the presence of 14.6 ml (0.12 mole) of N,N'-dimethylhydrazine dihydrochloride and 46 ml of tri-ethylamine for 16 hours. Then the reaction mixture is evaporated to dryness in vacuo. 400 ml of water are added to the residue and the aqueous phase is extracted three times with 200 ml of chloroform. The organic phase thus obtained is washed two times with 200 ml of water, dried over magnesium sulfate and evaporated in vacuo. The precipitated crystals are suspended in diethyl ether and fil-tered off.
Yield: 11.3 y (43 %) M.p.: 127 -to 128 C.

Example ~1 1-(5-Amino-3-diallylamino-lH-1,2,4-triazol-1-yl)-N-me~hyl-carbothiohydrazide 4.2 9 (0.0156 mole) of methyl (5-amino-3-diallyl-amino-lH-1,2,4-triazol-1-yl)carbodithioa-te and 1~38 ml (0.026 mole) of methylhydrazine are reacted in 20 ml of methanol at room temperature for 8 hours. Upon adding 10 ml of water to the thus-ob-tained solution 1.2 9 (29 %) of ' pure 1-(5-amino-3-diallylamino-lH-1,2,4--triazol-1-yl)-N-methyl-carbothiohydrazide get separated. M.p.: 86 to B8 C. When evaporating the mother liquor further 2 9 of crystalline product are obtained which melt at 85 to 88 C
So the total yield amounts to 77 %.

Example 22 1-(5-Benzylamino-3-morpholino-lH-1,2,4-triazol-1-yl)-N,N'-dimethyl-carbothiohydrazide 6.9B 9 (0.02 mole) of methyl (5-benzylamino-3-morpholino-lH-1,2,4-triazol-1-yl)carbodithioate are boiled `in 50 ml of methanol, in the presence of 2.92 ml (0.024 mole) of N,N'-dimethylhydrazine dihydrochloride and 9.4 ml of triethylamine for 8 hours. Then the reaction mixture is evaporated to dryness in vacuo. 100 ml of water are added to -the residue and the aqueous phase is extracted three times with 50 ml of chloroform. The thus-obtained organic phase is washed twice with 50 ml of water, dried over magnesillm sulfate and evapora-ted to dryness in vacuo. The thus-obtained crystals are suspended in diethyl e-ther and filtered off.
Yield: 3.25 9 (45 %) M.p.: 66 to 68 C.

Exa~ple 23 5-(4-Dimethylaminobenzylamino)-3-morpholino-lH-1,2,4-triazol-1-yl~carbothiohydrazide 1.96 9 (0 005 mole) of methyl ~5-(4-dimethylamino-benzylamino)-3-morpholino-lH-1,2,4-triazol-1-yl~carbodi-thioate are boiled in 20 ml of methanol, in the presence of 0.3 ml of hydrazine hydrate for 1 hour, under stirring.
The reaction mixture is cooled, the separated crystals are filtered off and recrystallized from methanol.
Yield: 1.43 9 (a3 %) M.p.: 127 to 129 C.

-ft ~ r~ r r Example 24 1-(4-Chlorobenzylamino-3-morpholino-lH-1,2,4-triazol-l-yl)-N-methyl-carbothiohydrazide 38.2 9 (0.1 mole) of me-thyl /5-(4-chlorobenzyl-amino)-3-morpholino-lH-1,2,4-triazol-1-yl/carbodithioate are boiled in 700 ml of methanol, in the presence of 6.4 ml (0.12 mole) of methylhydrazine for 1 hour, under stirring. The reaction mixture is cooled, the precipitated crystals are filtered off and recrystallized -from a mixture of benzene and cyclohexane.
Yield: 23.2 9 (61 %) M.p.: 152 to 154 C.

Example 25 1-/5-(4-chlorobenzylamino)-3-me-thylthio-lH-1,2,4-triazol-l-yltcarbothiohydrazide 17.2 9 (0.05 mole) of methyl /5-(4-chlorobenzyl-amino)-3-methylthio-lH-1,2,4-triazol-1-yl/carbodithioate are boiled in 200 ml of methanol, in -the presence of 6 ml of hydrazine hydrate for 0.5 hour, under stirring. The -~ reaction mixture is cooled, the separated crystals are filtered off and recrystallized from methanol.
Yield: 13.8 9 (84 %) M.p.: 140 to 142 C.
Example 26 1-(5-Benzylamino-3-morpholino-lH 1,2,4-triazQl-l~
yl)carbothiohydrazide 3.49 9 (0.01 mole) of methyl (5-benzylamino-3-mor-pholino-lH-1,2,4-triazol-1-yl)carbodi-thioate are stirred in 50 ml of methanol, in the presence of 0.64 ml (0.013 mole) of hydrazine hydrate for 4 hours, at room temperature.
The separated crystals are filtered off and recrystallized from methanol.
Yield: 2.84 9 (85 O) - . . :
..... ........ ........ ... ......... .... ..... ... ........ ............... .... ... ... ... ........... ,:
- ~ .
. : , ' ~: , -- , ~ .

,2 M.p.: 141 to 143 C.

Example 27 1-/5-(4-Chlorobenzylamino)-3-morpholino-lH-1,2,4-triazol-l-yl/carbothiohydrazide 1.9 9 (0.005 mole) of methyl /5-(4-chlorobenzyl-amino)-3-morpholino-lH-1,2,4-triazol-1-yl/carbodithioate are boiled in 40 ml of methanol, in the presence of 0.3 ml (0.0058 mole) of hydrazine hydrate for 1 hour, under stirring. Then the separated crystals are fil-tered off and recrystallized from methanol.
Yield: 2.64 9 (71 %) M.p.: 169 to 171 C.

Example 28 1-(3~5-Dîamino-lH-1,274-triazol-l-yl)-N-methyl-carbothiohydrazide 0.76 9 ~0.004 mole) of methyl (3,5-diamino-lH-1,2,4-triazol-1-yl)-N-methyl-carbodithioate is stirred in 75 ml of methanol, in the presence of 0.29 ml of hydrazine hydrate for 1 hour at room temperature. The separated crystals are filtered off and recrystallized from 2-propa-nol.
Yield: 0.68 9 (73 %) M.p.: 1~4 to 186 C.

Example 29 1-(5-Amino-3-diallyla~ino-lH-1~2,4-triazol-1-yl3 carbothiohydrazide 26.90 9 (0.1 mole) of methyl-(5-amino-3-diallyl-amino-lH-1,2,4--triazol-1-yl)carbodi-thioate are boiled in 200 ml of methanol, in the presence of 6 ml of hydrazine hydrate for 1 hour, under stirring. The precipitated crystals are filtered off and recrystallized from benzene~
Yield: 20.64 9 (82 %) : . :
: , , .

2~

M.p.: 142 to 144 C.

Example 30 1-(5-Amino-3-methyl-thio-lH-1,2,4-triazol-1-yl)-carbo-thiohydrazide To a mixture of 9 9 (0.1 mole) of carbohydrazide and 160 ml of methanol a solution of 14.6 9 (0.102 mole) of dimethyl N-cyanocarbonimidodithioate in 100 ml of me-thanol is added under stirring. The reaction mixture is boiled for 3 hours, then it is cooled, the separated crystals are filtered off and recrystallized from metha-nol.
Yield: 15.6 9 (83 %) M.p.: 163 to 164 C.
Example 31 1-(5-Amino-2H-1,2,4-triazQl-2.-yl)-N-methyl-carbothiohydrazide 0.61 9 (0.0035 mole) of 1-(5-amino-2H-1,2,4-tri-azol-2-yl)carbodithioate is stirred in lU ml of me-thanol, in the presence of 0.184 ml (0.004 mole) of methyl-~; hydrazine for 2 hours, at room temperature. The ; solution is evaporated to dryness in vacuo and the residue is recrystallized from isopropanol.
Yield: 0.4 9 (66 %) M.p.: 85 to 90 C.

Example 32 Tablets having the following composition are prepared by methods known per se of the pharmaceutical industry:
:
Compsnents Amount, g/tablet 1-(5-Amino-3-morpholino-lH-35 1,2,4-triazol-1-yl)carbothio-- . . .: .

' ' - - ' : ~: ' .. . .

r~

hydrazide 5 Lactose 1~.5 Po-tato starch 13.0 Polyvinylpyrrolidone 6.8 5 Stearic acid 2.7 Talc 4.0 Total weight 50.0 9 Example 33 Ointments having the following composition are prepared by me-thods known per se of the pharmaceutical industry:

Components Amount 15 1-(5-Amino-3-morpholino-lH-1 t 2,4-triazol-1-yl)-N-methyl-carbothiohydrazide 500 mg : Unguentum hydrophilicium nonbonicum10 9 The active ingredient is in the outer phase of the ointment, in dissolved state.

Example 34 Suppositories having the following compositiun are prepared by methods known per se of -the pharmaceutical industry:

Components Amnunt 3 mg/suppository 1-~5-Amino-3-morpholino-lH-1,2,4-triazol-1-yl)carbothio-.~ hydrazide 100 Lecithin 48 Cera alba 96 Cocoa butter 1870 : 35 .~

.

rl Distilled ~ater 386 Total weight 2500 mg Example 35 `: 5 Capsules having the following composition are ; prepared by methods known per se of the pharmaceutical industry:

Components Amount, mg/capsule 1-(5-Amino-3-morpholino-lH-1,2,4-triazol-l-yl)carbothio-hydrazide 50 Lactose Potato starch lO
Magnesium stearate Total weight 180 mg-:.
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Claims (15)

1. Triazolyl hydrazide derivatives of the general formula (I) and pharmaceutically acceptable salts thereof, (I) wherein Q represents hydrogen or a heterocyclic group optionally substituted by a C1-4 alkyl group; or a group of the formula SR1, wherein C1-4 alkyl or phenyl-(C1-4 alkyl), or a group of the formula NR2R3, wherein R2 and R3 each represent hydrogen, straight or branched chained C1-6 alkyl or C2-6 alkenyl;
Z represents hydrogen or a group of the formula (C=X)-(N-R4)-NR5R6, wherein X stands for oxygen or sulfur, R4, R5 and R6 each stand for hydrogen or C1-4 alkyl;
R7 denotes hydrogen, C1-4 alkyl or phenyl-(C1-4 alkyl) optionally substituted by one or more halogen atom(s), R8 stands for hydrogen or a group of the formula -(C=X)-(N-R4)-NR5R6, wherein X, R4, R5 and R6 are as stated above, with the proviso that if Z represents a group of the formula -(C=X)-(N-R4)-NR5R6, R8 stands for hydrogen, and if Z represents hydrogen, R8 stands for a group of the formula (C=X)-(N-R4)-NR5R6.

2. Compounds as claimed in claim 1, wherein Q
represents morpholino, methylthio, dimethylamino or N-me-thyl-piperazinyl and R7 and R8 each stand for hydrogen, and pharmaceutically acceptable acid addition salts thereof.

3. The following compounds of the general formula (I) according to claim 1:
1-(5-amino-3-morpholino-1H-1,2,4-triazol-1-yl)-N-methyl-carbo-thiohydrazide, 1-(5-amino-3-methylthio-1H-1,2,4-triazol-1-yl)carbo-thiohydrazide, 1-(5-amino-3-N-methylpiperazinyl-1H-1,2,4-triazol-1-yl)-carbothiohydrazide, 1-(5-amino-3-morpholino-1H-1,2,4-triazol-1-yl)-N,N'-di-methyl-carbothiohydrazide, and pharmaceutically acceptable acid addition salts thereof.

4. A process for the preparation of compounds of the general formula (I), w h i c h c o m p r i s e s a) reacting a triazolyl ester of the general formula (II), (II) wherein Y represents hydrogen or a group of the formula (C=X)-XR9, wherein X is as stated above, R9 is C1-4 alkyl or phenyl optionally substituted by one or more halogen atom(s), R7 and Q are as defined above, R10 represents hydrogen or a group of the formula (C=X)-XR9, with the proviso that if Y stands for hydrogen, R10 represents a group of the formula (C=X)-XR9, wherein X and R9 are as stated above, and if Y stands for a group of the formula (C-X)-XR9, R10 represents hydrogen, with a hydrazine derivative of the general formula (III), (III) wherein R4, R5 and R6 are as stated above; or b) for the preparation of isomeric compounds of the gen-eral formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), (Ib) (Ic) (Id) reacting a triazolyl ester of the general formula (IIa), (IIa) wherein R7, R9, X and Q are as stated above, with a hydrazine derivative of the general formula (III), heating the thus-obtained compound of the general for-mula (Ia), (Ia) and separating the isomers from each other by methods known per se; or c) for the preparation of isomeric compounds of the gen-eral formulae (Ib), (Ic) and (Id) representing subgroups of the compounds of the general formula (I), heating a compound of the general formula (Ia) and separating the isomers from the thus-obtained product by methods known per se; or d) for the preparation of compounds of the general formula (Ia) representing a subgroup of the compounds of the general formula (I), wherein R4, R5, R6 and R7 repre-sent hydrogen and Q stands for a group of the formula SR11, wherein R11 denotes C1-4 alkyl or phenyl-(C1-4 alkyl) optionally bearing one or more halogen, C1-4 al-kyl or nitro substituent(s), reacting a compound of the general formula (IV), (IV) wherein X is as stated above, with a compound of the general formula (V), (V) wherein R11 is as stated above;
and, if desired, converting the compound of the general formula (I) thus-obtained into a pharmaceutically acceptable acid addition salt thereof or setting free a base of the general formula (I) from an acid addition salt thereof, or converting an acid addition salt of a base of the general formula (I) into another acid addi-tion salt.

5. A process according to variants a) and b) of claim 4, w h i c h c o m p r i s e s carrying out the reaction in melt or in a solvent inert toward the reactants, preferably in methanol, 2-propanol, dimethyl sulfoxide or benzene, optionally in the presence of a base.

6. A process as claimed in claim 5, w h i c h c o m p r i s e s carrying out the reaction at a temperature between 0 °C and 190 °C, preferably between 20 °C and 110 °C.

7. A process according to claim 5 or 6, w h i c h c o m p r i s e s carrying out the reaction in the presence of an organic base, preferably triethyl-amine.

8. A process according to variants b) and c) of claim 4, w h i c h c o m p r i s e s heating the com-pound of the general formula (Ia) in melt or in a solvent, preferably in a protic or dipolar aprotic solvent.

9. A process according to variants b) and c) of claim 4, and according to claim 8 or 9, w h i c h c o m p r i s e s carrying out the isomerisation of the compound of the general formula (Ia) at a temperature between 50 °C and 250 °C, preferably between 100 °C and 190 °C.

10. A process according to variant d) of claim 4, w h i c h c o m p r i s e s carrying out the reaction in a protic or dipolar aprotic solvent, preferably in an aqueous methanol solution or dimethylformamide.

11. A process according to variant d) of claim 4 and according to claim 10, w h i c h c o m p r i s e s carrying out the reaction at a temperature between 0 °C
and 190 °C, preferably between 50 °C and 160 °C.

12. Pharmaceutical compositions c o m p r i s i n g as active ingredient at least one compound of the general formula (I) or a pharmaceutically acceptable salt thereof in admixture with suitable inert solid or liquid pharma-ceutical carriers.

13. A process for the preparation of pharmaceutical compositions according to claim 12, w h i c h c o m p r i s e s admixing a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof with suitable inert solid or liquid thera-peutical carriers.

14. Use of compounds of the general formula (I) or pharmaceutically acceptable acid addition salts thereof for the preparation of pharmaceutical compositions having particularly antianginal and/or gastric ulcer inhibiting effect(s).

15. Method of antianginal and/or gastric ulcer in-hibiting treatment, w h i c h c o m p r i s e s ad-ministering to a patient an effective amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof.