GB2170805A - Process for the preparation of 3, 5-diamino-1,2,4-triazole derivatives - Google Patents

Abstract

There is disclosed a process for the preparation of compounds of the general Formula I <IMAGE> wherein R<1> and R<2> are independently hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R1 and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and R3 is hydrogen or alkyl and pharmaceutically acceptable acid addition salts thereof, which comprises reacting a halogen compound of the general Formula III <IMAGE> [wherein X is halogen, which may be prepared from the hydroxy compound of general formula II, with an alkali metal of alkaline earth metal salt of a phenol derivatives of the general Formula IV <IMAGE> and, if desired, converting the compound of general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof. The compounds of general Formula I have a useful sustained histamine H2 blocking effect. The advantages of the process invention are that it requires readily available starting materials, provides high yields and is readily feasible on an industrial scale.

Description

SPECIFICATION Process for the preparation of 3,5-diamino-1,2,4-triazole derivatives This invention relates to a new and improved process for the preparation of 3,5-diamino-1,2,44riazole derivatives.

According to the present invention there is provided a process for the preparation fo 3,5-diamino-1,2,4triazole derivatives of the general Formula I

and pharmaceutically acceptable acid addition salts thereof /wherein R1 and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R, and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and R3 stands for hydrogen or alkyl/.

The compounds of the general Formula I are known histamine H2-blockers of sustained effect. These compounds are capable of antagonizing gastric acid secretion stimulated by histamine and are useful in antiulcus therapy.

Several procedures are known for the preparation of the compounds of the general Formula I. According to Belgian patent No. 875,846 an amine of the general Formula V

/wherein R1 and R2 are as stated above is reacted with a cyanoimino derivative of the general Formula VI

/wherein R4 and R5 are alkylthio or alkoxy/. The isourea or isothiourea derivative of the general Formula VII

thus obtained /wherein R, and R2 are as stated above/ is treated with a substituted hydrazine of the general Formula VIII R3 - NH - N = Z Nail/ /wherein R3 is as stated above and Z represents two hydrogen atoms/. In the reaction a mixture of the isomeric compounds of the general Formulae I and IX

is obtained /wherein R1, R2 and R3 are as stated above/.The compound of the general Formula I is separated from the mixture by crystallization.

The serious drawback of this process is that the isomers of the general Formulae I and IX - differing from each other in the position of the R3 substituent - are formed only in the last step of the synthesis and for this reason the desired isomer of the general Formula I is obtained with large losses. Moreover the fact that the said losses occur at the very end of the lengthy synthesis, consisting of several steps, makes the process very expensive.

In order to eliminate the formation of the isomeric compounds of the general Formula IX according to a further process described in Belgian patent No. 875,846 the isothiourea of the general Formula VII is reacted with a protected hydrazine derivative of the general Formula VIII /wherein R3 is as stated above and Z represents a protecting group/. From the protected cyano guanidine derivative of the general Formula X

thus obtained /wherein Ri, R2, R3 and Z are as stated above/the protecting group is removed and the cyano guanidine derivative of the general Formula Xl

/wherein R1, R2 and R3 are as stated above/ spontaneously cyclizes to the compound of the general Formula According to the said Belgian patent the key intermediate of the general Formula X can also be prepared by reacting a protected hydrazine derivative of the general Formula VIII with a cyanimino derivative of the general Formula VI. The protected cyano guanidine derivative of the general Formula XII

/wherein R3 and R4 are as stated above and Z stands for a protecting group/ is coupled with an amine of the general Formula V to yield the desired intermediate of the general Formula X.

The common disadvantage of both of the above processes is the use of the protecting group Z which aims the elimination of the isomeric triazole derivative of the general Formula IX in the ring closure step of the triazole ring. It is namely known [see J.Org.Chem. 39, 1522 /1974/] that an analoguous reaction of dimethyl-N-cyanoimino-dithio carbamate and N-methyl-hydrazine leads to the formation of the isomers of the type of the general Formulae I and IX.

According to a further reaction disclosed in Belgian patent No. 875,846 an isothiourea derivative of the general Formula XIII

/wherein R1 and R2 are as stated above and R8 stands for Cl lO alkyl/ is treated with an amino guanidine, semicarbazide or thiosemicarbazide of the general Formula XIV

/whrein Y is -NH-, oxygen or sulfur and R3 is as stated above/. The compound of the general Formula XV

/wherein R1, R2, R3 and Y are as stated above and Q represents -NH-/ thus obtained is converted into the triazole derivative of the general Formula I by ring-closure.

According to a further procedure disclosed in the said Belgium patent an addition reaction between an isocyanate of the general Formula XVI

/wherein R1 and R2 are as stated above and P is oxygen or sulfur/ and a compound of the general Formula XIV /wherein R3 is as stated above and Y represents -NH-/ is carried out, whereupon the compound of the general Formula XV is cyclized into the desired triazole derivative of the general Formula I.

The common drawback of both of the above processes is that the preparation of the reactants is rather complicated, the last condensation step is very lengthy and energy consuming and the yields are rather moderate.

According to a further reaction described in the said Belgian patent an isothiourea of the general Formula XIII is reacted with a protected hydrazine of the general Formula VIII whereupon the protecting group is removed. The amino guanidine derivative of the general Formula XVII

/wherein R1, R2 and R3 are as stated above/ is reacted with carbamoyl chloride to yield the desired compound of the general Formula I.

The disadvantage of this process is that in order to eliminate the formation of the undesired isomer of the general Formula IX a protected hydrazine derivative of the general Formula VIII is used /wherein Z is a protecting group/, the preparation of the reactants is complicated and the closing condensation step of the synthesis is lengthy and energy consuming.

A further reaction type disclosed in Belgian patent No. 875,846 differs from the reactions disclosed above in the fact that in the place of an amino compound of the general Formula V an acid amide of the general formula XVIII

/wherein R1 and R2 are as stated above/ or an acetale or cyclic acetale of the general Formula XIX

/wherein R, stands for alkyl or the /P6O/2CH- group represents a cyclic acetale/ is used. The last step of the said synthesis is the formation of the group of the general Formula R1R2N-CH2- from the intermediates of the general Formulae XX and XXI

thus obtained /wherein R1, R3, R3 and P6 are as above/ by means of known methods used in the synthesis of the compounds of the general Formula V.

According to a further method disclosed in Belgian patent No. 875,846 a key intermediate of the general Formula XXII

/wherein R3 is as stated above and X stands for halogne/ is condensed withan amine of the general Formula R1R2NH /wherin Ri and R3 are as stated above/.

According to European patent application No. 29,303 the compounds of the general Formula I are prepared by subjecting an aldehyde of the general Formula XXIII

/wherein R3 is as stated above/ and an amine of the general Formula R1R2NH /wherein R1 and R2 are as stated above/ to an amination reaction under reducing conditions.

According to a further reaction of the said European patent application a secondary amine of the gen eral Formula XXIV

/wherein R3 and R3 are as stated above/ is used as starting material which is either subjected to reducing condensation with an aldehyde of the general Formula R7CHO /wherein the R7-CH2- group formed on reducing R7CHO is the R, group/ or alkylated with a compound of the general Formula R7-CH2-X /wherein R7-CH2- is as stated above and X stands for halogen/ to yield the desired compound of the general Formula I.

In the last four reaction types the same reaction steps are used as in the previously disclosed methods, only the order of sequence of the steps is changed. Consequently, as a matter of fact the said four procedures are accompanied by the same drawbacks as the previously discussed methods.

According to a further process disclosed in Belgian patent No. 875,846 a narrower sub-group of the compounds of the general Formula I is prepared by reacting a phenoxy alkyl derivative of the general Formula XXV

/wherein R3 is as stated above/ with the ammonium chloride of the Formula XXVI.

Thus a compound of the general Formula I is obtained wherein both R, and R2 represent methyl. The disadvantage of the said process is that it is suitable for the preparation but of a narrow compound group. Moreover the preparation of the compound of the Formula XXVI and also the reaction itself is complicated and labour consuming.

According to a further process disclosed in belgian patent No. 875,846 an amino guanidine of the general Formula XIV /wherein R3 is as stated above and Y stands for imino/ is reacted with a carbamoyl chloride of the general Formula XXVII

/wherein R8 and R8 are suitable protecting groups/, the 3,5-diamino-1H-1,2,4-triazole derivative of the general Formula XXVIII

thus obtained /wherein R3, R8 and R8 are as stated above/ is reacted with an aldehyde of the general Formula XXIX

/wherein R1 and R2 are as stated above/ and the Schiff-base of the general Formula XXX

/wherein R1, R3, R3 and R8 and R8 are as stated above/ thus obtained is reduced and finally the protecting groups are removed.

According to a modification of the said process the amino triazole of the general Formula XXVIII is reacted with an activated acid derivative of the general Formula XXXI

/wherein R1 and R2 are as stated above and A represents halogen, hydroxy, alkoxy or acyloxy/ whereupon the acid amide of the general Formula XXXII

thus obtained /whereupon Rl, R2, R3, R8 and R8 are as stated above/ is reduced to the desired compound of the general Formula I.

According to a further modification of the above process an amino triazole of the general Formula XXVIII is reacted with an active ester of the general Formula XXXIII

/wherein R1 and R3 are as stated above and B is mesyloxy or toxyloxy/ to yield the desired compound of the general Formula I.

The above methods are accompanied by the disadvantages that the triazole ring is formed by the complicated methods earlier discussed and the appropriate selection and removal of the protecting groups R8 and P8 cause further problems and inconveniences.

It is the object of the present invention to overcome the above drawbacks of the known procedures and to provide an economical, readily feasible process for the preparation of the compounds of the general Formula I.

According to the present invention there is provided a process for the preparation of compounds of the general Formula I /wherein Rl and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or Rl and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and R3 stands for hydrogen or alkyl/, and pharmaceutically acceptable acid addition salts thereof, which comprises a/ converting a hydroxy compound of the general formula II

/wherein R3 is as stated above/ into a halogen compound of the general Formula III

/wherein R3 is as stated above and X stands for halogen/ and reacting the compound thus obtained with an alkali metal or alkali earth metal salt of a phenol derivative of the general Formula IV

/wherein Rl and R2 are as stated above/; or b/ reacting a halogen compound of the general Formula lil with an alkali metal or alkali earth metal salt of a phenol derivative of the general Formula IV and, if desired, converting the compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

The hydroxy compound of the general Formula II is converted into the halogen derivative of the general Formula III by methods known per se. It is preferred to react the compound of the general Formula II with a suitable halogenating agent - particularly with a thionyl halide, especially thionyl chloride - in an inert solvent. The excess of thionyl halide may preferably act as reaction medium. As reaction medium aromatic hydrocarbons /e.g. benzene, toluene or xylene/ may also be used. The reaction may be carried out at room temperature or under eating /e.g. between 20 "C and 80 C/.

The halogen derivative of the general Formula Ill is then reacted with an alkali metal /e.g. potassium, sodium or lithium/ or alkali earth metal /e.g. calcium or magnesium/ salt or a phenol compound of the general Formula IV. The reaction may be accomplished in a dipolar aprotic solvent /e.g. dimethyl formamide/.

The alkali or alkali earth metal salt of the compound of the general Formula IV may be formed in the reaction mixture by reacting the phenol derivative of the general Formula IV in a dipolar aprotic solvent / e.g. dimethyl formamide/ with a hydride or alcoholate of the corresponding alkali or alkaline earth metal / e.g. sodium hydride, calcium hydride or potassium tertiary butylate/.

The compound of the general Formula I thus obtained may be isolated by methods known per se.

The salt formation may be carried out in a known manner by reacting the compound of the general Formula I thus obtained in an organic solvent with the corresponding inorganic or organic acid /e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, lactic acid etc./.

The starting materials of the general Formulae II and IV are known and readily available compounds.

The compounds of the general Formula III are new, never described in prior art.

The term "alkyl" relates to straight or branched chained saturated aliphatic hydrocarbon groups having 1-5 carbon atoms /e.g. methyl, ethyl, n-propyl, isopropyl etc./. The term "alkenyl" relates to straight or branched chained olephinic hydrocarbon groups having 2-5 carbon atoms /e.g. allyl, propenyl etc./. The term "aralkyl" relates to alkyl groups substituted by an aryl radical /e.g. benzyl, p-phenylethyl etc./. The term "cycloalkyl" relates to saturated cyclic aliphatic hydrocarbon groups having 3-8 carbon atoms /e.g.

cyclobutyl, cyclopentyl, cyclohexyl etc./. The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms and represents preferably chlorine or bromine, particularly chlorine.

The "heterocyclic group"formed by R1 and R2 and the adjacent nitrogen atom may have 5 or 6 members, may comprise one or two nitrogen, oxygen and/or sulfur atoms and may be optionally substituted.

Preferred heterocyclic groups are the pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl groups.

Rl and R2 may preferably stand for methyl or together with the adjacent nitrogen atom may preferably form a pyrrolidino or piperidino group. R3 may preferably stand for methyl.

The process of the present invention is particularly suitable for the preparation of l-methyi-N5-(3-[3-[/1- piperidinyl/-methyl]-phenoxy]-propyl)-l H-l ,2,4-triazole-3,5-diamine and sa Its thereof.

The advantages of the process of the present invention may be summarized as follows: a/ The process is readily feasible on industrial scale, too.

b/ No specific apparatus or equipment is required.

c/ The starting materials are readily available in large quantities, too.

d/ Since the formation of the isomeric compounds of the general Formula IX is eliminated and the synthesis of the desired compounds of the general Formula I is carried out not stepwise but by the synthesis of two key intermediates of approximately the same size, the total yield of the synthesis is far superior to the total yields of the hitherto known methods.

Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples.

Example 1 Nó-13-Chloropropyll- 1K- 1,2,4-triazole-3, 5-diamin e hydrochloride 5 g /0,032 mole/ of Ns-/3-hydroxypropyl/-1 H-l ,2,4-triazole-3,5-diamine are dissolved in 15 ml of benzene.

To the solution 4.2 g /0,035 mole/ of thionyl chloride are added under stirring and cooling at 10 "C. The reaction mixture is slowly allowed to warm to room temperature. The reaction mixture is stirred for half an hour. The precipitated crystals are filtered off and washed with benzene. Thus 6.3 g of the desired compound are obtained, yield 92.8 %. A strongly hygroscopic white crystalline substance is obtained which liquifies on air. Mp.: 130-132 "C /in a closed tube/.

Example 2 N5-13-chloropropyll- 1K- 1,2,4-triazole-3,5-diamine-hydrochloride One proceeds according to Example 1 except that no benzene is used but 10.6 ml /0,15 ml/ of thionyl chloride are applied and this excess serves as reaction medium. Thus 6.8 g of the desired compound are obtained, yield 94,4 %. The product is identical with the compound prepared according to Example 1.

Example 3 1-Methyl-Nó-13-chloropropyll- 1H- 1,2,4triazole-diamine-hydrochloride One proceeds according to Example 2 except that 8,6 g/0.05 mole/ of 1-methyl-N5-/3-hydroxy-propyl/- 1H-1,2,4-triazole-3,5-diamine are used as starting material and the reaction mixture is heated to 60 "C and stirred at this temperature for 15 minutes. Thus 10.7 g of the desired compound are obtained, yield 94.7 %. Mp.: 170-172 "C /decomposition/.

Example 4 1-Methyl-N6X,3-l3-[l l-piperidinyll-methylJ-phenoxyJ-propyl'J - 1K- 1,2,4-triazo!e-3,5-diamine To a solution of an oily suspension of 1.0 g /0.033 molel of 80 % sodium hydride in 20 ml of an hydros dimethyl formamide 5.7 g /0/03 mole/ of 3-/1-piperidinylmethyl/-phenol are slowly added and the mixture is stirred for half an hour at room temperature. In a separate flask to a solution of 8.1 g /0.036 mole/ or 1 methyl-N5-/3-chloropropyl/-l H-'l ,2,4-triazole-3,5-diamine-hydrochloride in 15 ml of anhydrous dimethyl formamide 3.04 g /0.03 mole/ or triethyl amine are added under stirring at room temperature, the precipitated triethyl amine hydrochloride is filtered off and washed with some an hydros dimethyl formamide.

The solution thus obtained is added to the dimethyl formamide solution of the phenolate prpared above under stirring at room temperature. The reaction mixture is stirred for 72 hours, at room temperature, 30 ml of water are added and it is extracted three times with 20 ml of chloroform each. The united organic phases are extracted three times with 20 ml of water each, the chlorophorm phase is dried over anhydrous magnesium sulfate and the chloroform is distilled off in vacuo. The residual brown oil /9.6 gl becomes slowly crystalline on standing and is recrystallized from a 1:4 mixture of ethyl acetateand cyclohexane. Thus 5.6 g of the desired compound are obtained, yield 54,4 %, mp.: 93-94 "C.

Example 5 1-Methyl- N5-(3-[3-[1 1-piperidinyll-methylj-phenoxyj-propy]} - 1K- 1,2,4-triazole-3,5-diamine-fumarate The oily crude product prepared according to Example 4 is dissolved in 30 ml of ethanol whereupon at 50 "C 3.5 g/0.03 mole/ of fumaric acid are added. After dissolving the reaction mixture is cooled and allowed to stand in a refrigerator overnight. The precipitated crystals are filtered and washed with some ethanol. Thus 7,8 g of the desired compound are obtained, yield 56.4 %, mp.: 142-145 "C.

Example 6 1-Mothy/-N{3-[3-fl 1-piperidinyll-methyl]-phenoxyl-propyl} -1K- 7,24-triazole-3,5-diamine One proceeds according to Example 4 except that 10.2 g /0.045 mole/ of 1 -methyl-NS-/3-chloroprpyl/-l H- 1,2,4-triazole-3,5-diamine-hydrochloride are used. Thus 5.3 g of the desired compound are obtained, yield 51.4 %. The product is identical with the compound prepared according to Example 4.

Example 7 1-Methyl-N5- (3-[3-[1 1-piperidin yl]-meth ylJ-phonoxy]-prop yI\- 1K- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 6.8 g /0.03 mole/ or 1-methyl-N5-/3-chloropropyl/-1H- 1,2,4-triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.9 g of the desired compound are obtained, yield 47.6 %. The product is identical with the compound prepared according to Example 4.

Example 8 l-Meth yl-N5-{3-[3-[/1 1-piperidinyl]-methyl]-phenoxy]-propyl} - 1H- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 1.4 g /0.033 mole/ of calcium hydride are used in the place of sodium hydride. Thus 5.1 g of the desired compound are obtained, yield 49.5 %. The product is identical with the compound prepared according to Example 4.

Examples 9 1-Methyl-N5-{3-[3-[/1-pyrrolidinyl/-methyl]-phenoxy]-propyl}-1H-1,2,4-triazole-3,5-diamine One proceeds according to Example 4 except that 5.3 g /0.03 mole/ or 3-/1-pyrrolidinyl-methyl/-phenol are used as starting material of the general Formula IV. Thus 4.9 g of the desired compound are obtained, yield 49.4 %, mp.: 94-95 C.

Example 10 1-Methyl-N5-{3-[-[/1 1-pyrrolidinyl]-methyl]-phenoxy]y-propyl}- 1H- 1,2,4triazole-3,5-diamine fumarate One proceeds according to Example 5 except that as starting material the compound prepared according to Example 9 is used. Thus 7.2 g of the desired compound are obtained, yield 53,7 %, mp.: 140-142 "C.

Example 11 l -Methyl-Ns{3-[3-[ldimethylaminol-methyl7-phenoxyl-propyl}- 1H-1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 4.5 g /0.03 mole/ of 3-dimethylaminomethyl-phenol are used as starting material. Thus 4.1 g of the desired compound are obtained, yield 44.9 %, m.p.: 95-96 "C.

Example 12 N5-{3-[-[/1 [1-Piperidinyl]-methyl]-phenoxy]-propyl}- 1K- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 7.6 g /0.036 mole/ of N5-/3-chloropropyl/-1H-1,2,4- triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.7 g of the desired compound are obtained, yield 47.4 %, mp.: 100-101 C.

Example 13 Ns-(3-13-[lDimethylaminol-methyl ]-phenoxyl]-propyl}- 111- 7,24-triazole-3,5-diamine One proceeds according to Example 4 except that 4.5 g /0.03 mole/ of 3-dimethylaminomethyl-phenol and 7.6 g /0.036 mole/ or N5-/3-chloropropyl/-1H-1,2,4-triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.2 g of the desired compound are obtained, yield 48.2 %, mp.: 91-93 "C.

Claims (12)

1. A process for the preparation of 3,5-diamino-1H-1,2,4-triazole derivatives of the general Formula I

/wherein R, and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R1 and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and R3 stands for hydrogen or alkyl/ and pharmaceutically acceptable acid addition salts thereof, which comprises a/ converting a hydroxy compound of the general Formula II

/wherein R3 is as stated above/ into a halogen compound of the general Formula Ill

/wherein R3 is as stated above and X stands for halogen/ and reacting the compound thus obtained, optionally after having removed the hydrohalide moeity HX, with an alkali metal or alkaline earth metal salt of a phenol derivative of the general Formula IV

(wherein Rl and R2 are as stated above); or (b) reacting a halogeno compound of the general Formula III optionally after having removed the hydrohalide moeity HX, with an alkali metal or alkaline earth metal salt of a phenol derivative of the general Formula IV and, if desired, converting the compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

2. A process according to Claim 1, which comprises reacting a compound of the general Formula II with a thionyl halide, preferably with thionyl chloride.

3. A process according to Claim 2, which comprises carrying out the reaction in an excess of thionyl halide or in an inert organic solvent.

4. A process according to Claim 3, which comprises using an aromatic hydrocarbon - preferably toluene, benzene or xylene - as solvent.

5. A process according to Claim 1, which comprises using a sodium, potassium, calcium or magnesium - preferably sodium - salt of a compound of the general Formula IV.

6. A process according to Claim 1 or 5, which comprises preparing in the reaction mixture the alkali or alkaline earth metal salt of the compound of the general Formula IV.

7. A process according to Claim 5 or 6, which comprises carrying out the reaction in an inert dipolar aprotic organic solvent.

8. A process according to Claim 7, which comprises using dimethyl formamide as solvent.

9. A process according to any of Claims 1-8 for the preparation of 1-methyl-N543-[-[/1-piperidinyl/ methyl]-phenoxyl-propyl)-l H-l ,2,4-triazole-3,5-diamine and pharmaceutically acceptable acid addition salts thereof, which comprises using as starting material compounds of the general Formula II and IV, in which R, and P3 together with the adjacent nitrogen atom, they are attached to, form a piperidino ring and R3 represents methyl.

10. A process according to Claim 9 using thiionyl chloride as halogenating agent.

11. Compounds of the general Formula I and salts thereof whenever prepared acccording to the process claimed in any of Claims 1-9.

12. A process as claimed in claim 1 as substantially described herein, with particular reference to the Examples.