FI80685C - Process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives - Google Patents

Description

80685 PROCEDURE FOR THE PREPARATION OF DIHYDROARYLIOXYXYLAMINO-1,2,4-TRIAZOLE DERIVATIVES

The invention relates to a process for the preparation of dihydroaryaryloxyalkylamino-1,2,4-triazole derivatives of the following general formula (I) and their pharmaceutically acceptable salts:

<H

wherein in formula I, R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl ring; and R 3 represents C 1-4 alkyl or C 2-4 hydroxyalkyl.

The compounds of formula (I) have valuable pharmaceutical properties. They have potent activity as H2 antagonists and show inhibition of gastric acid secretion when stimulated by histamine receptors. Due to their blocking properties, histamine H2 can be used in the treatment of gastric ulcer.

A known process for the preparation of compounds of general formula (I) is described in European Patent Publication No. 28 H83. According to this method, the desired compounds are prepared by Birch reduction of the aryloxyalkylamino-1,2,4-triazole derivatives of the general formula (VI), NN (IV) rl h 2 80685 wherein R1, R2 and R3 in the formula VI have the same meanings as above. The reduction is performed with sodium in liquid ammonia in the presence of alcohol.

Disadvantages of the known production process are that, in addition to the desired 2,5-dihydro-3-alkylaminomethyl-aryloxyalkylamino derivative of the general formula (I), isomeric 3-alkylaminomethyl-3,6-dihydro compounds of the following general formula (VII) are also formed in the reaction. derivatives.

R3

Ή. ^ N-N

V A JL i i / / VII /

Rl h

Isolation of the desired product free of other isomers requires cumbersome reaction steps that result in greater losses of the final product.

Compounds of formula (I) may also be prepared in accordance with EP-A-57 564. Also in this method: a cumbersome separation method has to be used to separate the pure product, and the yield is reduced.

It is an object of the present invention to provide a more economical process for the preparation of compounds of general formula (I) which does not have said disadvantages.

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 the compound of the general formula (II); aryloxyalkylamine: 11 3 80685 R / | / NH / 111 / in which R1 and R2t have the meanings defined above, is reacted with a diethyl ester of N-cyanoiminodithiocarbamic acid, thus obtaining a slight isothiourea of general formula (IV).

/ H

* i in which R1 and R2 have the meanings defined above, are reacted with a substituted hydrazine of general formula (V) R3-NH-NH2 / γ / in which Rt311a has a group as defined above, and, if desired, the general formula (I) thus obtained. ), the dihydroaryloxyalkylamino-1,2,4-triazole is converted into a pharmaceutically acceptable salt.

The aryl-4,80685 oxyalkylamines of the general formula (II) used as starting materials are known compounds and can be prepared by the methods described in Belgian Patent No. 875,846. In this case, the reduction is carried out with sodium metal in liquid ammonia, at a temperature between -85 ° C and -33 ° C. The amount of sodium used in the reaction is preferably 1.1 to 4.5 molar equivalents. Particularly preferably, 2.5 molar equivalents of sodium feral metal are used.

The dihydroaryloxyalkylamine of general formula (III) obtained in the reaction has not been described in the literature so far. Under reduction conditions, the formation of compounds of general formula (III) involves the formation of small amounts of isomeric dihydroaryloxyalkylaraine derivatives of general formula (VIII),

P L

in formula (VIII) R 1 and R 2 are as defined above.

The isomers of general formulas (IIi) and (VIII) may, if desired, be separated by conventional methods (e.g. by distillation) or may be converted directly into a mixture of isothiocarbarides of general formulas (IV) and (IX).

R \ NCN

/ "νΛΛολ, ανΛ / ix / where in formula (IX) and Rp are the groups defined above.

The reaction of compounds of general formula (III) with N-cyano 5,80685 dimethyl ester of nominodithiocarbaric acid may be carried out either in the presence or absence of a solvent. It is preferred to carry out the reaction in a protic or aprotic solvent which is inert to the reactants. C 1-4 alkanols, dimethylformamide, ethers, halogenated organic solvents, aromatic solvents or acetonitrile can be used for this purpose. It is highly preferred to use isopropanol as the solvent. The reaction is preferably carried out at a temperature of 20 to 120 ° C. The amount of dimethyl ester of N-cyanoiminodithiocarbamic acid used in the reaction is preferably 1.0 molar equivalent.

When an isomeric mixture of compounds of general formulas (III) and (VIII) is reacted with dimethyl ester of N-cyanoiminodithiocarbamic acid, a mixture of isothioureas of general formulas (IV) and (IX) is formed and the isomer of general formula (IV) is separated by crystallization.

Isothioureas of general formula (IV) are novel compounds. Their reaction with a substituted hydrazine of general formula (V) may be carried out in a protic or aprotic solvent, preferably a C 1-4 alcohol, ether or an aromatic solvent, at a temperature of 20 to 120 ° C. It is preferable to use n-butanol as the solvent. The amount of the compound of general formula (V) used in the reaction is preferably 1.0 to 1.5 molar equivalents.

N-cyanoiminodithiocarbamic acid dimethyl ester, further substituted hydrazines of general formula (V), used as reagents in the synthesis of the invention are commercial products.

The compounds of formula (i) obtained in the reaction may, if desired, be converted into pharmaceutically acceptable salts. Particularly useful salts include 6,80685 hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, tartrates, benzoates, and furates. The salts may be formed in a conventional manner, e.g. by mixing appropriate amounts of the free base and the free acid in a suitable solvent.

The synthesis of the present invention provides compounds of general formula (I) in a purer form than the known method, namely the separation of intermediates of general formulas (VIII) and (IX) to form an undesired product of general formula (VII) can be carried out economically. early in the synthesis.

The invention is illustrated, but not limited, by the following examples:

Example 1 3- (5- (1-Pyrrolidinylmethyl-1,4-cyclohexadienyl) -oxy) -1-propanamine a) 19.8 g (0.4-25 moles) of ethanol are added to 19.9 g (0.085 moles) of 3- (3- (1-pyrrolidinylmethyl) -phenoxy) -1-propanamine, and 500 ml of ammonia gas are concentrated to solution. The reaction mixture is cooled to -85 ° C in an acetone-dry ice bath, and 10.00 g (0.425 moles) of crushed sodium metal is added portionwise so that the second and each additional batch are added to the solution after the solution is completely settled. After 1 g of sodium has already been added to the mixture, the cooling bath is removed and the reaction is allowed to proceed at -33 ° C. After the last portion of sodium has been added, the blue color of the mixture persists for 2.5-3 hours. After the solution has finally faded, it is refluxed for 30 minutes. 29.7 g (0.555 mol) of ammonium chloride are then added to the mixture. When the ammonia has evaporated, the residue is taken up in 400 ml of diethyl ether. The inorganic salt is removed by filtration and washed six times,

II

7,80685 was created with 100 ml of diethyl ether. The ether solutions are combined and the solvent is evaporated off in vacuo. The residue is partitioned in vacuo. 18.6 g (b.p. 162-168 ° C) (1 mm Hg) of the desired compound and 3 - ((3- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy) -1 -propanamine mixture 4: 1 · The isomer mixture is subjected to fractional distillation at 1 mm Hg. 16.5 g of product are obtained (b.p. 166-168 ° C) containing more than 90 desired isomers. Yield: 75 »9 ^ · b) The preparation is carried out as described in Example 1a), except that 4.4 g (0.19 mol) of sodium metal are used instead of 10 g. After repeated distillation, 15.1 g of product are obtained. : 165-167 ° C.

Yield 67.6

Example 2 Preparation of N-cyano-N'-5 - ((5- [1-pyrrolidinylmethyl)) - 1,4-cyclohexadienyloxy) -propyl] -carbamimidothioic acid methyl ester a) 9 g (0.038 mol) of 3 - ((5 - (1-Pyrrolidinylacetyl) -1,4-cyclohexadienyl) -oxy) -1-propanamine, obtained as detailed in Example 1, is dissolved in 10 ml of isopropanol at room temperature.

To the solution thus obtained is added 5.5 g (0.038 mol) of dimethyl ester of N-cyanoiminodithiocarbaric acid. The reaction starts at room temperature while mercaptan is evolved. After half an hour the reaction mixture was heated to the boiling point. It is boiled for 1.5 hours and evaporated in vacuo. The remaining honey-like product is dissolved in 40 ml of acetonitrile while heating. The solution is then cooled, the separated crystals are filtered off and washed with acetonitrile. 1.1 g of N-cyano-N'-3 - ((3- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy) -propylcarbaminidothioic acid methyl ester are obtained. M.p .: 117-119 ° C.

8 80685

Evaporation of the mother liquor gives 11.5 g of the desired product. Rf = 0.45 / ethyl acetate: pyridine: water: acetic acid = = 60: 20: 11: 6 / Kieselgel 60 on a silica plate b) The preparation is carried out as described in a), except 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 a honey-like product are obtained. Rf = 0.44 (The composition of the evolution mixture is hail as described in a). The product is identical to the product described in (a).

(c) The preparation is carried out as described in (a), except that 40 ml of chloroform is used as the solvent and the reaction mixture is boiled for 4.5 hours. In this way 11.5 g of honey-like product are obtained. Rf = 0.45 in the evolution mixture as detailed in a). The product is equivalent to the product obtained in (a).

(d) The preparation is carried out as described in (a), except that 100 ml of benzene is used as the solvent and the reaction mixture is boiled for 10 minutes. In this way 11.5 g of product are obtained, which is equivalent to the product prepared in accordance with a). Rf = 0.45- The composition of the evolution mixture is the same as defined in a).

(e) The preparation is carried out as described in (a), except 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 that obtained in (a) are obtained. Rf = 0.44 in the evolution mixture, as further defined in a).

Yield: practically quantitative.

f) 9 g (0.038 mol) of 3 - ((5- (1-pyrrolidinylacetyl) -1,4-cyclohexadienyl) oxy) -1-propanamine are dissolved in 10 g of

II

9 80685 ml of dime style formamide at room temperature. To the solution thus obtained, 5.5 g (0.038 mol) of dimethyl ester of N-cyanoamine dithiocarbaric acid are added, and the reaction mixture is allowed to stand at 120 ° C for 5 hours. It is then cooled and poured into 100 ml of water and extracted four times, each time with 30 ml of chloroform. The chloroform fractions are combined, dried over magnesium sulfate and filtered. The solvent is removed by distillation in vacuo. The residue is dissolved in 35 ml of acetonitrile while heating. The solution thus obtained is cooled, the separated crystals are removed by filtration and washed with acetonitrile. 0.8 g of methyl ester of N-cyano-N'-3 - ((3- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy) propylcarbamiminothioic acid is obtained. Melting point: 116-118 ° C. Evaporation of the mother liquor gives 9.2 g of a honey-like product. Rf = 0.46 (The composition of the developing solution is the same as described in a). The product is identical to the product prepared according to Example 2a).

Example 3 1-Methyl-N, N - (- 3 - ((5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy) propyl) -1H-1,2,4-triazole-3, Preparation of 5-diamine a) 9 g (0.027 moles) of N-cyano-N'-3 - ((5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy) propylcarbamiminothioic acid methyl ester prepared as described in Examples 2a) -2f), is dissolved in 200 ml of n-butanol at room temperature. To this solution is added 1.24 g (0.027 moles) of methylhydrazine. The reaction starts immediately while mercaptan develops. After 20 minutes, the reaction mixture is heated to reflux and maintained at the same temperature for 20 hours. The solvent is removed by distillation in vacuo. 20 ml of cyclohexane and 5 ml of acetonitrile ίο 80685 are poured into the honey-like product thus obtained and the mixture is cooled. The separated crystals are removed by filtration and washed with acetonitrile. 7.5 g (83.8 g) of the intended product with a melting point of 81 DEG-84 DEG C. are obtained. The crude product is recrystallized from 60 ml of a 1: 4 mixture of ethyl acetate and cyclohexane. melting point 86-87 ° C.

(b) The preparation is carried out as detailed in (a), except that di-n-propyl ether is used as solvent. After recrystallization, 5.4 g (60.3) of product are obtained, which is equivalent to the product prepared in (a). M.p .: 85-87 ° C.

(c) The preparation is carried out as described in (a), except that benzene is used as the solvent. After recrystallization, 5.1 g (57 #) of product are obtained, melting at 85-88 ° C. The compound is equivalent to the product prepared according to a).

d) The preparation is carried out as described in a), except that 1.86 g (0.041 mol) of methylhydrazine are used. After recrystallization, 6.6 g (73.9%) of product are obtained, which is equivalent to the product prepared in a). Sp. 85-87 ° C.

Example 4 Preparation of 3 - ((5- (1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy) -1-propanamine 4.62 g (0.1 mol) of ethanol are added to 5.97 g (0.02 mol). moles) of 3- (3- (1-piperidinylmethyl) phenoxy) -1-propanamine and 200 ml of ammonia are concentrated to the solution thus obtained. The mixture is cooled to -75 ° C with an acetone-dry-ice bath and crushed sodium ferrous is added.

II

11 80685 2.41 g (0.015 moles) in portions so that the second and each subsequent portion are added after the solution has completely faded. After the addition of 0.5 g of sodium, the blue color of the reaction mixture persists for 2.5-3 hours. After the mixture has finally faded, it is refluxed for 30 minutes and 6.89 (0.13 moles) of ammonium chloride is added. After evaporation of the ammonia, the residue is taken up in 200 ml of diethyl ether, the inorganic salt is removed by filtration and washed six times with 50 ml of ether each time. The ether solutions are combined and the solvent is removed in vacuo. The residual oily product is fractionally distilled in vacuo. 4.85 g of product (b.p. 130-135 ° C / 0.3 mm Hg) are obtained, which is the title compound and 3 - ((3- (1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy) -1- a mixture of propanamine. The isomer mixture is redistilled repeatedly at 0.3 mm Hg. The fraction boiling at 133-135 ° C contains more than 90 t of the intended compound.

Yield: 78.0

Example 5 Preparation of N-cyano-N, -3 - ((5-1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy) -propyl-carbamidothioic acid methyl ester 3.0 g (0.012 mol) of pure 3 - ((5- (1-Piperidinylmethyl) -1,4-cyclohexadienyl) oxy) -1-propanearamine prepared according to Example 4 is dissolved in 30 ml of diethyl ether and 1.75 g (0.012 mol) of dimethyl ester of N-cyanoiminodithiocarbamic acid are added. , as long as methyl mercaptan develops. The reaction mixture is boiled for two hours and evaporated. The remaining solid white product is slurried in a small amount of ether and filtered. In this way, 3.9 g (93.3%) of the desired compound are obtained. Sp. 90-95 ° C. After recrystallization from isopropanol, it melts at 95-97 ° C. The yield is 79%.

12 80685

Example 6 1-Methyl-N, 5- (3 - ((5- (1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy) propyl) -1H-1,2,4-triazole Preparation of -3,5-diamine 1.74 g (0.005 mol) of N-cyano-N'-3 - ((5- (1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy) propylurea- thionapo methyl ester prepared according to Example 5 is dissolved in 5 ml of butanol, and 0.62 g (0.054 mol) of methylhydrazine is added to the solution. The reaction starts immediately while mercaptan develops. After 20 minutes, the reaction mixture is heated to reflux and kept at the same temperature for 20 minutes. It is then cooled, the solvent is removed by distillation in vacuo, a small amount of cyclohexane-ethyl acetate-t (4: 1) is added to the residue and the solution is cooled. The separated crystals are removed by filtration. 1.5 g (86.2 lb) of the intended product are obtained.

Melting point: 100-103 ° C.

After recrystallization from cyclohexane-ethyl acetate (4: 1), the product melts at 105-106 ° C.

Il

Claims (3)

13 80685 A process for the preparation of dihydro-aryloxyalkylamino-1,2,4-triazole derivatives of the following general formula (i) and pharmaceutically acceptable salts thereof, wherein in said formula R 1 and R 2 together form R 1 with the nitrogen atom to which they are attached, a pyrrolidinyl or piperidinyl ring, and R 3 represents C 1-4 alkyl, characterized in that the aryloxyalkylamine of general formula (II) R 1 n R 1 in which R 1 and R 2 are as defined above reduced in an ammonia solution to -85 [deg.] C. at -33 [deg.] C. using 1.1 to 1.5 molar equivalents, preferably 2.5 molar equivalents of Na metal, to give the dihydroaryloxyalkylamine of the general formula (lii) thus obtained. React with dimethyl ester of N-cyanoiminodithiocarbamic acid in a protic or aprotic solvent Sa, preferably in isopropanol, is reacted with 1.0- to give the isothiourea of the general formula (IV) R1 ncn ΛΛ / IV / / o N ^ SCH, Rz H 3 in which R1 and R2 are as defined above, to give 1.0- With 1.5 molar equivalents of a substituted hydrazine derivative of general formula (V) (V) in which R3 is as defined above in a protic or aprotic organic solvent, preferably n-butanol, and, if desired, thus obtained, the dendehydroaryloxyisalkylamino-1 of general formula (I). The 2,4-triazole is converted into a pharmaceutically acceptable salt. 2. A dihydroaryloxyalkylamine is preferably a compound of formula (III) \ (\ ^ / ΠΙ / * L for R 1 and R 2) having the meaning of claim 1. Dihydroaryloxyalkylamines k, n II / m / R 2 of the general formula (III), characterized in that R 1 and R 2 are as defined in Claim 1. li is 80685 3. Isothioureas of general formula (IV), ^ 4 / N NCN v JijL. sK. / w R 1 H is characterized in that and R 2 are as defined in claim 1. A compound for the preparation of dihydroaryloxyalkylamino-1,2,4, -triazole derivatives according to the general formula (i) is also a pharmaceutically acceptable salt of R-j r4 I \ f || N- <H * i represents a form of R 1 and R 2 which may be used as a compound in the form of a pyrrolidinyl or piperidinyl ring, and R 3 represents a C 1-4 alkyl group, which may be substituted by an aryloxyalkylamine form '/ 11 / o --- sNHi R1 16 80685 i and a mixture of R1 and R2 are preferably added, reducing the amount of ammonia to -85 · ..- 33 ° C: s at a temperature of 1.1-1.5 molar equivalents, företrädesvis 2,5 raolar equivalents of sodium metal, later den erärna erhallna dihydroaryloxyalkylamine enligt formula (ill) XN. [^ χ / 111 / / 0⁇ * \ (| j | NCN; νΛΛ, λληΛ nv h 3 i form a formula R NHX / V / into which the Formel R 3 are as defined Ova, i protiskt eller aprotic organic solvent, "preferably in n-butanol, och om sa bandwidth, konventerar the man therewith erhallna dihydroaryloxialkylamino-l, 2,4-triazol till a farmaceu- tiskt acceptabelt salt.It 17 80685 3. An isothiocarbamide according to the formula (IV) Λ \ NCN N .. JL / IV / RZ H 3 for R 1 and R 2 The equivalents of the invention are defined in 1 frame.