CS244830B2 - Production method of dihydroaryloxyalkylamine-1,2,4-triazole derivatives - Google Patents

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

wherein ^R * 1 ^and * 2 ^form together with the adjacent nitrogen atom a pyrrolidinyl or piperidinyl radical and

R ₃ represents alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.

The compounds of formula I have valuable pharmaceutical properties. The compounds have potent H 1 -antagonism and suppress gastric acid secretion when stimulated by histamine receptors. Due to their histamine-blocking effect, they can be used to treat gastric ulcers.

The only known method for the preparation of compounds of formula I is described in European Patent Application Publication No. 28 483. According to this process, the desired compounds are produced by Birch reduction of aryloxyalkylamino-1,2,4-triazole derivatives of formula VI (VI)

wherein R 8, R _{2 and} R ₃ are as defined above.

The reduction is carried out with sodium in liquid ammonia in the presence of alcohol.

A disadvantage of the known process is that, in addition to the desired 2,5-dihydro-3-alkylaminomethyl-aryl-oxyalkylaminoOerivitiate of Formula I, isomeric 3-acetylaminomethyl-3,6-dihidroderivatives of Formula VII are also formed in the reaction

(VII) wherein R 8, R 2 and R 3 are as defined above.

Isolation of the desired product in the form of free of other isomers requires an uneasy reaction step causing undesired loss of the end product.

. It is an object of the present invention to provide a process for the preparation of compounds of formula (I) which is free from the above disadvantages.

According to the invention, the dihydroaryloxyilkylamino-α-triazole derivatives of the general formula I and their pharmaceutically acceptable salts are prepared by reducing the aryloxyalkylamine of the general formula II

(II) wherein R 8 and R 8 are as defined above, by reacting the thus obtained ethyl-α-1-floxyalkyl of formula III

(III) wherein Rg and Rg are as hereinbefore defined, with N-cyanoinododithiocarbimic acid dimethyl ester, by reaction of the isothoocarbamide thus obtained

Where Rg and Rg are as defined above, with the substituted hydrazine of formula V

R 3 - nh - NH 2 (V) wherein R ₃ is as defined above and, if desired, converts the dihydroaryloxyalkylamino-1,2,4-triazole thus obtained to a pharmaceutically acceptable salt.

The aryloxyalkylamines of the formula II used as starting materials are known compounds and can be prepared by the methods described in Belgian patent specification 875 846. Their reduction is carried out in sodium metal in liquefied ammonia at temperatures between -85 and -33 ° C.

The amount of sodium used for the reaction is preferably 1.1 to 4.5 molar equivalents. It is particularly preferred to use 2.5 molar equivalents of coffee sodium.

The dihydroaryloxyalkylamines of general formula (III) obtained in the reaction have not been previously described in the literature. Under reducing conditions, the formation of compounds of formula III is associated with the formation of small amounts of isomeric dihydroaryloxyalkylamine derivatives of formula VIII / VIII / nh ₂ wherein R 1 and R ₂ are as defined above.

Isomers of formulas III and VIII may be resolved as appropriate by conventional techniques, for example by distillation, or may be converted directly into a mixture of isothiocarbamides of formulas IV and ix

/ IX /

III dimethylaeterem N-cyano-iminodithiokde Ri and R ₂ £ maj defined above.

The reaction of the compound of the formula carbamic is carried out in the presence or absence of a solvent. Preferably, the reaction is carried out 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. Isopropyl alcohol is particularly preferably used as the solvent.

The reaction is preferably carried out at a temperature between 20 and 120 ° C. The amount of N -cyanoiminodithiocarbamic acid dimethyl ester used for the reaction is preferably 1.0 molar equivalent.

When a mixture of compounds of formulas III and VIII is used to react with N-cyano-iminodithiocarbamic acid dimethyl ester, a mixture of isothiocarbamides of formulas IV and IX is formed and the isomer of formula IV is separated by crystallization.

The isothiocarbamides of the formula IV are novel compounds. Their reaction with a substituted hydrazine of formula V can be carried out in a protic or aprotic organic solvent, preferably in a C 1 -C 4 alcohol, ether or aromatic solvent, at a temperature between 20 and 120 ° C.

Preferably n-butanol is used as the solvent. The amount of the compound of formula V used for the reaction is preferably 1.0 to 1.5 molar equivalents.

The N-cyano-di-thiocarbamic acid dimethyl ether and further substituted hydrazines of formula V used as reagents for the synthesis of the invention are commercially available products.

The compounds of formula (I) obtained in the reaction may be converted, if desired, into pharmaceutically acceptable salts. Particularly suitable salts include hydrochlorides, hydrobromides, sulfates, eehansulfonates, acetates, mesylates, succinates, citrates, tartrates, benzoates and fumarates.

The salts may be formed in a conventional manner, for example by mixing a suitable amount of free base and acid in a suitable solvent.

The synthesis of the invention provides the compounds of the formula I in a purer form than the known method, in particular the separation of the intermediates of the formulas VIII and IX from the undesired product of the formula VII can be carried out economically in the initial phase of the synthesis.

The invention is illustrated but not limited by the following examples.

Example 1

Process for the preparation of 3 '- [[5- (1-pyridylidinylmethyl) -1,4-cycloideadinyl] oxy] -1-propyl salt and 19.8 (0.425) ethanol / ethanol was added to 19.9 g (0.085 moo). [α- (1-Pyridlidinylmethyl) -, phenyloxy] -1-propaneate and 500 ml of ammonia in gaseous form are condensed in solution. The mixture is cooled to -85 ° C in a dry ice acetone bath and 10.00 g (0.425 mm o) of crushed sodium metal is added incrementally so that the second and each additional portion is added. added after complete decolorization of the solution.

After - added to smmsi 1. g of sodium, the cooling bath was removed and the reaction was allowed to proceed at -33 ° C. When the last portion of sodium was added, the blue color of the reaction mixture remained for 2.5 to 3 hours. *

After the final decolorization with stirring, the mixture was refluxed for 30 minutes. Thereafter, 29.7 g - (0.555 moo) of thorium chloride was added to the mixture. . After evaporation, the residue is taken up in 400 ml of diethyl ether. , ..

The inorganic salt was filtered off and washed six times with 100 ml of diethyl ether each time. The ether solutions were combined and the solvent was evaporated under reduced pressure. The residue is fractionated by distillation under reduced pressure to give 18.6 g of product, b.p. 162-168 ° C / 1 mm Hg, which is a mixture of 4 s of 1 of the desired compound and 3- [[3- / l- pyrimidyl-ethyl-1, 4-cyclohexylsilyl-1-proparine.

The isoradiene mixture was fractionated in a vacuum at 133 Pa. 16.5 g of product having a boiling point of 166 DEG-168 DEG C. are obtained which contains more than 90% of the desired isomer. The yield was 73.9%.

b) The procedure was as described in Example 1a except that 4.4 g (0.19 mro) of sodium metal was added to 10 g of sodium metal. After repeated distillation, 15.1 g of product are obtained, b.p. 165-167 ° C. Yield 67.6%.

Example 2

Manufacturing process mthhlesteru kyyrno N-N '-3 - (/ 5/1 - yyrc0idinydmtthl / -1,4-cyklohsxadisnyy / ° Proia y ^{y py} carbonyl] mut ^R LnodotOt okyyalin ^h · ^y / 9 g / 0.038 ml [3- ([5- (1-pyrrolidin-1-yl) methyl] -1,4-yyl-hexidioyl] -]

obtained as in Example 1 is dissolved in 10 ml of isopropanol at room temperature. 5.5 g (0.038 ml) of dithiocarbamic acid dimehyleether are added to the solution thus obtained.

The reaction starts at the temperature of mithiois, releasing the mercaptan. After half an hour, the reaction mixture is heated to boiling, boiled for 1.5 hours and evaporated under reduced pressure. The resulting honey character was dissolved in 40 ml of acetonitrile with heating.

Then. the solution was cooled and the separated crystals were filtered and washed with acetonitrile. 1.1 g of N-smear kyjanlNNз «3 / 3-31-ppjrolidinyl1№ehhj / ~ l, 4-Cjklohexadfenyj / ^l * ^j У pJfopylkarbamino ^0d lhУokyjeliny melting at 117 ^F and 119 ° C.

Evaporation of the mash liquors gave 11.5 g of the desired product. Rj is 0.45 • (ethyl acetate with pyridine: water: acetic acid · 60: 20: 11: 6) on silica gel plates (Kiesegel 60).

(b) Proceed as described in (a), except that 40 ml of di-i-piperidyl ether were used as solvents and the reaction mixture was boiled for 5 hours. In this way it is obtained

11.4 g prodxuct, which is similar to mdu. Rf 0.44. The composition of the elution mixture is the same as described in a). The product is identical to the compound obtained under a).

(c) Proceed as described in (a) except that 40 ml of chloroform is used as solvent and the reaction mixture is boiled for 4.5 hours. 11.5 g of a honey-like product are obtained. Rf is 0.45 in the elution mixture described in a). The product is identical to the compound obtained under a).

d) Proceed as described under a) except that the solvent is used. 100 ml of benzene and the reaction mixture was boiled for 10 minutes. In this way, 11.3 g of a product identical to the compound obtained in paragraph a) are obtained; Rf 0.45. (The composition of the elution mixture is the same as described in a).

e) Proceed as described under a) except that 40 ml of acetonitrile was used as solvent and the reaction mixture was boiled for 4.5 hours. In this way, 11.5 g of a product identical to that obtained in (a) are obtained. R 1 is 0.44 in the eluent described in a). The yield is practically quantitative.

i) 9 g (0.038 mb) of 3- [[5- (1-pyrrolidinylmethyl) -4,4-cyclohexyl] -1'-1-propionate was dissolved in 10 ml of dimethylformamide at room temperature. The solution thus obtained is added

5.5 g / 0.038. The reaction mixture was allowed to stand at 120 [deg.] C. for 5 hours.

The reaction mixture was then cooled / poured into 100 ml of water and extracted four times with 30 ml of chloroform each. The chloroform base is combined, dried with magnesium sulfate and filtered. The RolpPsUt11 was distilled off under reduced pressure. .

The abrasion dissolves at 35 m with heating. The solution thus obtained is cooled, the crystals are filtered off and washed; ^ β ^ ηΐ ΐ ^ ^^ .. 0.8 g metlyIbsberu * W kyaιni'N ^{3 N} 3- / 3- / liter ^i-ρyrrol diiιy lt ^{yy m} l / -l, 4-У ^to the ^L hhxaddlinyllχyy] PLP ^JL lkaraminltУil> sel k ^{y i} n ^j ', which temperature aul counting 116th to 118 ° C.

O 'Г. '

9.2 g of a honey-like Rj product are 0.46. (The composition of the meadow mission is the same as described in a). (The product is identical to the compound produced in Example 2a).

б

Example 3

1-Methyl-N ⁵ - [3 - [[5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl] oxy] propyl] -1H-1,2,4-triazole-3 ₁ 5-diamine a) 9 g (0.027 mol) of N-cyano-N * -3 - [[5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl] oxy] propylcarbamiminothioic acid methyl ester produced as described in any of Examples 2a (2f) is dissolved in 200 ml of n-butanol at room temperature.

To this solution is added 1.24 g (0.027 mol) of methylhydrazine. The reaction begins immediately and mercaptan develops. After 20 minutes, the reaction mixture is heated to boiling and kept at the same temperature for 20 hours.

Thereafter, the solvent was distilled off under reduced pressure, and the honey-like product thus obtained was poured into 20 ml of cyclohexane and 5 ml of acetonitrile and the mixture was cooled. The separated crystals were filtered off and washed with acetonitrile.

7.5 g (83.8%) of the title compound of melting point 81 DEG-84 DEG C. is obtained. The crude product was recrystallized from 60 ml of a 1: 4 mixture of ethyl acetate and cyclohexane. 6.8 g (76%) of the desired product with a melting point of 86-87 ° C are obtained.

b) The procedure is as described under a) except that di-n-propyl ether is used as the solvent. After recrystallization, 5.4 g (60.3%) of the product identical to the compound produced in a) are obtained, having a melting point of 85-87 ° C.

The procedure is as described in paragraph a, except that benzene is used as the solvent. After recrystallization, 5.1 g (57%) of the product is obtained, m.p. The compound is identical to the compound produced in a).

d) Proceed as in a) 8 except that 1.86 g (0.041 mol) of methylhydrazine is used. After recrystallization, 6.6 g (73.9%) of the product identical to the compound produced in a) are obtained, having a melting point of 85-87 ° C.

He attaches

Process for the 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) of 3- (3- (1-piperidinylmethyl) phenoxy] -1-propanamine and 200 ml are condensed in the solution thus obtained. The mixture is cooled to -75 ° C in a dry ice bath in acetone and 2.41 g (0.105 mpl) of crushed sodium metal is added in portions so that the second and each additional portion is added after complete decolorization of the solution.

After about 0.5 g of sodium was added, the blue color of the reaction mixture remained for 2.5 to 3 hours. After the final decolorization, the mixture was refluxed for 30 minutes and 6.89 g (0.13 mol) of ammonium chloride was added. When the ammonia is 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 time.

The ether solutions were combined and the solvent was evaporated under reduced pressure, and the resulting oily product was subjected to fractional distillation under reduced pressure. 4.85 g of products having a boiling point of 130 to 135 ° C / 40 Pa are obtained, which is a mixture of the intended compound ^and 3 - [(3- (1-piperidinylmethyl) -1,4-cyclohexadienyl) oxy] -1-propanamine. 4: 1 ratio.

The isomer mixture is subjected to repeated fractional distillation at 40 Pa. The fraction boiling at 133-135 ° C contained more than 90% of the desired compound. Yield 78.0%.

Example 5

Preparation of methyl N-cyano-NN3 ~ [/ 5- / i-piperidinylmthyy / "L4" ^of YKL hexdd.enyl ^c / oxyjpropylkarbamidothiokyselíny

3.0 g (0.012 mol) of pure 3 - [[5- (1-piperidinoyl) -tyl] -1,4-acycloytxa-1-yl] oxya-1-propanamine prepared according to Example 4 was dissolved in 30 ml of Oiethyl ether and 1.75 g (0.012) was added. Mo in N-cyano-amino-thiocarbamic acid dimethyl ester, releasing carcaptan.

The reaction mixture was boiled for 2 hours and evaporated. The resulting white solid was suspended in a small ether mesh and filtered. This gives 3.9 g (93.3%) of the title compound, m.p. 90-95 ° C. The compound melts after recrystallization from isopropanol at 95-97 ° C.

Example

Method of productions ^by 1-meth l- ^{yl N 5} / 3- [55- / 1-Pipe-htiy ^{Leet, and} y ^/ / -l _/ 4 ^{and e} cy ^l lo eaddiyny ^{/ l} oxy] prc ^ y ¹ / 1H- 1,2,4 &apos; tri-III-3,5 ^and Ormiya

1.74 ^g / 0.005 mo / Nk mehytesteru aaУ ^{to about} 3 N ^{NN -3} / 5 / lp patid ^{d and e} nýllУ ^HH / · ^- l, ^{4 h} exa ^di -caklo ^and the L / ^{lx] D} rl ^aa l ^to arbayidolhiok ^to Aelia ^a ccording varotenéto ^p ^ ^ 5 we Ikla margin ^ i in ⁵ mL of butanol and the solution we added 0.62 grams / 0.054 noo /

The reaction starts suddenly and releases the capsule. After. The reaction mixture is brought to reflux for 20 minutes and maintained at this temperature for 20 minutes. The mixture was then cooled, the solvent was distilled off under reduced pressure, and the residue was treated with a mixture of cyclohexane and ethyl acetate (4: 1) and the solution was cooled.

Separated. crystals st filter off. 1.5 g (86.2%) of the desired product are obtained at a temperature. mp 100-103 ° C. After recrystallization from the mixture. The product melts at 105-106 ° C in a ratio of 4 sec.

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of diadroaryl-alkylamino-1,2,4-triazole derivatives of the general formula I wherein Rg and R2 together with the adjacent nitrogen atom form pymlidinyl or piperidine ^{and a} radical group, R3 represents alkyl ^ ou group having 1 to 4 carbon atoms, and pharmaceutically přijatenných salts thereof, ^and St. znyřuUící that we reduce aryloxaalkalayin of formula II wherein R 3 and R vk defined as above, 1.1 to 4.5 molar equivalents, preferably 2.5 molar equivalents of sodium metal in liquid ammonia at a temperature between -85 and -33 ° C, the thus obtained dihydroaryloxyalkylimine of formula III (III) wherein R ₂ is as defined above, is reacted with the dimethyl N-cyymoimide, n (hithiocarbamic acid) dimethyl in a protic or aprotic solvent, preferably in isopropanol, the isothiocartamide of the formula IV thus obtained H SCH3 (IV) where R 1 and R ₂ vk defined as above, is reacted with 1.0 to 1.5 equivalents mlárními substituted hydrazine of the general formula V R3 - NH - NH3 (V) wherein R3 is as defined above,. in a protic or aprotic organic solvent, preferably n-butanol, and optionally the thus obtained dihydrooryloxyallimino-1,24,4 triazole of formula I is converted into a pharmaceutically acceptable salt.