HU185790B - Process for the preparation of new triazole derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel heterocyclic compounds, in particular to triazole derivatives of formula I wherein R 1 is hydrogen or C 1 -C 4 alkyl, R 2 is C 1-8 alkyl or benzyl, or R 1 and R 2 taken together. the nitrogen atom to which they are attached forms a 5-8 membered heterocyclic ring containing a saturated and optionally substituted hydroxy group with 1 N atom, Alk is a C 1-4 alkylene group, Q is a furan or thiophene-2,5-diyl group, and the furan ring is optionally substituted on the carbon atom adjacent to the bonding site of R1R2NAlk, and R6 is alkyl having 1 to 4 carbon atoms, or Q is a benzene ring attached at the 1- and 3- or 1- and 4-positions. , X is —CH2—, O or S, n is 0 if X = 0 and 1 is X = —CH2— or S, m 2, 3 or 4, R 3 is hydrogen or C 1-4 alkyl, and R 4 is benzyl, hydroxy (C 1 -C 4 -alkyl, C 1-6 -alkanoyloxy) or (C1-C4) alkoxy (C1-4alkyl, hydroxyl, or NR7R8, and R7 is hydrogen and R8-C09) wherein Rg is hydrogen having from 1 to 4 carbon atoms alkyl, C1 -C4 alkoxy, furyl, pyridyl, or optionally substituted C1-4 alkoxy, or -CONHR, wherein Rn is phenyl, with the proviso that that when X is O and n is 0, then Q is a benzene ring, and a pharmaceutically acceptable salt and hydrate thereof. These compounds can be prepared by methods commonly used in organic chemistry and act on histamine receptors, for example, in the treatment of gastric and peptic ulcers. * 3rd ‘N-N AA R1R2N-Alk-Q- (CH2) nX (CH2) mNH R4 (I) -1-

Description

The present invention relates to novel heterocyclic compounds, more particularly to triazole derivatives of formula I: wherein:

R 1 is hydrogen or C 1-4 alkyl,

R ₂ is C 1 -C 8 alkyl or benzyl, or

R 1 and R _{2 taken} together with the nitrogen atom to which they are attached form a 5-8 membered, saturated and optionally substituted 1 N atom heterocyclic ring,

Alk is an alkylene group containing from 1 to 4 carbon atoms,

Q represents a furan or thiophene-2,5-diyl, and the furan ring optionally R ₁ R ₂ NAlk-group adjacent to the place of attachment is a carbon atom substituted with R _ö substituents, and R ₆ represents an alkyl group containing 1-4 carbon atoms, or and Q is 1- and 3- or 1- and a

4-linked benzene ring,

X is -CH ₂ -, O or S, n is 0 if X = 0 and 1 if X = -CH ₂ - or S, m is 2, 3 or 4,

R ₃ is hydrogen or C 1-4 alkyl, and

R ₄ is benzyl, hydroxy (C 1-4) alkyl, (C 1-6) alkanoyloxy (C 1-4) alkyl, or (C 1-4) alkoxy (1-4). C ₇ alkyl, hydroxy, or -NR ₇ R ₈ , wherein R _{7 is} hydrogen and R _{8 is} -CO ₉ - wherein R _g is hydrogen, C 1-4 alkyl,

C1 -C4 alkoxy, furyl, pyridyl, or phenyl optionally substituted with C1 -C4 alkoxy, or -CONHR, wherein R _n is phenyl, provided that when X is O and n is 0, Q is a benzene ring - and pharmaceutically acceptable salts and hydrates thereof. These compounds are prepared by methods conventionally used in organic chemistry and act on histamine receptors, for example, in the treatment of gastric and peptic ulcers.

* 3rd

'N-N

AA

R ₁ R ₂ N-Alk-Q- (CH 2) _n X (CH ₂ ) _m NH R ₄ (I)

185,790

The present invention relates to a novel heterocyclic process. derivatives which act on histamine receptors in novel compounds.

It has been discovered that the new formula I tri- azoles _g - wherein R is hydrogen or C1-4 alkyl,

R ₂ is C 1 -C 8 alkyl or benzyl, or

R 1 and R _{2 taken} together with the nitrogen to which they are attached form a 5-8 membered, saturated and optionally substituted 1 N atom heterocyclic ring, "

Alk is an alkylene group containing from 1 to 4 carbon atoms,

Q represents a furan or thiophene-2,5-diyl, and the furan ring optionally _2Q adjacent carbon atoms are replaced by ^guide connection location R _t R ₂ NAlk group R ₆ substituents, and R _e represents C 1-4 alkyl or Q is 1- and 3- or 1- and a

4-linked benzene ring,

X is -CH ₂ -, O or S, n is 0 ^{to 25} when X = 0 to 1 where X = -CH ₂ - or S, m is 2, 3 or 4;

R ₃ represents a hydrogen atom or an alkyl group having 1-4 carbon atoms, and ³⁰

R ₄ is benzyl, hydroxy (C 1-4) alkyl, (C 1-6) alkanoyloxy (C 1-4) alkyl, or (C 1-4) alkoxy (1-4). to 4 carbons) sub ³⁵ alkyl, hydroxy, or-NR7R8, and the latter 7 is hydrogen and R -CORg group of the formula: - wherein R9 is hydrogen or contains 1 to 4 carbon atoms θ ⁴ alkyl, 1- Phenyl substituted with C4-alkoxy, furyl, pyridyl, or optionally C 1-4 -alkoxy, or -CONHRn wherein R _n 45 is phenyl, with the proviso that when X is oxygen and n is 0, then Q represents a benzene ring and their pharmaceutically acceptable salts, hydrates and bioprecursors are highly potent histamine 50 H ₂ antagonists, i.e., inhibit gastric acid secretion, provided that this secretion is stimulated by histamine receptors. This effect of these compounds was investigated by the method described in German Patent Publication No. 2 734 070 55 to the perfused stomach of rats, except that 50 mg / kg body weight of sodium-5-ethyl- (IU) was used instead of urethane as anesthetic. -methylbutyl) -barbiturate is used. In these 60 tests, the ED _S0 values obtained with some compounds of the invention are as follows:

Serial number of the working example ED _S0 (mg / kg) 23 0.06 2 0.05 4 0.05 24 (a) 0.07 6 (a) 0.15 II (c) 0.07 7 0.06 10 0.03 13 0.23 14 0.08

- The said compounds also antagonize the effect of histamine in isolated guinea pig right szívpitvara contraction frequency, while not affecting the isolated guinea gyomorbéltraktusbeli smooth muscle contractions induced by histamine, which are initiated by H _r histamine receptors. A further advantage of some of the compounds of the invention is the persistence of the effect.

Histamine H ₂ -blocking compounds may be used, for example, in the treatment of cases in which the reduction of gastric acidity is beneficial. Such cases include gastric and peptic ulcers.

The compounds of formula I form pharmaceutically acceptable salts with inorganic and organic acids. Particularly preferred salts are the hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, fumarates, tartrates and benzoates. The compounds of the formula I and their salts may also form hydrates, which are, of course, within the scope of the invention. Compounds of Formula I may also exhibit tautomerism. Therefore, Formula I is to be understood to include each tautomer. Where optical isomerism is possible, the general formula covers all diastereoisomers and optical enantiomers.

The compounds of formula I, preferably in the form of their salts, may be converted into conventional pharmaceutical compositions for administration by any conventional route. These pharmaceutical compositions contain at least one of the compounds of the present invention, as well as excipients and / or excipients commonly used in human and veterinary medicine. They are prepared by methods well known in the pharmaceutical art. The pharmaceutical compositions may optionally contain other active ingredients, such as histamine H 1 antagonists.

Thus, the compounds of the invention may be formulated into pharmaceutical compositions for oral, buccal, topical, parenteral or rectal administration. For oral administration, tablets, capsules, and syrups are preferred.

For intramuscular administration, the daily dose of the compounds of the present invention may vary from about 5 mg to about 1 g by the administration of 1 to 4 times a day, depending on the condition of the patient being treated.

185,790

Turning now to the preferred meanings of the substituents of formula I, it is first noted that the sum of m and n is preferably 3 or 4.

Preferably Q represents a benzene ring attached at the 1- and 3-positions and X represents an oxygen atom, n represents 0 and m represents 3 or 4. When Q represents an optionally substituted furan or thiophene ring, preferably n represents 1, X represents sulfur and m represents 2. .

R 1 and R _{2 are} preferably C 1-3 alkyl, such as methyl, or together with the nitrogen atom to which they are attached form pyrrolidyl, optionally substituted at the 4-position by hydroxy, piperidyl, hexamethylenimino or heptamethylimino. Of the heterocyclic groups, the most preferred is the piperidyl group.

Preferably R _{3 is} alkyl, such as methyl.

Preferably R ₄ is hydroxy (C 1 -C 4) alkyl (e.g., hydroxymethyl), benzyl, hydroxy, (C 1 -C 4) alkoxymethyl, or -NHCOR, wherein R _{9 is} is hydrogen or (1-4C) alkyl (e.g., methyl), phenyl or (1-4C) alkoxy (e.g., ethoxy), or -NHCONHR3j, wherein R _{n is} phenyl. Most preferably, R _{4 is} hydroxymethyl, formylamino or acetylamino.

Alk is preferably methyl.

A preferred narrower class of compounds of Formula I is that of Formula II

R and R ₂ represents methyl group or together a pyrrolidino, piperidino or hexametiléniminocsoportot form with the nitrogen to which they are attached, m is 3 or 4,

R _{3 is} hydrogen or methyl, and

R ₄ is hydroxyalkyl, alkoxyalkyl, benzyl, (C 1 -C 6) alkanoylamino, alkoxycarbonylamino, hydroxyl or phenylcarbamoylamino, and in these groups the alkyl groups are 1-4. carbon atoms. A particularly preferred compound is (1) 3- (hydroxymethyl) -1-methyl-5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1H-1,2,4 -triazole, (2) 3- (hydroxymethyl) -1-methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] propylamino} -1,5-1,2,4 -triazole, (3) N - {{1-methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] -propylamino} -1H-1,2,4-tria (ol-3-yl}} -formamide, and (4) 3- (methoxymethyl) -1-methyl-5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino } -1 Η -1,2,4-triazole and pharmaceutically acceptable salts thereof.

It will be appreciated by those skilled in the art that in carrying out the following processes for the preparation of the compounds of Formula I, it will be necessary to protect various reactive substituents in the starting materials and to deprotect these reactions in certain reaction steps. Such protection and deprotection is particularly relevant for intermediates used in the preparation of compounds of formula I wherein R, H and / or R _{4 is} hydroxyalkyl. Well known methods of protecting and deprotecting can be used; for example, phthalimide (for primary amides), benzyl, benzyloxycarbonyl or trichloroethoxycarbonyl. The phthalimido group can then be cleaved by treatment with a hydrazine (e.g., hydrazine hydrate) or a primary amine (e.g., methylamine). The benzyl or benzyloxycarbonyl protecting group may be cleaved by hydrogenolysis in the presence of a catalyst such as palladium, while the trichloroethoxycarbonyl protecting group may be removed by treatment with zinc powder.

In the following description of methods for the preparation of compounds of formula I or intermediates used in their preparation, R ₁ -R ₄ , R ₆ -R ₉ and R 11, Alk, Q, X, Y, n and m have the meanings given in formula I, unless otherwise stated not signaled.

a) Compounds of formula I wherein R ₄ is -NR ₇ R ₈ can be prepared by reacting an amino triazole derivative of formula III wherein R _{1 is} R ₂ , R ₃ , R ₇ , alk, Q, X, η and m are the same as in the formula I, the hydrogen atom of the group -NHR _{7 is} replaced by acylation with R ₈ .

For example, a compound of formula III may be reacted with a reactive derivative of a carboxylic acid of formula R ₉ COOH or an isocyanate compound of formula R ₉ NCO. R _{8 to} form compounds of formula I having the formula -COR ₉ or -CONHR _n .

Reactive derivatives of said carboxylic acids include acid halides (e.g., acid chlorides), alkyl formic acid chlorides, acid anhydrides, mixed acid anhydrides (e.g., mixed anhydrides of acetic acid and formic acid), esters [e.g., alkyl esters, ortho esters, derivatives of condensing agents (e.g., carbonyldiimidazole) or carbodiimides (e.g., dicyclohexylcarbodiimide).

The reaction with an acid halide is preferably carried out in the presence of a base such as an inorganic base (e.g. sodium hydroxide) or an organic base (e.g. triethylamine or pyridine). The reaction with an alkyl chloroformate is preferably carried out in the presence of a base such as potassium carbonate or triethylamine in a solvent such as dimethylformamide. The reaction with an acid anhydride may optionally be carried out in the presence of a solvent such as pyridine.

In carrying out the formylation, an aminotriazole derivative of the Formula III is heated in dimethylformamide in the presence of a base such as sodium hydride.

Reaction with isocyanate compounds at elevated temperatures, e.g.

At a boiling point of 185,790, the reaction mixture is worked up in a solvent such as acetonitrile.

b) Compounds of Formula I having a substituent other than R ₄ is an alkanoyloxyalkyl group may be prepared from a compound of Formula IV wherein V 'is XVIII, Y' is hydrogen [V is oxygen or sulfur and R ' ₄ is the same R ₄ or C 1 -C 4 alkoxy or acyloxy (C 1 -C 4 alkyl)] or V 'is an imino group and Y' is a group of formula XIX in which Y is sulfur or oxygen, R ' ₄ meaning through the cyclization of the above.

For example, compounds of Formula I other than R ₄ which are alkanoyloxyalkyl may be prepared by thermal cyclization of a compound of Formula VI wherein V is S or more preferably O and Z is two H, optionally in the presence of a solvent such as acetone or water.

Compounds of formula VI having two hydrogen atoms in Z are preferably prepared in situ from compounds of formula VI having a divalent protecting group such as benzylidene which is readily removable in Z, treated with an acid such as hydrochloric acid, preferably at elevated temperature. Under these conditions, not only the protecting group is cleaved, but also the cyclization to the compound of formula I occurs.

A compound of Formula VI may be prepared by reacting a diamine of Formula VII with a compound of Formula VIII, wherein all substituents are as defined above and L is a leaving group, preferably an alkylthio group such as methylthio, optionally in a solvent, for example in acetone or acetonitrile at room temperature to 70 ° C. Removal of the protecting group, if necessary, affords the desired compound of formula VI.

The compound of formula VIII can be prepared a compound of formula IX, for example by an R _'4 COC1 acylation with an acid chloride of formula VII. Alternatively, compounds of formula IX may be prepared by treating a compound of formula XX with a suitable hydrazine of formula XXI.

In the preparation of compounds of Formula I wherein R ₄ is hydroxyalkyl, it is preferred that the hydroxy group is present in the intermediates of Formulas VI and VIII as protected forms, such as an acyloxy group (e.g., alkanoyloxy group or aroyloxy group). The protecting group is usually cleaved during ring closure.

In another embodiment of the ring closure of compounds of formula I wherein R ₄ is other than alkanoyloxyalkyl, the compound of formula X can be cyclized by reacting V with Y and sulfur or oxygen.

The reaction is preferably carried out by heating the compound of formula X in a suitable solvent such as acetonitrile or dimethylformamide.

In general, intermediates of formula X may be prepared in a manner analogous to that described in British Patent Publication No. 2,023,133A.

NH and Y is oxygen a, V is In a particularly preferred embodiment compound of formula X can be prepared in situ in an XI aminoguanidine and by an _R4 C00H carboxylic acid or the latter one of the reactive derivative of the aforementioned reaction formula formula.

The acid and the aminoguanidine of formula XI may be co-heated to effect not only formation of the compound of formula X but also its conversion directly to one of the corresponding compounds of formula I. When a reactive derivative of the acid is used, an aprotic solvent such as tetrahydrofuran may be used and the reaction temperature may be between room temperature and the reflux temperature of the reaction mixture. When an acid chloride is used as the reactive derivative, the reaction is carried out in the presence of a base such as potassium hydroxide.

c) Compounds of formula I may be prepared by reduction of a compound of formula XII wherein at least one of D ^a , D ^b and D ^c represents a reducing group and the other represents a suitable substituent of formula I.

Thus, D ^a may be a group of the formula R, R 2NAlk - or a reducible group of the formula R, R 2 NHCO (CH 2) p - wherein p is 0, 1, 2 or 3 D ^{b -} CH 2 NH - or a reducible - CONH or Denotes -CH = N- and D ^c denotes R ₄ or a hydroxyalkyl group which can be reduced to - (CH ₂ ) _{q -} , CHO aldehyde or - (CH ₂ ) _{q -} , CO ₂ R ₁₂ ester group - where q is 1, 2, 3 or 4, the alkylene chain of the formula (CH ₂ ) _{q -} can be straight or branched and R ₁₂ is alkyl.

A variety of reducing agents can be used to carry out the reduction steps described above.

Thus, amides, imides, imines, esters, aldehydes, ketones and nitriles can be readily reduced as reducing agents using, for example, lithium aluminum hydride or aluminum hydride in a solvent such as tetrahydrofuran, dioxane or diethyl ether. The imines, aldehydes and ketones may be reduced with alkali or alkaline earth metal borohydrides such as sodium borohydride or hydrogen in the presence of a suitable metal catalyst such as platinum, palladium or Raney nickel in a suitable solvent such as methanol or methanol. ethanol. Imines can be reduced using formic acid;

185,790

In the case of reductive alkylation of an amine with aldehyde or ketone, the reaction is conveniently carried out without isolation of the intermediate, and the intermediate is reduced, for example, with sodium borohydride or hydrogen in the presence of a suitable catalyst.

so instead of R ₄

Compounds of formula I having a substituent other than NR ₇ R _e or an alkanoyloxyalkyl group can be reductively prepared to form an amide of formula XII

a) D ⁴ is R ₁ R ₂ NCO (CH ₂ ) _p -; a group of the general formula

D ^b is -CH ₂ NH-, and

D ^c represents R ₄ , or

b) D ⁴ is R, R _{2 is an} alkyl;

D ^{b represents a} CONH group, and

D ^c is as defined for R ₄ , the substituents being as defined above by treatment with a suitable reducing agent such as lithium aluminum hydride or aluminum hydride in a solvent such as tetrahydrofuran, dioxane or diethyl ether.

The I compound for the formula of R ₄ is hydroxy or alkyl may be prepared from a compound XII, wherein D ^c - (CH 2) q_, CO2R12 group, D ^represents RJR ^ NAlk- - (CH2) q_, CHO or and D ^{c is} -CH 2 NH. For example, a compound of Formula XII wherein D ^c is - (CH 2) q -, CO 2 R 12 can be reduced, for example, with lithium aluminum hydride to a compound of Formula I wherein R 4 is - (CH 2) q -, CH 2 OH. Compounds of formula XII bearing D ^{c as} - (CH 2) _{q -} , CHO may be reduced, for example, with sodium borohydride or lithium aluminum hydride to compounds of formula I wherein R 4 is - (CH ₂ ) _{q -} , CH ₂ OH group.

In some cases, it may be desirable to reduce more than one of D ⁴ , D ^b and D ^c at the same time. For example, compounds of formula XII having D ^{c as} - (CH 2) q -, CO 2 R 12, D ^{b as} - CONH, and D ⁴ as R ₁ R 2NAlk - may be reduced, for example, to lithium aluminum hydride to give compounds of formula I - (CH ₂ ) _q OH.

The amides of formula XII having D ^{b as} -CONH or -CH = N, D ⁴ with R ² R 2NAlk and D ^{c as} R ^{4 can} be prepared from a carboxylic acid or aldehyde of formula XIII wherein G is -CO 2 H or By reacting a reactive derivative of a -CHO group with an aminothiazole derivative of the Formula XIV wherein U is an amino group and R ⁴ is as defined in Formula I, in a manner analogous to that described in British Patent Application 2,023,133A. .

Carboxylic acids and aldehydes of formula XIII may be prepared from a suitable compound of formula XV wherein X is other than methyl. For example, a compound of formula R, R ₂ NAlkQOH may be reacted with a haloalkyl nitrile of formula Hal (CH ₂ ) _m , CN in a solvent such as dimethylformamide in the presence of four bases, for example sodium hydride, with a suitable R ₁ R ₂ NAlkQO _{(CH2) m} _, to give a compound of formula CN. Subsequent reduction, for example in the presence of Raney nickel, with hydrogen affords the corresponding aldehyde which is readily isolated in the form of its semicarbazone. The desired aldehyde XIII can then be prepared by treatment with hydrochloric acid and aqueous formaldehyde solution.

Alternatively RJR ₂ NAlkQOH a compound of formula Hal _{(CH2) m} _, the reaction of CO ₂ Alk halogénalkánkarbonsav alkyl ester of formula RIR ₂ NAlkQO _{(CH2) m} _, -CO ₂ Alk of formula to the ester, which is then for example, potassium hydroxide in aqueous ethanol can be hydrolyzed to the corresponding carboxylic acid of formula XIII.

Triazole derivatives of Formula XIV may be prepared by conventional methods, such as those described by Kurzer, F and Godfrey, LEA, in Angew, Chem. International Edition, 2, 459-475 (1963) or Potts, KT, Chem. 87 (1961).

XII chemical actions of the formula A ⁴ is RiR2NCO (CH2) p-, ^b where D is -CH 2 NH- and D ^c in which R is _{4-substituent} can be prepared from a XVI amine of formula - wherein W is R R ₂ NCO (CH _{2) p} - a group analogous to the methods previously described for the preparation of the corresponding compounds of formula I.

d) Compounds of formula I may be prepared by reacting a compound of formula XVII wherein E is - (CH ₂ ) _n X (CH ₂ ) _m P and P is a leaving group with a triazole compound of formula XIV. .

U is amino; R ₃ and R _{4 are} as defined for formula (I).

For example, Compounds of Formula I may be prepared at the point where E is - (CH ₂ ) _n X (CH ₂ ) _m P, such as a halogen atom (e.g. chlorine or bromine) or a sulfonyloxy group (e.g. mesyloxy or tosyloxy). of formula XIV and a compound of formula XIV wherein U is amino, in a suitable solvent such as dimethylformamide or acetonitrile.

e) Compounds of formula I wherein R ₄ is a secondary or tertiary hydroxyalkyl group can be prepared from the corresponding compounds of R ₄ where - (CH ₂ ) _q -, CHO or - (CH ₃ -, CO ₂ R ₁₂ ) - by an organometallic compound, Thus, with a Grignard reagent (e.g., alkyl having 1 to 3 carbon atoms in its alkyl moiety)

185,790 magnesium halide) or an organic lithium compound (e.g. an alkyl lithium) in a suitable solvent such as diethyl ether or tetrahydrofuran.

Containing compounds used as intermediates in the preparation of the compounds of formula I and R ₄ is converted into R ₄ substituted groups include aldehydes, ketones and esters. Such intermediates may be prepared in an analogous manner to those previously described for the preparation of compounds of formula I.

f) a compound of formula XXII may be prepared by any of the compounds of Formula I wherein L "RJR ₂ N- group of the formula L ^h and - (CH 2) a halogen or a group of formula I? halogen and I? R4 represents a substituent by reaction with a compound which is capable of replacing L 'with R ₁ R ₂ N - or converting L ^b to R ₄ where R _{4 is} alkoxyalkyl. Halogen atoms may be, for example, chlorine or bromine;

The halogen at L ^{a can} be substituted by treatment with an amine of formula R, R2NH to give a compound of formula I. The halogen in L ^{b can be} replaced by reacting a compound of formula XXII with an anion of a suitable alcohol, such as a suitable alcoholate, to give a compound of formula I wherein R 4 is alkoxyalkyl.

The substitution of the halide ions with the amine may optionally be carried out in a solvent such as acetonitrile. Substitution with an anion of a suitable alcohol may be accomplished by treatment with a suitable alkali metal derivative (e.g., sodium methylate) in a suitable solvent, such as dimethylformamide, or by treatment with an appropriate alcohol, the anion.

If desired, one of the substituents at R ₄ can be converted to another substituent within the meaning of formula I in a known manner.

For example, a compound of formula I having an IG-hydroxyalkyl group may be converted to a suitable R ₄ -alkoxyalkyl group, e.g., an alkyl halide in a suitable solvent (e.g., dimethylformamide) in the presence of a base (e.g., sodium hydride). response.

Compounds of formula I wherein R ₄ is alkanoyloxyalkyl may be prepared from the corresponding hydroxyalkyl derivatives by treatment of the latter with a suitable acid such as acetic acid or benzoic acid at elevated temperatures, for example 80-120 ° C, optionally in a suitable solvent. such as toluene.

However, compounds of formula I wherein R ₄ is hydroxyalkyl can be prepared by removal of a suitable hydroxy protecting group. Such suitable hydroxy protecting groups include ester bond-linked groups such as those derived from alkane carboxylic acids (e.g., hydrochloric acid or acetic acid).

Protective groups are conventionally disclosed, e.g., in "Protective Groups in Organic Chemistry", edited by McOmie, J. F. W. in 1973. can be removed using the methods described in this book. For example, ester bond protecting groups may be cleaved by acidic or basic hydrolysis.

Amino-triazole derivatives of formula III, amino-guanidine derivatives of formula XI, and compounds of formula XVII wherein E is - (CH ₂ ) _n X (CH ₂ ) _m P are disclosed in U.S. Patent No. 2,023,133 A. can be prepared as described in British Patent Application.

If the final product of formula I obtained by any of the methods described above is a free base and salt formation is desired, then salt formation may be carried out in the usual manner. For example, a generally preferred method of salt formation is by mixing suitable amounts of the appropriate free base and acid in a suitable solvent or solvent mixture. Alcohols such as ethanol and esters such as ethyl acetate may be used as the solvent.

The present invention is further illustrated by the following reference examples and embodiments. The following solvent mixtures were used for the thin-layer chromatography (hereinafter referred to as TLC) described in the Examples and carried out on silica:

Mixture A: 79: 1 by volume mixture of methanol and aqueous ammonium hydroxide solution (0.88 g / cm ³⁾ : mixture B: ethyl acetate, water, isopropanol and aqueous ammonia (0.88 g / cm ³⁾ . 25: 8: 15: 2 hydroxide solution: mixture C: ethyl acetate, ethanol and 20: 3: 2 aqueous ammonium hydroxide solution with a specific gravity of 0.88 g / cm ³

The preparative chromatography mentioned in the Examples is carried out on silica, using methanol as the eluent, unless otherwise indicated.

Reference Example 1

Preparation of 4- [3- (1-piperidinylmethyl) phenoxy] butane

a) 4- [3- (1-Piperidinylmethyl) phenoxy] butyl nitrile

At room temperature, a mixture of 1.5 g of sodium hydride and 11.2 g of 3- (1-piperidinylmethyl) phenol in 60 ml of dimethylformamide was stirred for 5 hours, then 9.0 g of 4-bromobutylnitrile was added and the mixture was stirred. Continue for 24 hours. The reaction mixture was poured onto ice and extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution, and subjected to vacuum distillation. 14.78 g of the title compound are thus obtained in the form of a hot colorless oil (0.08 mmHg, 200 ° C). TLC ( "A" mixture): _Rf = 0.8.

-6185,790.

b) 4- (3- (1-Piperidinylmethyl) phenoxy] butanal semicarbazone

A solution of 51.6 g of 4- [3- (1-piperidinylmethyl) phenoxy] butylnitrile, 73.8 g of sodium acetate and 77.6 g of semicarbazide hydrochloride in 1 liter of 50% aqueous ethanol is treated with 50 g of Raney. hydrogenation in the presence of nickel. After completion of the reaction, the catalyst was filtered off and the filtrate was partially concentrated, basified with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated and the resulting oil was purified by column chromatography to give 48.6 g of the title compound as a pale yellow oil. TLC (mixture "B"): _Rf = 0.8.

c) 4- (3- (1-piperidinylmethyl) phenoxy) butanal

At room temperature, a mixture of 9.43 g of 4- (3- (1-piperidinylmethyl) phenoxy) butanal semicarbazone and 80 ml of a 37% solution of formaldehyde in 80 ml of 2N hydrochloric acid was stirred for 2.5 hours and then diluted with water. The resulting aqueous solution was made basic with sodium carbonate and extracted with diethyl ether, and the organic extract was washed with brine and then vacuum distilled to give 5.59 g of the title compound of this step, 0.06 mmHg. pressure of 200 ° C as hot as a colorless oil: TLC (MeOH). _Rf = 0.7.

Similarly, from 12.08 g of 3-dimethylaminomethylphenol, 1.05 g of 4- (3-dimethylaminomethyl-phenoxy) -butanal is obtained in the form of a colorless oil which boils at 150 ° C at 0.06 mm Hg. TCL ( "A" mixture): _Rf = 0.59.

Reference Example 2

Preparation of 4- [3- (1-Piperidinylmethyl) phenoxy] butanoic acid

a) Ethyl 4- (3- (1-Piperidinylmethyl) phenoxy] butanoic acid

25'C-on 11.2 g of 3- (1-piperidinylmethyl) phenol,

A mixture of 1.5 g of sodium hydride and 1.7 g of 4-bromobutyric acid ethyl ester was stirred for 20 hours, then poured onto 300 g of ice and the ice mixture was extracted three times with 100 ml of ethyl acetate each. The combined extracts were subjected to vacuum distillation to obtain 16.9 g of the title compound, b.p. 250 DEG C. under 0.1 mm Hg. TCL (mixture "B"): _Rf = 0.9.

4- (3- (1-Piperidinylmethyl) phenoxy] butanoic acid

A solution of 6.1 g of 4- (3- (1-piperidinylmethyl) phenoxy) butanoic acid in ethyl acetate and 6.0 g of potassium hydroxide in a mixture of 50 ml of ethanol and 50 ml of water was refluxed for 0.5 hour. After cooling, the mixture was neutralized to pH 7 with 5N hydrochloric acid, then the aqueous solution was evaporated to dryness under reduced pressure, and the residue was dissolved in ethanol (100 mL), filtered, and the filtrate was evaporated, crystallized from methanol / diethyl ether. 4.91 g of the crude and, the title compound as a 73.5 ° C melting white crystalline solid: TLC (mixture "B"). R _f = 0.3.

Reference Example 3

5-Amino-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester

While stirring, a suspension of 9.1 g of 5-amino-1-methyl-1H-1,2,4-triazole-3-carboxylic acid in 100 ml of methanol was saturated with dry hydrogen chloride gas and refluxed for 4.5 hours. After cooling, the resulting solution was partially evaporated, diluted with 100 mL of water and adjusted to pH 7 with potassium carbonate. The solution was filtered and the filtrate was partially evaporated to give 4.6 g of the title compound as a white precipitate, m.p. 190-191 ° C. TLC (mixture B): R _f = 0.6.

Reference Example 4

3- [3- (1-Piperidinylmethyl) -phenoxy] -propionic acid a: 3- (3- (1-Piperidinylmethyl) -phenoxy] -propylnitrile from 3- (1-piperidinylmethyl) -phenol A mixture of 100 ml of acrylonitrile and 5 ml of 40% methanolic benzyltrimethylammonium hydroxide solution was refluxed for 40 hours, then evaporated in vacuo and diluted with 300 ml of diethyl ether. The filtrate was washed with 2N sodium hydroxide solution, then water, and then subjected to vacuum distillation to give 17.5 g of the title compound as a hot colorless oil at 0.07 mmHg at 170 ° C. "mixture): _Rf 0.8.

b) 3- [3- (1-Piperidinylmethyl) phenoxy] propionic acid

A solution of 1.5 g of 3- [3- (1-piperidinylmethyl) phenoxy] propylenitrile in 115 ml of 2N sulfuric acid was heated at reflux for 72 hours and then cooled to pH 7. The resulting slurry was treated with ethanol, filtered and the filtrate evaporated to dryness. The resulting residue was extracted with hot ethanol. After cooling, diethyl ether was added to the extract to precipitate 12 g of the title compound as a white solid, m.p. 178.5-179.5 ° C. TLC (mixture "B"): _Rf = 0.4.

Reference Example 5

N- [2- (Acetyloxy) acetyl] - (1-methyl-2- (phenylmethylene) hydrazino J-carboximidomethyl thioate

(a) 1-Methyl-2- (phenylmethylene) -hydrazinecarboximidomethyl-thiothate hydroiodide

Under a water-jet vacuum, a mixture of 10 g of dimethyldithiocarbamate hydroiodide and 5.4 g of 1-methyl2- (phenylmethylene) hydrazine was heated at 60 ° C for 1 hour and then the residue was triturated with 20 ml of hot ethyl acetate, 13.3 g. yielding the title compound as a yellow precipitate, m.p. TLC (mixture A): R _f = 0.75.

b) N- [2- (Acetyloxy) acetyl] - [1-methyl-2- (phenylmethylene) hydrazino] carboximidate methyl thioate

1.34 g of 1-methyl-2- (phenylmethylene) -hydrazinecarboximidomethylthioate hydroiodide are dissolved in saturated

-7185 790 in potassium carbonate solution and then extracted several times with diethyl ether. The combined organic extracts were dried and evaporated to give an off-white precipitate. This was then dissolved in 25 mL of acetone and added to the resulting solution

1.1 g of potassium carbonate was added followed by 0.85 g of 2-acetyloxyacetyl chloride. The resulting slurry was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is suspended in 50 ml of water. Filtration of the aqueous slurry gave 1.01 g of the title compound of the title compound, m.p. 115-117 DEG C. after recrystallization from ethanol. ·

Analysis results for C ₁₄ H ₁₇ N ₃ O ₃ S:

Calculated: C, 54.7; H, 5.6; N, 13.7; Found: C, 54.7; H, 5.6; N, 13.4.

Similarly, 3.4 g of 1-methyl-2- (phenylmethylene) hydrazinecarboximidomethylthioate hydroiodide and

From 1.6 g of phenylacetyl chloride, 1.3 g of N- (phenylacetyl) - [1-methyl-2- (phenylmethylene) hydrazino] carboximidomethylthioate, m.p. TLC (ethyl acetate): _Rf = 0.75.

Other corresponding 1-alkyl derivatives can be prepared in a similar manner.

Reference Example 6

In the same manner as in Reference Example 5, 5.6 g of 20 g of 1-methyl-2- (phenylmethylene) hydrazinocarboximidomethyl thioate and 12 g of malonic acid monoethyl ester 1-chloride are obtained in a melting point of 74-75 ° C. 1-Methyl-2- (phenylmethylene) -hydrazino] -methylthiomethyleneamino-3-oxopropionic acid ethyl ester can be prepared.

NMR (CDC1 _3): 2.2 (s, 1H), 2.2-2.4 (m, 2H), 2.5-2.7 (m, 3H), 5.82 (q, 2H ), 6.49 (s, 2H), 6.52 (s, 3H), 7.6 (s, 3H) and 8.73 (t, 3H).

Reference Example 7

The following compounds were reacted as described in Example 11 below.

3.61 g of 3- [3- (1-piperidinylmethyl) phenoxy] propanamine and 4.7 g of 3 - {[1-methyl-2- (phenylmethylene) hydrazino] methylthiomethylene amino ) -3-Oxopropionic acid ethyl ester 7.3 g of 3 - {[1-methyl-2- (phenylmethylene) hydrazino] - [3- (3-piperidinomethylphenoxy) propylamino] methylene amino } -3-oxopropionic acid ethyl ester. TLC ( "A" mixture): _Rf = 0.65.

If 1.84 g of this ethyl ester is acidified, 0.5 g of 1-methyl-3- (ethoxycarbonylmethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl is obtained. -amino} -1H-1,2,4-triazole is formed. TLC (mixture A): R _f = 0.63.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.77 (t, 1H), 3-3.3 (m, 3H), 5.4 (t, 1H), 5.0 (q, 2H), 5.9 ( t, 2H), 6.3-6.6 (3s + q, 9H), 7.6 (m, 4H), 8.5 (m, 6H) and 8.2 (t, 3H).

Reference Example 8

Preparation of 5- [3- (3-Formylphenoxy) propylamino] -1-methyl-3- (hydroxymethyl) -1R-1,2,4-triazole

a) N- [2- (Acetyloxy) acetyl] -N '- {3- [3- (1,3-dioxolan-2-yl) phenoxy] propyl} - [1-methyl-2 - (phenylmethylene) hydrazino-carboximidamide

Under a vacuum set up with a water jet pump

2.9 g of 3- (3- (1,3-dioxolan-2-yl) phenoxy] propylamine and 4 g of N- [2- (acetyloxy) acetyl] - (1-methyl-2) The mixture of (phenylmethylene) hydrazino] -carboximidomethylthioate was heated at 60 ° C for 3 hours and the resulting glassy precipitate was triturated with diethyl ether to give the title compound (5.39 g, 78-80 ° C). . as a white solid, mp TLC (methanol): _Rf = 0.8.

b) 5- [3- (3-Formyl-phenoxy) -propylamino] -1-methyl-3- (hydroxymethyl) -1H, 2,4-triazole g N- [2- (acetyloxy) - acetyl] -N '- {3- [3- (1,3-dioxolan-2-yl) phenoxy] propyl} [1-methyl-2- (phenylmethylene) hydrazino] carboximidamide in 100 ml of 2N hydrochloric acid and The slurry in ethanol (25 ml) was stirred at room temperature for 16 hours and then neutralized to pH 7 with potassium carbonate. Then 1.7 g of potassium hydroxide was added to the solution, which was diluted with 50 ml of ethanol and stirred for an additional 15 minutes. The solution was adjusted to pH 7 with 2N hydrochloric acid, the solvent was partially evaporated and the remaining aqueous solution was extracted several times with ethyl acetate. The combined extracts were dried and evaporated to give 2.63 g of the title compound as a foam. TLC (2: 1 ethyl acetate: methanol) R _f = 0.5.

NMR (CDC1 _3): 0.00 (s, lH), 2.5-2.9 (m, 4H), 5.4 (t, lH), 6.4 (q, 2H), 6, Δ (s, 3H) and 7.85 (m, 2H).

Example 1 (I) 0.5 g of 4- [3- (dimethylaminomethyl) phenoxy] butanal and 0.39 g of 5-amino-3- (phenylmethyl) -1H-1,2,4- A solution of triazole in anhydrous toluene (60 mL) was refluxed for 3 hours, then the solvent was evaporated and replaced with methanol (50 mL). Sodium borohydride (0.4 g) was added and the resulting mixture was stirred at 20 ° C for 2 hours. The methanol was then evaporated and the residue partitioned between water and ethyl acetate. The organic phase is evaporated and the residue is purified by column chromatography on N- {4- (3- (dimethylaminomethyl) phenoxy] butyl} -5amino-3- (phenylmethyl) -1H-1,2,4-triazole. to give the product as an ethyl acetate and cyclohexane, 0.09 g, m.p. 131-133'C pale yellow crystals after crystallization from TLC ( "A" mixture).. _Rf = 0.6.

(II) As described in the previous paragraph, 0.33 g of 3- (phenylmethyl) -5-amino-1H-1,2,4-triazole is prepared in 0.5 g of 4- [3- (piperidinylmethyl) phenoxy]. -butanal and the resulting intermediate was reduced with 0.4 g of sodium borohydride in 0.16 g of 3- (phenylmethyl) -5-amino-81 m.p. 145-146 ° C.

185,790

N- {4- [3- (1-piperidinylmethyl) phenoxy] butyl} -1,1,2,4-triazole is obtained. TLC (mixture A): R _f = 0.6.

Example 2

Preparation of 5- {4- [3- (1-Piperidinylmethyl) phenoxy-butylamino} -3-hydroxymethyl-1H-1,2,4-triazole

a) Ethyl 5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1H-1,2,4-triazole-3-carboxylic acid

A mixture of 0.568 g of 5-amino-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 4- (3- (1-piperidinylmethyl) phenoxy] butanal in 40 ml of ethanol was heated under reflux for 2 hours and After cooling, the reaction mixture was treated with sodium borohydride (0.4 g) and stirred at room temperature for 15 hours, the solvent was evaporated and the residue was dissolved in 2N hydrochloric acid, washed with ethyl acetate, then basified with potassium carbonate several times. The combined organic extracts were evaporated to give the title compound as a white precipitate, which was recrystallized from ethyl acetate: ethanol (1: 1) to give 0.5 g (m.p. 170-171 ° C). Mixture B): R _f = 0.8.

b) 5- {4- [3- (1-Piperidinylmethyl) phenoxy] butylamino} -3- (hydroxymethyl) -1H-1,2,4-triazole

At room temperature, 0.3 g of 5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1H-1,2,4-triazole-3-carboxylic acid ethyl ester and 0.1 g of lithium aluminum hydride in 50 ml. THF is stirred for 0.5 h and quenched with water. The solid was filtered off and washed with methanol. The filtrate and washings were combined and evaporated to dryness, and the resulting residue was extracted with hot ethyl acetate. Evaporation of the extract gave an oil which solidified. Crystallization from ethyl acetate gave 0.094 g of the title compound as an off-white solid, m.p. 127-128 ° C (dec.). TLC (mixture B): R _f = 0.7.

Example 3 Preparation of 1-Methyl-5- {4- [3- (1-piperidinyl) -phenoxy] -butylamino} -3-hydroxymethyl-1H-1,2,4-triazole

a) 1-Methyl-5- {1-oxo-4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1H-1,2,4-triazole-3-carboxylic acid methyl ester

At room temperature, a solution of 4- (3- (1-piperidinylmethyl) phenoxy] butanoic acid (2.77 g), thionyl chloride (2.5 ml) and dimethylformamide (6 drops) in methylene chloride (80 ml) was stirred for 2 hours and concentrated in vacuo. The resulting precipitate was dissolved in dimethylformamide (50 mL) and 5-amino-1-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester (1.56 g) was added and the resulting mixture was stirred at room temperature for 18 hours. After standing, the mixture was concentrated in vacuo and the residue was dissolved in water, the aqueous solution was extracted several times, and the combined extracts were washed with water and concentrated in vacuo to give a precipitate which was recrystallized from ethyl acetate / cyclohexane to give 2.0 g of the title compound. . mp 108-110 ° C as a white powder: TLC ( "B" mixture): _Rf = 0.7.

b) 1-Methyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1 H -1,2,4-triazole

In a nitrogen atmosphere at room temperature

1.25 g of 1-methyl-5- {1-oxo-4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1H-1,2,4-triazole-3-carboxylic acid methyl ester and a suspension of 1.0 g of lithium aluminum hydride in 30 ml of tetrahydrofuran was stirred for 5 hours, then cooled to 0 ° C and quenched with water. The reaction mixture was then diluted with ethyl acetate, filtered and the filtrate was concentrated in vacuo. The residue is chromatographed to give an oil which is then crystallized by trituration with diethyl ether. This gave 0.33 g of the title compound as a white solid, m.p. 84-85 ° C. TLC (mixture B): R _f = 0.6.

Example 4 Preparation of 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino] -1H-1,2,4-triazole

To a suspension of 1.84 g of 3- [3- (1-piperidinylmethyl) phenoxy] propionic acid in a mixture of 50 ml of methylene chloride and 5 drops of dimethylformamide is added 2.0 ml of thionyl chloride, and the resulting solution is After 2 hours at room temperature, it is concentrated in vacuo. The oily product thus obtained was dissolved in dimethylformamide (50 ml), followed by addition of 1.09 g of methyl 5-amino-1-methyl-1H-1,2,4-triazole-3-carboxylic acid. The reaction mixture was then stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in 8% sodium bicarbonate solution and extracted several times with ethyl acetate. The combined extracts were washed with water and concentrated in vacuo to give 0.832 g of 1-methyl-3- {1-oxo-4- [3- (1-piperidinylmethyl) phenoxy] propylamino} -1H1,2,4- triazole-3-carboxylic acid methyl ester as an oil, which is then dissolved in 30 ml of tetrahydrofuran. To the solution was added 0.6 g of lithium aluminum hydride at 0 ° C, and the resulting mixture was stirred at room temperature for 6 hours, quenched with water, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the resulting oil (0.586 g) was purified by column chromatography. The resulting oil was then crystallized by trituration with diethyl ether to give the title compound (0.136 mg) as a white solid, mp 118-119 ° C. TLC (mixture "B"): _Rf = 0.7.

-9185 790

Example J (I) 1-Methyl-5- {3- [3- (N, N-dimethylaminomethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole-3-carbamic acid ethyl ester. Preparation of the tartrate salt at ₅ DEG C. in 0.6 ml ethyl chloroformate and 2.0 g of 1-methyl-N1 ^{* * * 5} - {3- [3- (N, N-dimethylaminomethyl) phenoxy] ] propyl} -lH-l, 2,4-triazole-3,5-diamine in 30 ml of anhydrous dimethylformamide was stirred at 12 for ₁₀ hours, diluted with water and extracted several times with ethyl acetate. The combined extracts were evaporated and the residual yellow oil was triturated with diethyl ether, ethyl acetate and petroleum ether (b.p. 60-80 ° C). The insoluble material is filtered off ₁₅ and the residual oil was dissolved in ethyl acetate. A saturated solution of tartaric acid in ethyl acetate is added to the resulting solution until no more precipitate has formed. 0.88 g of the title compound is obtained in the form of a white precipitate, m.p. 110-115 * 20. TLC (mixture A): R _f = 0.61.

(II) In a similar manner 5 g of I-methyl-N ⁵ - {3- (3- (1-piperidinylmethyl) phenoxy] propyl} -1 Η-1,2,4-triazol-1 3,5diaminból Of 56 g of ethyl chloroformate in ₂ g of 0.85 g of 1-methyl-5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1}-1,2, m.p. , 4-Triazole-3-carbamic acid ethyl ester tartrate.

Nuclear Magnetic Resonance Spectrum (D ₂ O): 2.51 (m, 1H), 2.7-3.1 (m, 3H), 5.42 (s, 2H), 5.5-6.0 (m, 6H), 6.3-6.7 ₃₀ (m + s, 7H), 6.8-7.3 (m, 2H), 7.6 to 8.6 (m, 8H) and 8.71 (t , 3H).

Example 6 Preparation of (II) N- {5- [3- (3-Dimethylaminomethyl-phenoxy) -propylamino] -methyl-1H-1,2,4-triazol-3-yl} -acetamide tartrate g 1-Methyl-N ^{To a solution of 5-} [3- (3-dimethylaminomethyl-phenoxy) _-4H- propyl] -1H-1,2,4-triazole-3,5-diamine (compound A) in dry pyridine was added dropwise 0.35 g of acetic anhydride and the resulting reaction mixture was stirred at 25 ° C for 12 hours.

The solvent was removed and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium carbonate solution ( ⁴⁵ ), dried and evaporated. The residual oil was purified by chromatography and treated with a saturated solution of tartaric acid in ethyl acetate to give 1.2 g of the title compound, mp 103-106 ° C. TLC ^5U ( "A" mixture): _Rf = 0.5.

The following compounds were prepared in a similar manner to that described in the preceding paragraph: «(II) 2.5 g of 1-methyl-N ⁵ - {3- (3- (1-piperidinylmethyl) phenoxy] propyl} -1 Η-1 , 2,4-triazine-3,5-diamine and

0.75 g of acetic anhydride 2.7 g of N- [5- {3- (3- (1-piperidinylmethyl) phenoxy] propylamino} -1-methyl-1 1,2,4-triazol-3-yl (gives acetamide tartrate. TLC (mixture A): R _f = 0.6. ⁶⁰ (III) 1 g of compound A and 0.8 g of benzoic anhydride 0.48 g N- {5- [3- (3-dimethylaminomethyl-phenoxy) -propylamino] -1-methyl-1H-1,2,4-triazol-3-yl} -benzamide tartrate, m.p. 126-130'C ad.

(IV) 0.96 g of 1-methyl-N ⁵ - {2 - [(5-dimethylaminomethyl-4-methyl-2-furanyl) methylthio] ethyl} -1 H -1,2,4-triazol-3,5-diamine. and 1.0 g of benzoic anhydride 0.6 g of N - {{1-methyl-5- {2 - [(5-dimethylaminomethyl-4-methyl-2-furanyl) -methylthio] -ethylamino} -1Η-1,2 , 4-Triazol-3-yl}} benzamide. TLC (mixture "C"): _Rf = 0.42. NMR (CDC1 _3): 0.90 (s, IH), 2.10 (m,

2H), 2.5 (m, 3H), 4.06 (s, 1H), 5.10 (t, 1H), 6.43 (s, 2H), 6.52 (s, 3H), 6, 68 (s + q, 4H), 7.32 (t, 2H), 7.82 (s, 6H) and 8.10 (s, 3H).

(V) 0.98 g of 1-methyl-N ⁵ - {2 - [(5-dimethylaminomethyl-2-thienyl) -methyl-thio-ethyl} -1H-1,2,4-triazole-3,5-diamine and 1.0 g benzoic anhydride 0.5 g N - ({1-methyl-5- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino) -1H-1,2,4-triazole 3-yl}) - gives benzamide. TLC (mixture "C"): _Rf = 0.46.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 1.02 (bs, 1H), 2.07 (m, 2H), 2.5 (m, 3H), 3.30 (m, 2H), 5.43 (t , 1H), 6.18 (s, 2H), 6.5 (2s + q, 7H), 7.28 (t, 2H) and 7.77 (s, 6H).

Example 7

Preparation of N - {{1-Methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] propylamino} -1,2,4-triazol-3-yl}} formamide

0.72 g of sodium hydride and 3.44 g of 1-methyl-N ⁵ - {3- [3- (1-piperidinylmethyl) phenoxy] propyl} -1 H -1,2,4-triazole-3 The mixture of 5-diamine in 50 ml of dimethylformamide was refluxed for 8 hours, then cooled, poured into 300 ml of water and extracted with diethyl ether. Evaporation of the extract gave a yellow oil which was then extracted with boiling cyclohexane (500 mL). When the cyclohexane extract cools, a brown oil precipitates. This oil was discarded while the supernatant liquid was cooled to room temperature. The title compound was then recrystallized from ethyl acetate and petroleum ether (b.p. 60-80 ° C) to give a pale yellow precipitate (0.35 g, m.p. 68-75 ° C). TLC (mixture "C"): _Rf = 0.6.

Example 8

Preparation of N - {{1-methyl-5- {2 - [(5-dimethylaminomethyl-2-furanyl) methylthio] ethylamino} -1H-1,2,4-triazol-3-yl}} formamide

With stirring, 3.83 g of 1-methyl-N ⁵ - {2 - [(5-dimethylaminomethyl-2-furanyl) methylthio] ethyl} -1 H -1,2,4-triazole-3,5-diamine A suspension of dihydrochloride and 3.04 g of potassium carbonate in 60 ml of acetone was refluxed for 30 minutes and then cooled to 5 ° C. Then 1.32 g of a mixed anhydride of acetic acid and formic acid were added to the reaction mixture, which was allowed to warm to room temperature. The inorganic material was filtered off and the filtrate was concentrated to an oil. This was then purified by chromatography and the resulting clear oil dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous sodium bicarbonate solution and concentrated to give the title compound as a colorless oil (0.47 g). TLC (mixture B): R _f = 0.61.

-101

185,790

NMR (CDC1 _3): 0.28 (br d, IH), 0.93 (d, IH), 3.81 (s, 2H), 5.25 (br t, IH), 6.28 ( s, 2H), 6.47 (s, 3H), 6.52 (s + m, 2H), 7.16 (t, 2H) and 7.74 (s, 6H).

Example 9 (I) N - {{1-Methyl-5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -. Preparation of H-1,2,4-triazol-3-yl}} furan-2-carboxamide

1.0 g of 1-methyl-N ⁵ - {3- [3- (1-piperidinylmethyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine (Compound A) ) and a solution of furan-2-carboxylic acid chloride (0.42 g) in pyridine (25 ml) was allowed to stand at room temperature for 1 hour, then the pyridine was evaporated in vacuo and the residue azeotroped with toluene. The resulting oil was partitioned between ethyl acetate and 2N hydrochloric acid, the pH of the aqueous phase was adjusted to 9 and extracted with ethyl acetate. The combined organic phases are then evaporated to give a resin which is chromatographed on silica gel, eluting with ethyl acetate / methanol 9: 1 (v / v). 0.30 g of the title compound is obtained in the form of a glassy precipitate. TLC (mixture "B"): _Rf = 0.57.

NMR (CD1 _3): 1.5 (br s, IH), 2.53 (m, IH), 2.75 (t + m, 2H), 3.0-3.3 (m, 3H) , 3.5 (dd, 1H), 5.31 (t, 1H), 5.92 (t, 2H), 6.42 (q, 2H), 6.50 (s, 3H), 6.59 ( s, 3H), 7.6 (broad s, 4H), 7.9 (m, 2H) and

8.5 (m, 6H).

(II) Similarly, from 1 g of compound A and 0.57 g of pyridine-3-carboxylic acid hydrochloride, 0.98 g of N - {{1-methyl-5- {3- [3- (1-piperidinylmethyl)] is obtained. -phenoxy] -propylamino} -1Η-1,2,4-triazol-3-yl}} pyridine-3-carboxamide. TLC (mixture B): R _f = 0.64.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.85 (d, 1H), 1.07 (bs, 1H), 1.22 (dd, 1H), 1.78 (m, 1H), 2.62 (q , 1H), 2.77 (t, 1H), 3.0-3.3 (m, 3H), 5.35 (t, 1H), δ 92 (t, 2H), 6.48 (s, 3H) ), 6.50 (m, 2H), 6.55 (s, 2H),

7.5-7.7 (m, 4H), 7.90 (m, 2H) and 8.3-8.6 (m, 6H).

(III) Similarly, 2.0 g of Compound A and 1.1 g of 4-methoxybenzoic acid chloride were treated with 2.0 g of 4-methoxy-N - ({1-methyl-) m.p. 5- {3- [3- (1-Piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazol-3-yl}) - benzamide. TLC (mixture B): R _f = 0.78. Calcd for C ^ H ₃₄ N ₂ (based on good ₃ wherein:

Calculated: C, 65.2; H, 7.1; N, 17.5; Found: C, 65.0; H, 7.0; N, 17.0.

Example 10

Preparation of 1,2-Dihydro-5- {3- [3- (1-piperidinylmethyl) phenoxy] propylamino} -3H-1,2,4-triazol-3-one

To a solution of 3- [3- (1-piperidinylmethyl) -phenoxy] -propylamine (1.76 g) in tetrahydrofuran (70 ml) at room temperature was added N-methoxycarbonylcarboximid dimethyl dithioate (1.27 g) and the resulting mixture was stirred for 6 hours. Subsequently, 2 g of hydrazine hydrate are added and the reaction mixture is refluxed for 18 hours. The solution was evaporated and the residue was purified by chromatography (250 mg) to give the title compound as a colorless oil. TLC (mixture B): R _f = 0.5.

Nuclear Magnetic Resonance Spectrum (D ₂ O): 2.5 (t, 1H), 2.8-3.0 (m, 3H), 5.72 (s, 1H), 5.8 (t, 3H), δ , 5 (m, 2H), 6.65 (t, 2H), 7.05 (broad t, 2H) and 7.7-8.6 (m, 8H).

Example 11 Preparation of 1-Methyl-3- (phenylmethyl) -N- {3- [3- (1-piperidinylmethyl) -phenoxy] -propyl} -5-amino-1H-1,2,4-triazole tartrate

a) N - {[1-Methyl-2- (phenylmethylene) -hydrazino] - [3- (3-piperidinomethyl-phenoxy) -propylamino] -methylene} -phenylacetamide

0.38 g of 3- [3- (1-piperidinylmethyl) -phenoxy] -propylamine and 0.5 g of N- (phenylacetyl) - [1-methyl-2- (phenylmethylene) under a water pump vacuum After heating the mixture at -50 ° C for 4 hours, the resulting residue was dissolved in cyclohexane (20 ml) and petroleum ether (b.p. 60-80 ° C) was added. The precipitate was filtered off and the filtrate was evaporated to give the title compound as a colorless oil (0.65 g). TLC (mixture A): R _f = 0.7.

b) 1-Methyl-3- (phenylmethyl) -N- (3- [3- (1-piperidinylmethyl) phenoxy] propyl} -5-amino-1? -1,2,4-triazole tartrate salt

PH of a solution of 0.65 g of N - {[1-methyl-2- (phenylmethylene) -hydrazino] [3- (3-piperidinomethyl-phenoxy) -propylamino] -methylene} -phenyl-acetamide in 50 ml of acetone The reaction mixture was adjusted to 1 with 2N hydrochloric acid and the resulting mixture was refluxed for 4 hours. The resulting solution was washed with ethyl acetate, basified with potassium carbonate and extracted several times with ethyl acetate. After drying, the combined extracts were evaporated and the residue was purified by column chromatography. 0.4 g of an oil is obtained, which is dissolved in 10 ml of ethyl acetate, and a solution of 125 mg of tartaric acid in 50 ml of ethyl acetate is added. 0.42 g of the title compound is obtained in the form of a white powder. TLC ( "A" mixture): _Rf = 0.65.

Free base NMR (CDC1 _3):

2.6-3.0 (m, 6H), 3.0-3.4 (m, 3H), 5.65 (t, 1H), 5.95 (t, 2H), 6.12 (s, 2H), 6.47 (q, 2H), 6.57 (broad s, 5H), 7.67 (m, 4H), 7.93 (m, 2H) and 8.3-8.6 (m, 6H).

Example 12

Preparation of 5- {2 - [(5-Dimethylaminomethyl-2-furanyl) methylthio] ethylamino} -1-methyl-3- (hydroxymethyl) -1H-1,2,4-triazole

a) 2- (Acetyloxy) -N - {[2- (5-dimethylaminomethyl-2-furanylmethylthio) -ethylamino] - [1-methyl-2- (phenylmethylene) -hydrazino] -methylene} - acetamide

At room temperature, 0.92 g of N- [2- (acetyloxy) acetyl] - [1-methyl-2- (phenylmethylene) hydrazino] carboxyl

-11 185 790 Ximian metiltioát and 0.64 g of 5- (2-aminoethyl) thiomethyl mixture of 2-dimethylaminomethyl-furan in 5 ml of acetonitrile was stirred at room temperature for 3 hours and the resulting solution was concentrated in ₅ vacuo. The oily residue was slurried in diethyl ether (20 mL) and the slurry was filtered and the crystallized precipitate was collected. 0.8 g of the title compound is obtained, m.p. 78-80 ° C. TLC ( "A" mixture): _Rf = 0.65.

b) 5- {2 - [(5-Dimethylaminomethyl-2-furanyl) -methylthio] -ethylamino} -1-methyl-3- (hydroxymethyl) -1,5-1,2,4-triazole

0.74 g of 2- (acetyloxy) -N - {[2- (5-dimethylaminomethyl- _15)]

A solution of 2-furanylmethylthio) ethylamino] - [1-methyl-2- (phenylmethylene) hydrazino] methylene) acetamide in 2N hydrochloric acid was heated at 98-100 ° C for 1 hour, followed by 5 ml. water is added after cooling.

The aqueous mixture was then washed with ethyl acetate, basified with ₂ g of sodium carbonate and evaporated to dryness in vacuo. The residue was suspended in ethyl acetate (20 mL) and anhydrous sodium carbonate and charcoal with decolorizing properties were added. The resulting suspension is refluxed for 10 minutes, then cooled, filtered and the filtrate evaporated in vacuo. The residual oil was chromatographed on silica gel, eluting with a 79: 1 by volume mixture of methanol and aqueous ammonium hydroxide (0.88 g / cm ³ ). This gives 0.35 g of the title compound as a light brown oil. TLC (mixture A): R _f = 0.6.

Nuclear Magnetic Resonance Spectrum (CDC13): 3.92 (s, 2H), 5.18 (t, 5.32) (bs), 5.49 (s, 4H), 6.33 (s, 2H), 6 51 (s),

6.61 (s + q, 7H), 7.23 (t, 2H), and 7.78 (s, 6H).

Example 13 Preparation of 1-Methyl-3- (acetoxymethyl) -5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1,2,4-triazole

100 mg of l-methib3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1,5-1,2,4-triazole was prepared in 5 ml of glacial acetic acid. was heated at ⁴⁵ reflux for 8 hours, then evaporated and the residue triturated with diethyl ether. 97 mg of the title compound are obtained as a white precipitate, m.p. 119-120 ° C. TLC (mixture "B"): _Rf = 0.8. ⁵ θ

Example 14

3- (methoxymethyl) -l-methyl-5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} - 1,2,4-triazole ⁵⁵ Preparation of

149 mg 1-methyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1 H -1,2,4-triazole 3 ml solution of thionyl chloride was stirred at room temperature θθ for 0.5 h and then concentrated.

The residue was then dissolved in methanol (5 mL) and added to a solution of sodium hydride (200 mg) in methanol (5 mL). The reaction mixture was stirred at room temperature for 18 hours, evaporated and partitioned between ethyl acetate and water. The organic phase is dried and evaporated. The resulting oil was chromatographed on silica gel, eluting with 25: 15: 8: 2 ethyl acetate / isopropanol / water / 0.88 g / cm ³ aqueous ammonium hydroxide. 108 mg of the title compound are obtained. TLC (mixture B): R _f = 0.6.

NMR (CDC1 _3): 2.8 (t, IH), 3.0-3.3 (m, 4H), 5.67 (s, 2H), 5.75 (t, IH), 6, 00 (br t, 2H), 6.3-6.6 (m, 10H), 7.6 (m, 4H) and 8.0-8.7 (m, 10H).

Example 75 1-Methyl-5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -3- (2-hydroxy-ethyl) -1H-1,2,4-triazole tartrate salt

Under nitrogen, 0.3 g of ethyl 1-methyl-5- (3- (3- (1-piperidinylmethyl) phenoxy) propylamino) -1H-1,2,4-triazole-3-acetic acid at 25 ° C. and a suspension of lithium aluminum hydride (100 mg) in tetrahydrofuran (50 ml) was stirred for 24 hours, quenched with water and extracted several times with ethyl acetate. dissolved in cyclohexane and allowed to cool to room temperature, the resulting oil was treated with a solution of D-tartaric acid in saturated ethyl acetate to give the title compound (80 mg) as a white powder: TLC (mixture A): R _f = 0.55. Free Base NMR (CDCl3): 2.8 (t, 2H), 3-3.3 (m, 3H), 5.3 (t, 1H), 5.9 (t, 2H), 6.13 (t, 2H), 6.0 (bs, 1H), 6.4 (q, 2H), 6.52 (s, 3H), 6.57 (s, 2H), 7.2 (t, 2H) ), 7.65 (m, 4H), 7.88 (m, 2H) and 8.5 (m, 6H).

Example 16 (I) Preparation of 5- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -1-methyl-3- (phenylmethyl) -1H-1,2,4-triazole

a) 2-Phenyl-N - {[2- (5-dimethylaminomethyl-2-thienylmethyl-thio) -ethylamino] - [1-methyl-2- (phenylmethylene) -hydrazino] -methylene] -acetamide Under vacuum pump

1.0 g of 5 - [(2-aminoethylthio) methyl] -N, N-dimethylthiophene-2-methylamine (Compound C) and 1.42 g of N- (phenylacetyl) - [1- A mixture of methyl 2- (phenylmethylene) hydrazino] carboximidomethyl thioate (Compound A) was heated at 60 ° C for 3 hours to give 1.9 g of the title compound as a colorless oil. TLC (mixture A): R ^f = 0.61.

b) 5- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -1-methyl-3- (phenylmethyl) -1? -1,2,4-triazole

1.9 g of 2-phenyl-N - {[2- (5-dimethylaminomethyl-2-thienylmethylthio) ethylamino] - [1-methyl- (2-phenylmethylene) hydrazino] methylene] acetamide 20 ml To a solution of toluene in 5 ml of 2N hydrochloric acid was added and the reaction mixture was heated in a water bath for 30 minutes. Subsequently, the aqueous phase was toluene

-121

185,790 minomethyl-4-methyl-2-furanyl) methylthio] ethylamino} 3- (1-hydroxymethyl) -1-methyl-1,2,4-triazole. TLC (mixture "B"): _Rf = 0.53.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 4.02 (s, 1H), 5.32-5.48 (m, 3H), 6.37 (s, 2H), 6.50-6.7 (m, 7H). ), 7.25 (t, 2H), 7.82 (s, 6H) and 8.08 (s, 3H).

washed, treated with potassium carbonate and concentrated in vacuo. The residue was dissolved in ethyl acetate, the resulting solution was filtered and the filtrate was evaporated. Purification of the resulting oil by chromatography afforded 0.47 g of the title compound as a pale orange oil. TLC ( "A" mixture): _Rf = 0.55.

Analysis results based on the formula CmHjtNsSi:

Calculated: C, 59.8; H, 6.8; N, 17.4; Found: C, 60.0; H, 6.8; N, 17.1.

The following compounds may be prepared in a similar manner from a suitable -N-acyl- [1-methyl-2- (phenylmethylene) -hydrazmo] -carboximidomethyl-thioate and a suitable diamine:

(II) By reaction of 0.5 g of compound A and 0.33 g of 5 - [(2-aminoethylthio) methyl] -N, N-dimethylfuran-2-methylamine, 0.21 g of 5- { 2 - [(5-Dimethylaminomethyl-2-furanyl) -methyl-thio] -ethylamino} -1-methyl-3- (phenylmethyl) -1H-1,2,4-triazole is obtained by TLC ("A" mixture): _Rf = 0.61.

NMR (CDC1 _3): 2.6-2.8 (m, 5H), 3.95 (s, 2H), 5.60 (t, IH), 6.12 (s, 2H), 6, 32 (s, 2H), 6.55-6.63 (m, 7H), 7.25 (t, 2H) and 7.79 (s, 6H).

(III) By reaction of 1.21 g of compound A and 0.85 g of 5 - [(2-aminoethylthio) methyl] -3, N, N-trimethylfuran-2-methanamine in a yield of 0.42 g of a pale yellow oil. 5- {2 - [(5-dimethylaminomethyl-4-methyl-2-furanyl) -methyl-thio] -ethylamino} -1-methyl-3- (phenylmethyl) -1H-1,2,4-triazole is obtained. . TLC ( "A" mixture): _Rf = 0.58.

NMR (CDC1 _3): 2.6-2.9 (m, 5H), 4.06 (s, IH), 6.16 (s, 2H), 5.53 (t, IH), 6, 40 (s, 2H), 6.58-6.61 (m, 7H), 7.27 (t, 2H), 7.8 (s, 6H) and 8.1 (s, 3H).

(IV) 0.75 g of N- [2- (acetyloxy) acetyl] - [1-methyl-2- (phenylmethylene) hydrazino] carboximidate methyltoate (Compound B) and 0.64 g of - by reacting [3- (1-hexamethyleniminiminomethyl) phenoxy] -propanamine in 1-methyl-3-hydroxymethyl-5- {3- [3- (1-hexamethylenimino) m.p. 80-82 ° C. (methyl) phenoxy] propylamino} -1? -1,2,4-triazole.

NMR (CDC1 _3): 2.8 (t, IH), 3.0-3.3 (m, 3H), 5.42 to 5.45 (m, 3H), 5.88 to 7.0 (m, UH), 7.4 (m, 4H), 7.9 (m, 2H) and 8.4 (m, 8H).

(V) 0.2 g of 5- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} by reaction of 1.37 g of compound B and 1.0 g of compound C _; 3- (hydroxymethyl) methyl-1H-1,2,4-triazole is obtained. TLC (mixture B): R _f = 0.48.

NMR (CDC1 _3): 3.25 (m, 2H), 5.1 (m, 2H), 5.5 (s, 2H), 6.16 (s, 2H), 6.35 to 6, Δ (m, 7H), 7.22 (t, 2H) and 7.77 (s, 6H).

(VI) By reaction of 0.75 g of compound B and 0.57 g of 3- [3- (1-pyrrolidinylmethyl) phenoxy] propylamine, 0.4 g of 1-methyl3- (105-107 ° C) is obtained. Hydroxymethyl-5- {3- [3- (1-pyrrolidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole is obtained.

Analytical results using the formula C _lg H ₂₇ NjO ₂ :

Calculated: C, 62.6; H, 7.9; N, 20.3; Found: C, 62.9; H, 7.9; N, 20.7.

(VII) By reaction of 0.75 g of compound B and 0.5 g of 5 - [(2-aminoethylthio) methyl] -3, N, N-trimethylfuran-2-methylamine in 0.32 g. 5- {2 - [(5-Dimethyl-Example 17a, al-Trimethyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) -phenoxy] -butylamino} Preparation of -1H-1,2,4-triazole

a) N- [3- (1-Hydroxy-1-methylethyl) -1-methyl-1 H -1,2,4-triazol-5-yl] -4- [3- (1-piperidinylmethyl) phenoxy] ] butyramide

- 78 ° C at 508 mg 1-methyl-5- {1-oxo-4- [3- (1-piperidinylmethyl) phenoxy] butylamino} -1 H -1,2,4-triazole-3 To a solution of the methyl carboxylic acid in 10 ml of tetrahydrofuran was added 1.6 ml of a solution of 400 mg of magnesium turnings and 0.7 ml of methyl iodide in 10 ml of diethyl ether, and the reaction mixture was first heated at 78 ° C. After 0.5 hour, allow to warm to room temperature and quench with water. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried and evaporated in vacuo to give 358 mg of the title compound as an oil. TLC (mixture "B"): _Rf = 0.8.

b) a, a 1-Trimethyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) -phenoxy] -butylamino} -1 -1-1,2,4-triazole

With stirring under nitrogen, 308 mg of N- [3- (1-hydroxy-1-methylethyl) -1-methyl-1 H -1,2,4-triazol-5-yl] -4- [3- (1- To a solution of piperidinylmethylphenoxy] -butylamide in tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.5 g) while cooling in an ice bath, and the reaction mixture was stirred at room temperature for 24 hours, quenched with water and extracted several times with ethyl acetate. The combined extracts were dried and evaporated to give 300 mg of an oil. This was then ethyl acetate, isopropanol, water, and 0.88 g / cm ³ specific gravity aqueous ammonia solution 25: 15: silica gel 2 by volume mixture of as eluent chromatographic subjected, 224 mg quantities of the step and also the title compound to give an oil form. TEC (mixture B): R _f = 0.7.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.80 (t, 1H), 3.0-3.3 (m, 3H), 5.65 (t, 1H), 6.02 (s, 2H), δ 52 (m, 7H), 7.60 (m, 4H), 8.0-8.7 (m, 10H) and 8.46 (s, 6H).

Example 18 Preparation of 1-Methyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinylmethyl) -phenoxy] -butylamino] -1H-1,2,4-triazole

While stirring, 5 mg of 1-methyl-3- (acetoxymethyl) 5- {4- [3- (1-piperidinylmethyl) phenoxybutylamino} -1H-1,2,4-triazole was prepared in 1 ml of ethanol. solution of

-131

185,790

After adding 0.5 ml of 2N sodium hydroxide solution, the reaction mixture was allowed to stand at room temperature for 2 hours, concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried in vacuo to give the title compound (4 mg) as a white solid, m.p. 82-83 ° C. TLC is the same as in Example 3.

Example 19 Preparation of 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole

1.24 g of 3- [3- (1-piperidinylmethyl) phenoxy] propylamine and 1.535 g of N- [2- (acetyloxy) acetyl] - [1-methyl-2 (phenylmethylene) - The mixture of hydrazino] -carboximidomethyl thioate was heated at 50 ° C for 3 hours and the resulting oil was dissolved in acetone (30 ml) without purification. To the acetone solution was added 5 ml of 2N hydrochloric acid solution, and the resulting mixture was stirred at room temperature for 1.5 hours and then allowed to stand overnight. A further 5 ml of 2N hydrochloric acid was added and the reaction mixture was refluxed for 2 hours. After dilution with water (50 mL), the reaction mixture was washed with ethyl acetate and basified with excess solid sodium carbonate. The resulting basic solution was extracted several times with ethyl acetate and the combined extracts were evaporated to 1.1 g of the desired compound is obtained as a 119 ° C melting white solid, TLC ( "B" mixture): _Rf = 0.7.

Example 20

a) All of the following. Prepared according to the procedure described in Example 1c: 0.61 g of 3- (4- (1-piperidinylmethyl) phenoxy] -propylamine and 0.75 g of N- [2- (acetyloxy) acetyl] -1-methyl-2 - (phenylmethylene) hydrazine by reaction of 0-carboximidomethyl thioate

1.2 g of 2- (acetyloxy) -N - {[3- (4-piperidinomethyl-phenoxy) -propylamino] - [1-methyl-2- (phenylmethylene) -hydrazinomethylene] -acetamide receive. TLC ( "A" mixture): _Rf = 0.59.

b) treating the acetamide obtained in step a) with acid with 1-methyl-3- (hydroxymethyl) -N- {3- [4- (1-piperidinylmethyl) phenoxy] -propylamino} -1H-1, 2,4-Triazole can be prepared. TLC (mixture A): R _f = 0.6.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.78 (d, 2H), 3.20 (d, 2H), 5.48 (s, 2H), 5.94 (t, 2H), 6.42 (q, 2H), 6.52 (s, 3H), 6.62 (s, 2H), 6.8 (broad s, 1H), 7.68 (m, 1H),

7.9 (m, 2H) and 8.3-8.7 (m, 6H).

Example 21

a) 1-Methyl-3-formyl-5- {4- [3- (1-piperidinylmethyl) -phenoxy] -butylamino} -1H-1,2,4-triazole

- a solution of 254 mg of oxalyl chloride in 20 ml of dichloromethane at 60 ° C under a nitrogen atmosphere

Dimethyl sulfoxide (304 mg) was added and the resulting mixture was stirred at -50 ° C to -60 ° C for 2 minutes and then 0.5 g of 1-methyl-3- (hydroxymethyl-5- {4- A solution of [3- (1-piperidinylmethyl) phenoxy] butylamino] -1H-1,2,4-triazole in 10 ml of dichloromethane was added and the reaction mixture was stirred for 15 minutes at this temperature and The reaction mixture was allowed to warm to 25 ° C, diluted with water, extracted with dichloromethane, separated and the combined organic phases were dried and evaporated to give the title compound as a pale yellow oil (0.4 g). . TLC form ( "A" mixture): _Rf = 0.55 b), α, 1-dimethyl-3- (hydroxymethyl) -5- {4- [3- (1-piperidinyl) phenoxy. ] -butylamino} -1 Η -1,2,4-triazole To a solution of 0.4 g of the compound obtained in a) in 20 ml of tetrahydrofuran at 25 ° C 10 ml of a 0.6 M solution of methyl lithium in diethyl ether was added under nitrogen and the reaction mixture was stirred for 12 hours, quenched with water and extracted several times with ethyl acetate. The combined extracts were evaporated to give 0.3 g of the title compound as a yellow oil.

TLC (mixture "C"): _Rf = 0.3.

Example 22

In the same manner as in Example 16, 0.75 g of 'N- [2- (acetyloxy) acetyl] -1-methyl-2- (phenylmethylene) hydrazinecarboximidomethyl thioate and 0.65 g of

0.3 g of 1-methyl-5- {3- [3- (4-hydroxy-piperidin-1-yl) -methyl] starting from 3- [3- (4-hydroxy-piperidin-1-ylmethyl) -phenoxy] -propanamine ) -phenoxy] -propylamino} 3- (hydroxymethyl) -1H-1,2,4-triazole.

TLC (mixture B): R _f = 0.4.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.80 (t, 1H), 3.0-3.3 (m, 3H), 4.63 (t, 1H), 5.52 (s, 2H), δ 8-6.1 (m, 5H),

6.3-6.7 (m, 7H), 7.1-7.4 (m, 2H), and 7.7-8.7 (m, 8H).

Example 23

Preparation of 3- (phenylmethyl) -5- [3- (3-dimethylaminomethyl-phenoxy) -propylamino] -1H-1,2,4-triazole

A mixture of 3- (3-aminopropoxy) -N, N-dimethylbenzylamine (1.46 g) and methyl isothiosemicarbazide hydroiodide (2.75 g) was heated at 40 ° C for 6 hours and the resulting resin precipitate was dissolved in ethanol. To the ethanolic solution was added a solution of tartaric acid in ethyl acetate and the precipitate was filtered off and then heated with 3.0 g of phenylacetic acid in 50 ml of boiling ethanol for 72 hours. The reaction mixture was cooled, basified with sodium hydroxide and extracted with ethyl acetate. The extract was purified by column chromatography to give, after recrystallization from ethyl acetate, 0.06 g of the title compound as a precipitate, m.p. 140-141 ° C. TLC (mixture A): R _f = 0.49.

-14185,790.

Example 24 (II) N- {5- {3- [3- (1-Piperidinylmethyl) phenoxy] propylamino} -1-methyl-1H-1,2,4-triazol-3-yl} Preparation of -N'-phenylurea

1.5 g of 1-methyl-N ⁵ - {3- [3- (1-piperidinylmethyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine and 0.52 A solution of phenyl isocyanate (g) in anhydrous acetonitrile was heated under reflux for about 48 hours, then the solvent was removed and the residual solid was crystallized from ethyl acetate. This gave 1.07 g of the title compound, m.p. 137-139 ° C. TLC ( "A" mixture): _Rf = 0.57.

(II) Similarly, but crystallizing the product from a mixture of acetonitrile and methanol, 1 g of 1-methyl-N ⁵ - {2 - [(5-dimethylaminomethyl-4-methyl-2-furanyl) methylthio] ethyl} -1H-1 Starting from 2,4-triazole-3,5-diamine and 0.35 ml of phenyl isocyanate, 0.65 g of N- {5- {2- [5-dimethylaminomethyl-4-methyl- 2-Furanyl) methylthio] ethylamino} -1-methyl-1H-1,2,4-triazol-3-yl} N'-phenylurea. TLC (mixture A): R _f = 0.5.

Example 25

Preparation of 1,2-Dihydro-1-methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] -propylamino} -3H-1,2,4-triazol-3-one

In the same manner as in Reference Example 5, 2.65 g of [1-methyl-2- (phenylmethylene) hydrazide carboxyde methylthioate hydroiodide and 0.58 ml of methyl chloroformate were melted at 85-86 ° C.

N-methoxycarbonyl-1-methyl-2- (phenylmethylene) -hydrazinocarboximidomethyl thioate followed by 0.59 g and 0.62 g of 3- [3- (1-piperidinyl) -methyl) -phenoxy] -propanamine by the reaction of Example 11, 0.9 g of N- {1-methyl-2- (phenylmethylene) -hydrazino] - [3- (3-piperidinomethyl-phenoxy) -propylamino] - methylene} -carbamic acid methyl ester (TLC (methanol): _Rf = 0.35) can be prepared. Treatment of the latter with 0.6 g of acid afforded 0.03 g of the title compound as its tartrate salt. TLC (mixture B): R _f = 0.23.

Nuclear Magnetic Resonance Spectrum (D ₂ O): 2.50 (t, 1H), 2.8-3.0 (m, 3H), 5.45 (s, 2H), 5.8 (s + m, 4H) , 6.4-6.6 (m, 4H), 6.73 (s, 3H), 7.05 (t, 2H) and 7.7-8.6 (m, 8H).

Example 26

0.75 g of N- [2- (acetyloxy) acetyl] -1-methyl-2- (phenylmethylene) hydrazinecarboximidomethyl thioate and 0.51 g of 3- (3-aminopropoxy) - From N, N-dimethylphenylmethylamine as in Example 16, 0.3 g of 1-methyl-3- (hydroxymethyl) -5- [3- (3-dimethylaminomethylphenoxy) -propylamino] -1 Α-1,2,4-triazole can be prepared. TLC (mixture B): R _f = 0.52.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.76 (t, 1H), 3-3.3 (m, 3H), 5.4-5.9 (m, 6H), 6.42-6.64 (m , 8H) and

7.8-7.9 (m, 8H).

Example 27

Preparation of I-Methyl-3- (hydroxymethyl) -5- [3-benzylaminomethyl-phenoxy] -propylamino] -1Η-1,2,4-triazole

532 mg of 3- (hydroxymethyl) -5- [3- (3-formylphenoxy) propylamino] -1-methyl-1H-1,2,4-triazole (Compound A) were prepared in 15 ml of ethanol. To this solution was added benzylamine (5 mL) and the resulting mixture was stirred at room temperature for 1.5 hours. Sodium borohydride (500 mg) was added to the resulting solution and stirring was continued at room temperature for 16 hours. The reaction mixture was concentrated and the residue was partitioned between 2 hydrochloric acid and ethyl acetate. The resulting aqueous phase was washed with ethyl acetate, neutralized with potassium carbonate and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo to give an oil. This was then chromatographed on silica gel, eluting with a 1: 1 mixture of methanol and ethyl acetate. 315 mg of the title compound are obtained in the form of an oil. TLC (methanol): _Rf = 0.5.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.72 (s + t, 6H), 3.0-3.3 (m, 3H), 5.24 (broad t, 1H), 5.52 (s, 2H) ).

5.98 (t, 2H), 6.1-6.7 (m, 8H), 6.60 (s, 3H) and 7.9 * 1 (m, 2H).

In the same manner as in the preceding paragraph, but treating 558 mg of compound A with 5 ml of heptylamine, 153 mg of 1-methyl-3- (hydroxymethyl) -5- {3- [3- (1- heptylaminomethyl) phenoxy] propylamino} -1? -1,2,4-triazole. TLC (methanol): _Rf = 0.3.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.80 (t, 1H), 3.1-3.3 (m, 3H), 5.50 (s + m, 3H), 5.97 (t, 2H), 6.30 (s, 2H),

6.50 (q, 2H), 6.58 (s, 3H), 6.90 (broad s, 2H), 7.41 (t, 2H), 7.96 (m, 2H), 8.3-. 8.9 (m, 10) and 9.2 (broad t, 3H).

Example 28

Preparation of N- {5- [4-5-Dimethylaminomethyl-2-furanyl) -butylamino] -1-methyl-1H-1,2,4-triazol-3-yl} -N'-phenylurea

A mixture of 2.32 g of N-cyano-1-methyl-2- (phenylmethylene) hydrazinecarboximidimethylthioate and 1.96 g of 4- (5-dimethylaminomethyl-2-furanyl) -butylamine in a vacuum pump 60 After 1 hour at room temperature, the remaining oil was stirred directly in 10 ml of 2N hydrochloric acid solution for 0.5 hour without further purification. The pH of the acidic solution was then adjusted to 9 with potassium carbonate and then washed with toluene. An excess of potassium carbonate was added to the aqueous phase, followed by extraction with ethyl acetate. The organic extract was dried and evaporated to give a precipitate which was then recrystallized from ethyl acetate. Yield: 2.1 g as a white precipitate, mp 105 ° C

N ⁵ - [4- (5-dimethylaminomethyl-2-furanyl) butyl] -1-methyl-1H-1,2,4-triazole-3,5-diamine is obtained.

0.73 g of the latter compound is reacted with 0.25 ml of phenyl isocyanate as described in Example 24 to give 0.67 g of the title compound, m.p. 124-125 ° C. TLC (C ,, "mixture): _Rf = 0.42.

-151 _ 185,790

Example 29

The following compounds were prepared as described in Example 16:

(I) 1.96 g of 4- (5-dimethylaminomethyl-2-furanyl) butylamine and 3.25 g of N- (phenylacetyl) -1-methyl-2- (phenylmethylene) hydrazinecarboximidomethyl with thioate, 2.0 g of 5- [4- (5-dimethylaminomethyl-2-furanyl) -butylamino] -1-methyl-3- (phenylmethyl) -1H-1,2,4-triazole; TLC (mixture B): R _f = 0.52.

NMR (CDC1 _3): 2.6-2.9 (m, 5H), 3.98 (d, IH), 4.13 (d, IH), 5.80 (t, IH), 6, 13 (s, 2H), 6.60-6.65 (m, 7H), 7.38 (t, 2H), 7.80 (s, 6H) and 8.3 (m, 4H).

(II) 1.1 g of 4- (5-dimethylaminomethyl-2-furanyl) -butanamine and 1.9 g of N- [2- (acetyloxy) acetyl] -1-methyl-2- (phenylmethylene) hydrazino of 5- [4- (5-dimethylaminomethyl-2-furanyl) -butylamino] -1-methyl-3- (hydroxymethyl) -1H- with 0.5 g of carboximidomethylthioate. l, 2,4-triazole. TLC (mixture "C"): _Rf = 0.34.

The following examples are provided for the preparation of pharmaceutical compositions.

Component required for tableting mgitablet- mgjtabletta ta 20.0 40.0 microcrystalline cellulose: (British Pharmacopoeia) quality) 99.5 199.0 magnesium stearate (British pharmacopoeial quality) 0.5 1.0 pressing weight 120.0 2403)

The active ingredient is passed through 250 micron sieve ₃₅ and mixed with the excipients and using a 6.5 mm or 8.0 mm (20 mg or 40 mg of active substance) was subjected to compression stamps. Multiple active tablets can also be made by increasing the compression weight or the size of the stamp.

The tablets may be coated with suitable film-forming agents such as methylcellulose, ethylcellulose or hydroxypropylcellulose in conventional manner. Alternatively, the tablets may be sugar coated. ⁴⁵

Of course, other conventional formulations, such as capsules, may also be prepared.

Example 30 _E- 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinyl: * methyl) -phenoxy] -propylamino} -1H-1,2,4- triazole; Preparation of its salts

a) Preparation of a 1: 1 sulfate salt ₅ c

300 mg of 1-methyl-3- (hydroxymethyl) -5- (3- (1-piperidinylmethyl) phenoxy] propylamino} -1? -1,2,4-triazole are dissolved in 20 ml of heating ethyl acetate and a few drops of ethanol was added to give a clear solution. to this was added 1 mL of concentrated sulfuric acid and 9 ml of hot ethanol elegye- ⁰⁰ has a 0.45-ml aliquot dropwise. On cooling a precipitate was filtered off and the positions, diethyl washed with ether and dried in vacuo (400 mg)

170 ° C as a white crystalline solid to give the sulfate salt.

b) Preparation of a 2: 1 talarate salt

As described in part a), a solution of 300 mg of the free base is treated with a hot solution of 125 mg of tartaric acid in 10 ml of ethanol to give 50 mg of the tartarate salt as a crystalline solid.

c) Preparation of a 2: 1 succinate salt

As described in part a), a solution of 300 mg of the free base is treated with a hot solution of 99 mg of succinic acid in 10 ml of ethanol to give 150 mg of the succinate salt as a white crystalline solid, m.p.

Example 31 Preparation of 1-Methyl-3- (phenylmethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole

a) 1- [3- (3-Bromopropoxy) phenylmethyl] piperidine

At 20'C, 19.1 g of 3- (1-piperidinylmethyl) phenol and

A mixture of potassium hydroxide (5.4 g) in acetonitrile (150 ml) was stirred for 2 hours and then added dropwise over a period of 1 hour to a solution of 1,3-dibromopropane (80.7 g) in acetonitrile (50 ml). The resulting reaction mixture was stirred at 20'C for 18 hours and then concentrated in vacuo. The residue was dissolved in 2N hydrochloric acid and the resulting solution was washed with diethyl ether, the aqueous phase was basified with 5N sodium hydroxide solution and then extracted with diethyl ether. Evaporation of the organic extract gave 17.2 g of the title compound as an orange oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 2.7-2.9 (m, 1H), 3.0-3.3 (m, 3H), 5.9 (t, 2H), 6.35 (t, 2H), 6.5 (s, 2H),

7.4-7.7 (m, 6H) and 8.2-8.7 (m, 6H).

b) 1-Methyl-3- (phenylmethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole

0.050 g of l-methyl-3- (phenylmethyl) -5-amino-1H-1,2,4-triazole, 0.081 g of 1- [3- (3-bromopropoxy) phenylmethyl] piperidine, 0.012 g of sodium A mixture of hydroxide and 1 ml of 1-methyl-2-pyrrolidone was heated at 100 ° C for 2 hours and at 140 ° C for a further 4 hours. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase is seeded. dried over sodium sulfate and concentrated to give 0.06 g of an oil. Of this, 0.6 mg of the title compound can be isolated by high performance liquid column chromatography using a 20 cm 4.6 mm internal diameter 5 µm particle size particle with a flow rate of 2 mL · min ^-1 at room temperature with an ultraviolet detector at 210 nm.

The mobile phase is a mixture of hexane, ethanol, water and ammonia (1662: 332: 4: 1). Retention time of the title compound is 5.35 minutes. Ultraviolet spectrum: λ max. 265 nm and 270 nm.

-161

185,790

Example 32 Preparation of 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H1, 2,4-triazole a) 1 - [ 3- (3-amino-propoxy-benzoyl)] - piperidine

To a hot solution of 1.75 g of 1- (3-hydroxybenzoyl) piperidine in 40 ml of anhydrous acetonitrile was added 2.6 g of 3-chloropropylamine hydrochloride and 3.4 g of powdered potassium hydroxide, and the resulting reaction mixture was refluxed for 18 hours and then the solvent was removed in vacuo. The residue was dissolved in 20 ml of IN hydrochloric acid and the resulting solution was washed with ethyl acetate. Excess potassium carbonate was added to the aqueous phase, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was evaporated. 2.7 g of the title compound are thus obtained in the form of an oil having a boiling point of 165 DEG C. at 0.1 mm Hg.

b) 1 - {{3- {3- [3- (Hydroxymethyl) -1-methyl-1 H -1,2,4-triazol-5-ylamino] propoxy} benzoyl}} piperidine

1.5 g of 1- [3- (3-aminopropoxy) benzoyl] piperidine and 1.93 g of N- [2- (acetyloxy) acetyl] - [1-methyl-2- (phenylmethylene) hydrazino A solution of carboximidomethylthioate in 30 ml of toluene was heated at 50 ° C for 2.5 hours while nitrogen gas was slowly bubbled through the solution. Subsequently, 12 ml of a 5N hydrochloric acid solution are added, and the resulting biphasic mixture is stirred at 20 ° C for 18 hours. The acidic aqueous phase was then separated, washed with ethyl acetate, adjusted to pH 6 by addition of solid sodium carbonate, and finally extracted with ethyl acetate. The extract was dried and evaporated to give 1.3 g of the title compound as a resin which was used in the next step without further purification.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ); 2.7 (t, dd, 1H), 3.02-3.14 (m, 3H), 3.6 (broad s, 1H), 5.0 (t, 1H), 5.44 (s, 2H) ), 5.92 (t, 2H), 6.2-6.8 (m, 9H), 7.92 (m, 2H) and 8.25-8.6 (m, 6H).

c) 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] -propylamino} -1H-1,2,4-triazole

To a suspension of 0.45 g of lithium aluminum hydride in 30 ml of anhydrous tetrahydrofuran is added dropwise under a nitrogen atmosphere, 0.45 g of l - {{3- {3- [3- (3-hydroxymethyl) -1-methyl-1H-1,2, 4-Triazol-5-ylamino] -propoxy} -benzoyl}} -piperidine in 60 ml of anhydrous tetrahydrofuran. After stirring the reaction mixture at 20 'Con for 3.5 hours, water (0.45 ml), 15% aqueous sodium hydroxide solution (0.45 ml) and water (1.35 ml) were carefully added successively. The resulting mixture was stirred at room temperature for half an hour and then filtered through Hyflo (filter). The filtrate was concentrated under reduced pressure. The resulting colorless resin was triturated with 10 ml of anhydrous diethyl ether. This gave 0.32 g of the title compound as a white solid, m.p. 114-116 ° C.

Example 33 Preparation of 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole

To 6.67 mg of sodium borohydride was added 120 mg of 1-methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] propylamino} -1Η-1,2,4 triazole-3-carboxaldehyde in 2 ml of absolute alcohol was added and the resulting mixture was stirred at 21 ° C for half an hour and then poured into a saturated aqueous sodium chloride solution. The mixture was extracted several times with diethyl ether, and the combined organic extracts were dried over magnesium sulfate and evaporated. This gives an oil which solidifies. This gave 119 mg of the title compound as a white precipitate.

_Rf value 1 by volume mixture of, as determined by TLC developing solvent (0.55) of the same sample said end of Example 32 recorded in _CDCl3 NMR and chromatography on silica gel methanol and 0.880 g / cm ³ specific gravity aqueous ammonia solution 80 with appropriate identification features.

Example 34 1-Methyl-5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -3-hydroxymethyl-1-methyl. Preparation of H-1,2,4-triazole

a) 3- [3 - {{N- {3 - [(2-Methoxyethoxy) methoxymethyl] 1-methyl-1H, 2,4-triazol-5-yl} -N - [(2) methoxy-ethoxy) methyl] amino}} - propoxy] benzaldehyde

While stirring at room temperature, 2.0 g of 3- {3- [3- (hydroxymethyl) -1-methyl-1H-1,2,4-triazol-5-ylamino] propoxy} benzaldehyde were prepared in 20 ml of dichloromethane. to the suspension are added 2.23 g of diisopropylethylamine and 2.14 g of 2-methoxyethoxymethyl chloride. After the addition was complete, the reaction mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic phase is dried and concentrated in vacuo. The resulting yellow oil was purified by silica gel short column chromatography using chloroform as eluent. 1.62 g of a colorless oil are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.03 (s, 1H), 2.5-2.7 (m, 3H), 2.85 (m, 1H), 5.12 (s, 2H), δ 28 (s, 2H), 5.92 (t, 2H), 5.44 (s, 2H), 6.16-6.54 (m, 3H), 6.59 (s, 3H), 6.64 (s, 3H) and 7.9 (m, 2H).

b) 3- [3 - {{N- {3 - [(2-Methoxyethoxy) methoxymethyl] 1-methyl-1 H -1,2,4-triazol-5-yl} -N- [ (2-methoxyethoxy) methyl] amino}} - propoxy] -benzyl alcohol

To a solution of the title compound of step a) in ethanol (0.66 g) in 10 mL of ethanol was added small portions of sodium borohydride (0.13 g) at room temperature, and after 2 hours, Amberlite IR-120M ⁺ (US Rohm and Haas). US company product). The resulting mixture was filtered and the resin was washed with methanol using a pump. The filtrate and washings were evaporated in vacuo and the oily residue azeotroped with methanol

-171

185,790. The residual oil was purified by chromatography on a short column of silica gel, eluting with chloroform (2% v / v ethanol). 0.42 g of the product is obtained in the form of a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.75 (t, 1H), 3.00-3.28 (m, 3H), 5.15 (s, 2H), 5.28 (s, 2H), 5.33 (d, 2H), 5.47 (s, 2H), 6.0 (t, 2H), 6.22 (m, 2H), 6.26 (s, 3H), 6.35 (t, 2H) , 6.4 (m, 4H), 6.5 (m, 2H), 6.58 (s, 3H), 6.63 (s, 3H), 7.53 (t, 1H), and 7.95 (m, 2H).

c) 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] -propylamino} -1H-1,2,4-triazole

To a solution of the compound from step b) in 0.625 g of pyridine (2 ml) was added dropwise 1 ml of thionyl chloride at room temperature with stirring. One hour after the addition was complete, the reaction mixture was concentrated in vacuo and the dark residue was dissolved in piperidine (7 mL) and the resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo and the dark residue was dissolved in piperidine (7 mL) and the resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo and the dark residue was partitioned between water and ethyl acetate. The organic extract was evaporated and 2N hydrochloric acid was added to the resulting oily residue and the resulting mixture was stirred at room temperature for half an hour. The solvent was removed in vacuo and the residual dark oil was purified by column chromatography on silica gel using dichloromethane: ethanol: ammonium hydroxide (100: 8: 1) as eluent. This gave a yellow oil which crystallized on standing and triturated with diethyl ether to give 76 mg of the title compound as a white crystalline solid, m.p. 114-116 ° C.

The recorded in _CDCI3 NMR sample of the same said end of Example 32.

Claims (10)

Patent claims A process for the preparation of a novel triazole derivative of formula (I): wherein: R 1 is hydrogen or C 1-4 alkyl, R ₂ is C 1 -C 8 alkyl or benzyl, or R 1 and R ₂ together with the nitrogen atom to which they are attached form a 5-8 membered saturated and optionally substituted 1 N atom heterocyclic ring, Alk is an alkylene group containing from 1 to 4 carbon atoms, Q represents a furan or thiophen-2,5-diyl group and the furan ring is optionally substituted by _two adjacent attachment location of the RJR NAlK group carbon atom substituents R _6, and R is alkyl of 1-4 carbon atoms, or Q is 1- and 3- or 1- and 3- 4-linked benzene ring, X is -CH ₂ -, O or S, n is O if X = 0 and if X = -CH ₂ -> - or S, m is 2, 3 or 4, R ₃ is hydrogen or C 1-4 alkyl, and R ₄ is benzyl, hydroxy (C 1-4) alkyl, (C 1-6) alkanoyloxy (C 1-4) alkyl- or (C 1-4) alkoxy (C 1-4) alkyl, hydroxy, or -NR ₇ R ₈ , with the latter being R, hydrogen, and R _g -COR ₉ - in which R ₉ is phenyl or phenyl substituted with C 1-4 alkyl, C 1-4 alkoxy, furyl, pyridyl or optionally C 1-4 alkoxy, or - CONHR _n - wherein R _n is phenyl, with the proviso that when X is oxygen and n is 0, Q is a benzene ring, and pharmaceutically acceptable salts and hydrates thereof; a) for the preparation of a compound of formula (I) wherein R ₄ is NR ₇ R ₈ , wherein the other substituents are as defined above, in a aminotriazole derivative of formula (III): wherein R _{1 (} R ₂₎ , R ₃ , R ₇ , Alk, Q, X, n and m are as defined in formula (I), wherein the hydrogen atom of the -NHR ₇ group is acylated to R 'is as defined in formula (I), or b) for the preparation of a compound of formula (I) other than an alkanoyloxyalkyl group in which R ₄ is a substituent, as defined herein, a compound of formula (IV) wherein R ₁ , R ₂ , Alk, Q, X, R ₃ , n and m represent V 'XVIII of formula I (ebhen V is oxygen or sulfur and R' ₄ is the same as R _{4 in} this process or contains acyloxyC 1-4) ) is alkyl or C 1-4 alkoxy) and Y 'is hydrogen, or. and V 'represents an imino group and Y' represents a group of the general formula (XIX) (wherein Y represents an oxygen or sulfur atom and R ₄ represents a ring closure as defined herein and the acyl group of an acyloxyalkyl group optionally present at R _{4 in} the starting material or we cut it c) a compound of formula (XII): wherein Q 'η, X and R ₃ are at least one of the reductions given by D *, D ^b and D ^e as defined herein for formula (I); and the other meanings correspond to the meaning of the corresponding substituent of the formula I, in particular ^! D * RjRjNalk a reducible group or R, R ₂ NCO (CH _{2) p} moiety (wherein R, R ₂ and Alk are as stated, and p is 0, 1, 2 or 3) is, D ^b —CH ₂ NH— or a reducing agent -18. 185790 is -CONH- or -CH = N-, and D ^c is as defined for R 4 in the formula (I) or a ⁵ - (CH ₂ ) _q -, CH ₂ or - (CH ₂ ) _{q -} , CO ₂ R ₁₂ group which can be reduced from a hydroxyalkyl group [q is 1, 2, 3 or 4, the chain (CH ₂ ) _{q -} may be straight or branched and R ₁₂ is alkyl] ₁ θ is reduced, or d) a compound of formula XVII wherein E is - (CH ₂ ) _n X (CH ₂ ) _m P, wherein P is a leaving group! _And n, x and m are each represented by a triazole derivative of formula (XIV) - wherein U represents an amino group, R ₃ and R ₄ are as defined in the general formula I, or e) for the preparation of compounds of formula I wherein R ₄ is a secondary or tertiary hydroxyalkyl group, R ₄ is - (CH ₂ ) _q - CHO, - (CH ₂ ) _{q -} , CO ₂ R, ₂ or - (CH). _{2) r} COR ₂ groups of the formula - 25 in these groups, q is 1, 2 or 3, r is 0 or 1, and R ₂ represents an alkyl group - carrier, otherwise be characterized by the general formula (I) is reacted with an organometallic compound, or 30 f) a compound of Formula XXII wherein L ^is R, R2N, and R1 - (CH2) q are halogen, or L ^a is halogen and L ^b is R4; 1-4, R ₄ , Alk, Q, X, R ₃ n and 35 m are as defined in the scope - reacting a protected derivative of a compound of the formula wherein L ^a is halogen with a compound of the formula R, R ₂ NH - _R, and _R2 are as stated - and then the protecting groups leha- ⁴⁰ provide or an equally among the compounds of formula (XXII), L ^b represents - a compound containing a group of formula _q halo (CH ₂₎ a 1-4 is reacted with a lower alkanol, optionally in the preparation of a carrier ⁴⁵ R ₄ is alkano-yloxy group (I), compound of formula I wherein the corresponding valence hydroxyalkyl group (I) was reacted with an appropriate acid at elevated temperature or at R ₄ is for preparing a compound of formula hydroxyalkyl group (I), the acyl group is acylated to the corresponding R ₄ is compound carrying a hydroxyalkyl group (I) is removed and / or produced as above a The free base of formula (I) is converted into a pharmaceutically acceptable salt or hydrate. Process c) according to claim 1, wherein 1-methyl-3 (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl of formula I is provided. -amino} -1H-1,2,4-triazole, characterized in that 1-methyl-3- {1-oxo-4- [3- (1-piperidinylmethyl) phenoxy] propylamino} The methyl 1 -1-1,2,4-triazole-3-carboxylic acid is reduced with lithium aluminum hydride. Process b) according to claim 1, wherein 1-methyl-3 (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl of formula (I) is provided. amino} -lH-l, 2, For the preparation of 4-triazole, characterized in that 2-acetyloxy-N - {(1-methylhydrazino) [3- (3-piperidinomethyl-phenoxy) -propyl] -amino} -methylene} -acetamide is cyclized with an acid. . The process for carrying out any of the processes b), c), d) or f) according to claim 1, which is carried out on the l-methyl-3- (hydroxymethyl-5- {3- [3- (l- piperidinylmethyl) phenoxy] propylamino} 1 H -1,2,4-triazole in a 2: 1 ratio, characterized in that a b), c), d) or f) Reaction of 1-methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole prepared with process succinic acid. 5. A process for the preparation of any of the processes b), c), d) or f) according to claim 1, which is a process for the preparation of 1-methyl-3- (hydroxymethyl) -5- {3- (3- (l) -piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole in a 2: 1 ratio, characterized in that a b), c), 1-Methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) -phenoxy] -propylamino} -1H-1,2,4-triazole prepared by Method d) or f) with tartaric acid. 6. A process according to claim 1 for the preparation of any of the processes b), c), d) or fi according to claim 1, which is carried out on 1-methyl-3- (hydroxymethyl) -5- {3- [3- ( 1-piperidinylmethyl-phenoxy] -propylamino} -1H-1,2,4-triazole in a 1: 1 ratio, characterized in that a b), c), d) or f) reacting 1-methyl-3- (hydroxymethyl) -5 - {[3- (1-piperidinylmethyl) phenoxy] propylamino} -1H-1,2,4-triazole with sulfuric acid. Process c) according to claim 1, wherein 1-methyl-3 (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl of formula I is provided. -amino} -1H-1,2,3-triazole, characterized in that 1 - {{3- {3- [3- (hydroxymethyl) -1-methyl] -1,2,4,4-triazole- 5-Ylamino] -propoxy} -benzoyl}} piperidine is reduced with lithium aluminum hydride. Process c) according to claim 1, wherein the 1-methyl-3 (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl group of formula I amino} -1H-1,2,3-triazole, characterized in that 1-methyl-5- {3- [3- (1-piperidinylmethyl) phenoxy] propylamino} -1 -1-1,2 4-Triazole-3-carboxaldehyde is reduced with sodium borohydride. 9. Process for the preparation of process f) according to claim 1, wherein 1-methyl-3- (hydroxymethyl) -5- {3- [3- (1-piperidinylmethyl) phenoxy] propyl of formula I -amino} -1H-1,2,3-triazole, characterized in that 1-methyl-3- (hydroxymethyl) -5- {3- [3- (chloromethyl) phenoxy] -propyl- the protected derivative of amino} -1 Η-1,2,4-triazole is reacted with piperidine and deprotected. 10. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula (I) according to claim 1, wherein the substituents have the meaning given by or a pharmaceutically acceptable salt or hydrate thereof as defined in claim 1 in admixture with excipients and / or excipients conventionally used in the manufacture of a medicament to form a pharmaceutical composition.