FR2521993A1 - NITROGENIC HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS HISTAMINE ANTAGONISTS - Google Patents

Abstract

NITROGENIC HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THERAPEUTIC USE. THESE COMPOUNDS MEET GENERAL FORMULA I: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS H OR VARIOUS HYDROCARBON GROUPS; R AND R ARE HYDROCARBON GROUPS POSSIBLY CONNECTED WITH THEM WITH THE FORMATION OF A CYCLE, ALK IS AN ALKYLENE GROUP IN C A C, Q IS A FURAN, THIOPHENE OR BENZENE, XO, S, NH, CH OR A LINK; YO, S, CH, OR ONE LINK, N EQUAL 0, 1, 2 OR 3, M EQUAL 2 A 5 AND A AND B REPRESENT N OR A SUBSTITUTE CARBON ATOM AND R REPRESENTS VARIOUS SUBSTITUTS. THESE COMPOUNDS HAVE PROPERTIES OF H HISTAMINE ANTAGONISTS THAT CAN USE THERAPEUTICALLY, FOR EXAMPLE FOR THE INHIBITION OF GASTRIC ACIDITY SECRETIONS.

Description

The present invention relates to novel heterocyclic compounds

nitrogen, to processes

  for their preparation, and their therapeutic use

  particularly as a histamine antagonist.

  Certain heterocyclic compounds having potent H 2 antagonist activity have been found. These compounds, described in more detail below, cause, for example, an inhibition of the secretion of gastric acidity stimulated via histamine receptors (Ash et al. and Schild, Brit J Pharmacol, Chemother, 1966, 27, 427) This ability can be

  highlighted on the stomach of the rat subjected to perfusion

  by the procedure described in UK Patent No. 1,565,966 modified with the use of sodium pentobarbine (50 mg / kg) as an anesthetic in place of urethane, and on stand-up dogs with pockets. of Heidenhaini by the procedures described by Black et al.

  nature 1972, 236, 385 In addition, the antagonistic compounds

  feel the effect of histamine on the rate of contraction

  of guinea pig right atrium isolated.

  Compounds possessing H 2 blocking activity of histamine can be used in the treatment of conditions in which it is advantageous to reduce gastric acidity, in particular in cases of gastric and peptic ulceration, in prophylaxis. surgical operations, and in the treatment of allergic and inflammatory conditions for which histamine is a known mediator.

  they can be used for example, alone or in combination

  combination with other active components, in the treatment of allergic and jinflammatory conditions

skin.

  The invention firstly relates to the compounds corresponding to the general formula 2 -R 3 \ NA R 1 R 2 N-Alk-QX- (CH 2) Y (CH) NH N / 1 2 (2) n (C 2 NMO and their physiologically acceptable salts and hydrates, the various symbols of formula I having the following meanings: R 1 represents hydrogen, C 1 -C 14 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or alkyl bearing hydroxy, alkoxy, amino, alkylamino, dialkylamino, or cyclalkyl substituents; R 2 represents hydrogen or a C 1 -C 4 alkyl group

1

  or R 1 and R 2 may together form, with the nitrogen atom to which they are attached, a 5- to 10-membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted with one or more C 1 -C 3 alkyl groups, for example methyl, or with a hydroxy group, and / or may contain another heteroatom selected from the group consisting of oxygen and sulfur; "Alk" represents a straight or branched alkylene chain at C 1 C 3; Q represents an outhiophene furan ring connected to the remainder of the molecule by the bonds in the 2 and 5 positions, this furan or thiophene ring optionally bearing another substituent R 4 close to the R 1 R 2 N-Alk group; or Q represents a thiophene ring connected to the remainder of the molecule by bonds in the 2 and 4 positions, this thiophene ring optionally carrying another substituent R 4 close to the group R 1 R 2 N-Alk-, being specified as -3 when the group R 1 R 2 N-Alk is in position 4, the group R 4 is in position 5; or Q represents a benzene ring attached to the remainder of the molecule by bonds in positions 1 - and 3 or 1 and 4; R 4 represents a halogen or a C 1 -C 4 alkyl group which may be substituted by a hydroxy or C 2 alkoxy group; 1-C 4; X is oxygen, sulfur, -NH-, methylene, or a bond; Y represents oxygen, sulfur, a methyl group or a bond; n is 0, 1, -2 or 3 and m is a number from 2 to 5; being specified that (a) the total number of atoms of the chain X (CH 2) n Y (CH 2) m is from 3 to 8, (b) when X and Y represents oxygen or sulfur, N is equal to a 2 or 3, (c) where X is -NH-, Q is a benzene ring and Y is a group

  methylene or a bond, and (d) when Q represents

  benzene ring, X is oxygen and N is 1, m may furthermore be 1 and Y may further represent CHOR 14 wherein R 14 is hydrogen or acyl; and R 3 represents hydrogen, an alkyl, alkenyl, aralkyl group or a C 2 -C 6 alkyl group bearing a hydroxy or alkoxy substituent; or A is N and B is CR 5; or A is CR 5 and B is N; and R 5 represents: i) a straight or branched chain C 2 -C 6 alkyl group substituted with 2 or 3 hydroxy, alkoxy or acyloxy groups, or the dihydroxyalkyl group may form a cyclic acetal structure of the formula:

/ (CH 2)

-C-CH

I

O O O

C

6 R 7

  wherein p is 0 or 1 and R 6 and R 7, which may be identical or different, each represent hydrogen, C 1 -C 4 alkyl or phenyl; or ii) the group CH 2) q Z (CH 2) r R 8 wherein q is a number from 1 to 4 incl B, r is a number from 1 to 6 inclusive, Z represents oxygen or sulfur and when r is 1, R 8 is CH = CH, alkenyl or COR 9 wherein R 9 is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or NR 10 R 1 in wherein R 10 is hydrogen or alkyl and R 11 is hydrogen or alkyl, when r is 2 to 6;

  R 8 to any one of the above-mentioned

  or may further represent a hydroxy, alkoxy, aryloxy, or XU group NR 12 R 13 wherein R 12 is hydrogen or alkyl and R 13 is hydrogen, alkyl, acyl, alkoxycarbonyl alkylsulfonyl, or arylsulfonryil, being specified that the sum of q and r is preferably 6 or less; or iii) the group (CH 2) x S (CH 2) y R 15 wherein x is 1 or 2, y is 0 or 1 and R 15 is heteroaryl; or (iv) an aralkyl or heteroaralkyl group in which the alkyl part is substituted with

hydroxy, alkoxy or acyloxy groups.

  - In formula I, the term "alkyl" applying to a group or part of a group indicates that the group is straight-chain or branched and, unless otherwise indicated, contains 1 to 6 carbon atoms, more particularly 1 to 4 carbon atoms, such as for example the methyl or ethyl group, and the expression "alkenyl" indicates that the group

  preferably contains 3 to 6 carbon atoms.

  The term "cycloalkyl" indicates that the group contains from 3 to 8 carbon atoms. The term "aryl" applied to a group or part of a substituted phenyl group, for example phenyl bearing one or more alkyl substituents C 1 -C 3 alkyl or C 1 -C 3 alkoxy or halogen atoms, for example fluorine The expression "acyl" "N Lonnacyle" aroyl group, aralkanoyl or C 1 -C 6 alkanoyl, for example acetyl, formyl, phenylacetyl, or benzoyl The term "heteroaryl" applied to a part of a group in the definition of R 1 denotes a 5- or 6-membered monocyclic ring containing from 1 to 3 heteroatoms selected from oxygen , nitrogen and sulfur, for example a thienyl, pyridyl, furyl, thiazolyl ring The heteroaryl ring may be unsubstituted or substituted with C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy, hydroxyalkyl , aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or by halogens "heteroaryl" applied to a part of a group in paragraph (iv) of the definition of R 5 denotes a 5- or 6-membered mono ring ring containing 1 heteroatom selected from oxygen, nitrogen and sulfur, For example, a thienyl, pyridinyl or furyl ring optionally substituted with a C 1 -C 3 alkyl group. The alkyl portion of a heteroaralkyl group consists of a straight or branched C 1 -C 4 alkyl chain, and the ring heteroaryl is connected to the part

  alkyl by a carbon atom The expression "heterogeneous

  aryl used in the definition of R 15 denotes an unsaturated monocyclic or bicyclic ring containing from 5 to 10 atoms selected from carbon, oxygen, nitrogen or sulfur. If the heteroaryl ring is monocyclic, it preferably contains 5 or 10 carbon atoms. 6 links and if it is bicyclic it preferably contains 9

  or 10 links As an example of such heterogeneous cycles

  aryls, furyl, thienyl, pyrolyl,

  pyridinyl, pyrimidinyl, triazinyl, oxazolyl, tri-

  azolyl, tetrazolyl, thiazolyl, thiadiazolyl,

  isoquinoleil, quinoleil, indolile, or benzoxazolyl.

  The ring structure may be unsubstituted or substituted by one or more groups selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy

or hydroxy.

  In one of its aspects, the invention relates to the compounds of formula I in which R 1, R 2, R 3, Alk, Q, X, Y, N and m have the meanings indicated above but excluding the additional meanings of m and Y given in the specification

  d) and A represents N and B represent CR 5 or A represents

  CR 5 and B represents N when R 5 is significant.

  mentioned in (i) or (ii) (except that q does not

can represent only 1 or 2).

  In another aspect of the invention, this relates to compounds of formula I wherein R 1, R 2, R 3, Alk, Q, X, Y, N and m have the meanings given above at exclusion of meanings

  m and Y data in the specification.

  d), and A is N and B is CR 5 or A is CR 5 and B is N when R 5 is

  meaningindicated in (iv) above.

  The compounds of formula I which are preferred are those in which: R 1 represents a C 1 to C 8 alkyl group (for example methyl, propyl, butyl or heptyl), a substituted C 1 to C 4 alkyl group by a

  trifluoromethyl group (eg 2,2,2-tris)

  fluoroethyl) a C 2 -C 4 alkyl group substituted by a hydroxy group or a di-C 1 -C 3 alkylamino group (for example 3-hydroxypropyl or dimethylaminoethyl) or a C 5 -C 7 cycloalkyl group ( for example, cyclohexyl), C 3 -C 5 alkenyl (eg, allyl), phenyl (C 1 -C 3) alkyl (eg, benzyl), or heteroaryl (C 1 -C 3) alkyl in which the heteroaryl ring contains 1 heteroatom (for example 2-furylmethyl); R 2 represents hydrogen or a methyl group; or R 1 R 2 N represents a 5-8 membered ring optionally containing 1 double bond, an oxygen atom or an alkyl substituent (eg methyl), for example a piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethylene ring; imino or tetrahydropyridino; Alk represents the methylene group; Q represents a benzene ring connected to the remainder of the molecule by bonds in positions 1 and 3; or a furan ring connected to the rest of the molecule by bonds in the 2 and 5 positions and optionally carrying a substituent R 4 close to the R 1 R 2 N Alk group, R 4 being a C 1 -C 4 alkyl group (by methyl example); or a thiophene ring linked to the rest of the molecule by bonds in the 2 and 4 positions, with the substituent R R 2 N Alk at the 2-position; it being specified that when Q is a benzene ring as just defined, X is a bond, N is 0, Y is oxygen and m is 3.4, or 5, or X and Y are both oxygen and N and m are both 2, or X is oxygen Y is CHOH and N and m are both 1; and when Q represents a furan cycle

  thiophene as just defined, X represents

  binds and either Y is sulfur or CH 2, N is 1 and m to 2, or Y is oxygen, N is 1 and m to 3; R 3 represents hydrogen or an alkyl group (by

methyl example);

  R 5 represents a C 2 -C 4 alkyl group substituted with two hydroxy groups, or a 2,2-di group

  (C 1 -C 3) alkyl (e.g. dimethyl) -1-3

  dioxolan-4-yl or R 5 represents phenyl- (C 1 -C 3) alkyl (for example benzyl) or heteroaryl- (alkyl)

  C 1 -C 3) (for example furylmethyl or pyridyl

  methyl) wherein the alkyl portion is substituted with hydroxy, C 1 -C 4 alkanoyloxy (e.g. acetyloxy) or C 1 -C 2 alkoxy (e.g. methoxy); or R 5 represents the group (CH 2) q Z (CH 2) r Ra, wherein q is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z represents sulfur, and R 8 represents a hydroxy group, the group -CH = CH 2, a group

  di- (C1-C3) alkylamino (for example dimethyl-

  amino) or the group COR 9 in which R 9 is a C 1 -C 4 alkoxy group (for example ethoxy) or the group NHR 11 in which R 11 is a C 1 -C 3 alkyl group (for example methyl ); or 9 - R 5 represents the group (CH 2) x S (CH 2) y R 5, wherein x is 1 and the heteroaryl group R 15 is a tetrazolyl or thiadiazolyl group substituted by a C 1 alkyl group -C 3 (for example a methyl group), or R 15 represents a furyl group; preferably, y is 0 and R 15

  represents 1-methyl-1H-tetrazol-5-yl.

  As part of the preferred meaning

  of R 5, the compounds in which R 5 has the significances

  The following is a separate aspect of the invention: R 5 represents a substituted C 2 -C 4 alkyl group;

  two hydroxy groups, or a 2,2-di-

  (C 1 -C 3) alkyl (e.g. dimethyl) -1-3

  dioxolan-4-yl; or R 5 is phenyl (C 1 -C 3) alkyl (eg, benzyl) wherein the alkyl portion is substituted with C 1 -C 4 alkanoyloxy (e.g. acetyloxy) or C 1 -C alkoxy 2 (for example methoxy), or a heteroaryl-C 1 -C 3 alkyl group (for example furylmethyl or pyridylmethyl) in which the alkyl part is substituted with a C 1 -C 4 alkanoyloxy hydroxy group (for example acyloxy); ) or C 1 -C 2 alkoxy (for example methoxy); or represents a group (CH 2) Z (CH 2) r R 8 where q is 1, r is a value of 1 to 4 where Z is oxygen, or r is 1 when Z is the sulfur, and R 8 represents a hydroxy group, the group -CH = CH 2, a di- (C 1 -C 3 alkyl) amino group (for example dimethylamino), or the group COR 9 in which R 9 is C 1 -C 4 alkoxy (e.g. ethoxy) - or NH R 11 where R 1 is C 1 -C 3 alkyl (eg methyl) or R 5 is 2) x S (CH 2) y R 15 wherein x is 1a and the heteroaryl group R 15 is a tetrazolyl or thiadiazolyl group each substituted by a C 1 -C 3 alkyl group (eg methyl) or R 15 is a furyl group; preferably y is 0 and R 15 is the

  1-methyl-1H-tetrazol-5-yl group.

  A particularly preferred group of compounds are those which have the formula II ## STR1 ##

1 2 2 <

  N-JB wherein R 1 R 2 N is di (C 1 -C 3) alkylamino (e.g. dimethylamino), furylmethylamino

  or pyrrolidino, piperidino, 4-methyl-

  piperidino, tetrahydropyridino or hexamethylene

  imino, preferably piperidino; A represents N and B represents CR 5, or A represents CR 5 and B represents N, R 5 represents a C 2 -C 4 alkyl group substituted by 2 hydroxy groups, a 2,2-di (alkyl) group;

  C 1 -C 3) (eg dimethyl) 1,3-dioxolane

  4-yl, a (1-methyl-1H-tetrazol-5-yl) -

  thiomethyl, or R 5 is phenyl- (C 1 -C 3) alkyl, for example benzyl, or h 6 -teroaryl- (C 1 -C 3 -alkyl), for example furylmethyl or pyridylmethyl, in which the alkyl part is is substituted by a hydroxy group, or phenyl-C 1 -C 3 alkyl, for example benzyl, in which the alkyl part is substituted with a C 1 -C 4 alkanoyloxy group, for example acetyloxy, or C 1 alkoxy; -C 2, for example methoxy, or R 5 represents the group CH 2 Z (CH 2) r R 8 in which R 8 represents a hydroxy or di-C 1 -C 3 alkylamino group, for example dimethylamino, Z represents oxygen and r is equal to 4, or R 8 represents the group -CH = CH 2 or the group COR 9 in which R 9 is a C 1 -C 4 alkoxy group (for example ethoxy) Z represents oxygen or sulfur and remains equal to 1, or Q represents a 1,3-benzene residue and X is a bond, N is equal to 0, Y represents oxygen and m is equal to 3 or 4; , prefer at 3, or X is oxygen, N is -20 to 1, Y is -CHOH and m is 1; or Q is a 2,5-furan or 2,4-thiophene moiety, X is a bond, Y is sulfur, N is 1, and m is 2, with the proviso that R 1 R 2 N is a di- (C 1 -C 3 alkyl) amino group when Q is a furan or thiophene ring. Another particularly preferred group of compounds are those of formula II wherein either R 1 R 2 N is dimethylamino, Q is 2,5-furan, X is a bond, Y is sulfur, N is at 1 and m is 2; or R 1 R 2 N is dimethylamino or pyrrolidino, piperidino or hexamethyleneimino, preferably piperidino, Q is 1,3-benzene, X is a bond, Y is oxygen, N is at O and mn is 3 or 4, preferably 3; and A is N and B is CR 5 or A is CR 5 and B is N, R 5 is benzyl in which the methylene group bears a hydroxy substituent; being specified that when Q represents a furan ring, preferably A represents N and B represents

CR 5.

  The most preferred compounds are: dimethylamino-methyl-2-furanylmethyl, ethyl-3-methanol,

  1-methyl-3-EL (1-methyl-1H-tetrasazol-5-yl) -thio-methyl-1-methyl

  N- (3-piperidinylmethyl) -phenoxy) -propyl-1H-1, 2,4-diol

triazo 1 and 5-amnine,

  1-methyl-α-phenyl-5111-3 (1-piperidinylmethyl) -

  phenoxy-propyl-1-aminol-1H-1,2,4-triazole-3-methanol,

  * 4-methyl-α-phenyl-5-1 (1-3) (1-piperidinylmethyl) -

  phenoxyl-propyl) 1-aminol-4H-1,2,4-triazole-3-methanol,

  1-methyl-5-1H (1-piperidinylmethyl) -phenoxy-propyl) -

  (1-methyl-5111-3 (1-piperidinylmethyl) -phenyl) -

  propyll-aminol-1 H-1, 2, 4-triazol-3-yl -2-pyridine

  methanol, 11 2-hydroxy-3 1 (1-piperidinylmethyl) -phenoxyl-

  propyl) 1-amino) -1-methyl: o-phenyl-1H-1,2,4-triazole

  3-methanol, 11.31 E (dimethylamino) methyl) phenoxy-propyl-aminol-1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol,

  5-flu-5-l (dimethylamino) -methyl-3-thienyl

  methyl-thio-ethyl) -aminol-1-methyl-ca-phenyl-1H-

1,2,4-triazole-3-methanol, 13-

  and their pharmaceutically acceptable salts.

  The invention also includes the salts of the compounds of formula I and organic acids and

  acceptable minerals for pharmaceutical use.

  Particularly useful salts include hydrochlorides, hydrobromides, sulphates, methanesulfonates, acetates, maleates, succinates, citrates, tartrates, fumarates, benzoates. The compounds of formula I and their salts It is also within the scope of the invention to form hydrates and the hydrates of the compounds of formula I. The compounds of formula I may have a tautomerism and the given formulas must be understood to apply to all tautomers. there are optical isomers, the given formulas must be understood as applying to all diastereoisomers and

optical enantiomers.

  It will also be understood that the invention comprises the bioprecursors compounds of formula I The term "bioprecursors" applies to compounds having a structure different from that of the compounds of formula I but which, when administered to a human or to an animal, are converted in the body to a compound of formula I. The compounds of formula I, preferably in the salt state, may be put into any form suitable for administration and intravenous administration.

  therefore also includes the pharmaceutical compositions

  These compositions may be prepared in the usual manner using one or more vehicles or excipient acceptable for use.

  Where necessary, these composi-

  14 - tions may also contain other components

  active agents, for example H 1 antagonists.

  Thus, the compounds of formula I can be formulated for oral, oral, topical, parenteral, or rectal administration.

  Oral administration is preferred.

  For oral administration, the pharmaceutical composition may take the form, for example, of tablets, capsules, powders, solutions, syrups, or suspensions prepared by conventional procedures using an excipient acceptable for use. pharmaceutical For oral administration, the composition may take the form of tablets or lozenges prepared in the manner

usual.

  The compounds of formula I may be formulated for parenteral administration by batch injection or continuous infusion. Injection compositions may be presented as dosage units in ampoules or multi-dose containers, with addition. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain auxiliary products such as suspending agents, stabilizers and / or dispersing agents. component: active can also be in powder form for reconstitution using a soluble vehicle, for example sterile pyrogen-free water,

before use.

  The compounds of formula I can also

  be put in the form of compositions for the administration

  rectal treatment such as suppositories, or enemas to retain, containing for example conventional bases for suppositories such as cocoa butter

or other glycerides.

  For topical application, the compounds of formula I may be in the form of ointments, creams, gels, lotions, powders or aerosols.

in the usual way.

  For internal administration, a suitable daily dosage of the compounds according to the invention will consist of 1 to 4 doses in total of 5 mg to 1 g per day, preferably 5 to 500 mg per day, according to

the patient's condition

  It will be understood that in the processes for the preparation of the compounds of formula I described below, it may be necessary in certain reaction stage to protect various reactive substituents of the starting materials for a particular reaction, and then to eliminate the protective group. such protection and; the subsequent removal of the protecting group may be particularly appropriate when R 1 and R 2 are hydrogen atoms and / or when R 3 is a hydroxy-substituted alkyl group and / or when R 5 contains a hydroxy or amino group may employ conventional procedures for protection and removal of the protecting group; for example, the amines can be protected by forming a phthalimide group which can then be removed by treatment with a hydrazine, for example the hydrazine hydrate of an amine

  primary, for example methylamine.

  In the description of the usable processes

  for the preparation of the compounds of formula I or intermediate products of their preparation, the

  symbols R 1 to R 15, A, B, Alk, Q, X, Y, Z n m pi q.

  r, x and y of the various formulas have the meanings given with reference to formula I unless otherwise indicated. The compounds of formula I in which R 5 represents the group (CH 2) q Z (CH 2) r R 8 or (CH 2) XS (CH 2) y R 15 may be prepared by reacting a triazole of formula I wherein R 5 is R 5 a, R 5 a is - (CH 2) q L or - (CH 2) x L and L is a leaving group such as halogen, methanesulfonyloxy or toluenesulfonyloxy, with an anion Z (CH 2) r R 8 or S (CH 2) y R The anion can be produced from the corresponding alcohol by treatment with sodium or a base strong as sodium hydride in the absence or in the presence of a solvent, for example dimethylformamide, at a temperature in the inter

  from 20 to 120 ° C, or from the corresponding thiol

  by treatment with a base such as potassium or sodium carbonate in the presence of a solvent, for example acetone, at a temperature in

The above range.

  Intermediates of formula I wherein R 5 is R 5a, R 5a is - (CH 2) q L or - (CH 2) XL may be prepared by reacting the corresponding compound wherein R 5 a is - (CH 2) q OH or - (CH 2) x OH with an acid chloride such as thionyl chloride,

  methanesulfonyl chloride or p-chloride

  toluenesulfonyl. Intermediates of formula I in which R 5 is R 5a, R 5 being (CH 2) q OH or (CH 2) XOH may be prepared as described in British Patent No. 2,047,238 A

and European Patent No. 48,555.

  The compounds of formula I can also be prepared by cyclizing an appropriate intermediate product. Thus, the compounds of formula I wherein R 5 has a meaning other than a straight or branched C 2 -C 17 alkyl group 6 substituted by 2 or 3 acyloxy groups, or a dihydroxyalkyl group forming a structure of acetal or cyclic ketal or an aralkyl or heteroaralkyl group in which the alkyl part is substituted with an acyloxy group, or else Y is other than CHOR 14 in which R 14 is acyl, can be prepared by cyclization of a compound of formula III: ## STR1 ## wherein R 6 is a group as defined for R 3,

  V 'is the group NCR c and Y' is hydrogen, V represents

  V is oxygen or sulfur and R 5 c is a group as defined for R 5 or a group convertible to such a group under the conditions of the cyclization reaction, or V 'is NH, R 16 is a group as defined for R 3 and Y 'represents the group CR 5 in which Y "represents sulfur, Y- oxygen or the NH group; or V 'is sulfur or oxygen, Y' is CR and R 16 is a group as defined for R 3; or V 'is NR 3, R 6 is hydrogen and Y' is CR, 31 R 16 is the Y IR Y Y "wherein Y" has the meaning indicated above.

18 -

  Thus, for example, in one embodiment of

  By the method of cyclization, a compound of formula I wherein A is N and B is CR 5 can be prepared by cyclizing a compound of formula IV 1 R 2 N Alk QX (CH 2) n Y (CH 2 where V represents sulfur or, preferably, oxygen, and U represents 2 hydrogen atoms, in the absence or in the presence of a solvent, for example a hydrocarbon such as toluene, a ketone such as acetone, or water, optionally by heating, for example in the range of 50 to 90 C. It may be convenient to prepare in situ the compounds of formula IV in which U represents two hydrogen atoms by treating a compound of formula IV wherein U represents a divalent protecting group which can be easily removed by rendering two hydrogen atoms, for example a benzylidene group, with the aid of an acid, for example hydrochloric acid, preferably hot, and under such conditions, the cyclization resulting in the corresponding compound of formula I normally occurs. I 9 -

  In another embodiment of the invention.

  cyclization of the compounds of formula III, compounds of formula I can be prepared by cyclizing a compound of formula V: ## STR1 ## ## STR1 ## in which R 16 is a group as defined for R 3, and either V 'is NH and Y "is sulfur, oxygen or NH, or YV' is sulfur or oxygen and Y" NH, or R 16 is hydrogen, V 'is NR and Y "

16 3

sulfur.

  When Y "represents sulfur, there is a possibility of tautomerism with the neighboring NH group (that is, -N = CR 5) and the -SH group can be SH alkylated under the usual conditions. the S-alkylated compound in the operation

cyclisation.

  The cyclization can be carried out by heating compound VI, for example in the range of 80 to C, in the absence or in the presence of a solvent, for example acetonitrile or dimethylformamide, or in basic medium, for example using hydroxide

aqueous potassium.

  In a convenient embodiment of this process, an intermediate compound of formula V in which R 16 is a group as defined for R 3, V 'is NH and Y "is oxygen, or R 16 can be prepared. represents hydrogen, V 'represents NR 3 and Y "represents oxygen, in situ, by reacting an aminoguanidine VI A 16 R 1 R 2 N Alk QX (CH 2) n Y (CH 2) m NH-i CN-NH 2 VI V '

  with an R 5 COOH acid or an activated derivative of such an acid.

  Suitable activated derivatives include acid halides, for example acid chlorides, alkyl chloroformates, acid anhydrides including mixed anhydrides (eg formic acetic anhydride), esters, and the like. such as alkyl esters, orthoesters (such as trialkyl orthoesters, for example R 5 C (O Et) 3) and 1-alkyl-2-pyridinyl esters), or derivatives formed from a coupling agent such as carbonyldiimidazole or carbodiimide such as dicyclohexylcarbodiimide.

  The acid and amino can be heated together

  guanidine VI under conditions in which a cyclization of the intermediate compound group V occurs directly with formation of a compound 21 - of formula I In the case of an active derivative, it is possible to

  aprotonic solvent, for example tetra-

  hydrofuran, at a temperature ranging from room temperature to reflux temperature When an acyl chloride is used as the activated derivative, the reaction may also be carried out in the presence of a base, for example a tertiary amine such as pyridine,

  which can also be used as a solvent.

  In general, intermediates of formula IV may be prepared from appropriate diamines by procedures analogous to those described in British Patent No. 2,047,238 A, and intermediates of formula V may be prepared from the appropriate diamines. by procedures analogous to those described in British Patent No. 2,023,133 A and European Patent No. 48,555. Aminoguanidines VI can be prepared as described in British Patent No. 2,023,133 A

and European Patent No. 48,555.

  Compounds of formula I wherein Alk is CH 2 can be prepared by treating an aldehyde of formula VII:

2 N -B

  by an amine R 1 R 2 NH> for example in a solvent such as tetrahydrofuran or an alkanol, for example ethanol, then by carrying out a reduction, for example with the aid of a reducing agent of the hydride type such as an alkali or alkaline earth borohydride, for example sodium borohydride, or else lithium aluminum hydride, or else hydrogen with a metal catalyst such as palladium or platinum The reactions can be carried out at a temperature of 0 to 8 OCe The intermediates of formula VII may be prepared from the compounds of formula VIII: WQX (CH 2) n Y (CH 2) m NH 2 VIII wherein W represents a protected aldehyde group,

  for example a cyclic acetal, such as an ethylene-

  acetal, by procedures analogous to those described above for the preparation of the compounds

  of formula I from said suitable amine.

  Compounds of formula I wherein R 5 represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted with a hydroxy group may be prepared by reacting the appropriate aldehyde or ketone with an organo-lithium compound Ar Li or a reagent of Grignard, Ar M Hal, Ar representing an aryl, aralkyl, heteroaryl group

  or appropriate heteroaralkyl and Hal halogen.

  The reaction may be carried out in a suitable solvent such as an ether, for example ethyl ether, tetrahydrofuran or a mixture of such solvents at a temperature ranging from -70 to + 50, preferably from -70 to + For the reaction with Ar Li and O at 50 ° C. for the reaction with Ar Mg Hal. The starting aldehyde or ketone can be prepared as described in British Patent No. 2,075,007 A

and European Patent No. 48,555.

  Compounds of formula I wherein R 5 has particular significance can be converted to compounds of formula I wherein R 5 has another significance by conventional interconversion procedures.

  Thus, the compounds in which R 5 represents

  is a straight or branched chain C 2 -C 6 alkyl group substituted with 2 or 3 acyloxy groups, or R 5 represents an aralkyl or heteroaralkyl group in which the alkyl part substituted by an acyloxy group, or Y represents CHOR 14 , R 14 being an acyl group, can be prepared by reacting the corresponding alcohol with an activated derivative (for example an acid chloride or an anhydride) of a suitable acid. The reaction can be carried out at room temperature, optionally in presence of a solvent (for example pyridine, tetrahydrofuran, acetone or dimethylformamide) and preferably in the presence of a base (for example pyridine, triethanolamine or an alkali metal carbonate such as potassium carbonate Compounds in which R 5 represents a straight or branched chain C 2 -C 6 alkyl group substituted with 2 or 3 alkoxy groups or R 5 represents an aralkyl or heteroaral group in which the alkyl part is substituted by an alkoxy group, may be prepared from the alcohol

  corresponding by treatment with a halogen agent

  for example, thionyl chloride to give a halogenated compound which is reacted with a suitable alkanol in the presence of sodium at a temperature of 20 to 50 ° C. The halogenated intermediate compound can also be treated with a suitable alkanol in a solvent such as dimethylformamide in the presence of a strong base such as hydride of

  sodium at a temperature of 20 to 100 C.

  The compounds in which R 5 represents the group (CH 2) q Z (CH 2) r R 8 in which R 8 represents 24 - NR 12 R 13 and R 12 and R 13 each represent a hydrogen or an alkyl group, may be prepared from the corresponding alcohol in which R 8 is a hydroxy group by treating with a reagent capable of converting the R 8 group to a removable group, for example with the aid of thionyl chloride, which

  gives a compound of formula I in which Z represents

  wherein L is a leaving group, for example a halogen, which is then reacted with ammonia or an appropriate amine, R 2 R 13 NH, preferably in a solvent such as an alkanol, by

  for example ethanol, at a temperature of 80 to 120 C.

  Compounds wherein R 8 is NHR 12 may be converted to compounds wherein R 8 is NR 12 R 13, R 13 is

  either an acyl group, an aryl group or alkyl-

  sulfonyl, reacting with an activated derivative

  of the appropriate carboxylic or sulfonic acid.

  Suitable activated derivatives include acid halides, for example acid chlorides, alkyl chloroformates, anhydrides including mixed anhydrides (eg formic-acetic anhydride) and esters.

  such as alkyl esters and orthoesters.

  The reaction with an acid halide is preferably carried out in the presence of a base, for example a mineral base such as sodium hydroxide or an organic base such as triethanolamine or pyridine. The reaction with an alkyl chloroformate is preferably carried out in the presence of a base, for example potassium carbonate or triethylamine, in a solvent such as dimethylformamide. The reaction with an anhydride is carried out in the absence or in the presence of a solvent.

such as pyridine.

  Compounds in which R 8 represents the group -CONR 1 R 1 may be prepared by reacting an activated derivative of the corresponding carboxylic acid in which R 8 represents the group -CO 2 H, for example an ester, with the ammonia or an appropriate amine HNR R in a suitable solvent, for example an alcohol such as ethanol, at a

temperature of 20 to 120 ° C.

  Compounds in which R 5 represents the group -CH (CH 2) p CH may be converted into the

OH OH

  corresponding compounds in which R 5 represents the group -CH (CH 2) p CH by reacting with an aldehyde V vo

R 6 R 7

  or ketone R R Co, for example acetone in the presence of an acid such as p-toluenesulfonic acid The reaction is carried out in the absence or in the presence of a solvent such as benzene, at a temperature

  between room temperature and temperature

reflux.

  When the product obtained by any of the processes described above is a free base and an acid salt, in particular a pharmaceutically acceptable salt, is desired, this salt can be formed in the usual manner. for example, a general convenient procedure for forming the salts comprises mixing the appropriate amounts of the free base and the acid in a suitable solvent or solvent mixture, for example an alcohol such as

  as ethanol or an ester such as ethyl acetate.

  The invention also includes the conversion of a salt

  from a compound of formula I to another salt.

26 -

  The following examples illustrate the invention

  without, however, limiting its scope; in these examples, the parts and percentages are by weight unless otherwise indicated and the temperatures are given in C. Unless otherwise indicated, the silica used for the column chromatography is

  Kieselger 60 (7734) from the firm Merck.

  Abbreviation TLC refers to thin layer chromatography; this chromatography is the chromatography of preparation were performed on silica with, unless otherwise indicated, one of the following solvent systems: System A: dichloromethane / ethanol / ammonia d = System B: System C: System D: System E:

0.88, 50: 8: 1

  dichloromethane / ethanol / ammonia d =

0.88, 25: 8: 1

  dichloromethane / ethanol / ammonia d =

0.88, 100: 8: 1

  ethyl acetate / isopropanol / ammonia d = 0.88, 75: 8: 1 dichloromethane / ethanol / ammonia d =

0.88, 75: 8: 1

27 - Preparation 1

  N-C 2,3-diacetyloxypropionyl-1-methyl-2-

  Methyl (phenylmethylene) -hydrazine-carboximidothioate 13.8 g of diacetylglyceric acid were refluxed in 50 ml of thionyl chloride for 4 hours. The solution was evaporated in vacuo and azeotroped with toluene (3 g). x 50 ml); an oil is obtained which is used as it is, without further purification. This oil is dissolved in ml of dichloromethane and added dropwise to a solution of 15.4 g of hydrochloride.

  1-methyl-2- (phenylmethylene) -hydrazine-carboximido-

  methyl thioate in 250 ml of dichloromethane and 19.3 ml of triethylamine pre-stirred at 200 for 1/2 hour The reaction mixture is stirred at 20 ° for 15 hours and then water is added. The organic phase is separated, it is dried over MgSO 4 and evaporated to give 7 g of a residue, which is chromatographed with the eluent ether, to give 4.6 g of the compound in the form of a substance.

-Solid yellow waxy.

  NMR (CD C 13): 2.16, s, (1H); 2.2-2.7, m, (3H); 4.58-5.45, m, (3H); 6.57, s, (3H); 7.67, s, (3H); 7.85, s, (3H);

7.93, s, (3H).

28 - Preparation 2

  N-1 2-acetyloxy E 2- (phenyl) -acetyl] -1-methyl-

  Methyl 2- (phenylmethylene) -hydrazine-carboximidothioate A solution of 11.35 g of acetyl chloride in 50 ml of dry ether is slowly added to a solution of 20 g of mandelic acid in 100 ml of ether. refluxed for 3 days and evaporated; a pale yellow oil is obtained. This oil is refluxed for 3 hours with 31 g of thionyl chloride. Thionyl chloride is removed by azeotropic distillation with toluene; 27.7 g of an oil are obtained

  we use it without further purification.

  This oil is dissolved in 50 ml of toluene

  and to a suspension of 5.8 g of triethyl

  amine and 6.9 g of 1-methyl-2- (phenyl) hydrochloride

  methylene) -hydrazine-carboximidothioate in 180 ml of dry toluene The mixture is stirred at room temperature for 15 hours, poured into water and extracted with ether. The organic extract is dried over MgSO 4 and evaporated; 6.3 g of the title compound is obtained as a cream-colored solid. NMR (CDCl3): 2.25, s, (1H); 2.3-2.8, m, (10H); 3.95, s, (1H); 6.7, s, (3H); 7.8, s,

(3H); 7.9, s, (3H).

29 - Preparation 3

  (i) 2-E 2-hydroxy-3- (1-piperidinylmethyl) -

  phenoxyl-propyll-1H-isoindole-1,3- (2H) -dione A mixture of 9.10 g of 2 (oxirannylmethyl) -1H-isoindole is heated to 1300 under a nitrogen atmosphere for 10 minutes. 1- (2H) -dione and 8.55 g of 3- (1-piperidinylmethyl) -phenol The mixture is dissolved in 100 ml of chloroform, washed twice with 25 ml of sodium hydroxide, dried over Mg SO 4 and evaporated; 17.65 g of the desired compound are obtained

in the state of gum.

TLC, system C; Rf 0.60.

* (ii) 1-amino-3 1 (1-piperidinylmethyl) -

  phenoxyl-2-propanol is refluxed for 3 hours

  solution of 17.6 g of 2-E 2-hydroxy-3-E 3- (1-piperidinyl)

  methyl) -phenoxyl-propyll-1H-isoindole-1,3- (2H) -dione and 2.5 g of hydrazine in 60 ml of ethanol The mixture is evaporated; a solid residue is obtained which is suspended in 30 ml of hydrochloric acid N; The filtrate is basified with an excess of potassium carbonate and extracted with isopropanol (3 × 40 ml). The isopropanol extracts are dried over Na 2 CO 3 and evaporated; a gum is obtained which is chromatographed with system A Crystallization of the product in the mixture n-hexane / ether (20: 1)

  gives the desired compound in the form of

  lore (7.7 g), melting at 74-76.5 - Preparation 4

  Acetate (ester) of 5-ll 3- (3-formylphenoxy) -

  propyll-amino} 1-methyl-α-phenyl-1H-1,2,4-triazole-3

  methanol A solution is stirred at 20 for 4 hours

  6.0 g of 3- [3- (1,3-dioxolan-2-yl) -phenoxyl]

  propanamine and 11.33 g of methyl N-1 2-acetyloxy-2-

  (phenyl) acetyl-1-methyl-2-ohenylmethylene) hyirazine carboxylic acid

  Midothioate (co-formed A) in 300 ml of toluene is added 30 ml of 5 N hydrochloric acid and stirred at 20 for a further 18 hours. The acid layer is separated and washed with toluene after alkalinization with 2 N sodium carbonate. and extracted with ethyl acetate. The extract is dried and evaporated; 9.0 g of a gum are obtained which are chromatographed on activated alumina (from Phase Separations Ltd (UG 1)) using as eluent a mixture of ether / ethyl acetate / methanol, 50: 1; 1.4 g of the desired compound are obtained in the state

of foam.

TLC, System C: Rf 0.7.

EXEPLE 1 i

  1-Methyl-5-l-3-ll (1-piperidinyl) hemicitrate

  methyl) -phenoxyl-propyll-aminol-1 H-1,2,4-triazole-3

ethane-1,2-diol

  To a mixture of 2.69 g of N-1 2,3-diacetyloxy-

  propionyl-1-methyl-2- (phenylmethylene) hydrazine

  methyl carboximidothioate and 100 ml of toluene,

  1.5 g of 3- [3- (1-piperidinylmethyl) phenoxyl] are added

  propanamine and the solution is stirred at 20 for 16 hours; 25 ml of 5 N hydrochloric acid are added and the mixture is stirred vigorously for 2 hours for another 16 hours. The acid layer is separated and the toluene layer is washed with 2 N hydrochloric acid. The combined acid layers are washed with toluene, one

  alkalizes then saturates the dry sodium carbonate.

  The alkaline solution is extracted with ethyl acetate and the combined organic extracts are dried over MgSO 4 and then evaporated. 2.0 g of a residue are obtained which are chromatographed using a chroroform / methanol mixture as eluent. 5: 1; 0.6 g of a foam is obtained which is redissolved in 20 ml of ethyl acetate and 4 ml of methanol; it is treated with the theoretical amount of citric acid in 20 ml of ethyl acetate in a nitrogen atmosphere. The suspension is stirred for 1/2 hour, the compound is collected and dried under vacuum; 0.53 g of the desired compound is obtained in the state of a white solid.

  melting at 73-74 (softening).

TLC, System D: Rf 0.46

Example 2 (a)

  2-hydroxy-3-1-3- (1-piperidinylmethyl) -

  phenoxy-propyll-aminol-1-methyl-α-phenyl-1H-1,2,4-

  triazol-3-methanol A solution is stirred at 20 for 4 hours

  2.0 g of 1-amino-3-1- (1-piperidinylmethyl) -phenoxyl-

  2-propanol and 3.19 g of N-1 2-acetyloxy-1 2- (phenyl) -

  acétylll-l-methyl-2- (phenylmethylene) -hydrazine-

  methyl carboximidothioate (compound A) in 60 ml of toluene; 9 ml of 5 N hydrochloric acid are added and the mixture is stirred at 200 for 16 hours and then is heated on a water-bath for 15 minutes. The acidic layer is separated off, washed with toluene and rendered alkaline with a saturated aqueous solution of bicarbonate. Sodium hydroxide was washed with toluene and the aqueous layer was basified with 5 N sodium hydroxide. The basic layer was extracted with hot 4-methyl-2-pentanone (3 x 100 ml), the extracts were washed with brine, dried and concentrated in vacuo to a final volume of ml; crystallization occurs 1.2 g of solids are collected on the filter; recrystallized on 2-propanol; 0.63 g of the desired compound is obtained in the form of a solid substance

blanchelfondant at 154-1570.

  Elemental analysis Found: C, 66.2; H, 7.2; N, 15.2%;

  C 25 H 33 N 503 calculated: C, 66.5; H, 7.4; N, 15.5%.

  Example 2 (b) By a similar procedure, starting from

  1.5 g of compound A and 0.74 g of 3- [3- (dimethylamino)]

  methyll-phenoxyl-propanamine except that the 4-methyl-2-pentanone extract was evaporated in vacuo and the residue (1.3 g) was chromatographed using System A as eluent, 0.31 g was prepared. of

  the hydrate of 5-ll3-3-1 (dimethylamino) -methyl-

  phenoxyl-propyll-aminol-1-methyl-α-phenyl-1H-1,2,4-

  triazole-3-methanol in the state of white foam.

  Elemental analysis Found: C, 63.7; H, 7.3; N, 16.6;

  C 22 H 29 N 502 1H 2 calcd: C, 63.9; H, 7.59; N, 16.9%.

  NMR (CDCl3-DMSO): 2.4-2.92, min, (6H); 3.05-3.33, m, (3H); 4.4, s, (1H); 4.65, s, (1), (1H); 5.58, s, (1), (1H); 5.98, t, (2H); 6.46.75, s + s + q, (7H); 7.85, s,

(6H); 8.0, quintuplet, (2H).

33 -

Example 2 (c)

  By a similar procedure, starting from

  1.5 g of the compound A and 0.99 g of 2- [2- (1-piperidinyl)]

  methyl) -phenoxyl-ethoxyl-ethanamine, except that the aqueous phase is extracted with hot ethyl acetate (6 × 50 ml) at pH 7 and that the chromatography is carried out with a dichloromethane / ethanol / ammonia mixture d = 0.88 (80: 8: 1), 0.45 g of

  1-methyl-α-phenyl-5-ll-1,2-l-3- (1-piperidinylmethyl) -

  phenoxyl-ethoxyl-ethyl-aminol-1 H-1,2,4-triazole-3

  methanol in the form of clear gum.

  Elemental Analysis Found: C, 66.95; H, 7.75; N, 14.65;

  C 26 H 35 N 503 calculated: C, 67.07; H, 7.58; N, 15.04%.

  NMR (CD C 13): 2.4-2.9, m, (6H); 3-3.35, m, (3H); 4.3, s, (1H); 5.6, t, (1H); 5.95, m, (2H); 6.27-6.8, m, (5H); 6.67, 2 xs,

  (6H); 7.75, m, (4H); 8.56, m, (6H).

Example 2 (d)

  511 (dimethylamino) -methyl-3-ethyl

  thienyll-methyl-thiol-ethyl-aminol-1-methyl-a-

  phenyl-1H-1,2,4-triazole-3-methanol is stirred for 4 hours in a solution

  1.09 g of 4-lll 2- (aminoethyl) -1-thiol-methyl-N, N-

  dimethyl-2-thiophene-methanamine and 2 g of compound A in 40 ml of toluene 5 ml of 5 N hydrochloric acid are added and the mixture is stirred at 20 for 16 hours and then heated on a water-bath for 10 minutes. acid at pH 3 with sodium bicarbonate, washed with toluene, basified with sodium carbonate and extracted with ethyl acetate. The extract is dried in acetate 34.degree. ethyl and evaporated; a gum is obtained which is chromatographed using C-system as eluent; 0.45 g of the desired compound is obtained in the state

of fawn moss.

  NMR (CD C 13 + DMSO): 2.35-2.85, m, (5H); 3.01, s, (1H); 3.12, s, (1H); 4.33, s, (1H); 4.62, t, (1H); 5.75, 1, (1H); 6.40, s, (2H); 6, 45, s, (2H); 6.55, s, (3H); 6.5-6.7, t, (2H); 7.35, t, (2H); 7.75, s,

(6H).

TLC, System A, Rf 0.5

Example 3

  (a) 1-methyl-N-1,3-l-3- (1-piperidinylmethyl) -

  phenoxyl-propyll-3-1 (2-propenyloxy) -methyl-1H-1,2,4-

triazol-5-amine

  3.59 g of 1-methyl-5-ll-l-3-one are dissolved.

  piperidinylmethyl) -phenoxyl-propyll-aminol-1H-1,2,4-

  triazol-3-methanol in 10 ml of thionyl chloride and heated at reflux for 15 minutes The orange-colored solution is evaporated under vacuum; a gum is obtained which is stirred in 35 ml of water. To this is added sodium bicarbonate and sodium carbonate (3 g)

  and the suspension is stirred with ethyl acetate.

  The organic phase is separated, dried for 1 hour on sodium carbonate and evaporated under vacuum; an oil is obtained which is redissolved in 10 ml of allyl alcohol; To the solution of 0.3 g of sodium in 8 ml of allyl alcohol is added. The reaction mixture is heated in a water-bath for 6 hours and is poured into water and extracted with ethyl acetate. The organic phase is extracted with 2N hydrochloric acid. The acidic extract is alkalinized with potassium carbonate and extracted with ethyl acetate. The evaporation of the organic extracts gives 1.1 g. an oil that is chromatographed using

  the dichloromethane / ethanol / ammo-

  niaque; 0.4 g of the desired compound is obtained in the form of an oil. Elemental analysis Found: C, 65.64; H, 8.46; N, 17.44;

  C 22 H 33 N 502 calculated: C, 66.14; H, 8.33; N, 17.53.

  TLC, System C: Rf 0.4 (b) By a similar procedure, starting

  3.59 g of 1-methyl-5-11β-1 3- (1-piperidinylmethyl) -

  phenoxyl-propyll-aminol-1H, 2,4-triazole-3-methanol and 10 ml of thionyl chloride and then adding a solution of 0.3 g of sodium in 10 g of butane-1,4-diol, 0.87 g of ethanolate was obtained

  (2: 1) 4-ll-methyl-5-ll-3-l-3- (1-piperidinylmethyl) -

  phenoxyl -propyl-amino} -1H-1,2,4-triazol-3-y-13-methoxy-butanol. Elemental analysis Found: C, 63.12; H, 8.81; N, 15.56;

23 H 27 N 5031/2 C 2 H 50 H

  Calculated: C, 63.40; H, 8.87; N, 15.41.

  NMR CCDC 13): 2.8, t, (1H); 3.0-3.3, m, (3H); , 4, t, (1H); 5.62, s, (2H); 5.95, t, (2H); 6.4, m, (6H); 6.4, s, (3H); 6.6, s, (2H); 7.0, 1, (1H); 7.6, m, (4H);

  7.9, m, (2H); 8.1-8.7, m, (10H).

36 -

Example 4 a

  Llll-methyl-5-lll-3-l 3- (1-) hemihydrate

  piperidinylmethyl) -phenoxyl-propyll-aminol -1H-1,2,4-

  triazol-3-yll-methyl-thiol-ethyl acetate 7.2 g of 1-methyl-5-ll-3-one were dissolved in

  piperidinylmethyl) -phenoxyl-propyll-aminol-1H-1,2,4-

  triazol-3-methanol ("Compound B") in 30 ml of 20-thionyl chloride and refluxed for 15 minutes. After cooling, evaporated in vacuo and redissolved in 30 ml of water, Carefully basify with solid sodium carbonate, add 3 g of sodium carbonate and extract the mixture with ethyl acetate. The extract is dried over Na 2 CO 3 for 1 hour and evaporated to give a The oil is redissolved in ml of acetone and refluxed for 16 hours with 2.76 g of potassium carbonate anhydrous and 2.4 g of mercapto-ethyl acetate. The mixture is partitioned between potassium carbonate. The ethyl acetate extract was dried and evaporated and the residue (5.1 g) was chromatographed using E as eluent to give 2.9 g of desired compound in the oil state

pale yellow.

  Elemental analysis Found: C, 58.7; H, 7.6; N, 14.8;

C 25 H 35 N 503 S-1/2 H 20

  calculated: C, 58.7; H, 7.7; N, 14.9%.

  NMR (CDCl3) 1: 2.75, dd, (1H); 3-3.33, m, (3H); 5.45, t, (1H); 5.666, q + t, (4H); 6.23-6.7, s + s + q + s + s, (11H); 7.61 to 7.86,

m, (6H); 8.7, t, (3H).

  The following compounds were prepared analogously from the compound B and the others

appropriate starter products.

37 -

Example-4b

  Starting from 1.41 g of the compound B, 0.50 E g of -mercapto-1-methyltetrazole and 0.54 g of potassium carbonate but chromatographing the mixture with the system C which gives 1.0 g of a When the oil is redissolved in ethyl acetate and treated with an excess of hydrochloric acid in ether, 0.6 g of sodium dihydrochloride sesquihydrate are obtained.

  lal-methyl-3-lll (1-methyl-1H-tetrazol-5-yl) thiol

  Methyl-N-1,3L-3- (1-piperidinylmethyl) -phenoxyl-propyl-

  1H-1,2,4-triazol-5-amine in the form of white powder

  which slowly softens above 400.

  NMR (D 20): 2.6, 2.9-3.0, m, (4H); 5.7-5.9, m, (6H); 6.04, s, (3H); 6.4-6.6, s + m, (7H); 7.05, t, (2H); 7.9-8.6, m, (8H)

Example 4 c

  Starting from 1.41 g of compound B, 0.52 g of 2-mercapto-5-methyl-1,3,4-thiadiazole and 0.54 g of potassium carbonate but chromatographing the mixture with system C, got 0.62 g of

  1-methyl-3 H (5-methyl-1,3,4-thiadiazol-2-yl) thiol

  mthyll-N-1,3-3- (1-piperidinylmethyl) -phenoxyl-propyl-

  1H-1,2,4-triazol-5-amine in the form of a white powder.

  which softens to 63 and melts at 72-74.

  Elemental analysis Found: C, 55.9; H, 6.7; N, 20.7;

  C 22 H 31 N 7052 calculated: C, 55.8; H, 6.6; N, 20.7%.

38 -

Example 5

  3 (4-dimethylamino) -butoxyl-methyl 3 -1-

  methyl-N-1,3-l-3- (1-piperidinylmethyl) -phenoxyl-propyl

  1H-1,2,4-triazole-5-amine 0.5 g of 4-lll-methyl-5-ll-3-one were dissolved

  piperidinylmethyl) -phenoxyl-propyll-aminol-1H-1,2,4-

  triazol-3-yll-methoxyl-butanol in 10 ml of thionyl chloride and stirred for 1.5 hours. The solution is evaporated in vacuo and the residue is redissolved.

  in 20 ml of water, the mixture is basified with bicarbonate

  sodium nate and dry sodium carbonate (approximately 2 g) The mixture is extracted with ethyl acetate, the extract is dried over Na 2 CO 3 over one hour, the residue is evaporated and the residual oil is redissolved in 15 ml of 33% ethanolic dimethylamine and the solution is then heated in an autoclave at 80 for 8 hours. The solution is evaporated; 0.3 g of a residual oil are obtained which are chromatographed using System A as eluent; 0.2 g of the title compound is obtained as a pale yellow oil. NMR (CDCl3): 1.74, dd, (1H); 3-3.32, m, (3H); , 48, t, (1H); 5.58, s, (2H); , 86, t, (2H); 6.24-6.64, s + s + m, (9H);

  7.48-8, m + s, (14H); 8.21-8.68, m, (10H).

TLC, System B: Rf 0.55.

39 -

Example 6

  α- (2-furanyl) -1-methyl-5-11β-1-3- (1-piperidinyl)

  methyl) -phenoxyl-propyll-aminol-1H-1,2,4-triazole-3-

  methanol 5.96 ml of n-butyl lithium (1.55 M in n-hexane) are added dropwise with stirring to a

  solution of 0.61 ml of furan in 20 ml of tetrahydro-

  anhydrous furan, in a nitrogen atmosphere and at -40 The solution is allowed to warm slowly to 20 with stirring, heated at reflux for 3 hours, added dropwise at 0 to a solution of 1.0 g

  1-methyl-5-ll-3-l-3- (1-piperidinylmethyl) -phenoxyl-

  propyll-aminol-1H-1,2,4-triazole-3-carboxaldehyde in 10 ml of tetrahydrofuran and the solution is stirred at 20 for 18 hours 20 ml of water are added, the mixture is concentrated, the mixture is extracted with ethyl acetate, the extract is dried and the residual oil (0.9 g) is chromatographed using the E system; 0.16 g of the title compound is obtained as an oil.

color: brown.

  NMR (CDCl3): 2.6, m, (1H); 2.76, t, (1H); 3.06-3.08, m, (2H); 3.23, m, (1H); 3.65, m, (2H); 4.25, s, (1H); , 48, t, (1H); 5.86, t, (2H); 6.38, q, (2H); 6.45, s, (3H); 6.56, s, (2H); 7.62, m, (4H); 7.88, quintuplet, (2H);

8.36, m, (6H).

TLC, System A: Rf 0.7 -

Example 7

  3- (2,2-dimethyl-1,3-dioxolan-4-yl) -1-

  methyl-N-1,3L-3- (1-piperidinyl) methylphenylpropyl-

  H-1,2,4-triazol-5-amine is stirred at 200 for 16 hours.

  solution of 0.08 g of 1-methyl-5-ll-3-t 3- (1-piperidinyl)

  methyl) -phenoxyl-propyll-aminol -1 H-1,2,4-triazole-3-

  ethane-1,2-diol, 2.0 ml of 2,2-dimethoxypropane and 0.03 g of 4-toluenesulfonic acid in 10 ml of acetone, evaporated and partitioned between 2 N sodium carbonate and ethyl acetate The extract is dried in ethyl acetate and evaporated; 0.07 g of a residual oil is obtained which is chromatographed using the system E as eluent; 0.025 g of the desired compound is obtained in the form of gum

amber color.

  NMR (CDCl3): 2.78, t, (1H); 3.08-3.23, m, (3H); 4.96, dd, (1H); 5.48, t, (1H); , 72, dd, (1H); 5.80, t, (1H); 5.88, t, (2H); 6.37, q, (2H); 6.46, s, (3H); 6.55, s, - (2H); 7.62, m, (4H); 7.87, m, (2H);

8.4-8.6, m, (9H).

TLC, System D: Rf 0.7 -

Example 8

  N-methyl-III-methyl-5-11H-1-3- (1-piperidinyl)

  methyl) -phenoxyl-propyll-aminol-1H-1,2,4-triazole-3-

  Yll-methyl-thiol-acetamide is heated under reflux for 30 hours in

  nitrogen atmosphere a solution of 4 g of lll 1-methyl

  3- (1-piperidinylmethyl) -phenoxyl -propyl-aminool-1H-1,2,4-triazol-3-yl-methyl-thiol-ethyl acetate in 20 ml of 33% ethanolic methylamine, The mixture is cooled, evaporated in vacuo, the residue is redissolved in 20 ml of 2N hydrochloric acid and washed with ethyl acetate. The acidic layer is made alkaline with potassium carbonate and extracted with sodium acetate. ethyl, the extract is dried and evaporated; 0.28 g of an oil is obtained which is chromatographed using the system E as eluent; 0.13 g is obtained

  of the desired compound as an oil.

  NMR (CDCl3): 2.46, s (1), (2H); 2.79, t, (1H); 3.07, m, (2H); 3.22, dd, (1H); 5.34, t, (1H); 5.85, t, (2H); 6.4, s + q, (4H); 6.46, s, (3H); 6.56, s, (2H); 6.72, s, (2H); 7.19, d, (3H); 7.63, m, (4H); 7.86, m, (2H); 8.42, m, (4H);

8.57, m, (2H).

TLC, System A: Rf 0.7 42 -

Example 9

  Compound of 1-methyl-α-phenyl-5-ll-1-l 3- (1-

  piperidinylmethyl) -phenoxyl -propyl-aminol-1H-1,2,4-

  triazole-3-methanol, fumaric acid and ethyl acetate, 40:56: 5 melt-heated for 2 hours

  to 60 0.72 g of 3-l 3- (1-piperidinylmethyl) -phenoxy J-

  propanamine and 1,1 N-f 2-acetyloxy-1 2- (phenyl) -

  acétylll-l-methyl-2- (phenylmethylene) -hydrazine-

  methyl carboximidothioate; a gum is obtained which is redissolved in toluene; The pH of the aqueous phase is adjusted to 7 with sodium carbonate and washed with toluene and with ethyl acetate. The organic extracts are dissolved in sodium carbonate and extracted with ethyl acetate. The organic extracts are known from MgSO 4 and evaporated; 1.1 g of an oil are obtained, which is chromatographed using a dichloromethane / ethanol / ammonia mixture d = 0.88, 8: 1 as eluent; 0.25 g of white solids, m.p. 42-52, are obtained. 0.12 g of this solid are dissolved in ethyl acetate and treated with a solution of 0.03 g of fumaric acid in ethyl acetate. 'ethyl; the compound is sought precipitates; we collect it; Yield: 0.095 g

  a white solid substance melting at 80.

  NMR (CDCl3) of free base: 2.4-2.9, m, (6H); 3.0-3.4, m, (3H); B 4.31, s, (1H); 5.56, t, (1H); 5.93, t, (2H); 6.3-6.7, q + s + s, (7H); 7.5-7.75, m, (4H); 7.92, m, (2H); 8.3-8.7, m, (6H) 43 -

Example 10

  4-methyl-α-phenyl-5-11β-3- (1-piperidinyl)

  methyl) -phenoxyl-propyl-aminol-4H-1,2,4-triazole-3-

  methanol 40 to 1250 is heated and a mixture of 30.4 g of DL-mandelic acid is maintained at this latter temperature in the molten state for 6 hours

  and 22.35 g of N-amino-N-methyl-N 11-iodhydrate.

  D 3-1 3- (1-piperidinylmethyl) -phenoxyl-propyll-guanidine.

  The hot melt is extracted with 250 ml of hot water and the aqueous extract is alkalinized with dry sodium carbonate and then extracted with ether. The ethereal extract is cooled to 5 ° C. a white solid is obtained which is washed with boiling ethyl acetate; yield: 0.18 g of the title compound as a white solid, mp 186-188 Elemental analysis Found: C, 68.9; H, 7.7; N, 16.0;

  C 25 H 33 N 502 calculated: C, 68.9; H, 7.6; N, 16.1%.

Example 11

  Hydrate of the acetate (ester) of 4-methyl-a-

  phenyl-5-ll-3-l-3- (1-piperidinylmethyl) -phenoxy-propyl-

  aminol-4H-1,2,4-triazole-3-methanol The mixture is stirred at ambient temperature for 16 hours.

  hours a solution of 0.10 g of 4-methyl-a-phenyl-5-

  11 3 1 (1-piperidinylmethyl) -phenoxyl -propyl-aminol

  4 H-1,2,4-triazole-3-methanol and 0.03 ml of acetic anhydride in 2 ml of pyridine A saturated solution of sodium carbonate is added and the suspension is extracted with ethyl acetate The organic phase is washed with water and brine and evaporated in vacuo. The residue is crystallized from isopropyl acetate; the desired compound is obtained at 44 - the state of white solid, mp 89-91

with a yield of 0.074 g.

  Elemental analysis: found: C, 64.9; H, 7.5; N, 13.8; C 27 H 35 N 503 H 20 calculated: C, 65.3; H, 7.4; N, 14.1%.

Example 12

  1-methyl-5-ll-3-l-3- (1-piperidinylmethyl) -

  phenoxyl-propyll-aminol-1H-1,2,4-triazole-3-yll-2-

  pyridinemethanol is added dropwise in 15 minutes under

  stirring 8.12 ml of 1.6 M n-butyllithium in the n-

  hexane to a solution of 1.86 g (1.12 ml) of 2-bromine

  pyridine in 10 ml of anhydrous ether at -70 under a nitrogen atmosphere The brown solution is stirred at -7 ° C. for 1/2 hour and then added dropwise

  dropwise at -70 a solution of 2.0 g of 1-methyl-5-

  11β-1-3- (1-piperidinylmethyl) -phenoxyl-propyl-aminol

  1H-1,2,4-triazole-3-carboxaldehyde in 20 ml of anhydrous tetrahydrofuran and the solution is stirred at -40 for 2 hours; 20 ml of water are added and the mixture is allowed to stand overnight. The mixture is concentrated, extracted with ethyl acetate, the extract is dried and evaporated; 2.5 g of an oil are obtained which are chromatographed using the system E as eluent; 0.48 g of a solid substance is obtained which is crystallized from ethyl acetate; yield: 0.25 g of the desired compound

  the state of white powder melting at 152-154 (decomp).

  Elemental analysis: Found: C, 65.9; H, 7.4; N, 19.1;

  C 24 H 32 N 602 calculated: C 66.0; H, 7.4; N, 19.2%.

-

Example 13

  Dihydrochloride of 5-ll-lll-5-l (dimethylamino)

  methyll -2-furanyll-methyl-thiol -ether A -aminol-1-methyl-

  α-phenyl-1H-1,2,4-triazole-3-methanol is stirred at room temperature for 3 hours.

  hours a solution of 3.09 g of 2-lll 5-1 (dimethyl-

  amino) -methyl-2-furanyll-methyl-thiol-ethanamine

  and 5.9 g of N-E 2-acetyloxy-L 2- (phenyl) acetyl-1

  methyl-2- (phenylmethylene) -hydrazine-carboximidothioate methyl in 110 ml of toluene is added

  0.3 g of N-1 2-acetyloxy-1-phenylacetyl-1-methyl

  Methyl 2- (phenylmethylene) -hydrazine-carboximidothioate and the mixture is stirred at room temperature for 1.5 hours. Then 22.5 ml of 2M hydrochloric acid are added and the mixture is heated in a water bath for 1 hour. The aqueous layer is adjusted to pH 6 with potassium carbonate and washed with toluene (2 × 30 ml). The aqueous acidic layer is made alkaline with potassium carbonate and

  extracted with ethyl ether and ethyl acetate.

  The combined organic extracts are dried and evaporated; a brown gum is obtained which is chromatographed on silica using a dichloromethane / ethanol / ammonia mixture, 65: 8: 1; 1.35 g of a brown gum are obtained which is redissolved in methyl acetate; treated with hydrogen chloride in ether; a white solid is obtained which is triturated with dry ether; yield: 1.3 g of the title compound as a fine white solid

softening to 55-60.

  NMR (CD 3 OD): 2.5, m, (5H); 3.3, d, (1H); 3.6, d, (1H); 4.15, s, (1H); 5.6, s, (2H); 6.3, m,

(7H); 7.15, m, (8H).

46 -

Example 14

  3- (3- (3-furanylmethyl) -aminol-methyl-

  phenoxy-3-propyl-3-aminol-1-methyl-α-phenyl-1H-1,2,4-

  triazol-3-methanol is stirred at 21 for 1.5 hours a

  solution of 1.0 g of 5 ll-3- (3-formyl) acetate (ester)

  phenoxy) -propyl-aminol-1-methyl-phenyl-1H-1,2,4-

  triazol-3-methanol and 5 ml of furfurylamine in ml of ethanol and then a suspension of 1.3 g of sodium borohydride in 10 ml of ethanol is added and stirring is continued for a further 16 hours at 21 ml. ml of water, the mixture is concentrated to remove the ethanol and the aqueous residue is extracted with 4-methylpentan-2-one.

  extract and evaporate; we get an oil.

  The furfuryl extract is removed under vacuum; The residue is dissolved in 2N hydrochloric acid, the acid layer is washed with ethyl acetate, the mixture is basified with sodium carbonate and extracted with 4-methylpentan-2-one. extracted with water, dried and evaporated; 0.65 g of a brown gum are obtained which are chromatographed on silica (Merck No. 7729) using C-system as eluent; 0.5 g of the desired compound is obtained

  in the state of pale orange gum.

TLC System C: Rf 0.35.

  NMR (CD C 13): 2.50, db, (2H); 2.6-2.84, m, (5H); 3.14-3.4, m, (2H); 3.24, d, (1H); 3.70, dd, (1H); 3.82, dd, (1H); 4.28, s, (1H); 5.5, t, (1H); , 92, t, (2H); 6.23, s, (2H); 6.25, s, (2H); 4.44, q (dt), (2H); 6.56, s, (3H); 6.6-8, m, (2H);

7.94, m, (2H).

47 -

Example 15

  3 II (2-furanyl) -methyl-thiol-methyll -1-

  methyl-N-1,3L-3- (1-piperidinylmethyl) -phenoxyl-propyl-

  1H-1,2,4-triazole-5-amine Heated in a water bath for 10 minutes

  a solution of 3.59 g of 1-methyl-5-ll-l-3-one.

* piperidinylmethyl) -phenoxyl-propyll-aminol -1H-1,2,4-

  triazol-3-methanol in 10 ml of thionyl chloride.

  The solution is evaporated to dryness and the residue is redissolved in water. Sodium bicarbonate is added to the solution until the effervescence ceases. 3 g of sodium carbonate are added and the suspension is extracted with acetate. of ethyl The organic extract is dried and evaporated; we obtain 4.1 g of a

brown oil.

  3.2 g of this oil are dissolved in 40 ml of anhydrous ethanol and 5 g of a solution of 1.14 g of furfurylmercaptan and 0.34 g of sodium are added in 20 ml of anhydrous ethanol. The suspension is allowed to settle. room temperature during

  18 hours, filtered and the filtrate evaporated to dryness.

  The residue is dissolved in 0.2N hydrochloric acid, washed with ethyl acetate and basified with an excess of dry sodium carbonate. The basic solution is extracted with ethyl acetate. The extract is dried. organic and evaporated; 2.2 g of an oil are obtained which are purified by column chromatography using chloroform as eluent;

  yield: 1.2 g of the desired compound as an oil.

  TLC, System C: Rf 0.45 NMR (CDCl3): 2.7, d, (1H); 2.8, t, (1H); 3.03.4, m, (3H); 3.8, m, (2H); , 5, t, (1H); 5.95, t, (2H); 6.25, s, (2H); 6.3-6.7, m, (9H);

7.5-8.1, m, (6H); 8.5, m, (6H).

48 -

Example 16

  Composed of 5- (methoxyphenylmethyl) -4-

  methyl-N-11-3- (1-piperidinylmethyl) -phenoxylpropyl-

  4 H-1,2,4-triazoleamine and 1: 1 tartaric acid are stirred at room temperature for 1 hour.

  hour a solution of 0.37 g of 4-methyl-a-phenyl-5-

  11β-1-3- (1-piperidinylmethyl) -phenoxyl-propyll-amino J -

  4 H-1,2,4-triazole-3-methanol in 3.0 ml of thionyl chloride The solvent is removed in vacuo The residual pink foam is redissolved in ml of dry methanol and added dropwise at a temperature of solution of 0.17 g of sodium in 10 ml of dry methanol The solution is stirred at ambient temperature for 1/2 hour, poured into water and extracted with ethyl acetate. The organic extract is dried and we evaporate it; 0.3 g of a gum is obtained which is redissolved in ethyl acetate; treated with tartaric acid with ethyl acetate; 0.26 g of the desired compound is obtained in the form of

  white solid, softened at 88.

  NMR (CD 30 D): 2.5-3.1, m, (9H); 4.5, s, (1H); , 6, s, (2H); 5.8, s, (2H); , 9, t, (2H); 6.48, t, (2H); 6.60, s, (3H); 6.80, s, (3H); 6.85, m, (4H); 7.85, m, (2H);

8.2, m, (6H).

49 -

Example 17

  ll 2 lll 5 r (dimethylamino) -methyll -2-

  furanyll-methyl-3-thiol-ethyl-aminol-1-methyl-a-

  phenyl-1H-1,2,4-triazole-3-methanol The mixture is stirred at room temperature for 3 hours.

  hours a solution of 3.09 g of 2-ll 5-l (dimethyl-

  amino) -methyl-2-furanylméthyll-thiol-ethanamine

  and 5.9 g of N-1 2-acetyloxy-2- (phenyl) -acetyl-1-

  Methyl methyl 2- (phenylmethylene) -hydrazine-carboximidothioate (Compound A) in 110 ml of toluene and again 0.3 g of Compound A was added. The mixture was stirred at room temperature for another 1.5 hours, added 22.5 ml of 2M hydrochloric acid and

  the mixture is heated in a water bath for 1 hour.

  The aqueous layer is adjusted to pH 6 with sodium carbonate and washed with toluene. The aqueous acidic layer is made alkaline with potassium carbonate and extracted with ethyl ether and ethyl acetate. The extracts are dried. organic combined and evaporated; a brown gum is obtained which is chromatographed with dichloromethane / ethanol / ammonia 65: 8: 1; we obtain 1.95 g of a brown gum On

  redissemble 0.5 g of this gum in the tetrahydro-

  dry furan and filtered on 'Florisil' (a commercial activated magnesium silicate) The filtrate is concentrated to a small volume, giving 0.32 g of the desired compound as a solid substance

  white color melting at 121-122.5.

  Elemental analysis Found: C, 60.0; H, 6.9; N, 17.3;

  C 20 H 27 N 502 S calculated: C, 59.8; H, 6.8; N, 17.4%.

  - Examples of compounds Tablets Active component Microcrystalline cellulose for pharmaceutical use Magnesium stearate for pharmaceutical use pharmaceutical formulations mg / tablet

, 0 to 125.0

293.5 to 173.5

1.5 to compression weight

3000.0

  The drug is sieved through a 250 μm sieve, mixed with the excipients and tableted with 9 mm diameter punches. Other concentrations can be achieved by modifying the compression weight and using the punches.

appropriate.

  The tablets may be coated with film-forming polymers, such as hydroxypropyl methylcellulose, according to standard procedures. Tablets may also be coated.

sugar.

  Capsules Active ingredient Starch 1500 * for pharmaceutical use Magnesium stearate for pharmaceutical use mg / capsule

, 0 to 125.0

243.5 to 123.5

1.5 Filling weight 250.0

  * This is a form of starch directly compressed

  sible. The active drug is sieved through a 250 μm sieve and mixed with the excipients. The mixture is introduced into hard gelatin capsules. 2 on a suitable machine Other doses can be prepared by changing the filling weight and when necessary changing the size

of the capsule.

  Solution for intravenous injections g / l Active ingredient 2 to 5 Water for injection 1000 Sodium chloride can be added to adjust the tone of the solution and it can also be adjusted to the pH corresponding to the maximum stability using an acid or an alkali diluted The solution is prepared, clarified and packaged in a nitrogen or other inert gas atmosphere in appropriate sized ampoules which are fused with glass The solution for injection is sterilized by

  autoclave heating according to one of the cycles

  However, the solution can also be sterilized by filtration and introduced into

  sterile ampohles under aseptic conditions.

  Syrup mg / dose of 5 ml Active ingredient 5.0 to 250.0 Sucrose 2795.0 to 2550.0 Glycerine 500.0 * Buffer Aroma when necessary Colorant Distilled water Supplement to 5.0 ml 52 - Dissolve active component, the buffer, the aroma, the preservative and the dye in part of the water The remainder of the water is heated to about 80 and the sucrose is dissolved in this water and then cooled The two solutions are mixed, the final volume is adjusted and clarified by filtration. The active component, the sucrose, the buffer, the aroma, the dye and the preservative can also be mixed.

  and introduce the powder into vials to reconstitute

  subsequent formation by addition of water.

  In the examples above, the component

  active agent is preferably 5-ll-lll-5-l (dimethylamino) -

  methyl-2-furanyll-methyl-thiol--ethyl-amino-1-

  methyl-α-phenyl-1H-1,2,4-triazole-3-methanol

  salts acceptable for pharmaceutical use

that, for example the hydrochloride.

  The ability of the compounds of the invention to inhibit the secretion of gastric acidity induced by istamine was demonstrated in the rat stomach test in infusion discussed above. test, the compounds of Examples 1, 2a, 2b, 2d, 3a, 3b, 4a, 4b, 6, 8, 9, 11, 12 and 13 have values of

  the range of 0.019 to 0.20 mg / kg.

  The compounds according to the invention have a general low toxicity at the doses at which they cause an effective inhibition of the secretion of gastric acidity. For example, the compounds of Examples 1, 2a, 2b, 2d, 4b, 6, 9, 10, 11 and 13 have no toxic effect when administered intravenously to anesthetized rats

  at a dose of at least 14 times their DE 50 value.

53 -

Claims (1)

Compounds having the general formula (I) R 3 NA (I) R 1 R 2 N-Alk-QX- (CH 2) n Y (CH 2) m NH N the physiologically acceptable salts and hydrates of these compounds, wherein: R 1 is hydrogen, C 1 -C 4 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, or hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl substituted alkyl; R 2 represents hydrogen or a C 1 -C 4 alkyl group; or R 1 and R 2 may together form, with the nitrogen atom to which they are attached, a 5- to 10-membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted with one or more C 1 -C 3 alkyl groups or with a hydroxy group and / or may contain another heteroatom selected from oxygen or sulfur; Alku represents a straight or branched C 1 -C 3 alkylene chain; Q represents a furan or thiophene ring connected to the rest of the molecule by bonds in positions 2 and 5, the furan or thiophene ring optionally bearing another substituent R 4 adjacent to the group R 1 R 2 N Alk; or Q represents a thiophene ring connected to the rest of the molecule by bonds in the 2 and 4 positions, this thiophene ring optionally bearing another substituent R 4 54 - close to the group R 1 R 2 N-Alk-, being specified that when the group R 1 R 2 N-Alk is in position 4, the group R 4 is in position 5; or Q represents a benzene ring linked to the remainder of the molecule by bonds in positions 1 and 3 or 1 and 4; R 4 represents a halogen or a C 1 -C 4 alkyl group which may carry a hydroxy or C 1 -C 4 alkoxy substituent; X is oxygen, sulfur, -NH-, methylene, or a bond; Y represents oxygen, sulfur, a methylene group or a bond; n is 0.1, 2 or 3 and m is a number from 2 to 5; being specified that (a) the total number of atoms of the chain X (CH 2) n Y (CH 2) m is from 3 to 8, (b) when X and Y represent oxygen or sulfur, N is equal to 2 or 3, (c) when X represents -NU-, Q represents a benzene ring and Y represents a methylene group or a bond, and (d) when Q represents a benzene ring, X represents oxygen and N is equal to 1, m may further be 1 and Y may further represent the group -CHOR 14 wherein R 14 is hydrogen or acyl; and R 3 represents hydrogen, an alkyl, alkenyl, aralkyl or a C 2 -C 6 alkyl group substituted with a hydroxy or alkoxy group; or A is N and B is CR 5; or A is CR 5 and B is N; and R 5 represents: i) a straight or branched chain C 2 -C 6 alkyl group substituted with 2 or 3 hydroxy, alkoxy, or acyloxy groups, or the dihydroxyalkyl group may form an acetal structure or cyclic ketal of formula: - / (CH 2) p -C H 1 CH-IIO / R 6 R 7 in which p is equal to O or 1 and R 6 and R 7, which may be identical or different, each represent the hydrogen, C 1 -C 4 alkyl or phenyl; or ii) the group (CH 2) q Z (CH 2) r R 8, wherein q is a number from 1 to 4 inclusive, r is a number from 1 to 6 inclusive, Z represents the oxyhydrogen gene or sulfur and when r is 1, R 8 is CH = CH 2, alkenyl or COR 9 wherein R 9 is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or group N Wherein R 10 is hydrogen or alkyl and R 1 is hydrogen or alkyl and when r is 2 to 6, R 8 has any of the meanings indicated above or further represent hydroxy, alkoxy, aryloxy, or NR 12 R 13 wherein R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, alkyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl ; or iii) the group (CH 2) x S (CH 2) 5 wherein x is 1 or 2, y is 0 or 1 and R 15 is heteroaryl; or iv) an aralkyl or heteroaralkyl group in which the alkyl portion is substituted with hydroxy, alkoxy or acyloxy groups. Compounds according to claim 1, characterized in that: R represents a C 1 to C 8 alkyl group, a C 1 to C 4 alkyl group substituted with a trifluoromethyl group, a C 2 to C 2 alkyl group; C 4 substituted with hydroxy or di-C 1 -C 3 alkylamino, C 5 -C 7 cycloalkyl, C 3 -C 5 alkenyl, C 1-4 phenyl-C 1-4 alkyl C 3 or a heteroaryl (C 1 -C 3) alkyl group wherein the heteroaryl ring contains a heteroatom; R 2 represents hydrogen or a methyl group; or R 1 R 2 N represent a ring of 5 to 8 catkins possibly containing a double bond, an oxygen atom or an alkyl substituent; Alk represents a methylene group; Q represents a benzene ring connected to the remainder of the molecule by bonds in positions 1 and 3; or a furan ring connected to the rest of the molecule by bonds in positions 2 and 5 and optionally carrying a substituent R 4 adjacent to the group R 1 R 2 N Alk, R 4 being a C 1 -C 4 alkyl group; or a thiophene ring connected to the rest of the molecule by bonds in the 2 and 4 positions, with the substituent Ri R 2 N Alk at the 2-position; being specified that when Q is a benzene ring as just defined, X is a bond, n is 0, Y is oxygen and m is 3, 4 or 5, or X and Y both represent oxygen, N and m are both equal to 2, where X is oxygen, Y is CHOH and n and m are both equal to i; and when Q is a furan or thiophene ring as just defined, X is a bond and 57 - or Y is sulfur or CH 2, N is 1 and m is 2, or Y is 1 oxygen, N is equal to i and m to 3; R 3 represents hydrogen or an alkyl group; R 5 represents a C 2 -C 4 alkyl group substituted with two hydroxy groups, or a 2,2di (C 1 -C 3) alkyl, 1,3-dioxolan-4-yl group; or R 5 is phenyl- (C 1 -C 3) alkyl, or heteroaryl (C 1 -C 3) alkyl wherein the alkyl moiety is substituted with hydroxy, (C 1 -C 4) alkanoyloxy or C 1 -C 2 alkoxy; or R 5 represents the group (CH 2) q Z (CH 2) r R 8 in which q is equal to 1, r is a value of 1 to 4 when Z represents oxygen, or r is equal to 1 when Z is sulfur, and R 8 is hydroxy, -CH = CH 2, di- (C 1 -C 3 alkyl) amino or COR 9 wherein R 9 is C 1 alkoxy; C 4 or NHR 1 wherein R 1 is C 1 -C 3 alkyl; or R 5 represents the group (CH 2) S (CH 2) y R 15, wherein x is 1 and the heteroaryl group R 15 is a tetrazolyl or thiadiazolyl group substituted by a C 1 -C 6 alkyl group; 3, or R 15 represents the furyl group. Compounds according to claim 1, characterized in that R 1 represents a C 1 to C 8 alkyl group, a C 1 to C 4 alkyl group substituted with a trifluoromethyl group or a C 2 -C alkyl group. 4 substituted by a hydroxy group or a di- (C 1 -C 3) alkylamino, C 5 -C 7 cycloalkyl, C 3 -C 5 alkenyl, phenyl (C 1 -C 3) alkyl or betéroaryl group; C 1 to C 3 (alkyl) wherein the heteroaryl ring contains a heteroatom, R 2 is hydrogen or methyl; or else R 1 R 2 N represent a 5- to 8-membered ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Alk represents a methylene group; Q represents a benzene ring connected to the rest of the molecule by bonds in positions 1 and 3; or a furan ring connected to the rest of the molecule by bonds in the 2 and 5 positions and optionally carrying a substituent R 4 close to the R 1 R 2 N Alk group, R 4 being a C 1 to C 4 alkyl group; or a thiophene ring connected to the rest of the molecule by bonds in the 2 and 4 positions, the substituent R 1 R 2 N Alk being in the 2-position; being specified that when Q is a benzene ring as just defined, X is a bond, N is 0, Y is oxygen and m is 3, 4 or 5, or X and Y are oxygen and n and m are both 2, or X is oxygen, Y is CHOH and N and m are both 1; and when Q is a furan or thiophene ring as just defined, X is a bond and either Y is sulfur or CH 2, N is 1 and m is 2, or Y is 1 oxygen, N is 1 and m 3; R 3 represents hydxgene or an alkyl group; R 5 represents a C 2 -C 4 alkyl group substituted by two hydroxy groups or a 2,2-di (C 1 -C 3 alkyl) 1,3-dioxolan-4-yl group; or R 5 is phenyl (C 1 -C 3) alkyl in which the alkyl moiety is substituted with C 1 -C 4 alkanoyloxy or C 2 -C 4 alkoxy, or heteroaryl- (C 1 -C 3) alkyl group in which the alkyl part is substituted with a hydroxy, C 1 -C 4 alkanoyloxy or C 1 -C 2 alkoxy group. IR 5 represents the group (CH 2 q Z) ( CH 2 'Rdaslqeq is 1, r is 1 to 4 when Z is oxygen, or r is 1 when Z is sulfur, and R 8 is hydroxy, the group -CH = CH , di- (C1-C3) alkylamino or COR9 wherein R9 is (C1-C4) alkoxy, or NHR11 wherein R is (C1-C3) alkyl or R 5 represents the group <CH 2) S (CH 2 y 15 wherein x is 1 and the heteroaryl group R is a tetrazolyl or thiadiazolyl group substituted by a C 3 -C 3 alkyl group, or R 15 represents a furyl group. 4 Compo A compound according to claim 1, selected from the group consisting of: 1-mylyl-3-LZZ-1-methyl-1H-tetrazol-5-ylthio 7-methylt :: NZ-3-aj ( 1-Piperidinylmethyl) -phenoxy-7-propyl-7H-1,2,4triazol-5-amine, 1-methyl-at-phenyl-5-LZ 3 (1-piperidinylmethyl) phenoxypropylamino 7-4H-1, 2, 4-triazole-3-methanol, 1-methyl-5-Z-ZZ (1-piperidinylmethyl) phenoxy-7-propyl-17-amino-7H-1,2,4- triazole-3-ethane-1,2-diol, n-7-propyl-aminon-1H, 2,4-triazol-3-yl-17-pyridine-methanol, -Z-25-hydroxy-3-Z 3 <1-piperidinylmethyl> -phenoxy-7-propyl-7-amino-1-methyl-ca-phenyl-1H, 2-4-triazol-3-methanol, -Z-3-L-3-L (dimethylamino) Methyl 7-phenoxy-7-propyl 17-amino-7-1-methyl-c-phenyl-1H, 2,4-triazol-3-methanol, -Z 2 -LZZ-Z (dimethylamino) -methyl 7-3 thienyl-17-methyl-7-ethyl-17-amino-7-methyl-1-phenyl-1H-11,2,4-triazole-3-methanol, and their pharmaceutically acceptable salts. Process for the preparation of the compounds according to Claim 1, corresponding to formula I, in which R 5 represents the group (CH 2) q Z (CH 2) r 8 or (CH 2) XS (CH 2) y R 5, characterized in that a triazole of formula I in which R 5 is R 5a is reacted, R 5a is - (CH 2) q L or - (CH 2) XL and L is a leaving group, with anion Z (CH 2), R 8 or S (CH 2) y R 15. 6 Process for preparation and compounds according to claim 1, having formula I wherein R 5 has a meaning other than an alkyl group in a straight or branched chain C 2 -C 6 substituted with two or three acyloxy groups, or a dihydroxyalkyl group forming a cyclic acetal structure, or an aralkyl or heteroaralkyl group in which the alkyl part is substituted by an acyloxy group , or Y is other than CHOR 14 in which R 14 is acyl, characterized in that a compound of formula III in which RR 1 R 2 N Alk QX (CH 2) is cyclized wherein R 6 is a group as defined for R 3, V 'is XCR 5 C, Y' is hydrogen, VV is oxygen; or sulfur and R 5c a group as defined for R 5 or a group convertible into such a group under the conditions of the cyclization reaction; or V 'is NH, R 16 is a group as defined for R 3 and Y' is CR 5, Y "is sulfur, oxygen or NH, or V 'is sulfur or oxygen, Y 'is CR 5 NH and R 16 is a group as defined for R 3, or V' is NR 3, R 16 is hydrogen and Y 'is CR 5, Y "having the meaning indicated y" The process for the preparation of the compounds according to claim 1 having formula I wherein Alk is CH 2, wherein an aldehyde of formula VII OHC-QX (CH 2) n is treated. Y (CH 2) m NHI (VII) B by an amine R 1 R 2 NH followed by a reduction 8 Process for the preparation of the compounds according to claim 1, corresponding to formula I in which R 5 is an aralkyl group or heteroaralkyl wherein the alkyl part is substituted with a hydroxy group, characterized in that the aldehyde or ketone ap is reacted Suited with an Ar Li organolithium compound or a Grignard Ar Mg Hal reagent, Ar is a suitable aryl, aralkyl, heteroaryl, or heteroaralkyl group and Hal is a halogen. Process for the preparation of the compounds according to Claim 1, corresponding to formula I, in which R 5 represents a straight or branched C 2 -C 6 alkyl group substituted with 2 or 3 acyloxy groups, or R 5 represents an aralkyl or heteroaralkyl group in which the alkyl part is substituted with an acyloxy group, or Y represents CHOR 14, R 14 being an acyl group, characterized in that the corresponding alcohol is reacted with an activated derivative of a suitable acid. A process for the preparation of compounds according to claim 1, having formula I, wherein R 5 represents a C 2 -C 6 straight or branched chain alkyl group substituted with 2 or 3 alkoxy groups, or R 5 represents a group aralkyl or heteroaralkyl wherein the alkyl portion is substituted by an alkoxy group, characterized in that the corresponding alcohol is treated with a halogenating agent followed by a reaction of the resulting halogenated compound with an appropriate alkanol. Process for the preparation of the compounds according to Claim 1, corresponding to formula I, in which R 5 represents the group (CH 2) q Z (CH 2) R 8 R 8 representing NR 12 R 13 and R 12 and R 13 each representing hydrogen or an alkyl group, characterized in that the corresponding alcohol for which R 8 is hydroxy is treated with a reagent capable of converting the R 8 group to a removable group, after which the reaction is reacted. the compound obtained corresponding to formula I wherein R 5 represents (CH 2) q Z (CH 2) r L, L being an eliminable group, with ammonia or a suitable amine R 12 R 13 NH. Process for the preparation of the compounds according to claim 1, having the formula I, wherein R 8 is NR 12 R 13 and R 13 is an acyl group or an aryl or alkyl-sulfonyl group, characterized in that the corresponding compound for which R 8 is NHR 12 is reacted with an activated derivative of a suitable carboxylic or sulfonic acid. 13 Process for the preparation of the compounds according to claim 1 corresponding to formula I in which R 8 represents the group -CONR 10 R 11, characterized in that an activated derivative of the corresponding carboxylic acid is reacted for which R 8 represents -CO 2 H, with ammonia or an appropriate amine HNR 10 R11 14 A process for the preparation of compounds according to claim 1, having formula I wherein R 5 comprises -CH (CH 2) CH-OO 0 OCR 6 R characterized in that the corresponding compound for which R 5 comprises the group - H- (CH 2) p -CH is reacted with an aldehyde or a ketone R 6 R 7 CO OH OH in the presence of: an acid. Process according to one of Claims 5 to 14, characterized in that a compound obtained according to formula I is converted to a salt if desired. As intermediates in the preparation of the compounds of the formula I according to claim 1, the compounds having the general formula II 64 -MR 1 R 2 NCH 2 QX (CH 2) n Y (CH) 2) m NHBN (II) N their pharmaceutically acceptable salts, and hydrates of these compounds and salts, in which: R 1 R 2 N represents a di (C lq 3) mino, furylmethylamino or pyrrolidino group, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimino; A represents N and B represents CR 5, or A represents CR 5 and B represents N; R 5 represents a C 2 -C 4 alkyl group substituted with two hydroxy groups, a 2,2-di (C 1 -C 3) alkyl-1,3-dioxolan-4-yl group, a (1-methyl-1H-6-trazol-5-yl) -thiomethyl group, or R 5 is phenyl (C 1 -C 3) alkyl or heteroaryl (C 1 -C 3) alkyl wherein the alkyl moiety is substituted with a hydroxy group, or a phenyl group ( C1-C3 alkyl ) in which the alkyl part is substituted by a C 1 -C 4 alkanoyloxy or C 1 -C 2 alkoxy group, or R 2 the CH () group R in R 5 represents the CH 2 Z (CH 2) group wherein R 8 is hydroxy or di (C 1 -C 3) alkylamino, Z is oxygen and r is 4; or R 8 is -CH = CH 2 or COR 9 wherein R is C 1 -C 4 alkoxy, Z is oxygen or sulfur and r is I; and - or Q is the 1,3-benzene residue and X is a bond, N is 0, Y is oxygen, and m is 3 or 4; or X is oxygen, n is 1, Y is -CHOH and m is 1; or Q is a residue of 2,5-furan or 2,4-thiophene, X is a bond, Y is sulfur, N is 1 and m is 2; wherein R 2 N is a di (C 1 -C 3 alkyl) amino group when Q is a furan or thiophene ring. Compounds according to claim 16, having the general formula II wherein either R 1 R 2 N is dimethylamino, Q is 2,5-furan, X is a bond, Y is sulfur, N is 1, and m to 2; or R 1 R 2 N is dimethylamino or pyrrolidino, piperidino or hexamethyleneimino, Q is 1,3-benzene, X is a bond, Y is oxygen, N is 0 and m is 3 or 4; and A is N and B is CR 5, or A is CR 5 and B is N, R 5 is benzyl in which the methylene group is substituted with a hydroxy group. A compound according to claim 16 taken from the group consisting of 5-lE 2-lll-5-l (dimethylamino) -2-methyl-furanyll-methyl-thiol-ethyl-aminool-1-methyl-α-phenyl- 1H-1,2,4-triazole-3-methanol and its pharmaceutically acceptable salts. As novel medicaments, useful in particular as histamine H 2 antagonists, the compounds according to any of the claims 1 to 4 and 16 to 18.   Therapeutic composition characterized in that it contains as active component a   composed at least according to any one of the claims tions 1 to 4 and 16 to 18.   66 - 21 Forms of administration of compositions   therapeutics according to claim 20.