NO830643L - PROCEDURE FOR THE PREPARATION OF HETEROCYCLIC DERIVATIVES EFFECTING HISTAMINE RECEPTORS - Google Patents

Description

The present invention relates to heterocyclic derivatives

acting on histamine receptors, methods of their preparation, pharmaceutical compositions containing such derivatives and their therapeutic use.

. Certain new heterocyclic derivatives with P^ antagonists,

is now found. These compounds, which are described in more detail below, show, for example, an inhibitory effect on gastric juice secretion when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 21_, 427). Their ability in this respect can

is shown in perfused rat stomach using the method described in British Patent 1565966, modified by using sodium pentobarbitone (50 mg/kg) as anesthetic instead of urethane,

and in unanesthetized dogs, fitted with Heidenhain pockets,

according to the method described by Black et al., Nature 1972 , 236 , 385. The compounds also antagonize the action of histamine on the contraction frequency of isolated guinea pig right atria.

Compounds with histamine r^-blocking action can be used in the treatment of conditions where lowering the acidity of the gastric juice is beneficial, especially in gastric and peptic ulceration, as a prophylactic precaution in surgical interventions and in the treatment of allergic and inflammatory conditions where histamine has an alleviating effect effect. The compounds can, for example, be used alone, or in combination with other active components in the treatment of allergic and inflammatory skin disorders.

The present invention provides compounds with it

general formula (I):

and physiologically acceptable salts and hydrates thereof, wherein

R. means hydrogen, C^_^ alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted with hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and R 1 means hydrogen or C 1-4 alkyl; or and together with the nitrogen atom to which they are attached, form a 5 to 10 membered ring which may be saturated or contain one or more double bonds, be unsubstituted or substituted with one or more C 1 -3 alkyl groups, e.g. methyl, or with a hydroxy group and/or containing another heteroatom selected from oxygen and sulfur;

Alk means a straight or branched alkylene chain with 1-3 carbon atoms,

Q means a furan or thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 5-positions,

and where the furan or thiophene ring optionally has a further substituent, R^i adjacent to the group R^R^N-Alk-; or Q means a thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 4-positions, and optionally has a further substituent, R^, in a neighboring position to the R^2NAlk group, provided that when R^R2NAlk- group is in the 4-position, the R^ group is in the 5-position; or Q means a benzene ring which is incorporated into the rest of the molecule through bonds in the 1- and 3- or 1- and 4-positions;

R 2 means halogen or C 1-6 alkyl which may be substituted by hydroxy or alkoxy;

X means oxygen, sulfur, -NH-, methylene or a bond;

Y means oxygen, sulfur, methylene or a bond;

n stands for 0, 1, 2 or 3 and m is an integer from 2 to 5, provided that (a) the total number of atoms in the chain X(CH_) Y(CH0) is an integer from 3 to 8, (b ) when X and Y mean

2 n 2 m ^

oxygen or sulphur, that n is then 2 or 3, (c) when X means -NH-,. that Q then is a benzene ring and Y means the methylene or a bond, and (d) when Q means a benzene ring, X stands for oxygen and n is V, that then m can also mean 1 and Y can also mean

-CHOR^ where R^ means hydrogen or acyl; and

R 2 means hydrogen, alkyl, alkenyl, aralkyl or alkyl substituted with hydroxy or alkoxy;

A either means N and.B means CR,.; or A means CR,- and B means N; and R,- make up

i) a C~, straight or branched alkyl group which is substituted with 2 or 3 hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group forms a cyclic acetal or cyclic ketal structure of formula:

where p is 0 or 1 and R 1 and R 2 , which may be the same or different, represent hydrogen, a C 1-4 alkyl group or a phenyl group; or

ii) the group (CH2)^Z(CH2)rRg, where q represents an integer from 1 to 4, r an integer from 1 to 6, Z represents oxygen or sulfur, and

when r is 1, Rg stands for the group CH=CH2, alkenyl or the CORny group, where Rn y is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the NR1gR ^ group, where R^Q is hydrogen or alkyl and R^ is hydrogen or alkyl, and

when r is an integer from 2 to 6, Rg has one of the meanings stated above or can additionally stand for hydroxy, alkoxy, aryloxy or NR^ 2R-| 2~9ruPPen' where R^0 is hydrogen or alkyl and R^^ is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl. or arylsulfonyl, provided that the sum of q and r is preferably 6 or less; or

iii) the group (CH2)(CH2) R^5, where x means 1 or 2,

y means .0 or 1 and a heteroaryl group; or

iv) an aralkyl or heteroaralkyl group where the alkyl part is substituted with hydroxy, alkoxy or acyloxy.

In the formula (I) given above, the term "alkyl" as a group or part of a group means that the group is straight or branched and, unless otherwise stated, contains 1-6 carbon atoms, especially 1-4 carbon atoms, e.g. eg methyl or ethyl, and the designation "alkenyl" that the group preferably has 3-6 carbon atoms. The designation "cycloalkyl" indicates that the group has 3-8 carbon atoms. The designation "aryl" for a group or part of a group preferably means phenyl or substituted phenyl, for example substituted with one or more C 1-6 alkyl or C 1-2 alkoxy groups, or halogen atoms, for example fluorine. By the term "acyl" is meant an aroyl, aralkanoyl or C 1-6 alkanoyl group, e.g. . acetyl, formyl, phenylacetyl or benzoyl. By the term "heteroaryl" for part of a group within the R 1 definition, is meant a 5- or 6-membered monocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, f .eg thienyl, pyridyl, furyl or thiazolyl. The heteroaryl ring can v either unsubstituted or substituted with C^_^alkyl, C^_^ alkoxy, hydroxy, hydroxy-alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. By the term "heteroaryl" for a group within part (iv) of the R 1 definition is meant a 5- or 6-membered monocyclic ring containing one heteroatom selected from oxygen, nitrogen and sulphur, e.g. thienyl, pyridinyl or furyl, which is optionally substituted with a C^_^ alkyl group. The alkyl part of the hetero-aralkyl group is a straight or branched C^_^ alkyl chain and the heteroaryl ring is attached to the alkyl part via a carbon atom. By the term "heteroaryl" within the R 1 definition is meant a monocyclic or bicyclic unsaturated ring containing 5-10 atoms selected from carbon, oxygen, nitrogen or sulfur. If the heteroaryl ring is monocyclic, it preferably contains 5 or 6 members and if it is bicyclic, it preferably contains 9 or 10 members. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isoquinolyl, quinolyl, indolyl or benzoxazolyl. The ring structure can be unsubstituted or substituted with one or more groups selected from C^_^alkyl, C^_^ alkoxy or hydroxy.

One side of the invention relates to compounds of formula (I) where R , R 2 , R-j, Alk, Q, X, Y, n and m are as indicated above, but with the exception of the additional possibilities provided under condition d) for m and Y, and A means N and B means CR,- or A means CR,- and B means N, where R,- is as indicated above under

. possibility (i) or (ii) (except that q can only be

1 or 2).

Another side of the invention relates to compounds of formula (I) where, R^, R2, R^, Alk, Q, X, Y, n and m are as indicated above, but with the exception of the additional possibilities provided under the assumption d) for m and Y, and A means N and B means CR5 or A means CR^ and B means N, where R,- is as indicated above under possibility (iv). Preferred compounds of formula (I) are those where

R 1 means C 1-8 alkyl (e.g. methyl, propyl, butyl or heptyl), C 1-4 alkyl substituted with a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C 2-4 alkyl substituted with hydroxy or a di- C^ ^-alkylamino group (e.g. 3-hydroxypropyl or dimethylaminoethyl) , C,-_ 7 cycloalkyl (e.g. cyclohexyl) , C, - alkenyl (e.g. allyl) , phenyl-C^_^- alkyl (e.g. benzyl) or a heteroaryl-C^_^ alkyl group where the heteroaryl ring contains one heteroatom

(eg 2-furylmethyl);

R2 is hydrogen or methyl; or

R^R2N means a 5-8 membered ring optionally containing a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethyleneimino or

tetrahydropyridino);

Alk means methylene;

Q means a benzene ring which is incorporated into the rest of the molecule through bonds in the 1 and 3 positions;

or a furan ring that is incorporated into the rest of the molecule through bonds in the 2- and 5-positions and optionally has a substituent R^ in a position adjacent to the R^ R2NAlk group, where R^ is C^_4alkyl (e.g. methyl) ;

or a thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 4-positions with the R^R2NAlk substituent in the 2-position under the conditions that when Q has the just-mentioned benzene meaning, X stands for a bond, n for 0, Y for oxygen and m for 3, 4 or 5, or both X and Y stand for oxygen and n and m

both are 2, or X is oxygen, Y is CHOH and n and m

both are 1; and when Q has the furan or thiophene ring meaning just mentioned, X stands for a bond and Y for sulfur or CH2, while n is 1 and m is 2, or Y stands

for oxygen, while n is 1 and m is 3;

R 1 is hydrogen or alkyl (eg methyl);

Rj. means a C2_4 alkyl group which is substituted by 2

hydroxy groups, or a 2,2-di-C 1-6 -alkyl (e.g. dimethyl)-1,3-dioxolan-4-yl group or

R,- means phenyl-C 1 -g-alkyl (e.g. benzyl) or heteroaryl-C 2 -alk<y>l (e.g. furylmethyl or pyridylmethyl), where the alkyl part is substituted by hydroxy, C^_^ alkanoyloxy (e.g. acetyloxy) or C 1 -2~ alkoxy (e.g.

methoxy); or

R5 means the group (Cr^) Z (.CH,,) ^Rg , where q is 1, r is 1-4 when Z is oxygen, or r is 1 when Z is sulfur, and RoQ is hydroxy, -CK^Cr^- the group, di-C^_^-alkylamino (e.g. dimethylamino) or the CORg group, where Rg is C-|_4 alkoxy (e.g. ethoxy) or the NHR^^ group, where R . is C^_^alkyl

(eg methyl); or

R, - means the group (CH2) (CH2)^, where x means 1 and the heteroaryl group R^ is tetrazolyl or thiadiazolyl each of which may be substituted with C^_^alkyl (eg methyl), or R^ is furyl; y is preferably 0 and R 1 is 1-methyl-1H-tetrazol-5-yl.

Within the preferred meaning of R^, compounds where R<- have the following meanings can be considered as one

separate part of the invention:

R,- means a C2-4 alkyl group which is substituted by 2

hydroxy groups, or a 2, 2-di-C ^ _.j-alkyl (e.g.

dimethyl)-1,3-dioxolan-4-yl group; or

R,, means phenyl-C 1 -alkyl (e.g. benzyl) where the alkyl part is substituted by _4-alkanoyloxy (e.g. acetyloxy) or C 1-2_ alkoxy (e.g. methoxy) or heteroaryl-C 2 -alkyl (e.g. furylmethyl or pyridylmethyl), where the alkyl part is substituted with hydroxy, C 1-4 -alkanoyloxy (e.g. acetyloxy) or C 1-2 alkoxy (e.g. methoxy);

or

R means the group (CH_) Z(CH0) RQ, where q is 1, r is 1-4 when 5zq z r o

Z is oxygen, or r is 1 when Z is sulfur, and Rg is hydroxy, CH2 = the CH group, di-C^^-alkylamino (eg, dimethylamino) or the COR^ group, where R^ is C^_ ^-Alkoxy (e.g. ethoxy) or the group NHR^, where R^ is C^_^_ alkyl (e.g. methyl), or

R^ •• means the group (CH2) xS (CH2) R^ ^ , where x means 1 and the heteroaryl group R^ is tetrazolyl or thiadiazolyl which are both substituted with C^^-alkyl (e.g. methyl), or R^ is furyl; wherein y is preferably 0 and R 2 is 1-methyl-1H-tetrazol-5-yl.

A particularly preferred group of compounds are those of formula (II):

where

R 2 R 2 N means di-C 1 -g -alkylamino (eg dimethylamino), furylmethylamino, pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimino, preferably

piperidino;

A means N and B means CR^,. or A means- CR^ and B means N,

where

R^ denotes C 2-4 -alkyl substituted with 2 hydroxy groups, 2,2-di-C 1 -3-alkyl (e.g. dimethyl)-1,3-dioxolan-4-yl, (1-methyl-1H-tetrazol-5- yl)thiomethyl, or

R5 means phenyl alkyl (e.g. benzyl) or heteroaryl-C^^-alkyl (e.g. furylmethyl or pyridylmethyl), where the alkyl part is substituted with hydroxy, or phenyl-C^^-alkyl (e.g. benzyl) , where the alkyl part is substituted with C| _4~alkanoyloxy (e.g. acetyloxy) or C1_2~

alkoxy (e.g. methoxy), or

R5 means the group CH2Z(CH2)rRg, where Rg is hydroxy or di-.

C 1 -3-alkylamino (eg, dimethylamino)., Z is oxygen and r is 4; or Rg is the group -CH=CH2 or the group CORg, where Rg is _4-alkoxy (eg ethoxy), Z is oxygen or sulfur and r is 1; and where either Q is 1,3-benzene, X a bond, n is 0, Y is oxygen and m is 3 or 4, preferably 3; or X is oxygen, n is 1, Y is -CHOH- and m is 1; or Q is 2,5-furan or 2,4-thiophene, X is a bond, Y is sulfur, n is 1 and m is 2; provided that R 1 R 2 N is di-C 1 -4 alkylamino when Q is a furan or thiophene ring.

Another particularly preferred group of compounds are those of formula (II), where either R-|R2N is dimethylamino, Q is 2,5-furan, X is a bond,

Y is sulphur, n is 1 and m is 2;

or R^I^N is dimethylamino, pyrrolidino, piperidino or hexamethyleneimino, preferably piperidino, Q is 1,3-benzene, X is a bond, Y is oxygen, n is 0 and m is 3 or 4, preferably 3;

and A means N and B means CR,-,, or A means CR^ and B means N,

where .R 1 - is benzyl with a hydroxy-substituted methylene group;

provided that, when Q is a furan ring, A is preferably N and B is preferably CR,-.

Particularly preferred compounds are: 5-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-amino]-1-methyl-α-phenyl1-1H-1,2 ,4-triazole-3-methanol, (1-methyl-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-N-[3-[3-(1-piperidinylmethyl)phenoxy ]propyl]-1H-1,2,4-triazol-5-amine, 1-methyl-a-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino]-1H- 1,2,4-triazole-3-methanol,

4-methyl-α-phenyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino]-4H-1,2,4-triazole-3-methanol,

1-methyl-5-[3-[[(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-ethane-1,2-diol,

α-[1-methyl-5-[[3-[3-(1-pyridinylmethyl)phenoxy]propyl]-amino]-1H-1,2,4-triazol-3-yl]-2- pyridinemethanol, 5-[[2-hydroxy-3-[3-(1-piperidinemethyl)phenoxy]propyl]-amino]-1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol, 5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol,

5-[[2-[[[5-[(dimethylamino)methyl]-3-thienyl]methyl]thio]ethyl]-amino]-1-methyl-a-pheny1-1H-1,2,4-triazol- 3-methanol,

and their physiologically acceptable salts.

The invention includes compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful are hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formula (I) and their salts can also form hydrates which are also to be considered part of the invention. The compounds can exhibit tautomerism, and the formulas are to be understood as covering all tautomers. The same applies to any diastereoisomers and optical enantiomers. By implication, the invention includes bioprecursors of compounds of formula (I). The term bioprecursor means compounds which have a different structure, but which in the animal or human organism are converted into a compound of formula (I).

Compounds of formula (I), preferably in the form of a salt, can be used in pharmaceutical preparations for human or veterinary medicinal purposes. The preparations can be prepared according to usual techniques using one or more carriers or excipients. If necessary, such preparations may also contain other active substances, e.g. -antagonists. The compounds can thus be prepared for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred.

For oral administration, the preparations can be prepared in the form of tablets, capsules, powders, solutions, syrups or suspensions by usual methods and with acceptable excipients. For buccal administration, the preparations can be prepared as tablets or pastilles in the conventional manner.

The compounds of formula (I) can be given parenterally as bolus injection, or continuous infusion. Injection preparations can be produced in single-dose form in ampoules or in vials with an added preservative. The preparations can take the form of suspensions, solutions or emulsions in oily or aqueous carriers, possibly with suspending, stabilizing and/or dispersing agents. The active ingredient can alternatively be in the form of a powder which, before use, is mixed with a liquid carrier, e.g. sterile pyrogen-free water.

The compounds can also be prepared as preparations for

rectal use such as suppositories or retention enemas, e.g. containing a common base mass such as cocoa butter or other glycerides. For topical application, the compounds can be prepared as ointments, creams, gels, lotions, powders or sprays. For internal administration, a suitable daily dosage will be from 1 to 4 doses which together amount to from 5 mg. to 1 g, preferably 5-500 mg, depending on the patient's condition.

In the following methods for preparing compounds of formula (I), it may be necessary in some reaction steps to protect various reactive substituents in the starting materials and then, after the reaction in question, to remove the protecting group. Protection and subsequent unblocking may be particularly relevant when R. and R.sub.2 are hydrogen atoms. and/or when R^ is an alkyl group with a hydroxy substituent and/or when R^ contains a hydroxy or amino group. Commonly used techniques for protection and unblocking can be used below. Thus, for example, amines can be protected by forming a phthalimide group which can later be split off by treatment with a hydrazine, e.g. hydrazine hydrate or a primary amine, e.g. methylamine.

When describing the processes for the preparation of compounds of formula (I) or useful intermediates thereof, the meanings of R^ to R.,,-, A, B, Alk, Q, X, Y, Z, n, m, p , q, r, x and y in the various formulas as defined for formula (I) unless otherwise stated.

Compounds of formula (I) where R,, means the group (CH_) Z(CH„) RD or (CHJ S(CH_) R. _ can be prepared by zq z r o z x zylb

reaction of a triazole with formula (I) where R- stands for the group R^ 3. where R^ cl is -(CH2) L or -(CH^^L and L is a leaving group such as halogen, mesyloxy or tosyloxy, with an anion ZfCH^^Rg or S(CH2)^ R^^ The anion can be obtained

from the corresponding alcohol by treatment with sodium or one strong base, with or without the use of a solvent,

e.g. dimethylformamide, at a temperature of 20-120° or from the corresponding thiol by treatment with a base such as potassium or sodium carbonate in the presence of a solvent, e.g. acetone, at a temperature within the aforementioned temperature range.

The intermediates of formula (I) where R,- means the group

R5<a>where R5<a>is -(CH2)gL or -(CH^^L can be prepared by

to react the corresponding compound where R^<a>is -(CH„) OH or -(CH ) OH with an acid chloride such as thionyl chloride, methanesulfonyl chloride or p-toluenesulfonyl chloride.

The intermediates of formula (I) where R^ means the group R^<a>where R a is (CH_) OH or (CH„) OH can be prepared as described in British patent specification 2047238A and European

Patent Publication No. 48555.

Compounds of formula (I) can also be prepared by cyclization of a suitable intermediate. Compounds of formula (I) where R is not a C0, straight or branched alkyl-

D Z-D

group with 2 or 3 acyloxy substituents or a dihydroxy-alkyl group forming a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group where the alkyl part is substituted with an acyloxy group, or Y is different from CHOR^, where R^ is acyl, can be prepared by cyclization of a compound of formula (III):

where R^g is like the R^ group, V is and Y<1> is hydrogen where V is oxygen or sulfur and R,, is like the R,- group or a group which can be converted into this under the cyclization conditions ; or V is NH, R. g is a group which . indicated for R^ and Y<1> are where Y" is sulfur, oxygen or NH; or V is sulfur or oxygen, is as indicated for the R^ group; or V is NR^, R g is hydrogen and Y' is

where Y" is as above indicated.

The cyclization process when A in formula (I) stands for N and B for the CRj group can, for example, take place by a compound of formula (IV):

where V means sulfur or oxygen, preferably oxygen, and U represents two hydrogen atoms, is cyclized in or without the presence of a solvent, e.g. a hydrocarbon such as toluene, a ketone such as acetone, or water, optionally while heating to a temperature of e.g. 50-90°.

It may be appropriate to prepare compounds of formula (IV) where U represents two hydrogen atoms, in situ by treating a compound of formula (IV) where U means a divalent protecting group which can be easily removed and replaced by two hydrogen atoms, e.g. a benzylidene group, from an acid, e.g. hydrochloric acid, preferably under heating, and under such conditions that the cyclization gives the corresponding compound of formula (I).

In another embodiment of the cyclization of compounds of formula (III), compounds of formula (I) can be prepared by cyclization of a compound of formula (V):

wherein R^g is as indicated in conjunction with R^, and wherein either V is NH and Y" is sulfur, oxygen or NH, or V is sulfur or oxygen and Y" is NH; or R^^ is hydrogen, V is NRg and Y" is sulfur. When Y" is sulfur, tautomerism with the neighboring NH group is possible

and the -SH group can be alkylated under'

standard conditions. The S-alkylated compound can also be used in the cyclization process.

The cyclization can be carried out by heating the compound (V) (e.g. within the range 80-150°) in or without a solvent (e.g. acetonitrile or dimethylformamide) or under basic conditions (e.g. with aqueous potassium hydroxide).

According to this method, an intermediate of formula (V), where R^g has the meaning given for R^, V is NH and Y" is oxygen; or R^^ is hydrogen, V' is NR^ and Y" is oxygen, easily produced in situ by reacting an aminoguanidine (VI):

with an acid R^COOH or an activated derivative thereof. Suitable activated derivatives include acid halides,

e.g. acid chlorides, alkyl chloroformates, acid anhydrides, including mixed anhydrides (e.g. acetic-formic anhydride), esters such as alkyl esters, orthoesters (trialkyl orthoesters, e.g. R^CtOEt)^) and (1-alkyl-2- pyridinyl) esters, or derivatives obtained from a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide.

The acid and aminoguanidine (VI) can be heated together, whereby the cyclization of the intermediate product (V) to the compound of formula (I) takes place directly. When using an activated derivative, aprotic solvents, e.g. tetrahydrofuran, used at temperatures from room temperature up to the boiling point. With acyl chloride as activated derivative, the reaction can also be carried out in the presence of a base, e.g. a tertiary amine such as pyridine, which can also serve as a solvent.

In general, intermediates of formula (IV) can be prepared from suitable diamines by methods analogous to those described in British Patent Specification 2047238A, and intermediates of formula (V) can be prepared from the appropriate diamines by methods analogous to those described in British Patent Specification 2023133A and European Patent Specification 48555. The aminoguanidines (VI) can be prepared as described in British patent specification 2023133A and European patent specification 48555.

Compounds of formula (I) where Alk is CH^ r can be prepared by treating an aldehyde of formula (VII):

with an amine R^R2NH, for example in a solvent such as tetrahydrofuran or an alkanol, e.g. ethanol, followed by reduction for example with a hydride such as alkali or alkaline earth metal borohydride e.g. sodium borohydride or lithium aluminum hydride, or with hydrogen and a metal catalyst such as e.g. palladium or platinum. The reactions can be carried out within the temperature range 0-80°C.

The intermediates of formula (VII) can be prepared from compounds of formula (VIII):

where W means a protected aldehyde group, e.g. a cyclic acetal, such as an ethylene acetal, by methods analogous to those described herein for the preparation of compounds of formula (I) from the appropriate diamine.

Compounds of formula (I) where R 1 - is an aralkyl or heteroaralkyl group, where the alkyl moiety is substituted with hydroxy, can be prepared by reacting suitable aldehydes or ketories with an organolithium compound, ArLi or a Grignard reagent ArMgHal, where Ar is a suitable aryl, aralkyl, heteroaryl or heteroaralkyl group, and Hal is halogen. The reaction can be carried out in a suitable solvent, such as an ether, e.g. diethyl ether, tetrahydrofuran or a mixture of these, at temperatures from -70° to 50°, preferably from -70 to 20° when reacting with ArLi and at 0-50° when reacting with ArMgHal. The starting aldehyde or ketone can be prepared as described in British Patent Specification 2075007A and European Patent Specification 48555.

Compounds of formula (I), where R 1 - has one meaning, can be converted into corresponding compounds where R 1 - has a different meaning by means of usual standard methods.

Compounds where R^ means a C2_g straight or branched alkyl group which is substituted with two or three acyloxy groups, or where R,, means an aralkyl or heteroaralkyl group where the alkyl part is substituted with an acyloxy group, or Y means CHOR^, where R ^er acyl, can be prepared by reacting the corresponding alcohol with an activated derivative (eg an acid chloride or an acid anhydride) of a suitable acid. The reaction can be carried out at room temperature, optionally in the presence of a solvent (e.g. pyridine, tetrahydrofuran, acetone or dimethylformamide), and preferably in the presence of a base (e.g. pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate) .

Compounds where R,- means a C2-6 straight eHere branched alkyl group which is substituted by two or three alkoxy groups, or R^ means an aralkyl or heteroaralkyl group, where the alkyl part is substituted by' an alkoxy group, can be prepared from the corresponding alcohol by treatment with a

halogenating agent, for example thionyl chloride, whereupon

the resulting halogen compound is reacted with a suitable alkanol in the presence of sodium at a temperature within the range of 20-50°. Alternatively, the halogen intermediate can be treated, with a suitable alkanol in a solvent such as dimethylformamide, in the presence of a strong base such as sodium hydride, at a temperature within the range of 20-100°.

Compounds where R,, means the group (Cr^)gZ'CH2^r<R>8^vor

Rg is NR1 2R13 0<? R<->]2°^R13^egg st^ for hydrogen or alkyl, can be prepared from the corresponding alcohol where Rg is hydroxy, by treatment with a reagent that can convert the Rg group into■a leaving group, for example thionyl chloride, whereupon the resulting compound of formula (I) wherein R,. means (CH2)Z (CH2)rL, where L is a leaving group, e.g. halogen, is reacted with ammonia or a suitable amine<R>12R13NH'^preferably in a solvent such as an alkanol, e.g. ethanol, at a temperature within the range 80-120°.

Compounds where RD is the NHR.„ group can be converted into compounds where Rg constitutes the group NR 2^3/ where R^ ^ is either an acyl group or an aryl or alkylsulfonyl group, by reaction with an activated derivative of the corresponding carboxylic or sulfonic acid .

Suitable activated derivatives are acid halides, e.g. acid chlorides, alkyl chloroformates, acid anhydrides, including mixed anhydrides (e.g. acetic acid-formic anhydride) and esters such as alkyl esters and ortho esters.

The reaction with an acid halide is preferably carried out in the presence of a base, e.g. an inorganic base such as sodium hydroxide or an organic base such as triethylamine or pyridine. The reaction with an alkyl chloroformate is preferably carried out in the presence of a base such as e.g. potassium carbonate or triethylamine in dimethylformamide. The reaction with an acid anhydride is carried out with or without a solvent, e.g. pyridine.

Compounds where Rg stands for the group -CONR^qR^ can be prepared by reacting an activated derivative of the corresponding carboxylic acid, where Rg is the -CO 2 H group, e.g. an ester, with ammonia or a suitable amine HNR^qR^ in a suitable solvent (eg an alcohol such as ethanol) under a temperature of 20-120°C.

Compounds where R,, comprises the group

can be converted into corresponding compounds where R^ comprises the group

by reacting an aldehyde or ketone R^R^CO, e.g. acetone, in the presence of an acid, e.g. p-toluenesulfonic acid. The reaction is carried out with or without a solvent, e.g. benzene, at a temperature between room temperature and the boiling point.

If the product from any of the above-mentioned processes is a free base and the acid addition salt is required, this can be produced in a conventional manner. A handy method in this respect consists in mixing suitable amounts of the base and the acid in a solvent such as e.g. an alcohol such as ethanol, or an ester such as ethyl acetate. The invention also includes the conversion of a salt of a compound of formula (I) into another.

In the subsequent presentations and examples are

the temperature indicated in °C.

If nothing else is stated, it is as silica gel for

the column chromatography used Merck Kieselgel 60 (7734).

TLC stands for thin layer chromatography which, as well as preparative chromatography, was performed on silica gel with one of the following solvent systems:

System A: Dichloromethane:ethanol:0.88 ammonia (50:8:1)

System B: Dichloromethane:ethanol:0.88 ammonia (25:8:1) System C: Dichloromethane:ethanol:0.88 ammonia (100:8:1). System D: Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15:8:2) .

System E: Dichloromethane:ethanol:0.88 ammonia (75:8:1).

Production 1

Methyl- N- [ 2, 3- diacetyloxypropionyl]- 1- methyl- 2-( phenylmethylene)- hydrazine- carboximidothioate

Diacetylglyceric acid (13.8 g) was heated under reflux in thionyl chloride (50 ml) for 4 hours. The solvent was evaporated under vacuum and azeotropically distilled with toluene (3 x 50 mL) to give an oil which was used without further purification. The oil was dissolved in dichloromethane (100 ml) and added dropwise to a solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboxymidothioate hydrochloride (15.4 g) in dichloromethane (250 ml) and triethylamine (19.3 ml) which had previously been stirred at 20° for 0.5 hours. The reaction mixture was stirred at 20° for 15 hours before the addition of water. The organic phase was separated, dried (MgSO 4 ) and evaporated, whereupon the residue (7 g) was chromatographed with ether as eluent to give the title compound as a yellow waxy solid (4.6 g).

NMR (CDCl 2 ): 2.16, s, (1H); 2.2-2.7, m, (3H); 4 , 58-5.45, m, (3H); 6.57, p, (3H); 7.67, p, (3H); 7.85, p, (3H); 7.93, p, (3H).

Manufacturing 2

Methyl- N-[ 2- acetyloxy-[ 2-( phenyl)- acetyl]]- 1- methyl- 2-( phenyl Imethylene) hydrazin- carboxy. imidothioate.

A solution of acetyl chloride (11.35 g) in dry ether (50 ml) was slowly added to a solution of mandelic acid (20 g) in ether (100 ml). The solution was heated under reflux for 3 days and then evaporated to a pale yellow oil. The oil was heated under reflux for 3 hours with thionyl chloride (31 g). The thionyl chloride was removed by azeotropic distillation with toluene, and the remaining oil (27.7 g) used without further purification.

The oil was dissolved in toluene (50 ml) and added to a suspension of triethylamine (5.8 g) and methyl 1-2-(phenylmethylene)-hydrazine-carboxymidothioate hydrochloride (6.9 g) in dry toluene (180 ml) ). The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with ether. The organic extract was dried (MgSO 4 ) and evaporated to give the title compound as a cream yellow solid (6.3 g).

NMR (CDCl 3 ): 2.25, s, (1H); 2.3-2.8, m, (10H); 3.95, p, (1H);

6.7, p, (3H); 7.8, p, (3H); 7,9, p, (3H).

Manufacturing 3

(i) 2-[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-isoindole-1,3-(2H)-dione

A mixture of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (9.10 g) and 3-(1-piperidinylmethyl)phenol (8.55 g) was heated to 130°C under nitrogen for 10 minutes. The resulting mixture was dissolved in chloroform (100 mL), washed with 1N sodium hydroxide (2 x 25 mL), dried (MgSO 4 ) and evaporated to give

the title compound was obtained as a gummy mass (17.65 g).

TLC system C; Rf 0.60.

(ii) 1- amino- 3-[ 3-[ ( 1-piperidinylmethyl)phenoxy]- 2- propanol A solution of 2-[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]-propyl]- 1H-isoindole-1,3-(2H)-dione (17.6 g) and hydrazine hydrate (2.5 g) in ethanol (60 ml) were heated under reflux for 3 hours. The resulting mixture was evaporated to a solid residue which was suspended in 1N hydrochloric acid (30 mL) and filtered. The filtrate was basified with an excess of potassium carbonate and extracted with isopropanol (3 x 40 mL). The isopropanol extract was dried (Na 2 CO 3 ) and evaporated to a gummy mass which was chromatographed using system A. Recrystallization of the product from n-hexane:ether (20:1) gave the title compound as colorless granular particles (7.7 g), m.p. 74-76.5°.

Manufacturing 4

5-[[ 3-(3- formylphenoxy) propyl] amino]- 1- methyl- a- phenyl-1H- 1, 2, 4- triazole- 3- methanol- acetate (ester).

A solution of 3-[3-(1,3-dioxolan-2-yl)phenoxy]propanamine (6.0 g) and compound A<*> (11.33 g) in toluene (300 ml) was stirred at 20 ° for 4 hours, added. 5N hydrochloric acid (30 ml) and the mixture stirred at 20° for a further 18 hours. The acidic layer was separated, washed with toluene and basified with 2N sodium carbonate and then extracted with ethyl acetate. The extract was dried and evaporated to a gummy mass (9.0 g) which was chromatographed on activated alumina

[Phase Separations Ltd (UG1)] with ether:ethyl acetate:methanol 50:50:1 as eluent, which gave the title compound (1.4 g) as a foam.

TLG system C; Rf 0.7.

<*>Compound A methyl-N-[2-acetyloxy-[2-(phenyl)-acetyl]]-1-methyl-2-(phenylmethylene)hydrazine-carboxyimidothioate

Example 1

1- methyl- 5-[ 3-[[( 1- piperidinylmethyl) phenoxy] propyl] amino]-1H- 1 , 2, 4- triazole- 3- ethane- 1, 2- diol- hemicitrate

To a mixture of methyl N-[2,3-diacetyloxypropionyl]-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (2.69 g) in toluene (100 ml) was added 3-[3-(1 -piperidinylmethyl)-phenoxy]propanamine (1.5 g) and the resulting solution stirred at 20° for 16 hours before the addition of 5N hydrochloric acid (25 ml), whereupon the biphasic mixture was stirred vigorously for a further 16 hours. The acidic layer was separated and the toluene layer washed with 2N hydrochloric acid. The combined acidic layers were washed with toluene and then basified and saturated with solid sodium carbonate. The basic solution was extracted with ethyl acetate and the combined organic extracts dried (MgSO 4 ) and evaporated. The residue (2.0 g) was chromatographed with chloroform:methanol (5:1) as eluent to give a foam (0.6 g). The foam was dissolved in ethyl acetate (20 mL) using methanol (4 mL) and treated with a stoichiometric amount of citric acid in ethyl acetate (20 mL) under nitrogen. The suspension was stirred at 20° for 0.5 h and the compound collected and dried under vacuum to give the title compound as a white solid (0.53 g), m.p. 73-74° (softens)

TLC system D; Rf 0.46.

Example 2 (a)

5-[[ 2- hydroxy- 3-[ 3-( 1- piperidinylmethyl) phenoxy] propyl]-amino]- 1- methyl- a- phenyl- 1H- 1, 2, 4- triazole- 3- methanol A solution of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (2.0 g) and methyl-N-[2-acetyloxy-[2-(phenyl)-acetyl]]-1-methyl -2-(phenylmethylene)hydrazine-carboxymidothioate', compound A (3.19 g) in toluene (60 ml) was stirred at 20° in

4 hours, added 5N hydrochloric acid (9 ml) and stirred at 20° i

16 hours and then heated in a steam bath for 15 min. The sour

layer was separated, washed with toluene, basified with saturated aqueous sodium bicarbonate, washed with toluene, then the aqueous layer was basified with 5N sodium hydroxide. The basic layer was extracted with hot 4-methyl-2-pentanone (3 x 100 mL) and

the extracts washed with brine, dried and concentrated under vacuum to a volume of 150 ml, whereupon crystallization occurred. The resulting solid (1.2 g) was filtered off and recrystallized from 2-propanol to give the title compound

(0.63 g) as a white solid with m.p. 154-157°.

Found: C, 6 6.2; H, 7.2; N, 15.2;

C 25 H 33 N 5 O 3 requires: C, 66.5; H, 7.4; N, 15.5%

Example 2 (b).

Starting from compound A (1.5 g) and 3-[3-(dimethylamino)methyl]phenoxy]propanamine (0.74 g), the same procedure led, except that the 4-methyl-2-pentanone extract was evaporated under vacuum and the residue (1.3 g) was chromatographed with system A as eluent, to 5-[[3-[3-[(dimethylamino)methyl]-phenoxy]propyl]amino]-1-methyl-a- phenyl-1H-1,2,4-triazole-3-methanol hydrate (0.31 g) as a white foam.

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

C22H29N5°2'1H2° requires: C'63'9; H'7.59; N, 16.9%

NMR (CDCl 3 -DMSO): 2.4-2.92, rn, (6H); 3.05-3.33, m, (3H);

4.4, p, (1H); 4.65, s (br) , (1H); 5.58, p, (br)., (1H);

5.98, t, (2H); 6.4-6.75, s+s+q, (7H); 7.85, p, (6H);

8.0, quintet, (2H).

Example 2 (c)

Starting from compound A (1.5 g) and 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethoxy]ethanamine (0.99 g), the same procedure followed, except that the aqueous phase was extracted with hot ethyl acetate (6 x 50 ml) at pH 7 and

chromatographed with dichloromethane:ethanol:0.88 ammonia (80:8:1), to 1-methyl-α-phenyl-5-[[2-[2-[3-[(1-piperidinylmethyl)phenoxy]ethoxy]ethyl ]amino]-1H-1,2,4-triazole-3-methanol (0.45 g) as a clear gummy mass.

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

<C>26<H>35<N>5°3<fo>rdrer: c'67.07; H, 7.58; N, 15.04%

NMR (CDCl 3 ): 2.4-2.9, m, (6H); 3-3.35, m, (3H); 4.3, p, (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)

5-[[ 2-[[[ 5-[( dimethylamino) methyl]- 3- thienyl] methyl] thio] ethyl]-amino]- 1- methyl- a- pheny1- 1H- 1, 2, 4- triazol- 3- methanol A solution of 4-[[[2-(aminoethyl)]thio]methyl]-N,N-dimethyl-2-thiophene-methanamine (1.09 g) and compound A (2 g) in toluene (40 ml) was stirred at 20° for 4 hours. The mixture was added with 5N hydrochloric acid (5 ml) and stirred at 20° for 16 hours and then heated on a steam bath for 10 minutes. The acidic layer was added with sodium bicarbonate to pH 3, washed with toluene, basified to pH 9 with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to a gummy mass which was chromatographed with system C as eluent, giving the title compound (0, 45 g) was obtained as a light brown foam.

NMR (CDCl 3 + DMSO): 2.35-2.85, m, (5H); 3.01, p, (1H); 3.12, pp.

(1H); 4.33, p, (1H); 4.62, t, (1H); 5.75, br, (1H); 6.40, p, (2H); 6.45, p, (2H); 6.55, p, (3H); 6.5-6.7, t, (2H);

7.35, t, (2H); 7.75, p, (6H).

TLC System A; Rf 0.5.

Example 3

(a) 1- methyl- N-[ 3-[ 3-( 1- piperidinylmethyl) phenoxy] propyl]-3-[( 2- propenyloxy) methyl]- 1H- 1, 2, 4- triazol- 5- amine 1 -methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.59 g) was dissolved in thionyl chloride (10 mL ) and heated under reflux for 15 min. The orange colored solution was evaporated under reduced pressure to a gummy mass which was stirred in water (35 ml) at 20°. Sodium bicarbonate and sodium carbonate (3.g) were added and the suspension stirred with ethyl acetate. The organic phase was separated, dried for 1 hour with sodium carbonate and evaporated under vacuum to an oil. The oil was dissolved in allyl alcohol (10 ml) and added to a solution of sodium (0.3 g) in allyl alcohol

(8 ml). The reaction mixture was heated on a steam bath i

6 hours, poured into water and extracted with ethyl acetate. The organic phase was extracted with 2N hydrochloric acid. The acidic extract was basified to pH 9 with potassium carbonate and extracted with ethyl acetate. Evaporation of the organic extract gave an oil (1.1 g) which was chromatographed with dichloromethane:ethanol:ammonia: (70:8:1) as eluent, whereby the title compound was obtained as an oil (0.4 g).

Found: C, 6 5,6 4; H, 8.46; N, 17.44;

<C>22<H>33N5°2<fo>rdrer: c'66.14; H, 8.33; N, 17.53;

TLC System C; Rf 0.4.

(b) Following the same procedure, from 1-methyl-5-[[3-[3-(piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.59 g ) and thionyl chloride (10 mL), followed by the addition of a solution of sodium (0.3 g) in butane-1,4-diol (10 g), prepared 4-[[1-methyl-5-[[3- [3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl]methoxy]butanol compound with ethanol (2:1) (0.87 g).

Found: C, 63.12; H, 8.81; N., 15/56;.<C>23<H>27N5°3^C2H5OH requires: C'63.40; H, 8.87; N, 15.41;

NMR (CDCl 3 ): 2.8, t, (1H); 3.0-3.3, m, (3H); 5.4, br, t, (1H); 5.62, p, (2H); 5.95, t, (2H); 6.4, m, (6H); 6.5, p, (3H); 6.6, p, (2H) ; 7.0, br, (1H); 7.6, m, (4H); 7,9,irt, (2H); 8.1-8.7, m, (10H).

Example 4 (a)

Ethyl-[[[ 1- methyl- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy]-propyl] amino]- 1H- 1, 2, 4- triazol- 3- yl] methyl] thio] acetate - hemihydrate 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol, compound B, (7.2 g) was dissolved in thionyl chloride (30 ml) at 20° and heated under reflux for 15 min. The cooled solution was evaporated under vacuum and the resulting oil dissolved in water (30 ml) and carefully basified with solid sodium bicarbonate, sodium carbonate added (3 g), after which the mixture was extracted with ethyl acetate. The extract was dried (Na 2 CO 2 , 1 hour) and evaporated to an oil.

The resulting oil was dissolved in acetone (100 mL) and heated under reflux for 16 hours with anhydrous potassium carbonate (2.76 g) and ethyl mercaptoacetate (2.4 g). The mixture was partitioned between aqueous potassium carbonate and ethyl . acetate. The ethyl acetate extract was dried and evaporated and the residue (5.1 g) chromatographed with system E as eluent to give the title compound (2.9 g) as a pale yellow oil.

Found: C, 58.7; H, 7.6; N, 14.8; C25<H>35<N>5°3<S>'^H2° requires: C'58.7; H, 7.7; N, 14.9%

NMR (CDCl 3 )': 2.75, dd, (1H); 3-3.33, m, (3H); 5.45, t, (1H); 5.66-6, q+t, (4H); 6.23-6.7, s+s+q+s+s, (11H); 7.61-7.86, m, (6H); 8.45, m, (6H); 8.7, t, (3H).

The following compounds were prepared in a similar manner from compound B and appropriate starting materials.

4 (b) Compound B (1.41 g), 5-mercapto-1-methyltetrazole

(0.506 g) and potassium carbonate (0.54 g) except that the mixture was chromatographed using system C, resulting in an oil (1.0 g) which was dissolved in ethyl acetate and treated with an excess of ethereal hydrochloric acid , gave 1-methyl-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1, 2,4-triazol-5-amine dihydrochloride sesq.uihydrate (0.6 g) as a white powder which, in the melting point determination, slowly softened at temperatures above 40°.

NMR (D 2 O): 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). 4 (c) Compound B (1.41 g), 2-mercapto-5-methyl-1,3,4-thiadiazole (0.52 g) and potassium carbonate (0.54 g), except that the mixture was chromatographed using system C, gave 1-methyl-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl] — 1H—1,2,4-triazol-5-amine (.0.62 g) in the form of a white powder, m.p. 63° (softens) melts 72-74°.

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

C22H31N7OS2 requires: c'55'8'- H'6'6'" N'20.7%

Example 5

3- [[ 4- ( dimethylamino) butoxy] methyl]- 1- methyl- N-[ 3—[ 3—( 1 — piperidinylmethyl) phenoxy] propyl]- 1H- 1, 2, 4- triazol- 5- amine 4 - [[1-methyl-5-t[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino]-1H-1,2,4-triazol-3-yl]methoxy]butanol (0.5 g) was dissolved in thionyl chloride (10 ml) and stirred at 20° for 1.5 hours. The solution was evaporated under vacuum and the residue dissolved in water (20 ml) and basified with solid sodium bicarbonate and sodium carbonate (~2 g). The mixture was extracted with ethyl acetate, the extract dried (Na 2 CO 3 , 1 hour), evaporated and the oily residue dissolved in ethanolic dimethylamine (33%, 15 ml), whereupon the solution was heated in an autoclave at 80° for 8 hours. The solution was evaporated and the remaining oil (0.3 g) chromatographed with system A as eluent to give the title compound (0.2 g) as a pale yellow oil.

NMR (CDCl 3 ): 1.74, dd, (1H); 3-3.32, m, (3H); 5.48, t, (1H); 5.58, p, (2H); 5.86, 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.

Example 6

a-( 2- furanyl)- 1- methyl- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy 3- propyl] amino]- 1H- 1, 2, 4- triazole- 3- methanol

n-Butyllithium (1.55 M in n-hexane, 5.96 mL) was added dropwise to a stirred solution of furan (0.61 mL) in anhydrous tetrahydrofuran (20 mL) under nitrogen at -40°. The stirred solution was slowly allowed to reach 20° and was then heated under reflux for 3 hours and then added dropwise at 0° to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl ) phenoxy]propyl] amino]-1H-1,2,4-triazole-3-carboxaldehyde (1.0 g) in tetrahydrofuran (10 mL), and the resulting

solution stirred at 20° for 18 hours. Water (20 ml) was added, the mixture concentrated, extracted with ethyl acetate and the extract dried and evaporated. The remaining oil (0.9 g) was chromatographed using system E to give the title compound (0.16 g) as a brown oil.

NMR (CDCl 3 ): 2.6, m, (1H); 2.76, t, (1H); 3.06-3.08, m, (2H);

3.23, m, (1H); 3.65, m, (2H); 4.25, p, (1H); 5.48, t, (1H);

5.86, t, (2H); 6.38, q, (2H); 6.45, p, (3H); 6.56, p, (2H);

7.62, m, (4H); 7.88, quintet, (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-[ 3-[ 3-( 1 - piperidinyImethyl- phenoxy] propyl]- 1H- 1, 2, 4- triazol-5-amine A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]-propyl ] amino]-1 H-1 , 2 , 4-triazol-3-ethane-1 , 2-^diol (0.08 g), 2,2-dimethoxypropane (2.0 ml) and 4-toluenesulfonic acid (0.03 g) in

acetone (10 mL) was stirred at 20° for 16 h, evaporated and partitioned between 2N sodium carbonate and ethyl acetate. The ethyl acetate extract was dried and evaporated, and the resulting oil (0.07 g) was chromatographed using system E as eluent to give the title compound (0.025 g) as an amber gummy mass.

NMR (CDCl 3 ): 2.78, t, (1H); 3.08-3.23, m, (3H); 4.96, dd, (1H); 5.48, t, (1H); 5.72, dd, (1H); 5.80, t, (1H); 5.88 h

(2H); 6.37, q, (2H); 6.46, p, (3H); 6.55, p, (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-[[[ 1- methyl- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy]-propyl] amino]- 1H- 1, 2, 4- triazol- 3- yl] methyl] thio ] acetamide A solution of ethyl-[[[1-methyl-5-[[3-[3-(1-piperidinylmethyl)-phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl] methyl]thio]acetate (0.4 g) in ethanolic methylamine (33%, 20 mL) under nitrogen, was heated under reflux for 30 h, cooled, evaporated under vacuum, the residue dissolved in 2N hydrochloric acid (20 mL) and washed with ethyl acetate. The acidic layer was basified with potassium carbonate and extracted with ethyl acetate, after which the extract was dried and evaporated to an oil (0.28 g) which, after chromatography with system E as eluent, gave the title compound (0.13 g) as an oil.

NMR (CDCl 3 ): 2.46, s(br), (1H); 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, p, (3H); 6.56, p, (2H); 6.72, p, (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.

Example 9

1- methyl- a- pheny1- 5-[[ 3—[ 3—( 1- piperidinylmethyl) phenoxy] propyl]-amino]- 1H- 1, 2, 4- triazole- 3- methanol compound with fumaric acid and ethyl acetate: 40: 56:5

3-[3-(1-piperidinylmethyl)phenoxy]propanamine (0.72 g) and , methyl-N-[2-acetyloxy-[2-(phenyl)acetyl]]-1-methyl-2-(phenyl-methylene ) hydrazine carboxymidothioate (1.1 g) was melted at 60° for 2 hours to a gummy mass. This was dissolved in toluene and stirred for 15 hours with 5N hydrochloric acid. After adjustment to pH 7 with sodium carbonate, the aqueous phase was washed with toluene and ethyl acetate. The aqueous phase was then basified to pH 10 with sodium carbonate and extracted with

ethyl acetate. The pH 10 organic extracts were dried (MgSO 4 ) and evaporated to an oil (1.1 g). The oil was chromatographed with dichloromethane:ethanol:0.88 ammonia (150:8:1) as eluent to give a white solid (0.25 g) m.p. 42-52°. The solid (0.112 g) was dissolved in ethyl acetate and treated with a solution of fumaric acid (0.03 g) in ethyl acetate to precipitate the title compound which was filtered off as a white solid (0.095 g) m.p. 80°.

NMR (CDCl 3 ) of free base: 2.4-2.9, m, (6H); 3.0-3.4, m, (3H);

4.31, p, (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).

Example 10

4- methyl- a- pheny1- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy] propyl]-amino]- 4H- 1, 2, 4- triazole- 3- methanol

A mixture of DL-mandelic acid (30.4 g) and N-amino-N 1 -methyl-N 1 1 [3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine hydroiodide (22.35 g) was heated from 40° to 125° and held as a melt at 125° for 6 hours.

The hot melt was extracted with hot water (250 ml) and the aqueous extract brought to pH 8 with solid sodium carbonate and extracted with ether. The ether extract was cooled to 5°, resulting in a white solid which was washed with boiling ethyl acetate to give the title compound as a white solid (0.18 g), m.p. 186-188°.

Found: C, 68.9; H, 7.7; N, 16.0;

C25H33N5°2 requires: c'68'9'" H'7'6'* N'16^1%

Example 11

[ 4- methyl- a- pheny1- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy]-propyl] amino]- 4H- 1, 2, 4- triazole- 3- methanol] acetate-( ester) - hydrate A solution of 4-methyl-α-phenyl-5-[[3-[3-(1-piperidinylmethyl)-phenoxy]propyl]amino]-4H-1,2,4-triazole-3-methanol (0 .10 g) and acetic anhydride (0.03 mL) in pyridine (2 mL) was stirred at room temperature for 16 hours. Saturated sodium carbonate solution was

added and the suspension extracted with ethyl acetate. The organic phase was washed with water and brine and evaporated under reduced pressure. The residue was crystallized from isopropyl acetate, whereby the title compound was obtained in the form of a white solid (0.074 g), mp 89-91°C.

Found: C, 6 4.9; H, 7.5; N, 13.8;<C>27<H>35<N>5°3<H>2°<fo>rdrer: C'65.3; H, 7.4; N, 14.1%

Example 12

g-[ 1- methyl- 5-[[ 3-[ 3-( 1- piperidinylmethyl) phenoxy] propyl]-amino]- 1H- 1, 2, 4- triazol- 3- yl]- 2- pyridinemethanol n-butyllithium (1.6 M in n-hexane, 8.12 ml) was during

15 min. added dropwise to a stirred solution of 2-bromopyridine (1.86 g, 1.12 mL) in anhydrous ether (10 mL) at -70° under nitrogen. The brown solution was stirred at -70° for 0.5 hours and then a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1, was added dropwise. 2,4-triazole-3-carboxaldehyde (2.0 g) in anhydrous tetrahydrofuran

(20 ml) at -70°, and the solution stirred at -40° for 2 hours before adding water (20 ml), after which the mixture was allowed to stand

overnight at 20°. After concentration, the mixture was extracted with ethyl acetate and the extract dried and evaporated to an oil (2.5 g) which was chromatographed with system E as eluent and gave a solid - (0.48 g). This was recrystallized from ethyl acetate to give the title compound

(0.25 g) in the form of a white powder, m.p. 152-154° (decomp).

Found: C, 6 5.9; H, 7.4; N, 19.1;

C24H32N6°2 requires: c'66'°; H/ 7/4; N, 19.2%

Example 13

5-[[ 2-[[[ 5-[( dimethylamino) methyl]- 2- furanyl] methyl] thio] ethyl]-amino]- 1- methyl- a- phenyl- 1H- 1, 2, 4- triazole- 3- methanol- dihydrochloride A solution of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl]-thio]ethanamine (3.09 g) and methyl-N-[2-acetyloxy-[ 2-(Phenyl)-acetyl-[[-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate

(5.9 g) in toluene (110 mL) was stirred at room temperature for 3 hours. Then a new portion of methyl N-[2-acetyloxy-[2-(phenyl)acetyl]]-1-methyl-2-(phenylmethylene)hydrazine-carboxyimidothioate (0.3 g) was added and the mixture stirred at room temperature for 1.5 hours. After addition of 2M hydrochloric acid (22.5 ml), the reaction mixture was heated on a steam bath for 1 hour. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with toluene (2 x 30 mL). The acidic aqueous layer was basified with potassium carbonate and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to a brown gum which was chromatographed on silica gel with dichloromethane:ethanol:ammonia (65:8:1) as eluent to give a brown gummy product (1.35 g). This was dissolved in methyl acetate and treated with ethereal hydrochloric acid to a white solid which was triturated with dry ether to give the title compound (1.3 g) as a fine white solid, m.p. 55-60° (softens).

NMR (CD 3 OD) : 2.5, m, (5H); 3.3, d, (1H); 3.6, d, (1H);

4.15, p, (1H); 5.6, p, (2H); 6.3, m, (7H); 7.15, m, "(8H);.

Example 14

5-[[ 3-[ 3-[[( 2- furanylmethyl) amino] methyl] phenoxy] propyl]-amino]- 1- methyl- a- pheny1- 1H- 1, 2, 4- triazole- 3- methanol One solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol-acetate (ester)

(1.0 g) and furfurylamine (5 ml) in ethanol (30 ml) were stirred at 21° for 1.5 hours before adding a suspension of sodium borohydride (1.3 g) in ethanol (10 ml), after which the stirring was continued for an additional 16 hours at 21°. Water (20 mL) was added, the mixture concentrated to remove ethanol, and the aqueous residue extracted with 4-methylpentan-2-one. The extract was dried and evaporated to an oil. The excess furfurylamine was removed under vacuum and the residue dissolved in 2N hydrochloric acid, after which the acidic layer was washed with ethyl acetate and basified (pH 9) with sodium carbonate and extracted with 4-methylpentan-2-one.

The extract was washed with water, dried and evaporated to a brown gummy mass (0.65 g) which, after chromatography on silica gel (Merck no. 7729) with system C as eluent, led to the title compound (0.5 g) in the form of a slightly orange gummy product.

TLC system C; Rf 0.35.

NMR (CDCl 3 ): 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, p, (1H); 5.5, t, (1H); 5.92, t, (2H); 6.23, p, (2H); 6.25, p, (2H); 6.44 q(dt) (2H); 6.56, p, (3H); 6.6-6.8, m, (2H);

7.94, m, (2H) .

Example 15

3-[ [ [ ( 2- furanyl) methyl] thio] methyl]- 1- methyl- N[ 3-[ 3-( 1-piperidinylmethyl) phenoxy 3 propyl] — 1H- 1, 2, 4- triazole- 5- amine A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]-propyl]amino]-1H-1,2,4-triazole-3-methanol (3.59 g) in thionyl chloride (10 ml) was heated on a steam bath for 10 min. The solution was evaporated to dryness and the residue dissolved in water. Sodium bicarbonate was added until effervescence ceased. Sodium carbonate (3 g) was then added and the suspension extracted with ethyl acetate. The organic extract was dried and evaporated to a brown oil (4.1 g). A portion of the oil (3.2 g) was dissolved in absolute ethanol (40 ml) and added dropwise at 5° to a solution of furfuryl mercaptan (1.14 g) and sodium (0.34 g) in absolute ethanol (20 ml ). The suspension was allowed to stand at room temperature for 18 hours, and was then filtered, after which the filtrate was evaporated to dryness. The residue was dissolved in 0.2N hydrochloric acid, washed with ethyl acetate and basified with an excess of solid sodium carbonate and extracted with ethyl acetate. The organic extract was dried and evaporated to a . oil (2.2 g) which, after purification by column chromatography with chloroform as eluent, gave the title compound in the form of an oil (1.2 g).

TLC System C; Rf 0.45.

NMR (CDCl 3 ): 2.7, d, (1H); 2.8, t, (1H); 3.0-3.4, m, (3H);

3.8, m, (2H); 5.5, t, (1H); 5.95, t, (2H); 6.25, p, (2H);

6.3-6.7, m, (9H); 7.5-8.1, m, (6H); 8.5, m, (6H).

Example 16

5-(Methoxyphenyl,tyl)-4-methyl-N-[[3-[3-(1-piperidinylmethyl)-phenoxy]propyl]-4H-1,2,4-triazol-3-amine compound. with tartaric acid (1:1)

A solution of 4-methyl-α-phenyl-5-[[3-[3-(1-piperidinylmethyl)-phenoxy]propyl]amino]-4H-1,2,4-triazole-3-methanol (0.37 g) in thionyl chloride (3.0 mL) was stirred at room temperature for 0.5 h. The solvent was removed under vacuum and the remaining pink foam dissolved in dry methanol (10 mL) and added dropwise to a solution of sodium (0.17 g) in dry methanol (10 mL). The reaction mixture was stirred at room temperature for 0.5 h, poured into water and extracted with ethyl acetate. The organic extract was dried and evaporated to a gummy mass (0.3 g). This was dissolved in ethyl acetate and treated with an excess of tartaric acid in ethyl acetate, whereby the title compound was obtained as a white solid (0.26 g),

m.p. 88° (softens).

NMR (CD 3 OD): 2.5-3.1, m, (9H); 4.5, p, (1H); 5.6, p, (2H);

5.8, p, (2H); 5.9, t, (2H); 6.48, t, (2H); 6.60, p, (3H);

6.80, p, (3H); 6.85, m, (4H); 7.85, m, (2H); 8.2, m, (6H).

Example 17

5~[[ 2-[[[ 5-[( dimethylamino) methyl]- 2- furanyl] methyl] thio] ethyl]-amino]- 1- methyl- g- phenyl- 1H- 1, 2, 4- triazole- 3- methanol A solution of 2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]-thio]ethanamine (3.09 g) and methyl-N-[2-acetyloxy-[2-(phenyl)- acetyl]]-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (compound A) (5.9 g) in toluene (110 ml) was stirred at room temperature for 3 hours, after which another portion (0.3 g) of compound A was added. The mixture was stirred at room temperature for a further 1.5 hours and 2M hydrochloric acid (22.5 ml) was added and the mixture heated on a steam bath for 1 hour. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with toluene. The acidic aqueous layer was then basified with potassium carbonate and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to a brown gum which was chromatographed

dichloromethane:ethanol:ammonia (65:8:1) to a brown gummy mass (1.95 g). A portion of this (0.5-g) was dissolved in dry tetrahydrofuran and filtered through "Florisil" (an activated magnesium silicate). The filtrate was concentrated to a small volume, whereby the title compound (0.32 g) could be isolated as a white solid, mp 121-122.5°.

Found: C, 6 0.0; H, 6.9; N, 17.3;

C20<H>27<N>5°2<S><f>orders:c'59'8; H/6'8; N; 17.4%

Examples of pharmaceutical preparations

Pills

The active substance was sieved through a 2.50 µm sieve, mixed with the excipients and compacted using a 9 mm diameter ram. Other tablet strengths can be produced by changing the weight of the pressing body and a correspondingly adjusted piston size. The tablets can be coated with suitable film-forming polymers such as hydroxypropyl cellulose, following conventional techniques. Alternatively, the tablets can be coated with sugar.

Capsules

The active substance was sieved through a 250 µm sieve and mixed with the excipients. The mixture was filled into gelatin capsules No. 2 with suitable equipment. Other dosages can be prepared by changing the filling weight and possibly capsule size.

Injection preparation for intravenous administration

Sodium chloride can be added to regulate the solution's osmotic pressure, and the pH can be adjusted with dilute acid or alkali to achieve maximum stability. The solution is prepared, filtered and filled under nitrogen, or other inert gas,

into suitable ampoules which are remelted. The injection solution is sterilized using an accepted autoclave cycle.

Alternatively, the solution can be sterilized by filtration and transferred to sterile ampoules under aseptic conditions.

Active ingredient, buffer, flavoring agent, preservative and coloring agent are dissolved in some of the water. The rest of the water is heated to approx. 80°C for dissolution of the sucrose. After cooling, the two solutions are mixed, after which the volume is adjusted and the mixture is filtered. Alternatively, the active ingredient, sucrose, buffer, flavoring, color and preservative can be mixed and transferred in powder form to bottles for later dissolution by adding water.

In the examples given here, the active substance is preferably 5-[[ 2 - [[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-amino]-1-methyl-a-phenyl-1H- 1,2,4-triazole-3-methanol in the form of a physiologically acceptable salt, e.g. the hydrochloride.

Claims (8)

'1. Process for the preparation of compounds of the general formula (I): and physiologically acceptable salts and hydrates thereof, where R.j means hydrogen, C1-14 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl substituted with hydroxy, alkoxy, amino, alkylamino, dialkyl-amino or cycloalkyl; and R 2 means hydrogen or C^_^ alkyl; or R^ and R^, together with the nitrogen atom to which they are attached, form a 5 to 10 membered ring which may be saturated or contain one or more double bonds, be unsubstituted or substituted with one or more C^-g alkyl groups, or with a hydroxy group and/or contain another heteroatom selected from oxygen and sulfur; Alk means a straight or branched alkylene chain with 1-3 carbon atoms, Q means a furan or thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 5-positions, and where the furan or thiophene ring optionally has a further substituent, R^i adjacent to the group R^R2NAlk; or Q means a thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 4-positions, and optionally has a further substituent, R^, in a neighboring position to the R^R2NAlk group, provided that when R^R2NAlk- group is in the 4-position, the R^ group is in the 5-position; or Q means a benzene ring which is incorporated into the rest of the molecule through bonds in the 1- and 3- or 1- and 4-positions; R^ denotes halogen or C^_^alkyl which may be substituted by hydroxy or C^_4 alkoxy; X represents oxygen, sulfur, -NH-, methylene, or a bond; Y means oxygen, sulfur, methylene or a bond; n stands for 0, 1, 2 or 3 and m is an integer from 2 to 5, provided that (a) the total number of atoms in the chain X(CHJ Y(CH„) is an integer from 3 to 8, (b) when X means 2 n 2 m J oxygen or sulphur, that n is then 2 or 3, (c) when X means -NH-, that Q then is a benzene ring and Y means the methylene or a bond, and (d) when Q means a benzene ring, X stands for oxygen and n is 1 , that then m can also mean 1 and Y can also mean -CHOR^, where R ... means hydrogen or acyl; and R 8 means hydrogen, alkyl, alkenyl, aralkyl or C 2-6 alkyl substituted by hydroxy or alkoxy; A either means N and B means CR^; or A means CR,- and B means N; and R,- constitutes i) a C2_g straight or branched alkyl group which is substituted with 2 or 3 hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group forms a cyclic acetal or cyclic ketal structure with formula: where p is 0 or 1 and Rg and R^, which may be the same or different, represent hydrogen, a C^_^alkyl group or a phenyl group; or ii) the group (CH2)^Z(CH2)^Rg, where q represents an integer from 1 to 4, r an integer from 1 to 6, Z represents oxygen or sulfur, and when r is 1, Rg represents the group CH=CH2, alkenyl or the CORg group, where Rg is hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the NR^^R^^ group, where R1Q is hydrogen or alkyl and R^ ^ is hydrogen or alkyl, and when r is an integer from 2 to 6, Ro0 has one of the above meanings or can additionally stand for hydroxy, alkoxy, aryloxy or the NR^2R^^ group, where R12 is hydrogen or alkyl and R^^ is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl; or iii) the group (ett2)xS(CH2.) R1-5, where x means 1 or 2, y means 0 or 1, and R 1 a heteroaryl group; or iv) an aralkyl or heteroaralkyl group where the alkyl part is substituted with hydroxy, alkoxy or acyloxy, characterized in that (a) for the preparation of compounds where R,- means the group (CH2)gZ(CH2)^Rg or (CH2)xS( CH 2 ) 5 , a triazole of formula (I), where R 1 means the group R 1 . a , where R^a is -(CH2)^L or -(CH^^L and L is a leaving group, react with a 9Z(CH„) R_ or 9S(CH_) R,c anion; z r o z y lo (b) for the preparation of compounds where R^ is different from a C2-g straight or branched alkyl group with 2 or 3 acyloxy substituents, or a dihydroxyalkyl group forming a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group p>pe where the alkyl part is substituted with an acyloxy group, or Y is different from CHOR14, where R 4 is acyl, a cyclization of a compound of formula (III) is carried out: where R g is like the R^ group, V is and Y' is hydrogen where V is oxygen or sulfur and R^<c> is like the R^ group, or is a group which can be converted into this under the cyclization conditions; or V is. NH, R^g is a group as indicated for R^ and Y<1>'s where Y" is sulfur, oxygen or NH; or V is sulfur or oxygen, Y' is and R^ g is as indicated for the R^ group; or V is NR^, R^g is hydrogen and Y' is where Y" is as indicated above; (c) for the preparation of compounds where Alk is CH2, an aldehyde of formula'(VII): treated with an amine R^I^NH and then reduced; (d) for the preparation of compounds where R is an aralkyl or heteroaralkyl group, where the alkyl moiety is substituted by hydroxy, a suitable aldehyde or ketone is reacted with an organolithium compound ArLi or a Grignard reagent ArMgHal, where Ar is a suitable aryl, aralkyl, heteroaryl or heteroaralkyl group and. Hal is halogen; (e) for the preparation of compounds where R^ means a C2-g straight or branched alkyl group with 2 or 3 acyloxy substituents, or R^ constitutes an aralkyl or heteroaralkyl group where the alkyl part is substituted by an acyloxy group, or Y means CHOR^, where R^ 4 is acyl, the corresponding alcohol is reacted with an activated derivative of a suitable acid; (f) for the preparation of compounds where R,, means a C2_g straight or branched alkyl group which is substituted with 2 or 3 alkoxy groups, or R,, means an aralkyl or heteroaralkyl group where the alkyl part is substituted with an alkoxy group, the corresponding alcohol is treated with a halogenating agent, whereupon the resulting halogen compound is reacted with an appropriate alkanol; (g) for the preparation of compounds where R<- means the group (CH2)gZ(CH2)rRg, where Rg is NR12<R>1<3>and 2 and R1 3 both stand for hydrogen or alkyl, the corresponding alcohol where Rg is hydroxy, is treated with a reagent capable of converting the Rg group into a leaving group, whereupon the resulting compound of formula (I), where R^ means (CH2)(CH2)rL, where L is a leaving group, is reacted with ammonia or a suitable amine R^R^NH; (h) 'for the preparation of compounds where Rg is the group NR^2R-|3' where Ri 3 is an acyl group or an aryl or alkylsulfonyl group, the corresponding compound where Ro D is the NHR..I z- group, is reacted with an activated derivative of the corresponding carboxylic or sulfonic acid; (i) for the preparation of compounds where RoQ is the group -CONR^ qR^ ^, an activated derivative of the corresponding carboxylic acid where Rg is -CG^H, is reacted with ammonia or a suitable amine HNR^; or (j) for the preparation of compounds wherein R,, includes the group: the corresponding compound wherein R- includes the group is reacted with an aldehyde or ketone R^R^CO i presence of an acid; and the obtained compound of formula (I) is optionally converted into a salt. 2. Process as set forth in claim 1, characterized in that compounds of formula (I) are prepared where: R^ means C 1-8 alkyl, C^_^ alkyl substituted with a trifluoromethyl group, C 2-4 alkyl substituted with hydroxy or a di-C ^ _3-alkylamino group, C^_-y cycloalkyl, C^_^ alkenyl, phenyl-C^_3-alkyl or a heteroaryl-C^_3-alkyl group where the heteroaryl ring contains one heteroatom; R2 is hydrogen or methyl; or R^R2N means a 5-8 membered ring optionally containing one double bond, an oxygen atom or an alkyl substituent;. Alk means methylene; Q means a benzene ring which is incorporated into the rest of the molecule through bonds in the 1- and 3-positions; or a furan ring which is incorporated into the rest of the molecule through bonds in the 2- and 5-positions and optionally has a substituent adjacent to the R^R2NAlk group, where R^ is C-]-4alkyl; or a thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 4-positions with the R^R2NAlk substituent in the 2-position, under the conditions that when Q has the benzene meaning just mentioned, X stands for a bond, n for 0, Y for oxygen and m for 3, 4 or 5, or X and Y both represent 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 has the furan or thiophene ring meaning just mentioned, X stands for a bond and Y stands for sulfur or CE^, while n is 1 and m is 2, or Y stands for oxygen, while n is 1 and m is 3; R 1 means hydrogen or alkyl; R,- means a C2-4 alkyl group which is substituted by 2 hydroxy groups or a 2,2-di-C1-3-alkyl-1,3-dioxolan-4-yl group; or R1- means phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl, where the alkyl moiety is substituted with hydroxy, C^_^alkanoyloxy or C1_2 alkoxy; or Rc means the group (CH„) Z(CH0) RQ, where q is 1, r is 1-4 when 3 z q z r o Z is oxygen, or r is 1 when Z is sulfur, and Rg is hydroxy, the -Ct^CP^ group, the di-C^_3_alkylamino, or the CORg group, where Rg is C^_^alkyloxy or NHR^- the group wherein R^ is C^_^alkyl; or R,, means the group (Cl^^StCI-^) R-j^-, where x means 1 and the heteroaryl group R 1 is tetrazolyl or thiadiazolyl each of which may be substituted with C 1-3 alkyl, or R 1 is furyl. 3. Process as stated in claim 1, characterized in that compounds of formula (I) are prepared where: R^ means C^_g alkyl, C^_^alkyl substituted with a trifluoromethyl group, ^ 2-4 alkyl substituted with hydroxy or a di -C 1 -3-alkylamino group, C 1-3 cycloalkyl, C 1-5 alkenyl, phenyl-C 1-2 alkyl or a heteroaryl-C 1-4 alkyl group where the heteroaryl ring contains one heteroatom; R2 is hydrogen or methyl; or R^R2N means a 5-8 membered ring optionally containing one double bond, an oxygen atom or an alkyl substituent; Alk means methylene; Q means a benzene ring which is incorporated into the rest of the molecule through bonds in the 1- and 3-positions; or a furan ring which is. or a thiophene ring which is incorporated into the rest of the molecule through bonds in the 2- and 4-positions with the R2NAlk substituent in the 2-position;, under the conditions that when Q has the benzene meaning just mentioned, X stands for a bond, n for 0 , Y for oxygen and m for 3, 4 or 5, or X and Y both represent 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 has the furan or thiophene ring meaning just mentioned, X represents a bond and Y represents sulfur or CH 2 , while n is 1 and m is 2, or Y represents oxygen, while n is 1 and m is 3 ; R 2 is hydrogen or alkyl; Rj. means a C2_4 alkyl group which is substituted by 2 hydroxy groups or a 2,2-di-C1-3-alkyl-1,3-dioxolan-4-yl group; or Rc- means phenyl-C 3 -alkyl where the alkyl part is substituted with C 1-4 alkanoyloxy or C 1-2 alkoxy, or heteroaryl-C 1-4 alkyl where the alkyl part is substituted with hydroxy, C 1-4 alkanoyloxy or C 2 alkoxy; R5 means the group (CH2)(CH2)^Rg, where q is 1, r is 1-4 when Z is oxygen, or r is 1 when Z is sulfur, and RoQ is hydroxy, the -CH=CH2~ group, the di-C1-3-alkylamino or the CORg group, where Rg is C1-4 alkoxy or the NHR^ group, where R^ C 1 -C 4 alkyl; or Rj. means the group (CH2) (CH2) R^ 5 , where x means 1 and the heteroaryl group R^^ is tetrazolyl or thiadiazolyl each of which may be substituted with C^_^ alkyl, or R^ 5 is furyl. 4. Method as stated in claim 1, characterized in that compounds with the general formula (II) are produced: and physiologically acceptable salts and hydrates thereof, where R^F^N means di-C^^-alkylamino, furylmethylamino, pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimino; A means N and B means CR^, or A means CR^ and B means N, where R 1 means C 2 -4 alkyl substituted with 2 hydroxy groups, 2,2-di-C 3 -alkyl-1,3-dioxolan-4-yl, (1-methyl-1H-tetrazol-5-yl)thiomethyl, or Rj. means f-enyl-C^ _3-alkyl or heteroaryl-C^_^-alkyl, where the alkyl part is substituted with hydroxy or phenyl-C^_3-alkyl', where the alkyl part is substituted-with C^_^-alkanoyloxy or _2~ alkoxy, or R^ means the group CH2Z(CH2)rRg where Rg is hydroxy or di -C1-2-alkylamino, Z is oxygen and r is 4; or Rg is the group -CH=CH2 or the group•CORg, where Rg is C1-4 alkoxy, Z is oxygen or sulfur and r is 1; and Q is either 1,3-benzene and X is a bond, n is 0, Y is oxygen and m are 3 or 4; or X is oxygen, n is 1, Y is -CHOH- and m is 1; or Q is 2,4-furan or 2,4-thiophene, X is a bond, Y is sulfur, n is 1 and m is 2; with the proviso that R^R-^N is di-C^^-alkylamino when Q is a furan or thiophene ring. 5. Method as stated in claim 1, characterized in that compounds with the general formula (II) are produced: and physiologically acceptable salts and hydrates thereof, where either R-]R2N is dimethylamino, Q is 2,5-furan, X is a bond, Y is sulfur, n is 1 and m is 2; or R^R-^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 means N and B means CR5, or A means CR5 and B means N, where Rj- is benzyl where the methyl group is substituted with hydroxy. 6. Process as stated in claim 1, characterized in that 5-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino]-1-methyl-a- phenyl-1H-1,2,4-triazole-3-methanol and physiologically acceptable salts thereof. 7. Process as stated in claim 1, characterized in that the following compounds of formula (I) are prepared: 1-methyl-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-N-[ 3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazol-5-amine 1-methyl-α-phenyl1-5-[[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-amino]-1H-1,2,4-triazole-3-methanol 4-methyl-a-pheny1-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino] -4H-1,2,4-triazole-3-methanol and physiologically acceptable salts thereof. 8. Process as stated in claim 1, characterized in that the following compounds of formula (I) are prepared: 1-methyl-5-[3-[[(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2, 4-triazole-3-ethane-1,2-diol α-[1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino]-1H-1,2,4- triazol-3-yl]-2-pyridine-methanol 5-[[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-amino]-1methyl-a-phenyl-1H-1, 2, 4-triazole-3-methanol 5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol 5-[[2-[[[5-[(dimethylamino)methyl]-3-thienyl]methyl]thio]ethyl]-amino]-1-methyl-a-phenyl-1H-1,2,4-triazole- 3-methanol and physiologically acceptable salts thereof.