NL8300697A - HETEROCYCLIC DERIVATIVES, METHOD FOR PREPARING THE SAME; PHARMACEUTICAL PREPARATIONS. - Google Patents

Description

«- - - *.

VO 4605

Heterocyclic derivatives .; method for preparing it; pharmaceutical preparations. '

The invention relates to heterocyclic derivatives acting on histamine receptors, to methods of preparing said heterocyclic derivatives, to pharmaceutical preparations containing said derivatives and to the use of these derivatives in the pharmaceutical industry.

It has now been found that certain heterocyclic derivatives have strong activity as antagonists. For example, these compounds, which will be described in more detail below, exhibit an inhibition of gastric acid secretion when stimulated via histamine receptors (Ash and Schild, Brit.

J. Pharmacol. Chemother, 1966, 27, 427). Their ability to act in this way can be demonstrated in the method described in British Patent Publication 1565966 (the perfused rat stomach method), modified using sodium pentobarbitone (50 mg / kg) as an anesthetic instead of urethane, as well as in the methods described by Black et al, Nature 1972 236, 385 (dogs provided with Heidenhain pouches, which dogs are conscious). Furthermore, the compounds counteract the influence of histamine on the contraction frequency of isolated right atria of guinea pigs.

Compounds with histamine-blocking activity can be used in the treatment of conditions, it is advantageous that the acidity in the stomach is reduced, especially in the case of the formation of a gastric ulcer or peptic ulcer, as a prophylactic measure in operative procedures, and in the treatment of allergic and inflammatory states in which histamine is a known mediator. They can therefore be used, for example, alone or in combination with other active ingredients in the treatment of allergic and inflammatory skin conditions.

The present invention provides compounds of the general Formula 1 of the formula sheet, as well as physiologically acceptable salts and hydrates thereof, wherein R 1 is hydrogen, alkyl of 1 to 14 carbon atoms, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl, or alkyl, substituted 8300697 represents 2 * * substituted by hydroxy, alkoxy, amino, alleylamino, dialkylamino or cycloalkyl; and 1 * 2 represents hydrogen or alkyl of 1 to 4 carbon atoms; or 5 and R2 together with the nitrogen atom to which they are attached form a 5 to 10 ring which may be saturated or contain at least one double bond, be unsubstituted or be substituted by a. or may contain multiple alkyl groups of 1 to 3 carbon atoms, for example methyl, or a hydroxy group and / or another hetero-10 atom selected from oxygen and sulfur;

Al represents a straight or branched alkylene chain of 1 to 3 carbon atoms, Q represents a furan or thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 5 positions, which furan or thiophene ring is optionally a further substituent r 4 in addition to the group R 1, N-Alk-; or Q represents a thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 4 positions, the thiophene ring optionally bearing a further substituent R 1 next to the group R 1 N 1 Alk, provided that when the group R ^ 2NAk is in the 4 position, the group R ^ is in the 5 position; or Q represents a benzene ring incorporated into the rest of the molecule by bonds at the 1 and 3 or 1 and 4 positions; R 1 represents halogen or alkyl of 1 to 4 carbon atoms, optionally substituted by hydroxy or alkoxy of 1 to 4 carbon atoms; X represents oxygen, sulfur, -NH-, methylene or a bond; Y represents oxygen, sulfur, methylene or a bond; 30 n represents O, 1, 2 or 3, and m represents an integer from 2 to 5, with the proviso that (a) the total number of atoms in the chain X (CH “) Y (CH“) zn 2 m is a integer from 3 to 8, (b) when X and Y represent oxygen or sulfur, n is 2 35 or 3,

(c) when X represents -NH-, Q is a benzene ring and Y

8300697 Λ ...... «3 represents methylene or a bond, and (d) when Q represents a benzene ring, X represents oxygen, and n equals 1, in which case m may additionally be 1 and Y in addition, can represent the group -CHOR 1, where R 1 5 represents hydrogen or acyl; and R 1 represents hydrogen, alkyl, alkenyl, aralkyl, or hydroxy or alkoxy substituted alkyl of 2 to 6 carbon atoms;

either A N and B CRr; either A CR ,, and B

o 3 N proposals; 10 and Rg represents i) a straight or branched chain alkyl group of 2 to 6 carbon atoms substituted by two or three hydroxyl, alkoxy or acyl oxy groups or the dihydroxyalkyl group may form a cyclic acetal or cyclic ketal structure of formula 2, wherein p is 0 or 1 and R. and

O

R 1, which may be the same or different, each represent hydrogen, an alkyl group of 1 to 4 carbon atoms, or a phenyl group; or ii) the group (CH0) Z (CH2) R_, where q represents an integer from 1 to 4, r represents an integer from 1 to 6, Z represents oxygen or sulfur, and when r is 1 R0 is the group CH = CH_, alkenyl or the group o2.

CORq represents where Ra represents hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the group NR ^ q ^ II wherein R ^ q is hydrogen or alkyl and is hydrogen or alkyl, and when r is an integer from 2 to 6 , R. each of the

O

May have the above meanings or may additionally represent hydroxy, alkoxy, aryloxy or the group NR ^ S ^ wherein R ^ is hydrogen or alkyl and R13 represents hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, provided that the total of q and r is preferably 6 or less; or iii) the group (CH) S (CH) R _, wherein x is 1 or 2, y 2 X 4 y Ij is 0 or 1, and represents a heteroaryl group; or iv) an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, alkoxy or acyloxy.

In formula 1, the term alkyl as a group or as part of a group means that the group is straight or branched and, unless otherwise indicated, contains 1 to 6 carbon atoms, in particular 1 to 4 carbon 8300697 4 atoms, for example, is methyl or ethyl, and the term alkenyl means that the group preferably has 3 to 6 carbon atoms. The term cycloalkyl means that the group has 3 to 8 carbon atoms. The term aryl as a group or part of a group preferably means phenyl or substituted phenyl, for example phenyl, substituted with 1 or more alkyl groups with 1 to 3 carbon atoms or alkoxy groups with 1 to 3 carbon atoms, or halogen atoms, for example fluorine. The term acyl means an aroyl, aralkanoyl or alkanoyl group having 1 to 6 carbon atoms, for example, acetyl, formyl, phenylacetyl or benzoyl. The term heteroaryl 10 as part of a group within the meaning of R ^ means a monocyclic 5- or β-ring with 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, for example thienyl, pyridyl, furyl or thiazolyl. The heteroaryl ring may be unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term heteroaryl as part of a group in part (iv) of the definition of Rg means a monocyclic 5- or 6-ring with 1 heteroatom selected from oxygen, nitrogen and sulfur, for example thienyl, pyridinyl or furyl, optionally substituted by an alkyl group with 1 to 3 carbon atoms. The alkyl portion of a heteroaralkyl group is one. straight or branched chain alkyl of 1 to 4 carbon atoms, and the heteroaryl ring is connected to the alkyl portion by a carbon atom. The term heteroaryl in the definition of R ^ means a monocyclic or bicyclic unsaturated ring of 5 to 10 atoms selected from carbon, oxygen, nitrogen or sulfur. When the heteroaryl ring is monocyclic it preferably contains 5 or 6 members and when it is bicyclic it preferably contains 9 or 10 members. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxyzolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isoquinolyl, quinonyl, indolyl or benzoxazolyl. The ring structure may be unsubstituted or substituted by one or more groups selected from alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or hydroxy.

One aspect of the invention relates to compounds of formula .1. , in which the symbols, R ^, R ^ / Alk, Q, X, Y, n and 35 m are as defined, excluding the additional possibilities for m and Y, given by the reservation d), and A N and B

CR_ or A represents CR_ and B N, wherein R_ is as defined in possibility (i) or in possibility (ii) (except that q can represent only 1 or 2).

Another aspect of the invention pertains to compounds of formula 1, wherein the symbols R ^, R ^, R ^, Alk, Q, X, 5 Y, n and m are as defined, except for the additional possibilities for m and Y as given by the reservation d), and AN and B represent CR_ or A CR_ and BN, wherein Sc is as defined in possibility (iv).

Compounds of Formula. 1. preferred are 10 wherein R 1 represents alkyl of 1 to 8 carbon atoms (eg methyl, propyl, butyl or heptyl), trifluoromethyl group-substituted alkyl of 1 to 4 carbon atoms (eg 2,2, 2-trifluoroethyl), alkyl group substituted by hydroxy or a dialkylamino group (alkyl in each case with 1 to 3 carbon atoms) with 2 to 4 carbon atoms (e.g. 3-hydroxypropyl or dimethylarninoethyl), cycloalkyl with 5 to 7 carbon atoms (e.g. cyclohexyl) alkenyl of 3 to 5 carbon atoms (e.g. allyl), phenylalkyl whose alkyl group has 1 to 3 carbon atoms (e.g. benzyl), or a hetero-20 arylalkyl group wherein alkyl has 1 to 3 carbon atoms, the heteroaryl ring containing 1 heteroatom furylmethyl); represents hydrogen or methyl; or R R 'N represents a 5 to 8 ring, optionally containing an X.' double bond, an oxygen atom or an alkyl substituent such as methyl (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethylenimino or tetrahydropyridino);

Al represents methylene; Q represents a benzene ring incorporated into the rest of the molecule by bonds at the 1 and 3 positions; Or represents a furan ring, which is incorporated in the remainder of the molecule by bonds at the 2 and 5 positions, which optionally bears a substituent R 1 next to the group R 1 R N Alk, wherein R 1 alkyl having 1 is up to 4 carbon atoms (e.g. methyl); or represents a thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 4 positions with the substituent R 1 R 1 N Alk in the 2 position; with the proviso that when Q is a benzene ring as defined above, X is a bond, n is 0, Y is oxygen 830 0 89 7 6 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 CHGH, and n and m are both 1; and when Q represents a furan or thiophene ring as just defined, X is a bond and either Y represents sulfur or CH 2, η is 1 and m is 2, 5 or Y is oxygen, η 1 and i is 3; R 1 represents hydrogen or alkyl (e.g. methyl);

Rg represents an alkyl group of 2 to 4 carbon atoms, substituted by two hydroxy groups, or a 2,2-dialkyl (any alkyl group of 1 to 3 carbon atoms, e.g. dimethyl) -1,3-dioxolan-4-10 yl group or

Rg represents phenylalkyl wherein alkyl has 1 to 3 carbon atoms (e.g. benzyl) or heteroarylalkyl wherein alkyl has 1 to 3 carbon atoms (e.g. furylmethyl or pyridylmethyl) wherein the alkyl portion is substituted by hydroxy, alkanoyl-oxy with 1 to 4 carbon atoms (e.g. acetyloxy) or alkoxy with 1 to 2 carbon atoms (e.g. methoxy); or R_ represents the group (CHn) Z (CH2) Rn, where q is 1, r o z q z r o represents 1 to 4 when Z is oxygen, or r is 1 when Z is sulfur

and R0 represents hydroxy, the group -CH = CH4, dialkylamino o Z.

Wherein each alkyl group has 1 to 3 carbon atoms (eg dimethylamino), or the group CORg, wherein Rg is alkoxy of 4 to 4 carbon atoms (eg ethoxy) or the group NHR 4, wherein alkyl represents 1 to 3 'carbon atoms (e.g. methyl); or

Rg represents the group wherein x is 1 and the heteroaryl group is Rg g tetrazolyl or thiadiazolyl, each of which is substituted by alkyl of 1 to 3 carbon atoms (e.g. methyl), or Rg is furyl; y is most preferably 0 and R 1 g represents 1-methyl-1H-tetrazol-5-yl.

Within the preferred meanings of Rg, compounds in which Rg is defined as follows can be considered a separate aspect of the invention,

Rg represents an alkyl group of 2 to 4 carbon atoms, substituted by two hydroxy groups, or a 2,2-dialkyl (wherein each alkyl group has 1 to 3 carbon atoms, e.g. dimethyl) -1,3-35 dioxolan-4-yl group; or

Rg represents phenylalkyl in which alkyl has 1 to 3 carbon 830 0 69 7 * 7 atoms (e.g. benzyl) in which the alkyl moiety is substituted by alkanoyloxy of 1 to 4 carbon atoms (e.g. acetyloxy) or alkoxy of 1 to 2 carbon atoms (e.g. methoxy) or heteroarylalkyl wherein alkyl has 1 to 3 carbon atoms (e.g. furyl-5 methyl or pyridylmethyl) wherein the alkyl moiety is substituted by hydroxy, alkanoyloxy of 1 to 4 carbon atoms (e.g. acetyloxy) or alkoxy of 1 to 2 carbon atoms (e.g. methoxy) ; or R_ represents the group (CH2) Z (CH_) R_, where q is 1, szqzror represents 1 to 4 when Z is oxygen, or r is 1 when Z is sulfur 10, and Rg represents hydroxy, the dialkylamino group wherein each alkyl group has 1 to 3 carbon atoms (e.g. dimethylamino), or the group CORg wherein Rg is alkoxy of 1 to 4 carbon atoms (e.g. ethoxy) or the group NHR 1, wherein R 1 represents alkyl of 1 to 3 carbon atoms (e.g. methyl) , or R5 represents the group (CH2 ^ xS ^ CH2 ^ yR15f where x is 1 and the heteroaryl group is R ^ ^ tetrazolyl or thiadiazolyl, each substituted by alkyl of .1 to 3 carbon atoms (e.g. methyl), or R ^ 2 furyl is y preferably zero and represents 1-methyl-1H-tetrazol-5-yl.

A particularly preferred group of compounds are those of formula 3, wherein

RjR ^ N stands for dialkylamino in which each alkyl group has 1 to 3 carbon atoms (for example dimethylamino), furylmethyl-amino, or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimino, preferably piperidino? 25 represents AN and B represents CR 1, or A represents CR 1 and represents BN, wherein R represents alkyl of 2 to 4 carbon atoms, substituted by two hydroxy groups, 2,2-dialkyl (wherein each alkyl is 1 to 3 carbon atoms, for example dimethyl) -1,3-diaxolan-4-yl, (1-30 methyl-1H-tetrazol-5-yl) thiomethyl, or R represents phenylalkyl wherein alkyl is 1 to 3 carbon-

O

has atoms (e.g. benzyl) or heteroarylalkyl wherein alkyl has 1 to 3 carbon atoms (e.g. furylmethyl or pyridylmethyl), wherein the alkyl moiety is substituted by hydroxy, or phenylalkyl where alkyl has 1 to 3 carbon atoms (e.g. benzyl) in which it. alkyl moiety is substituted by alkanoyloxy of 1 to 4 carbon atoms 8300697 (e.g., acetyloxy) or alkoxy with. 1 to 2 carbon atoms (for example methoxy), or R_ represents the group CH 2 (CH 4) R, where R 0 represents hydroxy 3 ZZTO or dialkylamino in which each alkyl group has 1 to 3 carbon atoms (e.g. 5 dimethylamino), Z oxygen is and r is 4; or RQ de

O

group or group represents CORg, wherein Rg is alkoxy of 1 to 4 carbon atoms (e.g. ethoxy), Z represents oxygen or sulfur and r is 1; and either Q is 1,3-benzene and X represents a bond, n is zero, Y is oxygen and m is 3 or 4, most preferably 3; or X is oxygen, n is 10, Y represents -CHOH- and m is 1; either Q is 2,5-furan or 2,4-thiophene, X is a bond, Y represents sulfur, η is 1 and m is 2; with the proviso that R ^ R ^ N represents dialkylamino in which each alkyl group has 1 to 3 carbon atoms when Q is a furan or thiophene ring.

A further particularly preferred group of compounds are those with. formula 3, wherein either R 1, N is dimethylamino, Q is a 2,5-furan, X represents a bond, Y is sulfur, η is 1 and m is 2; either R ^ R ^ K dimethylamino or pyrrolidino, piperidino, or hexamethyleneimino, most preferably piperidino, Q represents a 1,3-benzene, 20 represents a bond, Y represents oxygen, "xr is zero -is, and m is 3 or 4, most preferably represents 3, and AN and B represent CR 1, or A CR, 1 and BN, wherein R 8 is benzyl in which the methylene group is substituted by hydroxy, with the proviso that when Q is a furan ring then preferably A 25 N and B CR ,, propose.

Particularly preferred compounds are 5- [[2- [[5- [(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] amino] -1-methyl-α-phenyl-1H-1,2,4 -triazole-3-methanol, 1-methyl-3- [[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -N- [3- [3- (1-piperidin-30-methylmethyl) phenoxy ] propyl] -1H-1,2,4-triazol-5-amine, 1-methyl-α-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, 35 1-methyl-5- [3- [[(1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triacoolol-3-ethane-1,2-diol, 83 0 0 69 7 9 α- [1-methyl-5- [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazol-3-yl] -r 2- pyridine methanol, 5 - [[2-hydroxy-3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1-methyl-1-phenyl-1H-1,2,4-triazole-3-methanol 5- [[3- [3- [(dime-thylamino) methyl] phenoxy-propyl] amino] -1-methyl-α-pheny 1- 13-1,2,4-triazole-3-methanol, 5 - [[2 - [[[5 - [(dimethylami no) methyl] -3-thienyl] methyl] thio] ethyl] amino] -1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol and their physiologically acceptable salts.

The invention includes the compound of formula 1 in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include the hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formulas 1 and 15 their salts can also form hydrates, and the hydrates of the compounds of formula 1 are also to be considered as part of the invention. The compounds of formula 1 may exhibit tautomerism and the formulas are intended to cover all tautomers. Where optical isomers can exist, the formulas aim to cover all diastereoisomers and optical enantiomers. It is noted that the present invention includes bio precursors of the compounds of formula 1. The term bioprecursors refers to compounds with a different structure than the compounds of formula 1, but which are converted into a compound of formula 1 when administered to animals or humans in the body.

The compounds of formula 1, preferably in the form of a salt, may be formulated for administration in any suitable manner and the invention includes pharmaceutical preparations containing at least one compound of formula, suitable for use in human or veterinary medicine. Such formulations can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such preparations may also optionally contain other active ingredients, e.g. antagonists.

The compounds of formula 1 can therefore be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred.

--- 8300697 10

For oral administration, the pharmaceutical preparations may be in the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions, those with conventional agents with acceptable excipients. are prepared. For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

The compounds of formula 1 can be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection can be presented in dosage units in 10 ampoules or in multi-dose containers with an added preservative. The compositions may have forms such as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain formulating agents such as suspending agents, stabilizing agents. and / or dispersants. On the other hand, the active ingredient 15 may be in powder form for reconstitution for use with a soluble carrier, for example sterile pyrogen-free water.

The compounds of formula 1 may also be formulated in rectal preparations such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

For topical administration, the compounds of formula 1 can be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner.

For internal administration, a suitable regimen for daily dosing of the compounds of the invention would be one to four doses up to a total of about 5 mg to 1 g per day, preferably 5 to 500 mg per day, depending on the condition of the patient.

It will be understood that in the preparation methods given below for compounds of formula 1, it may be necessary for certain reaction steps to protect various reactive substituents in the starting materials for a given reaction and to remove the protecting group later. Such protection and subsequent deprotection can be particularly useful when and are hydrogen atoms and / or when R1 is an alkyl group carrying a hydroxy substituent and / or when R1 is a hydroxy or amino group. Standard protection and deprotection procedures can be used, for example amines can be protected by the formation of a phthalimide group which can then be cleaved by treatment with a hydrazine, for example hydrazine hydrate or a primary amine, for example methylamine.

In describing the methods that can be used to prepare a compound of formula 1 or intermediates useful for their preparation, all symbols are R 1 to A, B, Alk, Q, X, Y , Z, n, m, p, q, r, x and y in the various formulas as defined in formula 1, unless otherwise indicated.

Compounds of formula 1 wherein Rg represents the group (CH_) Z (CH_) Re or (CEL) S (CH0) Re can be prepared by reacting 2 q 2 r 8 2x 2 y lo of a triazole of formula 1 wherein Rg represents group R g wherein Ra_ represents - (CH2) L or - (CH_) L and L is a leaving group 5 2 y 2 x 15 such as halogen, mesyloxy or tosyloxy, with an anion Z (CEL) R_ or

Z Γ O

Θ (S (CH „) R„ _. The anion can be formed from the corresponding alcohol 2 y ίο by treatment with sodium or a strong base such as sodium hydride in the absence or presence of a solvent, for example dimethylformamide, at a temperature in the range from 20 to 120 ° C, or 20 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.

The intermediates of formula 1, wherein Rg represents the group a a R _, wherein R represents - (CH_) L or - (CH_) L, may be

3 3 2. G 2 * X

* 25 prepared by reacting the corresponding compound in which Rg represents - (CH2) ^ 0H or - (C3-) OH with an acid chloride such as thio-

2m X

nyl chloride, methanesulfonyl chloride or p-toluenesulfonyl chloride.

The intermediates of formula 1 in which Rg represents the group aa R_ in which R1 represents (CH2) OH or (CH2) OH can also be prepared in the manner described in British Pat. No. 2Q47. 238A and European Patent Application No. 48555.

Compounds of formula 1 can also be prepared by cyclizing an appropriate intermediate. Thus, compounds of formula 1 wherein Rg has a meaning other than a straight or branched chain alkyl group having from 2 to 6 carbon atoms can be substituted by two or three acyloxy groups or a dihydroxyalkyl group having a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group in which the alkyl moiety is substituted by an acyloxy group or Y is other than -CHOR ^ where acyl represents are prepared by cyclizing a compound of formula 4 wherein R ^ g is a group

Q

5 as defined for R_, V 'represents the group NCR- and Y' represents hydrogen 3 II 3

V

c is when V is oxygen or sulfur and R ^ is a group as defined for Rg or is a group that can be converted therein under the conditions of the cyclization reaction; or V 'is the group NH, Rg is a group as defined for R and Y' represents the group CRc wherein Y "3 I. 5 γιο represents sulfur, oxygen or NH; or V" is sulfur or oxygen, Y - represents the group CR_ and R. - is a group as defined for R_, or ii 5 16 3

NS

V 'is the group NR ^, R ^ g represents hydrogen and Y' represents the group CRg Ϋ "wherein Y" is as defined above.

For example, in one embodiment of the cyclization process, a compound of formula 1 wherein AN represents B and the group is CRg can be prepared by cyclizing a compound of formula 5 wherein V represents sulfur or, more preferably, oxygen and twee two represents hydrogen atoms, in the absence or presence of a solvent, for example, a hydrocarbon such as toluene, a ketone such as acetone, or water, and optionally under heating, for example in the range of 50 to 90 ° C.

It. may be appropriate to prepare in situ compounds of formula 5 wherein voor represents two hydrogen atoms by a compound of formula 5 wherein 'represents a divalent protecting group which can be easily removed to form two hydrogen atoms, eg a benzylidene group, to be treated with an acid, for example hydrochloric acid, preferably under heating, and under conditions such that cyclization to the corresponding compound of formula 1 will normally take place.

In a further embodiment of the cyclization of compounds of formula 4, compounds of formula 1 can be prepared by cyclization of a compound of formula 6 wherein R16 is an 8300697 13 group as defined for, and either V1 represents H and Y "sulfur oxygen is or NH, or V 'is sulfur or oxygen and Y' is NH; or R ^ g is hydrogen, V 'NR ^. and Y "represents sulfur.

When Y "represents sulfur, tautomerism with the adjacent NH group is possible (ie -N = CR_) and the -SH group can be supported by default.

i 5 SH

standard conditions are alkylated. The S-alkyl bonding can also be used in the cyclization process.

The cyclization can be performed by heating the compound of formula 6 (for example, in a range from 80 to 150 ° C) in the absence or presence of a solvent (for example, acetonitrile or dimethylformamide), or under basic conditions (for example, using aqueous potassium hydroxide ).

In a suitable embodiment of this method, an intermediate of formula 6, wherein R 1 is a group as defined for R 1, V 1 represents NH and Y "is oxygen; or R is hydrogen, 3 L V * Represents NR 1 and Y is oxygen, to be prepared in situ by the reaction of an aminoguanidine of formula 7 with an acid R 2 COOH or with an activated derivative thereof Suitable activated derivatives include acid halides, for example acid chlorides, alkyl chloroformates, acid-20 anhydrides including mixed anhydrides (e.g. acetic-formic acid anhydride), esters such as alkyl esters, orthoesters (such as trial alkyl esters, e.g. R, .C (0Et) and (1-alky1-2-pyridinyl) esters, or derivatives formed from a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide.

The acid and the aminoguanidine of formula 7 can be heated together, under which conditions cyclization of the intermediate of formula 6 takes place directly to form a compound of formula 1. In the case of an activated derivative, an aprotic solvent, for example tetrahydrofuran be used at temperatures from room temperature to the reflux temperature. When an acyl chloride is used as an activated derivative, the reaction can 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.

Generally, intermediate and formula 5 8300 69 7 14 can be prepared from the appropriate diamines * by methods analogous to those described in British Patent Publication 2,047,233A, and intermediates of formula 6 can be prepared from the appropriate diamines by methods , analogous to that described in British patent publication 2.023.133A 5 and in European patent publication no. 48555. The aminoguanidines of formula 7 can be prepared as described in British patent publication 2,023,133A, and. European Patent Publication No. 48555.

Compounds of Formula 1 wherein Alk is can be prepared by treating an aldehyde of Formula 8 with an amine, for example, in a solvent such as tetrahydrofuran or an alcohol, for example ethanol, followed by reduction using, for example, a hydride reducing agent such as an alkali metal or aralkali metal borohydride, for example sodium borohydride or lithium aluminum hydride, or hydrogen and a metal catalyst such as palladium or platinum is used. The reactions can be carried out at a temperature from 0 to 80 ° C.

The intermediates of formula 8 can be prepared from compounds of formula 9, wherein W represents a protected aldehyde group, for example a cyclic acetal such as an ethylene acetal, according to methods analogous to the methods described herein for preparing compounds of formula 1 from the appropriate diamine.

Compounds of formula 1 wherein R_ is an aralkyl or heteroaralkyl group in which the alkyl moiety is substituted by hydroxy can be prepared by reacting the appropriate aldehyde or ketone with an organolithium compound ArLi or a Grignard reagent ArMgHal wherein Ar is a appropriate aryl, aralkyl, heteroaryl or heteroaralkyl group and Hal halogen. The reaction can be carried out in a suitable solvent such as an ether, eg diethyl ether, tetrahydrofuran or a mixture thereof at a temperature of -70 ° C to 50 ° C, preferably at -70 ° C to + 20 ° C before the reaction with ArLi and at 0 to 50 ° C for the reaction with ArMgHal. The aldehyde or ketone starting material can be prepared as described in British patent publication 2,075,007A and European patent publication no. 48555.

Compounds of formula 1 in which a certain significance can be converted into compounds of formula 1 in which Rj. has a different meaning, using standard methods 83 0 0 69 7 15 for interconversion. ,

Thus, compounds in which Rg represents a straight or branched chain alkyl group having 2 to 6 carbon atoms substituted by two or three acyloxy groups, or Rg may represent an aralkyl or heteroaralkyl-5 group in which the alkyl moiety is substituted by an acyl oxy group, or Y CHOR where R is acyl are prepared by reacting the corresponding alcohol with an activated derivative (e.g. an acid chloride or an anhydride) of an appropriate acid. The reaction can be carried out at room temperature, optionally in the presence of a solvent (eg pyridine, tetrahydrofuran, acetone or dimethylformamide), and preferably in the presence of a base (eg pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate).

Compounds in which Rg represents a straight or branched chain alkyl -15 group of 2 to 6 carbon atoms substituted by two or three alkoxy groups or Rg represents an aralkyl or heteroaralkyl group in which the alkyl moiety is substituted by an alkoxy group may be prepared from the corresponding alcohol by treatment with a halogenating agent, for example thionyl chloride, followed by reaction of the resulting halogen compound with an appropriate alkanol in the present. of sodium at a temperature ranging from 20 to 50 ° C. Alternatively, the intermediate halogen compound can be treated with an appropriate alkanol in a solvent such as dimethylformamide, in the presence of a strong base such as sodium hydride, at a temperature ranging from 20 to 100 ° C.

Compounds in which R_ represents the group (CH2) Z (CH) RQ d δ q 2 * o, where Rg and R ^ 2R13 νοθΓΞΐ: ε ^ and R ^ and R ^ each represent hydrogen or alkyl, may be from the corresponding alcohol in which Rg is hydroxy, by treatment with a reagent containing the group Rg.

30 can convert to a leaving group, for example thionyl chloride, followed by reaction of the obtained compound of formula 1 wherein R 9 (CH 2) Z (CH 2) L, wherein L represents a leaving group for example 2 q 2 r halogen, with ammonia or an appropriate amine ^ 2 ^ 13 ^ 'preferably in a solvent such as an alkanol, for example ethanol, at a temperature ranging from 80 to 120 ° C.

Compounds in which Rg is a group NHR ^ can be converted into compounds in which Rg is the group ^ ^ 2 ^ 13 where - * - n ^ 3 is either an acyl group or an aryl or alkyl sulfonyl group, by reaction with an activated derivative of the appropriate carboxylic acid or sulfonic acid.

Suitable activated derivatives include acid halides, eg acid chlorides, alkyl chloroformates, acid anhydrides including mixed anhydrides (eg acetic formic acid 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 an inorganic base such as sodium hydroxide or an organic base such as triethyl amine or pyridine. The reaction with an alkyl chloroformate is preferably conducted in the presence of a base, for example, potassium carbonate or triethylamine, in a solvent such as dimethylformamide. The reaction with an acid anhydride is carried out in the absence or presence of a solvent such as pyridine.

Compounds in which R represents the group -CONR.nR .., 1U 11 can be prepared by leaving an activated derivative of the corresponding carboxylic acid, wherein Rg is the group -COOH, for example an ester, reacting with ammonia or a suitable amine HNR ^ qR ^ in a suitable solvent (for example an alcohol such as ethanol) at a temperature of 20 to 120 ° C.

Compounds wherein R_ includes the group -CH (CH2) CH-, 5.2 p,

OH OH

the corresponding compounds in which R 1 represents the group of formula 25 can be converted by reaction with an aldehyde or ketone R 8 R 2 CO, for example acetone in the presence of an acid, for example p-toluenesulfonic acid. The reaction is carried out in the absence or presence of a solvent, for example benzene, at a temperature between room temperature and the reflux temperature.

In case the product of any of the above processes is a free base and an acid addition salt, especially a physiologically acceptable salt, is desired, the salt can be formed in a conventional manner. For example, a generally suitable method of forming the salts is to mix appropriate amounts of the free base and the acid in one or more suitable solvents, for example, an alcohol such as ethanol or an ester such as 8300697 ethyl acetate. The invention also includes interconversion of the one salt of the compound of formula. 1 in the other.

The invention is illustrated / further illustrated by the following examples and preparation examples, in which the temperatures are indicated in ° C. Unless otherwise specified, the silica Merck silica gel used for column chromatography was 60 (7734). t.l.c. indicates thin layer chromatography, which was performed on silica as well as preparative chromatography using one of the following solvent systems (unless otherwise indicated): 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) 15

Preparation example 1

Methyl N-C 2,3-diacetyloxypropionvi] -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate 13.8 g Di-acetylglyceric acid was refluxed in 50 ml thionyl chloride for 4 hours. The solution was evaporated under reduced pressure and treated azeo-tropically with 50 ml of toluene three times to yield an oil which was used without further purification. This oil was dissolved in 100 ml of dichloromethane and added dropwise to a solution of methyl 1-methyl-2- (phenylmethylene) hydrazine carboximidothioate hydrochloride (15.4 g) in 250 ml of dichloromethane and 19.3 ml of triethylamine, which had previously been stirred at 20 ° C for 1 hour. The reaction mixture was stirred at 20 ° C for 15 hours before water was added. The organic phase was separated, dried over MgSO4, and evaporated to leave 7 g of a residue which was chromatographed with ether as eluent to afford the title compound as a yellow waxy solid (4.6 g).

NMR (CDCl 3): 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).

Preparation example 2

Methyl N- [2-acetyloxy-C2- (phenyl) -acetyl]] - 1-methyl-2- (phenylmethylene) hydrazine carboximidothioate 8300697 18

A solution of 11.35 g of acetyl chloride in 50 ml of dry ether was slowly added to a solution of 20 g of α-hydroxybenzene acetic acid in 100 ml. ether. The solution was refluxed for 3 days before being evaporated to leave a light yellow oil. This oil was refluxed with 31 g of thionyl chloride for 3 hours. The thionyl chloride was removed by azeotropic distillation with toluene to leave 27.7 g of an oil which was used without further purification.

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

NMR (CDCl 3): 2.25, s, (1H); 2.3-2.8, m, (10H) -; 3.95, s, (1H); 6.7, s, (3H); 7.8, S, (3Ξ); 7.9, S, (3H).

Preparation Example 3 (i) 2- [2-Hydroxy-3- [3- (1-piperidinylmetfayl) phenoxypropyl] -1H-isoindole- 1,3- (2H) -dione

A mixture of 9.10 g of 2- (oxyranylmethyl) -1H-isoindole-1,3- (2H) -dione and 8.55 g of 3- (1-piperidinylmethyl) phenol was heated under nitrogen at 130 ° C for 10 minutes . The resulting mixture was dissolved in 100 ml of chloroform, washed twice with 25 ml of 1N sodium hydroxide, dried over MgSO 4 and evaporated to give the title compound as a gum (17.65 g).

T.l.c. system C; Rf 0.60.

(ii) 1-Amino-3- [3- [(1-piperidinylmethyl) phenoxy] -2-propanol

A solution of 17.6 g of 2- [2-hydroxy-3- [3- (1-piperidin-30methyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) dione and 2.5 g of hydrazine hydrate in 60 ml ethanol was refluxed for 3 hours. The resulting mixture was evaporated to a solid residue, which was suspended in 30 ml of 1N hydrochloric acid and filtered. The filtrate was made basic with an excess of potassium carbonate and extracted three times with 40 ml of isopropanol. The isopropanol extracts were above

After ^ CO ^ dried and evaporated to a gum, which was subjected to chromatography with system A. Crystallization of the product from n-hexane: ether (20: 1) gave the title compound as colorless granules (7.7 g), mp 74-76.5 ° C.

Preparation Example 4 5 5- [[3 - (3-Formylphenoxy) propyl] amino 3 -1-methyl-ctr-phenyl-15-1,2,4-triazole-3-methanol acetate (ester)

A solution of 6.0 g of 3- [3- (1,3-dioxolan-2-yl) phenoxy] propanamine and 11.33 g of. compound A in 300 ml of toluene was stirred at 20 ° C for 4 hours, 30 ml of 5N hydrochloric acid was added and the mixture was further stirred at 20 ° C for an additional 18 hours. The acidic layer was separated, washed with toluene, made basic with 2N sodium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to give 9.0 g of a gum which was chromatographed on activated alumina [Phase Separations Ltd (UGl) I using ether: ethyl acetate: methanol 50: 50: 1 as the eluent, the title compound (1.4 g) as a foam was obtained.

T.l.c. system C Rf 0.7.

x Compound A = methyl N- [2-acetyloxy- [2- (phenyl) -acetyl]} -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate

Example I

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

To a mixture of 2.69 g of methyl N- [2,3-diacetyloxy-propionyl] -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate in 100 ml of toluene, 1.5 g of 3 - 3 - (1- piperidinylmethyl) phenoxy] propanamine was added and the resulting solution was stirred at 20 ° C for 16 hours before adding 25 ml of 5N hydrochloric acid and stirring the two-phase mixture vigorously for an additional 16 hours. The acidic layer was separated and the toluene layer was washed with 2N hydrochloric acid. The combined acidic layers were washed with toluene before being made basic and then saturated with solid sodium carbonate. The basic solution was extracted with ethyl acetate and the combined organic extracts were dried over MgSO 4 and evaporated. The 2.0 g residue was chromatographed with chloro-35 formalethanol (5: 1) as eluent to yield 0.6 g of a foam. The foam was dissolved in 20 ml of ethyl acetate using 4 ml of 8300597 methanol and treated with a stoichiometric amount of citric acid in 20 ml of ethyl acetate under nitrogen. The suspension was stirred at 20 ° C for 1 hour, the compound was collected and dried under reduced pressure to afford the title compound as a white solid 5 (0.53 g), mp 73-74 ° C (softened) ).

T.l.c. system D. Rf. 0.46 Example 11 (a) 5- [[2-Hydroxy-3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1-methyl-α-phenyl-1H-1,2,4-triazole -3-methanol iff A solution of 2.0 g of 1-amino-3- [3- (1-piperidinylmethyl) phenoxy] -2-propanol and 3.19 g of methyl N- [2-acetyloxy- [2 - (phenyl) -acetyl]] -1-methyl 1-2- (phenylmethylene) hydrazine carboximidothioate, compound A in 60 ml toluene was stirred at 20 ° C for 4 hours, 9 ml 5N hydrochloric acid was added and the mixture was stirred for Stirred at 20 ° C for 16 hours and heated on a steam bath for 15 minutes. The acidic layer was separated, washed with toluene, made basic with saturated aqueous sodium bicarbonate, washed with toluene, and the aqueous layer made basic with 5N sodium hydroxide. The basic layer was extracted with three times 100 ml. Hot 4-methyl-2-pentanone and the extracts were washed with brine, dried and concentrated under reduced pressure to a volume of 150 ml after which crystallization occurred.

The resulting solid (1.2 g) was collected on a filter and recrystallized from 2-propanol to give the title compound (0.63 g) as a white solid, mp 154-157 ° C.

Found: C 66.2; H 7.2; N 15.2; C25H33N503 calculated: C 66.5; H 7.4; N 15.5%

Example 11 (b)

In the same manner, from 1.5 g of the compound A and 0.75 g of 3- [3- (dimethylamino) methyl] phenoxy] propanamine, with the exception that the 4-methyl-2-pentanone extract was extracted under reduced pressure was evaporated and the residue (1.3 g) was chromatographed on system A as eluent 5 - ((3- (3- ((dimethylamino) methyl) phenaxy] propyl] amino3-1-methyl-a-phenyl-1H- 1,2,4-triazole-3-methanol hydrate (0.31 g) as a white foam.

3'5 found: C 63.7; H 7.3; N 16.6; C22 H29 N5 ° 2 * 12 ° C calculated C 63.9; H 7.59; N 16.9% 8 3 0 0 6 9 7 21 N.m.r. (CDCl3-DMS0): 2.4-2.92, m, (65); 3.05-3.33, m, (3H) 4.4, s, (1H); 4.65, s (br), (1H); 5.58, s, (br), ClH); 5.98, t, (2H); 6.4-6.75 s + s + q, (75); 7.85, s, (6H); 8.0, quintet, (2H).

Example 11 (c) 5 Similarly, from 1.5 g of the compound A and 0.99 g of 2-E2- [3- (1-piperidinylmethyl) phenoxy] ethoxy] ethanamine, with the exception that the aqueous phase was extracted with six times 50 ml of hot ethyl acetate at pH 7 and chromatographically treated with dichloromethane: ethanol: 0.88 ammonia (80: 8: 1), 1-methyl-a-10 phenyl-5 - [[2- [2 - [3- (1-piperidinylmethyl) phenoxy] ethoxy] ethyl] amino] -1H-1,2,4-triazole-3-methanol (0.45 g) obtained as clear gum, found: C 66.95; H 7.75; N 14.65; C26H35N503 calculated: C 67.07; H 7.58; N 15.04% N.m.r. (CDCl 3): 2.4-2.9, m, (6H); 3 - 3.35, m, (3H); 4.3, s, (15; 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 IX (d) 5- E [2-E [[5- [(Dimethyl amino) methyl] -3-thieny 1] methyl 3 thop] thy 1] amino] -1-methyl-g-pheny1-15- 1,2,4-triazole-3-methanol 20 A solution of 1.09 g of 4 - [[[2- (aminoethyl)] thio] methyl] -N, N-dimethyl-2-thlophene-methanamine and 2 g of compound A in 40 ml of toluene was stirred at 20 ° C for 4 hours. 5 ml of 5N hydrochloric acid were added and the mixture was stirred at 20 ° C for 16 hours, followed by heating on a steam bath for 10 minutes. The acidic layer was brought to pH 3 with sodium bicarbonate, washed with toluene, brought to pH 9 with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extract was dried, and evaporated to give a gum which was chromatographed with system C as eluent to yield the title compound (0.45 g) as a yellow-brown foam.

N.m.r. (CDCl 3 + DMSO): 2.35-2.85, m, (5H); 3.01, s, (1H); 3.12, s, (15); 4.33, s, (1H); 4.62, t, (1H); 5.75, br, (15); 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, (65). T.l.c. system A. Rf 0.5.

Example III

(a) 1-Methyl-N- [3- (3- (1-piperidinylmethyl) phenoxypropyl) -3- ((2-propenyloxy) methyl] -15-1,2,4-triazogb-5 -amine 8300697 22 3.59 g of 1-Methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] -propyl] amino] -1H-1,2,4-triazole-3-methanol was dissolved in 10 ml of thionyl chloride and refluxed for 15 min. The orange-colored solution was evaporated under reduced pressure to leave a gum 5 which was stirred at 20 ° C in 35 ml of water. Sodium bicarbonate and sodium carbonate (3 g) were added and the suspension was stirred with ethyl acetate The organic phase was separated, dried with sodium carbonate for 1 hour and evaporated under reduced pressure to yield an oil, which was dissolved in 10 ml of allyl alcohol-10 and added to a solution of 0.3 g of sodium in 8 ml allyl alcohol The reaction mixture was heated on a steam bath for 6 hours, poured into water and extracted with ethyl acetate The organic phase was extracted with 2N hydrochloric acid mastered. The acidic extract was adjusted to a pH of 9 with potassium carbonate and extracted with ethyl acetate. Evaporation of the organic extracts gave 1.1 g of an oil which was chromatographed with dichloromethane: ethanol: ammonia (70: 8: 1) as the eluent with the title compound as an oil (0.4 g) was obtained.

Analysis: Found: C 65.64; H 8.46; N-17.44; C22 H33 N5 O2 calculated: C 66.14; H8.33; N 17.53.

T.l.c. system C Rf 0.4 (b) according to this procedure, 3.59 g of 1-methyl-5- [[3-C3 - (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4- triazole-3-methanol and 10 ml of thionyl chloride, followed by addition of a solution of 0.3 g of sodium in 10 g of butane-1,4-diol 4 - [[1-methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino-1Ξ-1,2,4-triazol-3-yl] methoxy] butanol with ethanol (2: 1) (0.78 g).

Analysis: Found: C, 63.12; H 8.81; N 15.56; C23H calculated 63.40; H 8.87; N 15.41; NMR (CDCl3): 2.8, t, (1H); 3.0 -3.3, m, (3H); 5.4, br.t (1H); 5.62, s, (2H); 5.95, t, (2H); 6.4, m, (6Ξ); 6.5 s (3H)? 6.6, s, (2Ξ); 7.0, br, (1H); 7.6, m, (4H); 7.9, m, (2H); 8.1-8.7, m, (10H).

Example IV (a)

Ethyl [CC 1-methyl-5- [[3 - [3 - (1-piperidinylmethyl) phenoxy] propyl] amino] -35 1H-1,2,4-triazol-3-yl] methyl] thop] acetate hemihydrate 7 1.2 g of 1-Methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] pro- 8300697 23 pyllamino] -1,2-1,2,4-triazole-3-methanol, compound B, was dissolved in 30 ml of thionyl chloride at 20 ° C and refluxed for 15 min. The cooled solution was evaporated under reduced pressure and the oil was dissolved in 30 ml of water, cautiously made basic with solid sodium bicarbonate, 3 g of sodium carbonate added, and the mixture extracted with ethyl acetate. The extract was dried over Na2CO3 for 1 hour and evaporated to yield an oil.

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

15 found: C 58.7; H 7.6; N 14.8; C2SH35N503S.iH2 O calculated: C 58.7; H 7.7; N 14.9% N.m.r. (CDCl 3): 2.75, dd, (1H); 3 -3.33, m, (3H); 5.45, t, (1H); 5.66-6, g + 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 the same manner from compound B and the appropriate starting materials.

IV (b) 1.41 g of compound B, 0.506 g of 5-mercapto-1-methyltetrazole and 0.54 g of potassium carbonate, with these exceptions that the mixture was chromatographed on system C to give 1.0 g of an oil dissolved in ethyl acetate and treated with excess hydrogen chloride in ether gave 0.6 g of 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 sesquihydrate as a white powder, which slowly softened above 40 ° C.

N.m.r. (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).

IV (c) 1.41 g of compound B, 0.52 g of 2-mercapto-5-methyl-1,3,3,4-thiadiazole and 0.54 g of potassium carbonate (except that the mixture was treated by chromatography on system C, gave 0.62 g of 8300697 24 1-methyl 1-3 - [[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl] -N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] -1H-1,2,4-triazoQb-5-amine as a white powder which softened at 63 ° C and melted at 72-74 ° C, found: C, 55.9; H 6, 7; N 20.7; 5 C22H31N7OS2 calculated: C 55.8; H 6.6; N 20.7%

Example V

3- [[4- (Dimethylamino) butoxy] methyl] -1-methyl-N- [3- [3- (1-piperidinylmethyl] enoxy] propyl 3 -1B-1,2,4-triazole-5-amine 0.5 g 4 - [[1-Methyl-5 - [[3— [3— (1-piperidinylmethyl) pheno-10-yl] propyl] amino] -1H-1,2,4-triazol-3-yl methoxy] butanol was dissolved in 10 ml of thionyl chloride and stirred at 20 ° C for 1.5 hours. The solution was evaporated under reduced pressure and the residue was dissolved in 20 ml of water, made basic with solid sodium bicarbonate and sodium carbonate (about 2 g). The mixture was extracted with ethyl acetate, the extract was dried over Na 2 CO 3 for 1 hour, evaporated and the residual oil was dissolved in 15 ml of 33% ethanolic dimethylamine, and the solution was heated in an autoclave at 80 ° C for 8 hours. The solution was evaporated and the residual oil (0.3 g) was chromatographed on system A as the eluent to obtain 0.2 g of the title-20 compound as a light yellow oil.

N.m.r. (CDCl 3): 1.74, dd, (1H); 3 ~ 3.32, m, (3H); 5.48, t, (1H); 5.58, S, (2H); 5.86, t, (2H); 6.24-6.64, s + s + m, (9H); 7.48-8, m + s, (14HJ, 8.21-8.68, m, (10H).

T.l.c. system B Rf 0.55.

Example VI

ct- (2-Furanyl -1-methyl-5- [[3- (3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-methanol 5.96 ml of a 1.55 molar solution of n-butyllithim in n-hexane was added dropwise under nitrogen at -40 ° C to a stirred solution of 0.61 ml of furan in 20 ml of anhydrous tetrahydrofuran. slowly warm to 20 ° C, then refluxed for 3 hours, added dropwise at 0 ° C to a solution of 1.0 g of 1-methyl-5 - [[3- (3- (1-piperidinylmethyl) enoxypropy 1] amino] -1 H-1,2,4-triazole-3-carboxalde-35 hyde in 10 ml tetrahydrofuran, and the resulting solution was stirred at 20 ° C for 18 hours. , concentrated the mixture / extracted with ethyl acetate 'and dried the extract and evaporated The 0/9 g residual oil was chromatographed on system E to obtain 0.16 g of the title compound as brown oil .

N.m.r. (CDCl3): 2/6, m, (1H); 2.76, t, (1H); 3.06-3.08, m, (2H); 3.23, m, 5 UH); 3.65, m, (2Ξ); 4.25, S, (1H>, 5.48, t, (1Ξ)? 5.86, t, (2H); 6.38, q, (2Ξ) i 6.45, s, (3H) 6.56, s, (2H), 7.62, m, (4Ξ) j 7.88, quintet, (2H), 8.36, m, (6H).

T.l.c. system A Hf 0.7.

Example VII

10 3- (2,2-Dimethyl-1,3-dioxolan-4-yl) -1-methyl-N- [3- [3- (1-piperidinylmethylphenoxy] propyl] -15-1,2,4 triazole-5-amine

A solution of 0.08 g of 1-methyl-5 - [[3— [3- (1-piperidinyl-methyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-ethane-1, 2-diol, 20 ml of 2,2-dimethoxypropane and 0.03 g of 4-toluenesulfonic acid in 10 ml of acetone were stirred at 20 ° C for 16 hours, evaporated and partitioned between 2N sodium carbonate and ethyl acetate. The ethyl acetate extract was dried and evaporated and the 0.07 g of residual oil was chromatographed on system E as eluent to yield 0.025 g of the title compound as an amber gum.

20 N.m.r. (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, 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).

T.l.c. system D Hf 0.7.

Example VIII

N-Methyl [[[1-methyl-5-C C3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazol-3-ylmethyl] thio] acetamide

A solution of 0.4 g of ethyl [[[1-methyl-5-C [3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazol-3-yl3methyl] thio] Acetate in 20 ml of 33% ethanolic methylamine under nitrogen was refluxed for 30 hours, cooled, evaporated under reduced pressure, the residue dissolved in 20 ml of 2N hydrochloric acid, and washed with ethyl acetate. The acidic layer was made basic with potassium carbonate, extracted with ethyl acetate, and the extract was dried and evaporated, yielding 0.28 g of an oil which was chromatographed on system E as the eluent yielding 0.13 g of the titre. fa 8300697 26 count compound as an oil was obtained.

N.m.r. (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, 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).

T.l.c. system A, Rf 0.7.

Example IX

1-Methyl-g-phenyl-5- [f 3- [3- (1-piperidinylmethyl) phenoxy-3-propyl] amino] -1H- 1,2,4-triazole-3-methanol compound with fumaric acid and ethyl acetate: 40:10 56: 5 0.72 g 3 - 3 - (1-piperidinylmethyl) phenoxy] propanamine and 1.1 g methyl N- [2-acetyloxy- [2- (phenyl) acetyl]] -1-methyl 1-2- (Phenyl methylate hydrazine carboximidothioate were heated together as a melt for 2 hours at 60 ° C to give a gum. This gum was dissolved in 15 toluene and stirred with 5N hydrochloric acid for 15 hours. The pH of the water phase was adjusted with sodium carbonate. A value of 7 was set and washed with toluene and methyl acetate The aqueous phase was adjusted to a pH of 10 with sodium carbonate and extracted with ethyl acetate The organic extracts at pH 10 were dried over MgSO 4 and evaporated to give 1.1 g of an oil remained This chromatographically treated with dichloromethane: ethanol: 0.88 ammonia (150: 8: 1) as the eluent yielding 0.25 g of a white solid. cool with melting point 42 - 52 ° C was obtained. This solid (0.112 g) was dissolved in ethyl acetate and treated with a solution of 0.03 g of fumaric acid in ethyl acetate to precipitate the title compound, which was collected as a white solid (0.095 g), m.p. 80 ° C.

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

30 Example X

4-Methyl-α-phenyl-5- [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -4Ξ-1.2.4-triazole-3-methanol

A mixture of 30.4 g DL α-hydroxybenzene acetic acid and 1 11 22.35 g N-amino-N -methyl-N - (3- [3- (1-piperidinylmethyl) phenoxy] propyl] 35 guanidine hydroiodide was obtained from 40 heated to 125 ° C and held as a melt at 125 ° C for 6 hours.

The hot melt was extracted with 250 ml of hot water and the aqueous extract was adjusted to pH 8 with solid sodium carbonate *. and extracted into ether. The ether extract was cooled at 5 ° C to give a white solid, which was washed with boiling ethyl acetate leaving the title compound as a white solid (0 * 18 g), mp 186-188 ° C. analysis; found C 68.9; H 7.7; N 16.0; C25H33N502 calculated: C 68.9; H 7.6f N 16.1%

Example XI

[4-Methyl-α-phenyl-5- [f 3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -4H-10 1,2,4-triazole-3-methanol3acetate (ester) hydrate

A solution of 0.10 g of 4-methyl-α-phenyl-5 - [[3- [3- (1-piperidinyimethyl} phenoxy] propyl] amino] -4H-1,2,4-triazole-3-methanol and 0 .03 ml of acetic anhydride in 2 ml of pyridine was stirred at room temperature for 16 hours Saturated sodium carbonate solution was added and the suspension was 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 as a white solid (0.074 g), mp 89-91 ° C.

20 Analysis: found; C 64.9; H 7.5; N 13.8; C27H35N5O3H2 O Calcd C 65.3; H 7.4; N 14.1%

Example XII

ct- [1-Methyl-5- [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazol-3-yl] -2-pyridine thanol 25 8 12 ml of 1.6 molar solution of n-butyl lithium in n-hexane was added dropwise over 15 min to a stirred solution of 1.86 g, 1.12 ml of 2-bromopyridine in 10 ml of anhydrous ether at -70 ° C, under nitrogen. The brown solution was stirred at -70 ° C for 1 hour before a solution of 2.0 g of 1-methyl-5 - [[3- [3- (1-piperidinyl-30 methyl) phenoxy] propyl] amino] -1H -1,2,4-triazole-3-carboxaldehyde in 20 ml anhydrous tetrahydrofuran was added dropwise at -70 ° C and the solution was stirred at -40 ° C for 2 hours before adding 20 ml of water and the mixture was left overnight Allowed to stand at 20 ° C. The mixture was concentrated, extracted with ethyl acetate and the extract was dried and evaporated to give 2.5 g of an oil which was chromatographed on system E as eluent.

8300 69 7 * 28

0.48 g of a solid were obtained. This was crystallized from ethyl acetate to yield the title compound (0.25 g) as a white powder, mp 152-154 ° C (d), found: C 65.9; H 7.4; N 19.1; 5 C 25 H 25 ClC calculated: C 66.0; H 7.4; N 19.2%

Example XIII

5- [f2 - [[[5- [(Ρ ^ 6ΐ2 ^ ΐ3Μΐηο) & Β ^ ν1] -2 ^^ η ^ 1] ιηΒίΙ ^ 1Ι · ίΙι1ο36ΐ ± γ133ΒΰηοΙ-1-methyl-enyl-1H-1,2 4-triazole-3-methanol dihydrochloride

A solution of 3.09 g of 2 - [[[5 - [(dimethylamino) methyl-10-2-furanyl] methyl] thio] ethanamine and 5.9 g of methyl N- [2-acetyloxy- [2- ( phenyl) acetyl] -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate in 110 ml toluene was stirred at room temperature for 3 hours.

An additional 0.3 g of methyl N- [2-acetyloxy- [2- (phenyl) acetyl]] -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate was added and the mixture was stirred for 1 hour. stirred at room temperature for an hour. Then 22.5 ml of 2 molar hydrochloric acid was added to the reaction mixture and the mixture was heated on a steam bath for 1 hour. The water layer was covered with. potassium carbonate adjusted to a pH of 6 and washed with two times 30 ml of toluene. The acidic aqueous layer was made basic with potassium carbonate ... and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to give a brown gum, which was chromatographed on silica with dichloromethane: ethanol: ammonia (65: 8: 1) to obtain 1.35 g of a brown gum. This gum was dissolved in methyl acetate and treated with a solution of hydrogen chloride in ether to give a white solid, which was triturated with dry ether to give the title compound (1.3 g) as a fine white solid, m.p. from 55 - 60 ° C (softening).

Ninr (CD30D): 2.5, m (5Ξ); 3.3, d, (1H); 3.6, d, (1H); 4.15, s, (1H); 5.6, s, (2H); 6.3, m, (7H); 7.15, m, (8H).

Example XIV

5- [[3- [3- [[(2-Furanylmethyl) amino] methyl] phenoxy3propyl] amino] -1-methyl-ct-phenyl-1H-1,2,4-triazole-3-methanol

A solution of 1.0 g of 5 - [(3- (3-formylphenoxy) propyl]

35 amino] -1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol acetate (ester) and 5 ml furfurylamine in 30 ml ethanol was heated at 21 ° C for 1 h

8300 69 7 29 before adding a suspension of 1.3 g sodium borohydride in 10 ml ethanol and stirring was continued for an additional 16 hours at 21 ° C. 20 ml of water was added, the mixture was concentrated to remove ethanol and the aqueous residue was added. extracted with 4-methyl-pentan-2-one. The extract was dried and evaporated to yield an oil. Excess furfurylamine was removed under reduced pressure and the residue was dissolved in 2N hydrochloric acid, the acidic layer was washed with ethyl acetate, adjusted to pH 9 with sodium carbonate, and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give 0.65 g of a brown gum, which was chromatographed on silica (Merck No. 7729) using System C as the eluent yielding 0.5 g of the title compound was obtained as a light orange-colored gum.

T.l.c. system C Hf 0.35.

15 N.m.r. (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, s, (1H); 5.5, t,

(1H); 5.92, t, (2H); 6.23, s, (2H); 6.25, s, (2H)? 6.44 g (dt) (2H); 6.56, s, (3E); 6.6-8, m, (2Ξ); 7.94, m, (2H). example XV

3- [C [g-guran] methyl-thiol-methyl-1-methyl-Np-Cl-piperidinylmethyl) -phenoxy] propyl] -1H-1,2,4-triazole-5-amine

A solution of 3.59 g of 1-methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxypropyl] amino] -1H-1,2,4-triazole-3-methanol in 10 ml of thionyl chloride was added heated on a steam bath for 10 min. The solution was evaporated to dryness and the residue was dissolved in water. Sodium bicarbonate was added to the solution until it was no longer bubbling. 3 g of sodium carbonate was added, and the suspension was extracted with ethyl acetate. The organic extract was dried and evaporated to give 4.1 g of a brown oil.

Part of this oil (3.2 g) was dissolved in 40 ml absolute ethanol and added dropwise at 5 ° C to a solution of 1.14 g furfuryl mercaptan and 0.34 g sodium in 20 ml absolute ethanol.

The suspension was allowed to stand at room temperature for 18 hours, filtered and the filtrate was evaporated to dryness. The residue was dissolved in 0.2N hydrochloric acid, washed with ethyl acetate, and made basic with excess solid sodium carbonate. The basic solution was extracted with ethyl acetate.

83 0 0 69 7 30

The organic extract was dried and evaporated to give 2.2 g of an oil which was purified by column chromatography using chloroform as the eluent. 1.2 g of the title compound were obtained as an oil.

5 T.l.c. system C Rf 0.45.

N.m.r. (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) f 6.25, s, (2H); 6.3-6.7, m, (9H);

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

5- (Methoxyphenylmethyl) -4-methyl-N- [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] -4Ξ-1,2,4-triazole-3-amine compound with tartaric acid (1: 1)

A solution of 0.37 g of 4-methyl-α-phenyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -4H-1,2,4-triazole-3-methanol in . 3.0 ml of thionyl chloride was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residual rose foam was dissolved in 10 ml of dry methanol and added dropwise to a solution of 0.17 g of sodium in 10 ml of dry methanol. The reaction solution was stirred at room temperature for 1 hour, poured into water, and extracted with ethyl acetate. The organic extract was dried and evaporated to yield 0.3 g of a gum. This gum was dissolved in ethyl acetate and treated with an excess of tartaric acid in ethyl acetate to obtain 0.26 g of the title compound as a white solid, mp 88 ° C (soften).

25 N.m.r. (CD30D) 2.5-3.1 m, (9H); 4.5, s, (1H); 5.6, s, (2Ξ); 5.8, s, (2H); 5.9, 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).

Example XVII

5- [[2- [[5- [(Dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] amino] -1-30 methyl-g-phenyl-1H-1,2,4-triazole- 3-methanol

A solution of 3.09 g of 2- [[5- [(dimethylamino) methyl] -2-furanylmethyl] thio] ethanamine and 5.9 g of methyl-N- [2-acetyloxy- [2- (phenyl) acetyl]] -1-methyl-2- (phenylmethylene) hydrazine carboximidothioate (compound a) in 110 ml of toluene was stirred at room temperature for 3 hours and a further 0.3 g of compound A was added. The mixture% rd was stirred at room temperature for an additional 1 hour at room temperature, 22.5 ml of 2 molar. hydrochloric acid, and the mixture was heated on a steam bath for 1 hour. The water layer was adjusted to a pH of 6 with potassium carbonate and washed with toluene.

The acidic aqueous layer was then made basic with potassium carbonate and extracted with diethyl ether eauethyl acetate. The combined organic extracts were dried and evaporated to leave a brown gum which was chromatographed with dichloromethane: ethanol: ammonia (65: 8: 1) to obtain 1.95 g of a brown gum. A portion of this gum (0.5 g) was dissolved in dry tetrahydrofuran and filtered through "Elorisil" (an activated magnesium silicate). The filtrate was concentrated to a small volume to obtain 0.32 g of the title compound as a white solid, mp 121-122.5 ° C.

found: C 60.0? H 6.9; N 17.3; 15 C 20 H 27 N 5 ° 2S calculated C 59.8; Ξ 6.8; N 17.4%

Examples of pharmaceutical preparations. Tablets mg / tablet active ingredient 5.0 to 125.0 20 microcrystalline cellulose USP 293.5 to 173.5 magnesium stearate BP _lr5_ compression weight 300.0

The drug was sieved through a 250 µm sieve, mixed with the excipients and compressed with 9 mm diameter 25 ter punches. Other strengths could be obtained by changing the compression weight and using modified stamps.

The tablets could be film coated using suitable film-forming polymers such as hydroxypropylmethylcellulose in standard techniques. On the other hand, the tablets could be coated with sugar.

Capsules mg / capsule active ingredient 5.0 to 125.0 starch 1500 * (ÜSP) 243.5 to 123.5 magnesium stearate BP _ _I_j5_ 35 fill weight 250.0

A form of directly compressible starch 8300697 32

The active ingredient was sieved, through a 250 µm sieve and mixed with the excipients. The mixture was filled into No. 2 hard gelatin capsules using appropriate equipment. Other doses could be made by changing the fill weight and, if necessary, the dimensions of the capsule.

Injection for intravenous administration% w / v active ingredient 0/20 to 0.50 water for injection B.P. up to 100.0 Sodium chloride could be added to adjust the tone of the solution and the pH adjusted to maximum stability with dilute acid or base. The solution was prepared, clarified and filled under nitrogen or other inert gas into appropriately sized ampoules which were sealed by melting the glass. The injection preparation was sterilized by autoclaving using one of the acceptable cycles. Alternatively, the solution could be sterilized by filtration and filled into sterile ampoules under aseptic conditions.

Syrup 'mg / 5 ml dose 20 active ingredient' ----- 5.0 to 250.0 sucrose 2795.0 to 2550.0 glycerine 500.0 buffer) flavoring j as required 25 coloring) distilled water to 5.0 ml

The active ingredient, buffer, flavoring, preservative and colorant were dissolved in part of the water. The rest. of the water was heated to about 80 ° C and the sucrose was dissolved in this amount of water and then cooled. The two solutions were mixed, adjusted in volume and clarified by filtration. Alternatively, the active ingredient, sucrose, buffer, flavor, colorant and preservative could be mixed and the powder filled into bottles for later reconstitution by the addition of water.

83 0 0 69 7 - »33

In the above examples, the active ingredient is preferably 5 - [[2 - [[[5 ~ [(dimethylamino) methyl] -2-uranyl] methyl3thio] ethyl] amino] -1-methyl-a-phenyl-1H- 1,2,4-triazole-3-methanol in the form of a physiologically acceptable salt, for example the hydrochloride.

8300697

Claims (10)

1 V Rg represents hydrogen or alkyl; Rg represents an alkyl group of 2 to 4 carbon atoms, substituted by two hydraxy groups, or a 2,2-dialkyl (each alkyl group 1 to 3 carbon atoms) -1,3-dioxolan-4-yl group; or R 5 represents phenylalkyl in which alkyl has 1 to 3 carbon atoms, the alkyl portion being substituted by alkanoyloxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms, or heteroarylalkyl in which alkyl has 1 to 3 carbon atoms, the alkyl portion is substituted by hydroxy, alkanoyloxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms; R_ represents the group (CH2) Z (CH, J RQ, where q equals dzc [. Zxo is 1, r represents 1 to 4 when Z is oxygen or r equals 1 when Z is sulfur, and Rg is hydroxy the group -CHCHg, dialkylamino in which each alkyl group has 1 to 3 carbon atoms, or the group CORg 15, wherein R 9 represents alkoxy of 1 to 4 carbon atoms or the group NHR 4, wherein R 1 is alkyl of 1 to 3 carbon atoms; or Rg represents the group (CHg ^ SfCHgJ ^ R ^ g wherein x is 1 and the heteroaryl group is R ^ <tetrazolyl or thiadiazolyl, each substituted by alkyl of 1 to 3 carbon atoms, or R ^ g furyl. 1. Compounds of formula I of the formula sheet, as well as physiologically acceptable salts and hydrates thereof, which represents hydrogen, alkyl of 1 to 14 carbon atoms, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or 5 alkyl, substituted by hydroxy, alkoxy, amino, alkylamino, dialkyl amino or cycloalkyl; and R 1 represents hydrogen or alkyl of 1 to 4 carbon atoms; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5 to 10 ring which may be saturated or at least. may contain a double bond, be unsubstituted or be substituted by one or more alkyl groups of 1 to 3 carbon atoms or may contain a hydroxy group and / or another heteroatom selected from oxygen and sulfur, Alk pre-treats a straight or branched alkylene chain of 1 to 3 carbon atoms; Q represents a furan or thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 5 positions, the furan or thiophene ring optionally having a further substituent R ^ next to the group R ^ R ^ N-Alk- bears; or Q represents a thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 4 positions, the thiophene ring optionally bearing a further substituent in addition to the group R 1 R 1 N Alk, provided that when the group R ^ R ^ NAlk is in the 4-25 position, the group R ^ is in the 5 position; or Q represents a benzene ring incorporated into the rest of the molecule by bonds at the 1 and 3 positions or 1 and 4 positions; R 1 represents halogen or alkyl of 1 to 4 carbon atoms, which may be substituted by hydroxy or alkoxy of 1 to 4 carbon atoms; X represents oxygen, sulfur, -NH-, methylene or a bond; Y represents oxygen, sulfur, methylene or a bond; 35 83 0 0 69 7 π is equal to zero, JL, 2 or 3, and m is an integer from 2 to 5, with the proviso that (a) is the total number of atoms in the chain X (CHJ Y (CH „ ) is an integer from 3 to 8, (b) when X 2 is n 2 m and Y is oxygen or sulfur, n is 2 or 3, (c) when X is 5 -NH-, Q is a benzene ring and Y is methylene or represent a bond, and (d) when 2 represents a benzene ring, X represents oxygen, and n equals 1, m may additionally be equal to 1, and Y may additionally represent the group -CHOR ^, wherein R ^ is hydrogen or acyl; and Rg represents hydrogen, alkyl, alkenyl, aralkyl, or 10 alkyl of 2 to 6 carbon atoms substituted by hydroxy or alkoxy; either A represents N and B represents CRg; or A represents CR ^ and B represents N; and Rg represents i) a straight or branched alkyl group having 2 to 6 carbon atoms, substituted by two or three hydroxyl, alkoxy or acyloxy groups or the dihydroxyalkyl group a cyclic ac can form a language or cyclic ketal structure of formula 2 wherein p is zero or 1 and Rg and Rjr which may be the same or different each represent hydrogen, an alkyl group of 1 to 4 carbon atoms or a phenyl group; or ii) the group (CH2) Z (CH2) R0, where q represents an integer 2 q 2 number from 1 to 4, r represents an integer from 1 to 6, Z oxygen or sulfur, and when r is 1, Rg represents the group CHCl, alkenyl or the group CORg, wherein R 1 represents hydrogen, hydroxy, alkyl, aralkyl, alkoxy, or the group NR 1 R 1, wherein R 1 is hydrogen or alkyl and R ^ is hydrogen or alkyl, and when r is an integer from 2 to 6, Rg may have any of the above meanings or may additionally represent hydroxy, alkoxy, aryloxy or the group * ® £ 2Ri3 wherein R ^ 2 hydrogen is 30 or alkyl and R 1 represents hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl; or iii) the group (CH ^) (CH ^) ^ R ^ g, wherein x is 1 or 2, y is zero or 1, and R ^ g represents a heteroaryl group; or iv) an aralkyl or heteroaralkyl group in which the alkyl-35 portion is substituted by hydroxy, alkoxy or acyloxy. Compounds according to claim 1, characterized in that 8300 69 7 * R 1 represents alkyl of 1 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms, substituted by a trifluoromethyl group, alkyl of 2 to 4 carbon atoms, substituted by hydroxy or a dialkylamino group in which each alkyl group has 1 to 3 carbon atoms, I 5 cyeloalkyl of 5 to 7 carbon atoms, alkenyl of 3 to 5 carbon atoms, phenylalkyl in which alkyl has 1 to 3 carbon atoms, or a heteroaryl alkyl group in which alkyl 1 has up to 3 carbon atoms in which the heteroaryl ring contains a heteroatom; represents hydrogen or methyl; or R 1 R 2 N represents an optionally containing a double bond, an oxygen atom or an alkyl substituent; Al represents methylene; q represents a benzene ring incorporated into the rest of the molecule by bonds at the 1 and 3 positions; or represents a furan-15 ring, which is included in the rest of the molecule by bonds at the 2 and 5 positions, and optionally carries a substituent adjacent to the group R 1 N Alk wherein R 4 represents alkyl of 1 to 4 carbon atoms; or represents a thiophenic acid incorporated in the rest of the molecule by bonds at the 2 and 4 positions with the substituent, R 1 R 2 NAlk at the 2 position; with the proviso that when Q is a benzene ring as ..... just defined, X is a bond, n is zero, Y is oxygen and m is 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 is a furan or thiophene ring as just defined, 25. is a bond and either Y represents sulfur or CH2, n equals 1 and m equals 2, or Y represents oxygen, n equals 1 and m equals 3; R 1 represents hydrogen or alkyl; Rg represents an alkyl group of 2 to 4 carbon atoms, substituted by two hydroxy groups, or a 2,2-dialkyl (each alkyl group 1 to 3 carbon atoms) -1,3-dioxolan-4-yl group; or Rg represents phenylalkyl wherein alkyl has from 1 to 3 carbon atoms or heteroarylalkyl wherein alkyl has from 1 to 3 carbon atoms, the alkyl portion being substituted by hydroxy, alkanoyloxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms; or Rj represents the group (CH2) gZ (CH2) rRg, where q equals 8 3 0 0 6 9 7 * ..... equals 1, r is 1 to 4 when Z is oxygen or r is 1 when Z sulfur, and Rg is hydroxy, the group -CE = CE ^, dialkylamino in which each alkyl group has 1 to 3 carbon atoms, or represents the group CORg, wherein Rg is alkoxy of 1 to 4 carbon atoms or the group is NHR ^, wherein R ^ is alkyl 5 is with 1 to 3 carbon atoms; or Rg represents the group (C 1 J 3 SCC 3 Jy R 4, where x is 1 and the heteroaryl group is R 1, tetrazolyl or thiadiazolyl, each substituted by alkyl of 1 to 3 carbon atoms, or R 1 furyl. Compounds according to claim 1, characterized in that R 10 represents alkyl of 1 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms, substituted by a trifluoromethyl group, alkyl of 2 to 4 carbon atoms, substituted by hydroxy or a dialkylamino group in which each alkyl group has 1 to 3 carbon atoms cycloalkyl of 5 to 7 carbon atoms, alkenyl of 3 to 5 carbon atoms, phenylalkyl in which the alkyl group has 1 to 3 carbon atoms, or a heteroarylalkyl group in which alkyl has 1 to 3 carbon atoms, the heteroary ring containing a heteroatom, R 1 represents hydrogen or methyl ; or R 1 R 2 NT represents a 5 to 8 ring optionally containing a double bond, an oxygen atom or an alkyl substituent; Al represents methylene; Q represents a benzene ring incorporated into the rest of the molecule through bonds at the 1 and 3 positions; or a furan ring incorporated into the rest of the molecule by bonds at the 2- and 5-positions, optionally bearing a substituent R ^ in addition to the group R ^ R ^ NAlk, wherein R ^ alkyl having 1 to 4 represents carbon atoms; or a thiophene ring incorporated into the rest of the molecule by bonds at the 2 and 4 positions with the substituent R 1 R 1 N Alk at the 2 position; with the proviso that when Q 30 is a benzene ring as just defined, X represents a bond, n equals zero, Y is oxygen and m equals 3, 4 or 5, or X and Y represent oxygen and n and m both 2, or X is oxygen, Y CHCH 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 35, n equals 1 and m equals. 2, or Y is oxygen, n is 1 and m is 3; 8300697 Λ 4. Compounds of formula III of the formula sheet, as well as physiologically acceptable salts and hydrates thereof, wherein R 1, R 1, N is dialkylamino wherein alkyl has 1 to 3 carbon atoms, furylmethylamino, or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimino; 25. represents N and B represents CRg, or A represents CRg and B represents N, where Rg represents alkyl of 2 to 4 carbon atoms, substituted by two hydroxy groups, 2,2-dialkyl (each alkyl group 1 to 3 carbon atoms ) -1,3-dioxolan-4-yl, (1-methyl-1H-tetrazol-5-yl) thiom-30 thyl, or R represents phenylalkyl wherein alkyl has 1 to 3 carbon-5 atoms or heteroarylalkyl where alkyl has 1 to 3 has carbon atoms, the alkyl moiety being substituted by hydroxy, or phenylalkyl wherein alkyl has 1 to 3 carbon atoms, the alkyl moiety being too substituted by alkanoyloxy of 1 to 4 carbon atoms or alkoxy of 1 to 2 carbon atoms, or 83 0 0 69 7 k «R_ represents the group CHOZ (CH0) RQ, wherein RQ is hydroxy OZZ Σ O o or dialkylamino in which each alkyl group has / represents 1 to 3 carbon atoms / Z is oxygen and r is 4; or Rg represents the group -CH 1 CH 2 or the group CORg, wherein Rg alkoxy of 1 to 4 carbon atoms is 5, Z represents oxygen or sulfur and r is 1; and either Q represents 1,3-benzene and X is a bond, n is zero, Y is oxygen and m is 3 or 4; whether X is oxygen, n is 1, Y is -CHOH- and m is 1; either Q represents 2,5-furan or 2,4-thiophene, X is a bond, Y is sulfur, n is 1 and m is 2; with the proviso that R1 is N dialkylamino in which each alkyl group has 1 to 3 carbon atoms when Q is a furan or thiophene ring. 5. Compounds of formula III, as well as physiologically acceptable salts and hydrates thereof, characterized in that either R 1, R 1, N is dimethylamino, Q is 2,5-furan, X is a bond, Y is sulfur, n equals 1 and m equals 2; either R 1 R 2 N dimethylamino or pyrroludino, piperidino, or hexamethyleneimino, Q is 1,3-benzene, X is a bond, Y is oxygen, n is zero, and m is 3 or 4; and A represents N and B represents CRg, or A represents CR_ and B represents N, wherein R_ is benzyl wherein the methylene group is OD substituted by hydroxy. 6. 5-C [2-E [[5- [(Dimethylaini.no) methyl] -2-furany 1] methyl] thio] ethyl] amino] -1-methyl-α-phenyl-1H-1,2 4-triazole-3-methanol and its physiologically acceptable salts. Compounds according to claim 1, namely: 1-methyl-3 - [[(1-methyl-1H-tetrazol-5-yl) thio] methyl] - Nt 3- [3- (1-piperidinylmethyl) phenoxy] propyl] -1H-1,2,4-triazol-5-amine-1-methyl-α-pheny1-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1, 2,4-triazole-3-methanol 4-methyl-en-enyl-5- [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -4H-1,2,4-triazole-3 - methanol as well as its physiologically acceptable salts. Compounds according to claim 1, namely: 1-methyl-5- [3 - [[(1-piperidinylmethyl) phenoxy] propyl] 8300697 V * 1 amino] -1H-1,2,4-triazole-3-ethane -1,2-diol a- [1-methyl-5- [[3- [3- (1-piperidinylmethyl} phenoxy] propyl] amino] -1H-1,2,4-triazol-3-yl] -2 -piperine methanol 5 - [[2-hydroxy-3- [3- (1-piperidinylmethyl) phenoxy] propyl] 5 amino] -1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol 5 - [[3— [3- (dimethylamino) methyl] phenoxy] propyl] amino] -1-methyl-enyl-1H-1,2,4-triazole-3-methanol 5 - [[2 - [[ [5-6 (dimethylamino) methyl] -3-thienyl] methyl] thio] ethyl] amino] -1-methyl-ct-phenyl-1H-1,2,4-triazole-3-methanol 10 as well as physiologically acceptable salts thereof. Process for the preparation of compounds of formula 1, as defined in claim 1, characterized in that (a) for the preparation of compounds in which R 1 - the group (CH 2) Z (CH 2) Ra or (CH ") S (CE") R, _ represents a triazole with 6 (7 ώ Γ O / X 6 V Ij *. * ^ 15 formula 1 where R, - represents the group Ra, where R_ represents - (CH_ ) L or - (CH 2) L and L is a leaving group, to react with a ^ A anion, ZCCH ^ Rg or ® S (CH2) R15; (b) for the preparation of compounds wherein R ^ is otherwise is then a straight or branched chain alkyl group having 2 to 6 carbon atoms, substituted by two or three acyloxy groups, or a dihydroxyalkyl group which forms a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group or Y is other than -CHOR ^ where R ^ represents acyl, a compound of formula 4 wherein a group is Q 25 as defined for R_, V represents NCR_ and ï 'is hydrogen, where II -3 V Q at V is oxygen or sulfur and Rg is a group as defined for R1. or is a group that can be converted therein under the conditions of the cyclization reaction; or V 'stands for NH, R.r is a group as lo defined for R, and Y' stands for CR_ where Y "is sulfur, oxygen or ^ II ^ Y" 30 is NH; or V 'represents sulfur or oxygen, Y' represents CRc and R. is a II 5 16 NH group as defined for Rg; or V stands for NRg, R ^ is hydrogen and Y 'represents CR_ wherein Y "as defined above; I ^ Y" is cycled; 83 0 0 69 7 ί __- * S "X 7 (c) for the preparation of compounds in which Alk is CH, an aldehyde of formula 8 is treated with an amine, R ^ R ^ NH, followed by reduction; (d) for the preparation of compounds in which Rg is a S aralkyl or heteroaralkyl group in which the alkyl portion is substituted by hydroxy, the appropriate aldehyde or ketone is reacted with an organolithium compound ArLi or a Grignard reagent ArMgHal wherein Ar is a suitable aryl , aralkyl, heteroaryl or heteroaralkyl group and Hal represents halogen; 10 (e) for the preparation of compounds in which Rg represents a straight or branched chain alkyl group of 2 to 6 carbon atoms substituted by two or three acyloxy groups, or Rg represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by an acyloxy group, or Y CHOR In which R @ 4 is acyl, the corresponding alcohol is reacted with an activated derivative of a suitable acid; (f) for the preparation of compounds in which Rg represents a straight or branched chain alkyl group of 2 to 6 carbon atoms substituted by two or three alkoxy groups, or Rg represents an aralkyl or heteroaralkyl group in which the alkyl portion is substituted by a alkoxy group, the corresponding alcohol is treated with a halogenating agent, followed by reaction of the obtained halogen compound with a suitable alkanol, (g) for the preparation of compounds in which Rg represents the group (CH2) Z (CH2) rRg in which Rg represents NR12Ri3 01 R12 011 R ^ g each representing hydrogen or alkyl, the corresponding alcohol in which Rg is hydroxy is treated with a reagent capable of converting the group Rg into a leaving group, followed by reaction of the obtained compound of formula 1 wherein Rg represents (CH2) ^ Z (CH2) 30 where L is a leaving group, with ammonia or a suitable amine R12R13NH; (h) for the preparation of compounds in which Rg is the group NR ^ R ^, wherein R ^ g represents an acyl group or an aryl or alkylsulfonyl group, the corresponding compound in which Rg represents the group NHR ^ g 35 is reacted with an activated derivative of the appropriate carboxylic acid or sulfonic acid; 8300 69 7 * 4 φ (i) for the preparation * of compounds in which R_ is the O group -CONR ^ qR ^, an activated derivative of the corresponding carboxylic acid in which Rg represents -COOH, is reacted with ammonia or an appropriate amine HNR ^ gR ^; or (j) for the preparation of compounds wherein R ^ includes the group of formula II, the corresponding compound wherein R ^ comprises the group -CH- (CH2) -CH- is reacted with an aldehyde or 4 p OH OH ketone RR-CO in the presence of an acid; o 7 and, if desired, the compound of formula 1 obtained is converted into a salt. A pharmaceutical composition comprising a compound of formula 1 as defined in claim 1, together with at least. a pharmaceutically acceptable carrier or diluent. 83 0 0 6 9 7 1 r3 1 \ .N — A / A R1R2N-Alk-QX “(CH2) nY (CH2) mNH ~ <^ B 2 / (ch2> P \ 3. R f11". / N " AOO R1R2Nch2QX (CH2) nY (CH2) mNH -C l | c ^ R6 ^ R7 ^ R16 R1R2NAlkQX '(CH2) RY (CH2) ^ NH-C-NNHY' V '5 --¾ R, R ^ NAlkQX (CH ~) Y (CH0) NHC-NN = U LA A Tl Zulff - N-CR® II 3 6 v R-jR ^ AlkQX (CH2) ï (CH2) NHCMMHC-Rj V 'Y ”1? 16 E R.R2NAlkQX (CH2) Y (CH2) mHH-CN-NH2 8 \ 3 V '/ »" * OHC-QX (CH2) nY (CH2) mNH-C ll NB g WQX (CH2) nY (CH2) mNH2 Glaxo Group Limited 83 0 0 69 7