GB2063874A - Triazole derivatives processes for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Description

1

GB 2 063 874 A 1

SPECIFICATION Heterocyclic derivatives

5 This invention relates to novel heterocyclic derivatives having action on histamine receptors, to processes 5 for the preparation thereof, to pharmaceutical compositions containing them and to their use in therapeutics.

Certain novel heterocyclic derivatives have now been found which have potent activity as H2-antagonists.

These compounds, which are more particularly described below, for example show inhibition of the 10 secretion of gastric acid when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. 10 Chemother, 1966,27427). Their ability to do so can be demonstrated in the perfused rat stomach using the method described in German Offenlengungsschrift No. 2,734,070, modified by the use of sodium pentobarbitone (50 mg/kg) as anaesthetic instead of urethane, and in conscious dogs equipped with Heidenhain pouches using the method described by Black etal, Nature 1972 236,385. Furthermore the 15 compounds antagonise the effect of histamine on the contraction frequency of isolated guinea pig right 15

atrium but do not modify histamine induced contractions of isolated gastro-intestinal smooth muscle which are mediated via Hrreceptors.

Compounds with histamine H2-blocking activity may be used in the treatment of conditions where there is an advantage in lowering gastric acidity particularly in gastric and peptic ulceration, as a prophylactic 20 measure in surgical procedures, and in the treatment of allergic and inflammatory conditions where 20

histamine is a known mediator. Thus they may be used for example, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions of the skin.

The present invention provides compounds of the general formula (I)

and physiologically acceptable salts, hydrates and bioprecursors thereof, in which R-i and R2, which may be the same or different, each represent hydrogen, C-mo alkyl, cycloalkyl, alkenyl, 35 aralkyl, trifluoroalkyl, heteroaraikyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino 35 or cycloalkyl, or Rn and R2 may together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more ^.3 alkyl groups, e.g. methyl, or a hydroxy group and/or may contain another heteroatom, e.g. oxygen or sulphur;

40 Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms preferably 1 to 4 carbon atoms, 40 and is attached to the cyclohexadiene ring at eitherthe4or 5-position;

X represents -CH2 or -0-;

m represents 2,3,4 or 5 and when X is -O- the chain (CH2)m may be interrupted by an oxygen atom provided that there are at least two methylene groups between any two heteroatoms in the moiety 45 —X(CH2)mNH—; 45

R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C2.6 alkyl substituted by hydroxy or alkoxy; and R4 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkyloxyalkyl, aminoaikyl, alkylaminoalkyl, dialkyl-aminoalkyl, hydroxy or alkoxy or the group NRSR6 where

50 R5 represents hydrogen, alkyl, alkyl substituted by hydroxy or C^ alkoxy, alkenyl, aralkyl or heteroaraikyl 50 and R6 represents any of the groups defined for R5or may represent the group COR7 where R7 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or monocyclic heteroaraikyl or R6 represents the group S02R8 where Rs represents alkyl or aryl, or R6 represents the group

55 C-NHRg 55

li

Y

where Y is oxygen or sulphur and 60 Rg represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl, 60

or R5and R6 taken together may represent the group =CR10Rn where R10 represents aryl or heteroaryl and R„ represents hydrogen or alkyl.

The term "alkyl" as a group or part of a group means that the group is straight or branched and has unless otherwise stated preferably 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms e.g. methyl or ethyl and 65 the term 'alkenyl' means that the group has preferably 3 to 6 carbon atoms. The term "cycloalkyl" means 65

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GB 2 063 874 A

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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 one or more Cv3 alkyl or alkoxy groups or halogen atoms e.g. fluorine. The acyl portion of an acyloxyalkyl group means an aroyl, aralkanoyl orCi_6 alkanoyl group. Examples of acyloxyalkyl groups include acetoxymethyl,formyloxymethyl, 5 benzoyloxymethyl and phenylacetoxymethyl. The term "heteroaraikyl" within the definition of F?i and R2 means a group that is made up of a heteroaryl portion which is a 5- membered unsaturated ring e.g. furan or pyrrole, and a straight or branched alkyl portion; the heteroaryl ring is linked to the alkyl portion through either a carbon or nitrogen atom. The term "heteroaryl" within the definition of R4 means a 5- or 6-membered monocyclic unsaturated ring which may contain one or more heteroatoms selected from oxygen, 10 nitrogen and sulphur, e.g. furyl, pyridyl, thiazolyl and thienyl.

The invention includes the compounds of formula (I) in the form of physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, acetates, maleates, succinates, citrates, tartrates, benzoates and fumarates. The compounds of formula (I) and their salts may also form hydrates, which hydrates are also to be considered 15 as part of the invention. The compounds of formula (I) can exhibit tautomerism and the formula is intended to coverall tautomers. Where optical isomers may exist the formula is intended to coverall diastereoisomers and optical enantiomers. The term bioprecursors as used herein means compounds which have a structure different to that of the compounds of formula (I) but which, upon administration to an animal or human being, are converted in the body into a compound of formula (I).

20 The compounds according to the invention, preferably in the form of a salt, may be formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions may also contain if required other 25 active ingredients, e.g. Hrantagonists.

Thus the compounds according to the invention may be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred.

For oral administration, the pharmaceutical composition may take the form of for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable 30 excipients. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, 35 solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride. 40 For topical application, the compounds of the invention may be formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner.

For internal administration a convenient daily dosage regime of the compounds according to the invention would be 1 to 4 doses to the total of some 100 mg to 2 g per day, preferably 100 mg to 1 g per day, dependent upon the condition of the patient.

45 Examples of suitable meanings for the groups R^! to R4 are as follows:

Ri: alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl ordecyl), C5.7 cycloalkyl (e.g. cyclopentyl, cyclohexyl orcycloheptyl), alkenyl (e.g. ally! or3,3-dimethylallyl), aralkyl (e.g. phenylalkyl such as benzyl or phenethyl), Cv4 alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), hydroxy C2.4 alkyl (e.g. 3-hydroxypropyl), alkoxy C2.4 alkyl (e.g. methoxyethyl or ethoxyethyl) or di-C^ 50 alkylaminoalkyl (e.g. dimethylaminoethyl, diethylaminoethyl or dimethylaminopropyl);

R2: hydrogen or alkyl (e.g. methyl or ethyl); or

R^N may represent a 5-8 membered ring optionally containing one double bond and/or substituted by one or two C-i_3 alkyl (e.g. methyl) groups or a hydroxy group and/or containing an oxygen or sulphur atom (e.g. pyrrolidino, piperidino, hexamethylenimino, heptamethyienimino,tetrahydropyridino, 4-55 hydroxypiperidino, 4-C1_3 alkylpiperidino (e.g. 4-methylpiperidino), morpholino, 2,6-di-C1_3 alkylmorpholino (e.g. 2,6-dimethylmorpholino), orthiomorpholino;

R3: hydrogen, Ci_4 alkyl (e.g. methyl, ethyl or propyl), or hydroxy C2-4 alkyl (e.g. 2-hydroxyethyl);

R4: hydrogen, hydroxy, alkyl (e.g. methyl, ethyl, or isobutyl), hydroxy C-|_4 alkyl (e.g. hydroxymethyl, 2-hydroxyethyl or 1-hydroxy-1-methylethyl), C-,.3 alkoxy C-i_4 alkyl (e.g. methoxymethyl or methoxyethyl), 60 phenyl (^.3 alkyl, (e.g. benzyl or phenethyl), C2.4 alkanoyloxy C-i.4 alkyl (e.g. acetoxymethyl), amino C^ alkyl (e.g. aminomethyl), amino, C-|_4 alkylamino (e.g. methylamino or ethylamino) or di-Cv4 alkylamino (e.g. dimethylamino, diethylamino or dipropylamino), phenyl C1-3 alkylamino (e.g. benzylamino), or a heteroaryl C-].3 alkylamino group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom (e.g. 3- or 4- pyridylmethyl); or the group NHCOR7 where R7 represents hydrogen, Ci_3 alkyl (e.g. methyl or ethyl), 65 alkoxy (e.g. methoxy or ethoxy), furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C1.3

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GB 2 063 874 A 3

alkyl (e.g. methyl) or C1.3 alkoxy (e.g. methoxy) group; or the group NHS02R8 where Rs represents C^ alkyl (e.g. methyl), or phenyl optionally substituted by a C-i.3 alkyl (e.g. methyl) or C-i_3 alkoxy (e.g. methoxy)

group; or the group NHCONHRg where R9 is (^.3 alkyl (e.g. methyl), C5_7 cycloalkyl (e.g. cyclohexyl), or phenyl optionally substituted by a (^.3 alkyl (e.g. methyl) or C-,_3 alkoxy (e.g. methoxy) group; or the group N=CHR10 5 where Rno is a phenyl or pyridyl (e.g. 3- or 4- pyridyl) group. 5

In particular the groups R-i to R4 may have meanings as follows:

Rt : 0^7 alkyl (e.g. methyl, propyl, butyl, isobutyl or heptyl), C^ alkyl substituted by a trifluoromethyl group (e.g. 2,2,2-trifluoroethyl), C2-4 alkyl substituted by hydroxy or a di-C-|.3 alkylamino group (e.g. 3-hydroxypropyl or 2-dimethylaminoethyl), C5.7 cycloalkyl (e.g. cyclohexyl), alkenyl (e.g. aliyl), or phenyl Ci_3 10 alkyl (e.g. benzyl); 10

R2: hydrogen or methyl or

RtR2N may represent a 5 to 7 membered ring optionally containing a double bond or an alkyl (e.g. methyl) substituent (e.g. piperidino, 4-methylpiperidino, pyrrolidino, or hexamethylenimino or tetrahydropyridino); R3 hydrogen, methyl, ethyl or 2-hydroxyethyl;

15 R4 hydroxy, phenyl Ci.3 alkyl (e.g. benzyl), C-,.4 alkyl substituted by hydroxy, Ci_3 alkoxy, C2.4 alkanoyloxy or 15 amino (e.g. hydroxymethyl, 2-hydroxyethyl, acetoxymethyl or aminomethyl); amino, di-C-i_4 alkylamino (e.g. diethylamino), NHCOR7 where R7 represents hydrogen, methyl, C-|.3 alkoxy (e.g. ethoxy) or phenyl,

NHCONHRg where R9 represents phenyl, or N=CHR10 where R10 is phenyl or pyridyl (e.g. 4-pyridyl).

The group Alk may be for example the group (CH2)n where n is 1,2 or 3, and is in particular a methylene or 20 ethylene group, more particularly methylene. 20

The group R^NAlk is preferably attached at the 5- position of the cyclohexadiene ring. X is preferably oxygen, m is preferably 3 or 4, more preferably 3.

A preferred group of compounds of formula (I) are those of formula (II)

fa

25 r 25

N—N \\

R^NCI^—O—(CH2)m-NH R4

30 30

(n)

where Rt and R2 are methyl groups or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethylenimino group; m is 3 or 4, R3 is hydrogen or methyl; and R4is an amino, hydroxyalkyi, aikanoyloxyalkyl, alkoxyalkyl, aminoalkyl, benzyl, formamido, alkoxycarbonylamino, 35 hydroxy, aroylamino, phenylcarbamoylamino alkanoylamino or pyridylmethylenamino group. 35

Particularly preferred compounds are

1-methyl-N5-[3-[[5-(1-piperidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazole-3,5-diamine;

and

1-methyl-5-[[3-[[5-(1-piperidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]amino]-1H-1,2,4-triazole-3-40 methanol 40

and their physiologically acceptable salts.

According to one aspect the invention provides compounds of formula (I) in which m represents 2,3 or 4 and R4 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyi, alkoxyalkyl, hydroxy or alkoxy orthe group NR5R6 where R5 represents hydrogen, alkyl, hydroxyalkyi, alkenyl, or aralkyl and R6 represents hydrogen,

45 alkyl or hydroxyalkyi or COR7 where R7 represents hydrogen, alkyl, aryl, aralkyl or alkoxy, or R6 represents 45 the group S02R8 where Rs represents alkyl or aryl, or R5 and Rs together represent the group =CR10Rn where R10 represents aryl or heteroaryl and R-,-, represents hydrogen or alkyl.

It will be appreciated in the methods for the preparation of compounds of formula (I) given below, that for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for 50 a particular reaction and subsequently to remove the protecting group. Such protection and subsequent 50

deprotection may be particularly pertinent where Rt and R2 in intermediates used to prepare compounds of formula (I) are hydrogen atoms. Standard protection and deprotection procedures can be employed for example formation of a phthalimide group which may be cleaved by treatment with a hydrazine e.g.

hydrazine hydrate or a primary amine for example methylamine.

55 In describing the processes which may be used for preparing the compounds of formula (I) or 55

intermediates used in the preparation thereof, any of Rt to R4, Alk, X and m in the various formulae are as defined in formula (I) unless otherwise stated.

Compounds of formula (I), except when R4 represents an acyloxyalkyl group orthe group -N=CRi0Rn can be prepared by a Birch reduction of compounds of formula (III)

5

R1R2NAIK 1— II N— N

x(ch2^—NH R.

4

(in)

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GB 2 063 874 A

4

in which R4 is other than acyloxyalkyl.

The reaction is carried out using an alkali metal, e.g. sodium, in liquid ammonia in the presence of an alcohol, e.g. absolute ethanol, at a temperature of from -60°Cto -33°C.

Underthe conditions of the Birch reduction formation of a product of formula (I) may be accompanied by 5 the formation of a small quantity of an isomeric cyclohexadienyl material. For example, reduction of a 5

compound of formula (III) wherein the group R1R2IMAIk is in the 3-position gives the 1,4-cyclohexadiene derivative of formula (I) wherein the group R-jR2NAIk is in the 5-position and a small amount of the 1, 4-cyclohexadiene derivative wherein the group R^NAlk- is in the 3-position. The isomers may be separated if necessary and/or desired by conventional techniques.

10 Compounds of formula (I) in which R4 represents the group N=CR10Rn may be prepared from compounds 10 of formula (I) in which R4 represents NH2 by reaction with an aldehyde or ketone R10RnCO in a solvent such as benzene, ethanol or methanol. The reaction is preferably carried out with heating, e.g. at reflux.

Compounds of formula (I) in which R4 is an acyloxyalkyl group may be prepared by treating the corresponding hydroxyalkyi compound with an activated derivative of an appropriate acid, e.g. an acid 15 chloride such as acetyl chloride in the presence of a base. e.g. pyridine. 15

Compounds of formula (I) in which R4 is the group NR5R6 where R6 is -COR7, -S02R8 or -C(=Y)NHR9 may be prepared by treating an amino triazole (IV)

P3

20 A-n 20

a, »2Na,k

(BZ)

25 25

in which R1f R2, R3 and R5 are as defined in formula (I) or are groups readily convertible thereto with a reagent capable of replacing the hydrogen atom in the group NHRS by the group R6 where R6is as defined in formula (I).

Thus for example the aminotriazole (IV) may be reacted with an activated derivative of either a carboxylic

30 acid R7CQOH or a sulphonicacid R8S03H orthe aminotriazole (IV) may be reacted with an isocyanate or 30

isothiocyanate R'9NCY in which R'9 has any of the meanings defined for R9 in formula (I) except hydrogen or represents an alkali metal atom such as potassium or sodium or an alkoxycarbonyl group, e.g.

ethoxycarbonyl,to give a compound of formula (I) in which R6 is respectively the group COR7, S02R8 or

35 C-NH-R9. 35

Suitable activated derivatives include acid halides e.g. acid chlorides, alkylchloroformates, acid 40 anhydrides including mixed anhydrides (e.g. acetic formic anhydride), or esters such as alkyl esters, ortho 40 esters and (1 -alkyi-2-pyridinyl) 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 astriethylamine or pyridine. The reaction with an alkylchloroformate is preferably carried out in the presence of a base, e.g. potassium carbonate or 45 triethylamine, in a solvent such as dimethylformamide. The reaction with an acid anhydride may be carried 45 out in the absence or presence of solvent such as pyridine.

In the reaction with an isocyanate or isothiocyanate compounds of formula (I) in which R9 is other than hydrogen are conveniently prepared by carrying out the reaction in a solvent such as acetonitrile at an elevated temperature, e.g. reflux. Compounds of formula (I) in which R9 is hydrogen may be prepared by 50 heating the aminotriazole (IV) with an appropriate organic isocyanate or isothiocyanate such as 50

ethylcarbonisothiocyanatidate, at an elevated temperature followed by hydrolysis of the resulting ester, for example with a base such as aqueous ethanolic sodium hydroxide.

Intermediates of formula (III) may in general be prepared by the methods described in British patent specification No. 2023133Aand in European patent specification publication No. 0016565, or by processes 55 analogous to these methods. 55

Where the product of any of the above processes is a free base and a salt is required, the salt may be formed in a conventional manner. Thus, for example, a generally convenient method of forming the salts is to mix appropriate quantities ofthefree base and the acid in an appropriate solvent(s), e.g. an alcohol such as ethanol or an ester such as ethyl acetate.

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GB 2 063 874 A

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

In the following examples temperatures are in °C "T.l.c." refers to thin layer chromatography carried out on silica using, unless otherwise stated, one of the following solvent systems:

5 System A methanol: 0.88 ammonia (80:1)

System B ethyl acetate:water:isopropanol:

0.88 ammonia (25:8:15:2)

10 EXAMPLE 1

a) 1-methyl-Ns-[3-[[5-( 1-piperidinylmethyl)- 1,4-cydohexadien- 1-yl]oxy]propyl]- 1H- 1,2,4-triazole-3,5-diamine

Ammonia gas was condensed onto a solution of 1-methyl-Ns~[3-[3-(1-piperidinyl-methyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0g) in absolute ethanol (0.67 g) to give a total volume of 30 ml. Sodium (0.35 15 g) was added in small lumps such that the blue colour remained for almost 1 min before dispersing. The mixture was allowed to reflux during 0.5 h before adding ammonium chloride (1.0 g). The ammonia was allowed to evaporate at 20° and the white residue triturated with ethyl acetate (3 x 50 ml) and filtered through diatomaceous earth. The filtrate was evaporated to leave a colourless oil which was crystallised by trituration under cyclohexane (30 ml) and recrystallised from a mixture of ethyl acetate (20 ml) and 20 cyclohexane (30 ml) to give a crude white crystalline solid (0.41 g) m.p. 99-101°.

The crude product was partitioned between chloroform (25 ml) and water (25 ml). The chloroform layer was dried (MgS04), filtered and evaporated. The solid residue was crystallised from a mixture of ethyl acetate (10 ml) and cyclohexane (40 ml) to give the title compound as a white powder (0.31 g) m.g. 104-104.5° TLC System A Rf 0.62.

25 The following compounds were similarly prepared:

b) 1-Methyl-N5-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (4 g) gave 1-methyl-N5-[3-[[5-(1-pyrrolidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazole-3,5-diamine as a white powder (1.8 g)

30 m.p. 84-5°

Assayfound: C,61.44; H,8.43; N,25.30;

C17H28N60 requires: C, 61.34; H,8.48; N, 24.92%

c) 1-Methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]-propyl]amino]-1H-1,2-4-triazole-3-methanol (3.1 g)

35 gave 1-methyl-5-[[3-[[5-(1-piperidinylmethy!)-1,4-cyclohexadien-1-yl]oxy]propyl]amino]-1H-1,2,4-triazole-3-methanol as a white powder (1.3 g)

m.p. 122-3°

Assayfound: C,63.13; H,8.64; N, 19.38;

Cn9H31N502 requires: C, 63.12; H,8.39; N, 19.34%

40

d) 1-Methyl-IM5-[3-[3-[(dimethyl)aminomethyl]phenoxy] propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g) gave 1-methyl-N5-[3-[[5-[(dimethyl)aminomethyl]-1,4-cyclohexadien-1-yl]oxy]propyl-1H,1,2,4-triazole-3,5-diamine as a brown oil (0.1 g).

T.l.c. System A Rf 0.6

45 N.m.r. (CDCI3) 4.48, br.s, (1H); 5.4, br.s. (1H); 6.2,t, (2H); 6.5,s, (3H); 6.5,m,(2H); 7.2-7.4,m, (6H); 7.8,s, (6H); 8.0,m, (2H)

e) 3-Phenylmethyl-N5-[4-[3-(1-piperidinylmethyl)-phenoxy]butyl]-1H-1,2,4-triazole-5-amine (0.23 g) gave 3-phenylmethyl-N5-[4-[1-[5-(1-piperidinylmethyl)cyclohexa-1,4-dienyl]oxy]butyl]-1H-1,2,4-triazole-5-amine

50 as a white powder (0.06 g) m.p. 122°

T.l.c. System B Rf 0.6

N.m.r. (CDCh)2.75,s, (5H); 4.35,s, (1H); 4.45,brs, (IH): 5.20,m, (1H); 5.45,brs, (1H); 6.12,s, (2H); 6.36,m, (2H); 6.8,m, (2H); 7.2-7.4,several s, (6H); 7.7,m, (4H); 8.2-8.8,m, (10H).

55 f) 1-Methyl-Ns-[3-[4-(1-piperidinylmethyl)phenoxy]-propyl]-1H-1,2,4-triazole-3,5-diamine (0.92 g) gave 1-methyl-N5-[3-[1-[4-(1-piperidinylmethyl)cyclohexa-1,4-dienyl]oxy]-propyl]-1H-1,2,4-triazole-3,5-diamine as a white powder (0.10 g) m.p. 107°

T.l.c. System B Rf 0.6

60 EXAMPLE 2

1-Methyl-N3-(4-pyridinylmethylene)-Ns-[3-[[5-( 1-pyrrolidinyl-methyl)- 1,4-cydohexadien- 1-yl]oxy]propyl]- 1H-1,2,4-triazole-3,5-diamine

A stirred solution of 1-methyl-N5-[3-[[5-(1-pyrrolidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazo!e-3,5-diamine (0.95 g) and 4-pyridinecarboxaldehyde (0.35 g) in benzene (30 ml) was heated 65 under reflux in a Dean-Stark separator for 30 h. The solution was evaporated in vacuo to give a solid which

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GB 2 063 874 A

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was recrystallised from ethyl acetate (10 ml) to afford the title compound as a yellow solid (0.35 g).

m.p. 166-167°C

N.m.r. (CDCI3) 0.86,s, (1H); 1.25,m, (2H); 2.2,m, (2H); 4.4,brs, (1H); 5.2.t, (1H); 5.4,brs, (1H); 6.1,t, (2H); 6.4,s+q (5H); 7.0,s, (2H); 7.2,brs, (4H); 7.6,m, (4H); 8.0-8.2,m, (6H). 5 5

Examples of pharmaceutical compositions

Tablets

10 Active ingredient

Microcrystalline Cellulose BPC Magnesium stearate BP

mg/tablet

100.00 198.50 1.50

Compression weight 300.00

10

15 The active ingredient is sieved through a 250 jxm sieve, blended with the excipients and compressed using 9.5 mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.

The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxypropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.

20

Injection for intravenous administration

Active ingredient Water for injections B.P. to

% w/v

1.00 100.00

25

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using either dilute acid or alkali.

The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the 30 solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.

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EXAMPLE 3

Following the method of Example 1, N-[5-[[3-[3-(1-Piperidinylmethyl)phenoxy]propyl]amino]-1-methyl-1H-35 1,2,4-triazol-3-ylj-acetamide (1.4g) gave, after redissolving the crude product in ethyl acetate, washing with sodium carbonate, drying (MgS04) and evaporating the oganic layer, N-[5-[[[3-[3-(1-piperidinylmethyl) cyclohexa-1,4-dienyl] oxy]propyl]amino]-1-methyl-1H-1,2,4-triazol-3-yl]-acetamide as a white powder (0.6g). m.p. 51-52°.

T.l.c. system B Rf 0.7.

40

35

40

Claims (9)

CLAIMS 45

1. Compounds of the general formula (I)

F?1 F?2 NAIK-

X(CH2)m—NH'

N—N \\

45

R4

50

(I)

50

and physiologically acceptable salts, hydrates and bioprecursors thereof, in which

R-i and R2, which may be the same or different, each represent hydrogen, Ci_io alkyl, cycloalkyl, alkenyl, 55 aralkyl, trifluoroalkyi, heteroaraikyl, or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino 55 or cycloalkyl, or R-i and R2 may together with the nitrogen atom to which they are attached form a 5 to 10 membered ring which may be saturated or may contain at least one double bond, may be unsubstituted or may be substituted by one or more C1.3 alkyl groups, or a hydroxy group and/or may contain another heteroatom selected from oxygen and sulphur;

60 Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms and is attached to the 60

cyclohexadiene ring at either the 4- or 5- position;

X represents —CH2 or — O—;

m represents 2,3,4 or 5 and when X is -O- the chain (CH2)m may be interrupted by an oxygen atom provided that there are at least two methylene groups between any two heteroatoms in the moiety 65 —X(CH2)mNH—; 65

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GB 2 063 874 A

7

R3 represents hydrogen, alkyl, alkenyl, aralkyl, or C2_6 alkyl substituted by hydroxy or alkoxy; and R4 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyi, acyloxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy or alkoxy orthe group NR5R6 where R5 represents hydrogen, alkyl, alkyl substituted by hydroxy or alkoxy, alkenyl, aralkyl or heteroaraikyl 5 and R6 represents any of the groups defined for Rs or may represent the group COR7 where R7 represents hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or monocyclic heteroaraikyl or R6 represents the group S02R8 where R8 represents alkyl or aryl, or R6 represents the group

C-NHRg

10 II

Y

where Y is oxygen or sulphur and Rg represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl,

15 or R5 and R6 taken together may represent the group =CRi0Rn where Ri0 represents aryl or heteroaryl and Rn represents hydrogen or alkyl.

2. Compounds as claimed in Claim 1 in which the groups R-i to R4 have the following meanings:

R,: alkyl, C5.7 cycloalkyl, alkenyl, aralkyl, C-|_4 alkyl substituted by a trifluoromethyl group, hydroxy C2_4

alkyl, CV3 alkoxy C2_4 alkyl, or di-Ci.3 alkylaminoalkyl;

20 R2-" hydrogen or Cv4 alkyl; or

RtR2N may represent a 5-8 membered ring optionally containing one double bond and/or substituted by one or two C^ alkyl groups or a hydroxy group and/or containing an oxygen or sulphur atom; R3: hydrogen, C,.4 alkyl, or hydroxy C2.4 alkyl;

R4: hydrogen, hydroxy, C-i_4 alkyl, hydroxy C^ alkyl, C^ alkoxy C^ alkyl, phenyl Ci_3 alkyl, C2.4

25 alkanoyloxy C^ alkyl, amino C^ alkyl, amino, C^ alkylamino, di—Ct.4 alkylamino, phenyl Cu3

alkylamino or a heteroaryl C^ alkylamino group where the heteroaryl ring is 5 or 6 membered and contains one heteroatom; orthe group NHCOR7 where R7 represents hydrogen, C-|.3 alkyl, C^ alkoxy, furyl, pyridyl, thiazolyl, thienyl, or phenyl optionally substituted by a C^ alkyl or C^

alkoxy group; orthe group NHS02R8 where Rs represents C^ alkyl, or phenyl optionally 30 substituted by a C^ alkyl or C|_3 alkoxy group; orthe group NHCONHRg where Rg is C^ alkyl, C5.7

cycloalkyl, or phenyl optionally substituted by a Ci_3 alkyl or C^ alkoxy group; orthe group N=CHR10 where R10 is a phenyl or pyridyl group; and the group Alk is the group (CH2)n where n is 1,2 or 3.

3. Compounds as claimed in Claim 1 or 2, in which the group R^NAlk is attached at the 5- position of 35 the cyclohexadiene ring, X is oxygen and m is 3 or 4.

4. Compounds as claimed in Claim 3 corresponding to formula (II)

?3

N—N

•O—(CH2Jm—NH'

cm

45

where Rt and R2 are methyl groups or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexamethylenimino group; m is 3 or 4, R3 is hydrogen or methyl; and R4 is an amino, hydroxyalkyi, alkanoyloxyalkyl, alkoxyalkyl, aminoalkyl, benzyl, formamido, alkoxycarbonylamino, hydroxy, aroylamino, phenylcarbamoylamino, alkanoylamino or pyridylmethylenamino group.

50

5. Compounds as claimed in Claim 1 which are:

1-methyl-N5-[3-[[5-(1-piperidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazole-3,5-diamine; and

1-methyl-5-[[3-[[5-(1-piperidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]amino]-1H-1,2,4-triazole-3-methanol

55 and their physiologically acceptable salts.

6. Compounds as claimed in Claim 1 in which m represents 2,3 or 4 and R4 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyi, alkoxyalkyl, hydroxy or alkoxy orthe group NR5R6 where Rs represents hydrogen, alkyl, hydroxyalkyi, alkenyl, or aralkyl and R6 represents hydrogen, alkyl or hydroxyalkyi or COR7 where R7 represents hydrogen, alkyl, aryl, aralkyl, or alkoxy, or R6 represents the group S02R8 where R8

60 represents alkyl or aryl, or R5and R6 together represent the group =CR10Rn wherein R10 represents aryl or heteroaryl and R^ represents hydrogen or alkyl.

7. A process for the production of compounds of formula (I) as defined in Claim 1 which comprises:

(a) for the production of compounds in which R4does not represent an acyloxyalkyl group orthe group -N=CR10Rn, reducing a compound of formula (III)

5

10

15

20

25

30

35

40

45

50

55

60

GB 2 063 874 A

Ri R2NAIK

X(CH2)m NH

N—N

w

(in)

in which R4 is otherthan any acyloxyalkyl group, using an alkali metal in liquid ammonia in the presence of 10 an alcohol; 10

(b) for the production of compounds in which R4 represents the group -N=CRi0Rn, reacting a compound of formula (I) in which R4 represents NH2 with an aldehyde or ketone R10RnCO;

(c) forthe production of compounds in which R4 represents an acyloxyalkyl group, reacting a compound of formula (I) in which R4 represents a hydroxyalkyi group with an activated derivative of an appropriate

15 acid; 15

(d) forthe production of compounds in which R4 represents the group NR5R6 where R6is -COR7, -S02R8 or -C(=Y)NHRg, treating an amino triazole (IV)

?3

20 | 20

N—N

R1 R2NAIK f^jLX(CH2)m—NH'^^n/^NHRS

(ET)

25 _ 25

in which R1f R2, R3 and R5 are as defined in formula (I) or are groups readily convertible thereto, with a reagent capable of replacing the hydrogen atom in the group NHR5 by the group R6 where R6 is as defined above;

30 and where the compound of formula (I) is produced in the form of a free base, optionally converting the 30 free base into a salt.

8. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 6 together with at least one pharmaceutically acceptable carrier or diluent, and optionally one or more further active ingredients.

35 9. Compounds as claimed in Claim 4 in which R4 represents amino, alkanoylamino, hydroxyalkyi, 35

benzoyl or pyridylmethylenamino.

New claims or amendments to claims filed on 12 Feb. 1981.

40 New or amended claims:- 40

9. Compounds as claimed in Claim 4 in which R4 represents amino, alkanoylamino, hydroxyalkyi, benzyl or pyridylmethylenamino.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.