Heterocyclic derivatives

This invention relates to compounds of the general formula (I) ##STR1## and physiologically acceptable salts and hydrates thereof, in which R.sub.1 represents a hydrogen atom or an alkyl, alkanoyl, aroyl or trifluoroalkyl group; PA0 R.sub.2 represents a hydrogen atom or an alkyl or alkenyl group or C.sub.2-6 alkyl group substituted by a hydroxy or alkoxy group; PA0 X represents a sulphur atom or NH; PA0 Y represents an oxygen or sulphur atom or a bond; PA0 m represents 1, 2 or 3; and PA0 n represents 2, 3 or 4. The compounds show pharmacological activity as selective histamine H.sub.2 -antagonists.

This invention relates to novel heterocyclic derivatives having action on 
histamine receptors, to processes 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 H.sub.2 -antagonists. These compounds which are more 
particularly described below, for example show inhibition of the secretion 
of gastric acid when this is stimulated via histamine receptors (Ash and 
Schild, Brit. J. Pharmacol. Chemother. 1966, 27, 427). Their ability to do 
so can be demonstrated in the perfused rat stomach using the method 
described in British Patent Specification No. 1,565,966, 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 et al Nature 1972 236, 385. Furthermore, the 
compounds antagonise the effect of histamine on the contraction frequency 
of isolated guinea pig right atrium. Certain compounds according to the 
invention have the advantage of an extended duration of action. 
Compounds with histamine H.sub.2 -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 
measure in surgical procedures, and in the treatment of allergic and 
inflammatory conditions where 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) 
##STR2## 
and physiologically acceptable salts and hydrates thereof, in which 
R.sub.1 represents a hydrogen atom or an alkyl, alkanoyl, aroyl or 
trifluoroalkyl group; 
R.sub.2 represents a hydrogen atom or an alkyl or alkenyl group or 
C.sub.2-6 alkyl group substituted by a hydroxy or alkoxy group, 
X represents a sulphur atom or NH; 
Y represents an oxygen or sulphur atom or a bond; 
m represents 1, 2 or 3; and 
n represents 2, 3 or 4. 
In the above formula (I) the term `alkyl` as a group or part of a group 
means that the group is straight or branched and, unless otherwise stated, 
contains 1 to 6 carbon atoms, and in particular 1 to 4 carbon atoms, e.g. 
methyl or ethyl, and the term `alkenyl` means that the group has 
preferably 3 to 6 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 C.sub.1-3 alkyl or C.sub.1-3 alkoxy groups, 
or halogen atoms, e.g. fluorine. 
According to one aspect the invention relates to compounds of formula (I) 
in which R.sub.1 is other than a trifluoroalkyl group. 
The following are examples of suitable meanings for the groups R.sub.1 and 
R.sub.2 : 
R.sub.1 may be for example a hydrogen atom or a methyl, ethyl, propyl, 
isopropyl, butyl, acetyl, propionyl, benzoyl or 2,2,2-trifluoroethyl 
group. 
R.sub.2 may be for example a methyl, ethyl, propyl, allyl, 2-hydroxyethyl 
or 2-methoxyethyl group. 
Examples of suitable chains --(CH.sub.2).sub.m Y(CH.sub.2).sub.n -- are 
--CH.sub.2 S(CH.sub.2).sub.2 --, --CH.sub.2 O(CH.sub.2).sub.3 and 
--(CH.sub.2).sub.4 --. 
Within the definition of formula (I) 
R.sub.1 is preferably a hydrogen atom; 
R.sub.2 is preferably a hydrogen atom, a C.sub.1-4 alkyl group (e.g. 
methyl) or a C.sub.2-6 alkyl group substituted by a hydroxy group (e.g. 
2-hydroxyethyl). 
X is preferably a sulphur atom; 
Y is preferably a sulphur atom; 
m is preferably 1; 
n is preferably 2. 
Particularly preferred compounds according to the invention are 
N-[4-[[[2-[(1-methyl-1H-tetrazol-5-yl)amino]ethyl]thio]methyl]-2-thiazolyl] 
guanidine, and physiologically acceptable salts thereof; and 
N-[4-[[[2-[[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]amino]ethyl]thio]methyl]-2- 
thiazolyl]guanidine, and physiologically acceptable salts thereof. 
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, fumarates and benzoates. The compounds of formula (I) and their 
salts may also form hydrates, which hydrates are also to be considered as 
part of the invention. The compounds of formula (I) can exhibit 
tautomerism and the formula is intended to cover all tautomers. Where 
optical isomers may exist the formula is intended to cover all 
diastereoisomers and optical enantiomers. The present invention also 
extends to bioprecursors of the compounds of formula (I). Bioprecursors 
are compounds which have a structure different to that of the compounds of 
formula (I) but which, upon administration to the animal or human being 
are converted in the body into a compound of formula (I). 
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 active 
ingredients, e.g. H.sub.1 -antagonists. 
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 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 
multidose containers, with an added preservative. The compositions may 
take such forms as suspensions, 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. 
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 is 1 to 4 doses to a total of 5 mg to 
1 g per day, preferably 5 to 500 mg per day, dependent upon the condition 
of the patient. 
It will be appreciated that in the methods for the preparation of compounds 
of formula (I) given below, for certain reaction steps it may be necessary 
to protect various reactive substituents in the starting materials for a 
particular reaction and subsequently to remove the protecting group. Such 
protection and subsequent deprotection may be particularly pertinent where 
R.sub.2 is an alkyl group bearing a hydroxy substituent. Standard 
protection and deprotection procedures can be employed, for examples 
amines may be protected by formation of a phthalimide group which may 
subsequently be cleaved by treatment with a hydrazine, e.g. hydrazine 
hydrate or a primary amine, for example methylamine. Hydroxyl groups may 
for example be protected by formation of ethers e.g. tetrahydropyranyl, or 
esters of carboxylic acids such as alkanoic acid, e.g. acetic acid, which 
may subsequently be removed by hydrolysis. 
In describing the processes which may be used for preparing the compounds 
of formula (I) or intermediates useful in the preparation thereof, any of 
R.sub.1, R.sub.2, Alk, X, Y, Z, n and m in the various formulae are as 
defined in formula (I) unless otherwise stated. 
Compounds of formula (I) may be prepared by reacting an amine of formula 
(II) 
##STR3## 
preferably in the form of a salt, e.g. a hydrochloride, with a tetrazole 
of formula (III) 
##STR4## 
where L is a leaving group such as halogen, e.g. bromine, and R.sub.2 ' is 
the group R.sub.2 or a group convertible thereto. The reaction is 
preferably carried out with heating, for example within the range 
80.degree. to 200.degree. C, in the absence or presence of a solvent such 
as an alkanol, e.g. butanol, optionally in a sealed vessel and preferably 
in the presence of a base such as triethylamine. 
The compounds of formula (II) may be prepared as described in British 
Patent Specification No. 2001624A. The tetrazoles of formula (III) in 
which L represents a leaving group such as halogen are either known 
compounds or may be prepared by methods analogous to those described in 
British Patent Specification No. 1364917 and G. B. Barlin, J. Chem. Soc., 
(B), 1967, 641, e.g. by halogenation e.g. bromination of a compound of 
formula (IV) 
##STR5## 
Tetrazoles of formula (IV) are either known compounds or, when R.sub.2 is 
a hydroxyalkyl group or a group convertible thereto, may be prepared by 
reaction of a corresponding 2-aminoalkanol derivative NH.sub.2 --R.sub.2 
with sodium azide and triethylorthoformate in the presence of a solvent 
such as acetic acid. 
Compounds of formula (III) in which L is a leaving group such as halogen, 
e.g. bromine or chlorine and R.sub.2 ' is the group CH.sub.2 CH.sub.2 
OR.sub.3 where R.sub.3 is a hydrogen atom or a hydroxyl protecting group, 
e.g. tetrahydropyranyl ether, are novel compounds and represent a further 
aspect of the present invention. 
Where the product of any one of the above processes is a free base and an 
acid addition salt, in particlar a physiologically acceptable salt is 
required, the salt may be formed in conventional manner. Thus, for 
example, a generally convenient method of forming the salts is to mix 
appropriate quantities of the free base and the acid in an appropriate 
solvent(s) e.g. an alcohol such as ethanol or an ester such as ethyl 
acetate. The invention also includes interconversion of one salt of the 
compound of formula (I) into another.

The invention is illustrated but not limited by the following Examples and 
Preparations, in which temperatures are in .degree.C. 
PREATION 1 
1H-Tetrazole-1-ethanol acetate (ester) 
2-Aminoethanol acetate (ester) hydrochloride (4.19 g), sodium azide (2.34 
g), triethylorthoformate (6.67 g) and acetic acid (6 ml) were stirred at 
70.degree. for 24 h. The mixture was cooled and acidified to pH 1 with 
concentrated hydrochloric acid. After 2 h, excess saturated potassium 
carbonate solution was added and the mixture was extracted with ethyl 
acetate to give the title compound (4 g) as a pale yellow oil. 
N.m.r. (DMSO): 0.49, s, (1H); 5.23, s, (2H); 5.57, t, (2H); 8.00, s, (3H). 
PREATION 2 
5-Bromo-1H-tetrazole-1-ethanol acetate (ester) 
Bromine (69.1 g) in chloroform (80 ml) was added to a stirred refluxing 
solution of 1H-tetrazole-1-ethanol acetate (ester) (33.8 g) in acetic acid 
(200 ml) and chloroform (400 ml). After 72 h the mixture was cooled and 
evaporated, excess, saturated potassium carbonate solution was added and 
the mixture was extracted with ethyl acetate to give the title compound 
(48.2 g) as a cream solid, m.p. 55.degree.-6.degree. (from diethyl ether). 
PREATION 3 
5-Bromo-1H-tetrazole-1-ethanol 
5-Bromo-1H-tetrazole-1-ethanol acetate (ester) (40 g) and 2N hydrochloric 
acid (216 ml) were stirred at room temperature for 22 h. 
The solution was concentrated to ca. 75 ml and basified with excess solid 
potassium carbonate. Any solid present was dissolved by the addition of 
water and the solution was extracted with ethyl acetate. 
The combined extracts were dried and evaporated to give a yellow oil which 
solidifed. Recrystallisation from isopropyl gave the title compound (24.7 
g) as a white solid m.p. 73.degree.-4.degree.. 
PREATION 4 
5-Bromo-1-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-1H-tetrazole 
A suspension of 5-bromo-1H-tetrazole-1-ethanol (5.79 g) and pyridinium 
4-toluenesulphonate (0.5 g) in dichloromethane (50 ml) and dihydropyran (4 
ml) was stirred at room temperature for 16 h to give a colourless 
solution. Water (25 ml) and sodium carbonate solution (25 ml) were added, 
the phases were separated and the aqueous phase was extracted with 
dichloromethane. The combined extracts were washed with water and brine, 
dried and evaporated to give the title compound (6.5 g) as a colourless 
oil. 
Assay Found: C, 35.1; H, 4.81; N, 20.0; C.sub.8 H.sub.13 BrN.sub.4 O.sub.2 
requires: C, 34.7; H, 4.73; N, 20.2%. 
EXAMPLE 1 
N-[4-[[[2-[(1-Methyl-1H-tetrazol-5-yl)amino]ethyl]thio]methyl]-2-thiazolyl] 
guanidine 
A solution of N-[4-[[(2-aminoethyl)thio]methyl]-2-thiazolyl]guanidine 
dihydrochloride (1.53 g) and triethylamine (2.5 ml) in n-butanol (45 ml) 
was stirred at 20.degree. for 0.5 hours and then 
5-bromo-1-methyl-1H-tetrazole (0.82 g) was added. The mixture was heated 
at reflux for 24 hours and the solvent removed in vacuo. The dark brown 
residue was partitioned between ethyl acetate and aqueous sodium 
carbonate. The ethyl acetate extract was washed with brine and evaporated 
to leave a brown gum which was chromatographed on silica using methanol: 
ammonia (250:1) to give a dark brown gum (0.6 g). This gum was 
chroamtographed on alumina using dichloromethane: ethanol:0.88 ammonia 
(100:8:1) to give a brown solid (0.16 g) which was crystallised from 
acetone to give the title compound (0.038 g) as a cream white solid m.p. 
80-3.degree.. 
N.m.r. (CD.sub.3 OD): 3.46, s, (1H); 6.25, s, (3H); 6.32, s, (2H); 6.44, t, 
(2H); 7.23, t, (2H). 
EXAMPLE 2 
N-[4-[[[2-[[1-(2-Hydroxyethyl)-1H-tetrazol-5-yl]amino]ethyl]thio]methyl]-2- 
thiazolyl]guanidine, d, l-tartarate 
A solution of N-[4-[[(2-aminoethyl)thio]methyl]-2-thiazolyl]guanidine, 
dihydrochloride (1.3 g) and triethylamine (1.3 ml) in butan-1-ol (10 ml) 
was stirred under nitrogen for 1 h, and 
5-bromo-1-[2-[tetrahydro-2H-pyran-2-yl]oxy]ethyl]-1H-tetrazole (1.2 g) in 
butan-1-ol (5 ml) was added. The reaction solution was gently refluxed for 
26 h and evaporated in vacuo to leave a black solid residue which was 
chromatographed on a column of alumina using 
dichloromethane:ethanol:ammonia--(150:8:1), to give a brown gum. This was 
dissolved in dilute hydrochloric acid, stirred for 2 h at room temperature 
and washed with diethyl ether. The pH of the aqueous phase was adjusted to 
pH 8 with sodium carbonate and extracted with diethyl ether. The organic 
extract was dried (MgSO.sub.4) and evaporated to leave a light brown foam. 
This foam was chromatographed on a column of silica using 
dichloromethane:ethanol:ammonia--(50:8:1) to give a colourless gum (0.1 g) 
which was dissolved in absolute ethanol and added to a solution of d, 
l-tartaric acid in absolute ethanol. The resulting solution was stirred 
for 2 h and dry diethyl ether was added to precipitate the title compound 
(0.105 g) as a white hygroscopic solid m.p. 60.degree.-65.degree.. 
N.m.r. (D.sub.2 O): 3.00, s, (1H); 5.62, s, (2H); 5.72, t, (2H); 6.06, t, 
(2H); 6.20, s, (2H); 6.52, t, (2H); 7.15, t, (2H). 
Examples of Pharmaceutical Compositions 
Tablets 
______________________________________ 
mg/tablet 
______________________________________ 
Active ingredient 20.0 
Microcrystalline Cellulose USP 
178.5 
Magnesium Stearate BP 
1.5 
Compression weight 200.0 
______________________________________ 
The active ingredient is sieved through a suitable sieve, blended with the 
excipients and compressed using 7 mm diameter 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, such 
as hydroxypropyl methylcellulose, using standard techniques. Alternatively 
the tablets may be sugar coated. 
Injection for Intravenous Administration 
______________________________________ 
% w/v 
______________________________________ 
Active ingredient 0.2 
Sodium Chloride BP as required 
Water for Injection BP to 
100.00 
______________________________________ 
Sodium chloride may be added to adjust the tonicity of the solution and the 
pH may be adjusted, using acid or alkali, to that of optimum stability 
and/or facilitate solution of the active ingredient. Alternatively 
suitable buffer salts may be used. 
The solution is prepared, clarified and filled into appropriate size 
ampoules sealed by fusion of the glass. The injection is sterilised by 
heating in an autoclave using one of the acceptable cycles. Alternatively 
the 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 or another suitable gas.