CA1249822A - Guanidine derivatives as histamine h-2 receptor antagonists - Google Patents

Abstract

ABSTRACT
"Guanidine Derivatives as Histamine H-2 Receptor Antagonists"
The invention relates to guanidine derivatives which are histamine H-2 antagonists and which inhibit gastric acid secretion. According to the invention where is provided a guanidine derivative of the formula I:-.

in which R1 and R2, same or different, are hydrogen or 1-10C alkyl, 3-8C cycloalkyl or 4-14C cycloalkyl-alkyl, each alkyl, cycloalkyl or cycloalkylalkyl optionally carrying one or more F, Cl or Br atoms, provided that one of R1 and R2 is halogen substituted, or R2 is hydrogen and R1 is R5-E-W in which W is 2-6C
alkylene optionally substituted by 1 or 2 1-4C alkyls, E is O,S or NR6 in which R6 is H or 1-6C alkyl, R5 is H or 1-6C alkyl optionally substituted by 1 or 2 1-4C alkyls, or R5 and R6 are joined to form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring; ring X is a heterocyclic ring as defined in the specification; A is phenylene or 5-7C cycloalkylene, or a 1-8C alkylene into which is optionally inserted one or two groups; D is O or S; and R3 and R4 are hydrogen or a variety of radicals described in the specification: and the pharmaceutically-acceptable acid-addition salts thereof. Manufacturing processes and pharmaceutical compositions are also described.

Description

~ 31724B

This application is a division of Serial No.
396,836 filed February 23, 198~.
This invention relates to guanidine derivatives wnich are histan~ine ~-2 antagonists and whlch inhibit yastric acid secreti~n.
It is postulated tnat tr.e ph~sioloyically-active com~ouna nist~,ine, wnicn occ~rs naturall~ witnin the ani~l body, is a~le to co~ine, in tne course oi exertiny its activity, witn certain s~ecific r~ceptors or whicn tllere are at least t~o aistinct ana separate types. l'he first ~,as Deen nan-ed t~e ~-1 r~ceptor (Asn and ~child, Brit.~.Pnarn~ac. 1966, 27, 427) and the action of nista~ine at this receptor is blocKed (antagonised) ~y classical "ar,tihist~.line" ~rugs sucn as ~l~epyr~.line. Tne second histamine receptor nas ~een nal.~ea tne H-2 receptor (~lack et al., ~ature, 1972, 236, 385) and tne action of nista~ine at tnis receptor is blocked by drugs sucn as cimeti~ine. lt is known that one of tne results of the blockaae of the action 20 OI nistaline at the -~-2 receptor is the inni~ition of tne secretion of gastric acid and a cornpouna which possesses tnis ability is therefore useful in ti~e treatment of peptic ulcers and other conaitions caused or exacer~atea by sastric aciaity.
In Ul~ Patent ~p~lication No. GB205~478~ and Ja~anese Patent Application i~o. ~56108777 l~rwent Accession ~o.74736 D/41) there are aescribed nistan.ine n-2 receptor antagoni-~ts wnicn are 2-guanidinothiazole aerivatives carrying a siae cnain in the 4-position to the end of which is attached a carbamoyl gr~up. It has now been discovered that a haloalkylguanidin heterocycle carrying a side chain to the end of which is attached ~noptionally substituted carbamoyl group is a potent histamine H-2 r~ceptor antagonist.

2 - ~ 9 ~d ~ 31724 According to the invention there i5 provided a guanidine derivative of the formula I:-~N \N

1 2in which R and R , which may be the same or different, are hydrogen atoms or branched or unbranched l-lOC alkyl, 3-8C
cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl, cycloalkyl or cycloalkylalkyl radical being optionally substituted by one or more halogen atoms selected from fluorine, ehlorine and bromine atoms, provided that at least one of Rl and R2 is a halogen-substituted alkyl, halogen-substituted cycloalkyl or halogen-substituted cycloalkylalkyl radical and provided there is no halogen-substituent on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radical which is directly attached to the nitrogen atom, or _R2 is a hydrogen atom and -Rl is a radical of the formula II:-R5-E_W_ II

in which W is an unbranched 2-6C alkylene chain which is optionally substituted by one or two 1-4C alkyl radicals, E
is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical~ or a radical of the formula NR~ in which R6 is a hydrogen atom or a l-6C alkyl radical, R5 is a hydrogen atom or an unbranched 1-6C alkyl radical which is option-ally ~ubstituted by one or two 1-4C alkyl radicals, or R5 and ~6 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine rin~;

q`~ 51 /,!L~

in ring X the do~ted line is a double bond on one side of the nitrogen atom N and Z is a carbon or nitrogen atom such that ring X is a 5- or S- membered aromatic heterocyclic ring which contains at least one nitrogen atom and may optionally contain one or two additional hetero atoms selected from oxygen, nitrogen and sulphur atoms, which heterocyclic ring may, where possible, carry one or two optional substituents, the optional substituents on ring X
being selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, trifluoromethyl, hydroxy and amino radicals;
A is a phenylene or 5-7C cycloalkylene radical or a 1-8C
alkylene chain which is optionally substituted by one or two 1-3C alkyl radicals and into which is optionally inserted, as part of the backbone of the chain, one or two groups selected from oxygen and sulphur atoms and NH, 1-6C
N-alkyl, cis and trans vinylene, ethynylene, phenylene and 5-7C cycloalkylene radicals, provided that the shortest link between ring X and C-D is of at least 3 atoms, pro-vided that when an optional insertion is made in chain Awhich results in the inser~ed group being directly attached to C=D the inserted group is other than an oxygen or sulphur atom or an NH or N-alkyl radical, and provided that no two insertions selected from oxygen and sulphur atoms and NH and N-alkyl radicals are directly attached one to the other;
D is an oxygen on sulphur atom, in particular an oxygen atom;
R3 is a hydrogen atom or a hydroxy, amino, 1-6C
alkylamino, 1-6C haloalkylamino, 1-6C alkanoylamino, 1-6C
alkyl, 3-8C cycloalkyl, 4-12C cycloalkylalkyl, 2-6C
alkenyl, 2-6C alkynyl, 1-6C haloalkyl, -4- ~ 3172~-(the halo or halos of ~he 1-6C haloalkylamino and the 1-6C haloalkyl being selected from one or more of the group of fluorine, chlorine, bromine and iodine), 1-6C alkoxy, 1-6C hydroxyalkyl, 2-lOC al koxyalkyl, 2-lOC alkylthioalkyl~ 1-6C aminoalkyl, 2-8C
alkylaminoalkyl, 3-12C dialkylaminoalkyl, 2 8C alkanoyl-aminoalkyl, 8-14C aroylaminoalkyl, 3-lOC alkoxycarbonyl-alkyl, 2-8C carbamoylalky~, 6 lOC aryl, 7-llC arylalkyl, heteroaryl or heteroarylalkyl radicals, wherein the hetero-aryl part is a heterocyclic aromatic ring containing one,two or three hetero atoms selected from oxygen, nitrogen and sulphur atoms, wherein the alkyl part of the hetero-arylalkyl radical is 1-6C and wherein, when R3 is or contains an aryl or heteroaryl ring, that ring is option-ally substituted by one or two groups selected from fluor-ine, chlorine, bromine and iodine atoms and 1-6C alkyl, l-~C alkoxy, 1-6C alkylthio, 2-6C dialkylamino, 2-6C
alkanoyl, trifl~oromethyl, hydroxy and amino radicals;
R4 is a hydrogen atom or R3 is alkyl and R3 and R4 are joined to form, together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated ring which optionally contains a double bond or an additional oxygen atom, NH or 1-6C N-alkyl radical; and the pharmaceu-tically-acceptable acid-addition salts thereof.
It is to be understood that, in the above formula I and throughout this specification, although the double bond in the guanidine residue attached to ring X has been inserted in a particular position, other tau~omeric forms are possible, and this invention includes such tautomeric forms within its scope, both in terms of the compounds of the in`vention and in terms of the manufacturing processes.
It is also to be understood that when A is or contains a cycloalkylene radical the groups attached to this radical may be in the cis or trans configuration. When A is or contains a 5 ~

cycloalkylene radical and/or when A is an alkylene chain substituted ky one or two alkyl radicals the compound of the formula I will, in nlost i~stances, contain at least one asyr~etric centre. In such ca~es the compounu of the formula I will therefore exist in at least two enantiomeric for~ns, the precise num~er being determine~
by the nun~er of asyr~letric centres. The biological activity, as hereinafter d~fined, of these enantiomeric forms ~ay differ, and it is therefore to be understood that this invention encompasses the racemate of the formula I, includiny any possible diastereoisol.leric form~, and any enantiomeric form which possesses the ~isclvsed biological activity, it being a matter of common gen~ral knowledge to one skilled in the art hOW to separate lS diastereoisomeric forms and now-to separate a racemate into its enantiomexs and determine the biologica activity of each.
~ particular value for K or R when it is a nalosen-substi-uted alkyl radical is a 2,2,2-trifluoro-etnyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroet`nyl, 2,2-dicnloro-2-fluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 25 2,2-difluoroethyl, 2p2-aichlorGethyl, 2-chloro-2-fluoro-ethyl, 2-bromo-_-fl~oroeihyl, 2,2,3,3-tetrafluoro-- propyl, 2,2,3,3,3-pentafluoropro~yl, 1,1,1,3,~,3-hex~-I luoroisopropyl, 1,3-dicnloro-1,1 r 3,3-tetrafluoro-isopropyl, l-chloro-1,1,3,3,3-pen~alluoroiso~r_pyl, 30 1,3-difluoroisopropyl or 2,2,3,3,4,4,4-heptafluoro-butyl radical.
Aparticularvalue for R or R w~en it is a halogen-substituted cycloalkyl radical is a 2,2,3,3-tetrafluorocyclopropyl, 2-cnloro-2,3,3-trifluorocyclo-35 propyl, 2,2-difluorocyclopropyl, 2-chloro-3,3-difluoro-cyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl or 2-chloro-2,3,3,4,4-pentafluorocyclobutyl radical.

A particular value for Rl or R2 when it is a halogen~substituted cycloalkylalkyl radical is a (1 J2 ,2,3,

3-pentafluorocyclopropyl)methyl, (2-chloro-1,2,3,3-tetra-fluorocyclopropyl)methyl, (1,2,2,3,3,4,4-heptafluorocy-clobutyl~methyl or (2-chloro-1,2,3,3,4,4-hexafluorocyclo-butyl)methyl radical.
A particular value for Rl or R when it is an alkyl radical is a methyl, ethyl, n-propyl, isopropyl or butyl radical.
A particular value for R1 or R2 when it is a cy-cloalkyl radical is a cyclopropyl or cyclobutyl radical.
A particular value for R1 or R2 when it is a cy-cloalkylalkyl radical is a cyclopropylmethyl or cyclobutyl-methyl radical.
A particular value for the optional su~stituent on W is a methyl radical.
A particular value for R5 is a hydrogen atom or a methyl radical.
A particular value for R6 is a hydrogen atom or a methyl radical.
A particular value for the radical of the formula II is a 2-methoxyethyl, 2-hydroxyethyl, 2-methylthioe~hyl or 2-dimethylaminoethyl ra~ical.
A particular value for ring X is an oxazole, thiazole, imidazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazine, pyri-dine, pyrimidine or 1,3,5-triazine ring, each being option-ally substituted, where possible, by one or two substi-tuents selected from fluorine, chlorine and bromine atoms and methyl, methoxy, trifluoromethyl, hydroxy and amino radica~s.
A particular value for -A- is a phenylene, cyclo-pentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylene, thiotrimethylene 9 thiotetra-methylene, thiopentamethylene, oxyethylene, oxytrimethy-lene, oxytetramethylene, methylenethiomethylene, methylene-thioethylene, methylenethiopropylene, methyleneoxymethy-lene, methyleneoxyethylene, ethyleneoxyethylene, oxy-2-methyl-7 ~ 2 ethylene, thiopropylenethiomethylene, oxyethylene-oxymethylene, iminoethylene, iminopropylene~ vinylene-propylene, oxymethylenevinylene, 1,3-phenylene, 1,3~yclopentylene, methylene-1,4-phenylene, ethylene-oxymethylene-1,4-phenylene, oxy-1,3 phenylenemethylene or thiomethyleneethynylenemethylene radical. These values for -A- are written reading ~rom left to right in formula I such that the first named part of the radical is attached to ring X and the last named part of the radical is attached to C=D. Thus, for example, when -A- is a thiomethyleneethynylenemethylene radical, the compound of the formula I contalns the part structure III:~
,_~ D
- C X Z - S-Ch2~C_C-C~-C- III
~l 1~ A particular value for R is ~ hydrogen atom or a hydroxy, ~nino, metnylamino, 2,2,2-trifluoroethyl-amino, acetylamino, methyl, cyclohexyl, cyclohexylmethyl, allyl, propargyl, 2,2,2-trifluoroethyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2~
~0 aminoethyl, 2-methylaminoethyl, 2-dimetnylaminoethyl, 2-acetylaminoethyl, 2-benzoylaminoethyl, methoxycarbonyl-ethyl, 2-carbamoylpropyl, phenyl, benzyl, heteroaryl and heteroarylmethyl, in the latter two of which the heteroaryl part is a furan, thiophene, pyrrole, thiazole, oxazole, imidazole, thiadiazole, oxadiazole, triazole, pyrazole, pyridine or pyrimidine_ring,and wherein when R3 is or contains a phenyl or heteroaryl ring, that ring is optiona1ly substituted by one or two groups selected from fluorine, chlorine, bromine and iodine atoms and methyl, methoxy, methylthio, dimethylamino, acetyl, trifluoromethyl, hy~roxy and amino radicals.
A particular value for the ring formed when R3 and R4 are joined is a pyrrolidine, piperidine, n.orpnoline, piperazine or N-metnylpiperazine riny.
The following are 7 preferre~ features of the guaniaine derivative of the formula I. hnen any one of these features is taken, either sinsly or in ~om~-5 ination, with tne other general or particular featuresof tl.e guanidine ~erivative of tne xormula I liste~
a~ove, there are oDtaine~ preferre~ sub groups of con~pounQs within tne above general definition.
1. ~3 and R4 are hydrogen atoli~s~
2. R is a hyarogen atom and ~ is a 2,2, 2-trifluoroethyl, 2-chloro-2,2-difluoroetilyl or 2,2,3,3-tetrafluoropropyl radical.
3. Ring X carries no optional substituent.

4. Ring X i5 a pyrazole, 1, 2, 3-triazole J 1, 2, 4-triazole in wnicn ~ is linke~ at the l-position, pyr~,idine in ~hicn A is linke~ at the 2-position, or thiazole in whicn ~ is linked at tne 4-positior" rlng

5. ~ing X is a pyrazole, 1,2,3-triazoie, or 1,2,4-triazole in which A is lin~ed at tne l-position, rin~.

6. ~ing X is a pyrazole ring.

7. -A- is a tetramethylene, pentamethylene, oxytririethylene, oxytetramethylene, thiatrin~etnylene or thiatetramethylene radical.
~5 ~p~cific con-,pounds of the inv~ntion are set out ir, the Lxamples. The following is a preferre~ group of compounds 4-14-(2-[2,2,2-trifluoroethyl~guanidino)pyrir~iG-2-ylthio~-butyramide (~xample 6~;
5-[3-(2-[2,2,2-trifluoroethyliguanidino)pyrazol-1-yljvaleramiae (Example 10);
5-[3-(2-[2,2,3,3-tetrafluoropropyl~suaniuino)pyrazol-l-ylJvaleramide (Lxan,ple 19), 5-[3-(2-[2-chloro-202-difluoroetnyliguanidino)pyrazol-l-ylJvaleramide (Lxample 20), _ 9 ~ 3s~

5-14-~2-[2,2,2~trifluoroethyllguanidino)-l,2,3-triazol-2-yl]valeramide (~xample 21);
5-14-(2-[2,2,3,3-tetrafluoropropyl~guaniaino)l,2,3-tria~ol-2-ylivaleramide (~xample 23);
6-14-(2~12,2,2 trifluoroethyljguani~ino) l,2,3-triazol-2-yl3hexanoamide (Example 24), - 4-L4-(2-12,2,3,3-tetrafluoropropyl]guanidino)pyrimid-2-ylo~yjbutyramide (~xample 44);
4-[2 (2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrid-6-ylthiojbutyramide ~Example 62);
and the pharmaceutically-acceptable acid-ad~ition salts thereof.
~,long this group of compounds~ the compounds of ~xamples lO, l9 and 44 are preferred and the compound of ~xample lO is particularly preferred.
~ suitable pharmaceutically-acceptable acia-addition salt of the guanidine derivative of the formula I is, for example, a salt formed ~ith hydrochloric, nydrobromic, phosphoric, sulphuric, acetic, citric or maleic acid.
The guanidine aerivative of the invention may be manufactured by llethods in which the actual chemical reactions involved are known in themselves. The following processes, R , R , R3, R , A, D and ring X
having the ~leanings stated above, unless indicated otherwise, are therefore provided as further features of the inv~ntion.
The process of the invention is characterised l~y: -(a) reaction of a compound of the formula IV:-R
R2 / \~ ~ C ~ Z--A--C--D~
N

or an activated derivative thereof with a compound of the formula R3R NH. The activated derivative may, for example be an ester, for example a 1-6C ester, for example a methyl or ethyl ester, or an acid halide, or example an acid chloride or acid bromide. Alternatively the activated derivative may be an anhydride, for exampl'e, a mixed anhydride. Particularly useful rlixed anhydrides are those for~ed by reaction of the compound of the formula IV with a chloroformate, for example ethyl chlorformate or isobutyl chlorofonnate. The reaction may be conducted in a diluent or solvent such as methanol, ethanol, methylene dichloride, tetrahydrofuran or d~nethyl-form~ide and the reaction may be accelerated or completed ~y the application of heat, for example by heating to the boiling point of the diluent or solvent. ~hen the activated derivati~e is an acid halide it is advantageous to conduct the reaction in the presence of a base such as triethylamine and to use a non-alcoholic diluent or solvent.
(b~ for those compounds in which R3 and R4 are ~o hydrogen atoms and D is an oxygen atom, hydrolysis of a compound of the formula V :-Rt ~
* \C=tJ-c.X Z~A--c~
~l2~

The hydrolysis is preferably carried out by use of a strong mineral acid such as concentrated sulphuric acid or by the use of hydrogen peroxide in a basic medium, for example in the presence of sodium hydroxide.
(c) construction of the guanidine radical attached to ring X by reaction of the appropriate thiourea, or a 1-6C S-alkyl (e.g. S-methyl) or S-benzyl derivative thereof, or a salt of such a derivative, with the approp-riate ~nine. The guanidine radical in the compound of the formula I contains three nitrogen atoms each of which caxries different substituents. The appropriate anline for use in this reaction may therefore be an~lonia, an amine of the formula R R NH or an amine of the formula VI :-~ - D
~4. ~ z ~--c--~R3R4 ~
~^.~

Tne reaction may be conducted using an excess of one of the reactants a~ a diluent or solvent, or an additiona diluent or solvent, for example methanol or ethanol, may be added. In many cases it is advantageous to use a catalyst such as mercuric oxide, lead oxide or sodium hypochlorite. The reaction may be conducted at ambient temperature or it may be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or solvent.
(d~ construction of the guanidine radical attached to ring X by reaction of the appropriate cyanamide with the appropriate amineO Since the guanidine radical in the c~ pound of the formula I contains only one unsub-~ stituted nitrogen atom there are two appropriate amines, namely the amine of the formula R R2NH or of the formula VI given above.
(e) for those compounds in whicn the group inserted into A is an oxygen or sulphur atom or an l~ or N-alkyl radical, reaction of a compound of the formula VII or VIII:-' R'~

,C- ~J ~ ~ Z--- A--~,-H

- 12 ~ 2 ~1 ~2\~ 7 H2.

with a compound of the formulaIXor X respectively:

R7_A2_C_~ R3 I X

~_G-A2-C-N X
\ R4 in which G is an oxygen or sulphur atom or an Nh or ~-alkyl r~dical, R7 is a displaceable radical and Al and A2 are fra~ments of A, including direct bonds, and are such that Al-G-A2 falls within the definition of A given above. R is,for example,a halogen atom, for example a chlorine, bromine or iodine atQm. When R7 is directly attached to ring X R7 may, for example, be a methyl-sulphinylor methylsulphonyl radical.
~f) for those compounds in which Z is a nit~ogen atom, reac~ion of a compound of the formula XI:-R' ~ ~ `~
C=1~1~C;~

with a compound of the formula XII :-R -A-C-N \ XII

- 13 ~

in which R7 is a displaceable radical. R is, for example, a halogen at~n, for example a chlorine, bromine or iodine atom.
(g) for those c~mpounds in which ring X is a thia~ole ring, reaction of a compound of the formula XIII:-Rl N S
~2 / \ C-N~-~-N~ XIII
NH

with a compound of the formula XIV:-Hal-C~-CO-A-~-N ~IV
\ R

in which Hal is a chlorine or brQmine at~ and R8 is a hydrogen atQm or the optional substituent on the thiazole ring. The reaction may be conducted in a diluent or solvent such as acetone and may be accelerated or comp-leted by the application of heat, for example by heating to the boiling point of the diluent or solvent.
When the process of the inYention manufactures the c~npound of the formula I in the form of the free base and an acid-addition salt is required, the compound of the fonnula I in the free base form is reacted with an acid which affords a pharmaceutically-acceptable anion.
The starting material of the formulaIv for use in process (a) may be obtained by separate construction of the two side chains on the appropriate ring X. Thus the left-hand side chain may be constructed by reduction of a nitro group to an ~nino group, reaction of this amino group with an isothiocyanate of the formula RlR N=C=S, and finally reaction of the resulting thiourea - 14 ~

with ammonia in the presence of mercuric oxide. The Method of construction of the right hand side chain may ~ary depending on the nature of ring X, the nature of the atom in ring X to which A is attached (carbon or nitrogen~ and the presence or absence of inserted atoms or groups in chain A. In thisconstruction it may be - necessary to protect the acid function as a cyano or ester group and to hydrolyse to the acid as a final step. When A contains no inserted group or the inserted group is a phenylene radical and Z is a carbon atom, it is preferable to construct the ring X with the right hand chain already in place. Thus when ring X is a thiazole ring a process similar to that described in process ~g~ may be used~ for example as illustrated in 15 Examples 51, 52, 53 and 54. When ring X is a 1,2,3-triazole ring, it may be formed by reaction of methazonic acid with a suitable azide, for example as illustrated in Example 26. When ring X is a pyrimidine, it may be formed by reaction of a suitably substituted imino ether 2C with 2-chloroacrylonitrile, for example as illustrated - in Example 31. When the inserted group in A is vinylene or ethynylene radical, A may be introduced by formation of the double or triple bond by standard coupling methods, for example as illustrated in Example 48. When the inserted group in A is a cycloalkylene radical, the chain A may be constructed by a conjugate addition to the corresponding cycloal~-2~enone, for ~xample as illustrated . - 15 -in Example 25. When the inserted group in A is an oxygen or sulphur atQm or an NH or ~-alkyl radical, the right . hand chain may be built up by a method similar to that described in process (e), for example as illustrated in Examples l, 6, 29, 41, 47, 49, 56, 57, 59, 60, 61 and 62.
When Z is a nitrogen atom,.~the right hand chain may ~e formed by a method similar to that described in process (f)~ for example as illustrated in Examples 11, 21~ 55 and 58.
The starting material of the formula V for use in process (b) may be prepared by methods exactly analogous to the methods of preparation of the compound of the formulaIV~ Indeed, as already explained, the compound of the formula V may be an immediate precursor of the compound of the formulaIV.
The starting material of the formula VI for use in process (c) may be prepared by the methods described above for the preparation of the compounds of the formula IVor V in which the ri~ht hand chain is constructed first, followed by use of one of the processes ~a~ or (b~.
The cyanamide, corresponding to the amine of the formula VI , for use in process (d) may be prepared by reaction of the compound of the formula VI with cyanogen bromide.
The starting materials of the formulae VII
andVIIIfor use in process (e) ? and of the formula XI
for use in process (fl, may be prepared by construction of the guanidine chain on a suitably substituted ring X.
The starting material of the formula IV for use in process (a~ is a particularly useful intermediate for preparing the compounds of the formula I. This starting material, and the activated derivatives (1-6C alkyl ester, acid chloride~ acid bromide,mixed anhydride) thereof are therefore pro~ided as a further feature of this invention. Particularly useful mLxed anhydrides are 3~ ~
l6 -those formed with 1-6C alkyl chloroformates, for example ethyl and isobutyl chloroformates.
The starting materiai of the formula V for use in process (b) is a particularl~ useful intermediate for preparing the compounds of the formula I. This starting material is therefore provided as a further - feature of the invention.
As noted above, the guanidine derivative of the invention is a histamine H-2 antagonist, inhibits the secretion of gastric acid in warm-blooded animals and is therefore useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity, including stress ulcers and gastrointestinal bleeding due to trauma.
The histamine H-2 antagonist activity may be demonstrated on standard tests, for example by the ability of the compound of the formula I to inhibit the histamine-induced positive chronotropic response in the spontaneously beating right atrium of the guinea pig or by its ability to inhibit the histamine-induced uptake of aminopyrine into the acid space of parietal cells.
The guinea pig atrium test is carried out as follows:-A guinea ~ig right atrium is suspended at 1 g.
~, t~nsloll (is~ etric) in a thermostatically~controlled(30C) tissue bath (25 ml.) containing oxygenated (95% 2'5~ C02) Krebs-~enseleit buffer (pH 7.4). The tissue is allowed to stabilise over 1 hour during which time it is washed 2-4 times. Individual contractions are recorded with a force-displacement transducer through a strain gauge coupler, and instantaneous rates are monitored with a cardiotachometer. A control response to 1 ~M histamine is obtained after which the tissue is washed 3 times and allowed to re-equilibrate to basal rate. After re-equilibration for 15 minutes, the test compound is added to the desired final concentration.

Ten minutes after addition of the cQmpound histamine (1 ~M) is again added and the response lo histamine in the pxesence of antagonist is compared to the histarnine control response. The result is expressed as a percentage of the histamine control response.
Thereafter the apparent dissociation constant of the - H-2 antagonist is determined by standard procedures.
The aminopyrine test is carried out as follows:-Gastric mucosa frQm the New Zealand white rabbit is remoyed from the underlying muscle and washed in Buffer 1 lcontaining per litre ~aCl;(8.007 g.), KCl ~0.201 g.), Na~HP04 (0.113 g.), KH2P04 (0.204 g.), CaC12.2H20 10.132 g~, MgC12 (0.101 g.) and glucose (1 g.), adjusted to pH 7.4 with NaOH~ The tissue is f~nely choppad~ su ~ nded ln ~uffer 1 ana washed th~ tir~s with Buffer 1. The tissue is then suspended in dispersion medium ~collagenase (Siyma Chemical Co., Type V; 100 mg.) and bovine ~erum albumin (Miles Laboratories Ltd,, Fraction V; 100 mg.2 in Buffer 1 (100 ml~); 50 ml. per 10 g. net weight of tissue~ and incubated at 30 Cand pH 7.4 (maintained by continuous monitoring~ with stirring under an oxygen atmosphere. After 30 minutes the tissue is allowed to settle and the supernatant liquid is rernoved.
Fresh dispersion medium (50 ml. per 10 g. wet weight of tissue) is added and incubation is continued with the tissue being largely dispersed into ~lands and whole cells after 40-60 minutes. Any rernaining large pieces of tissue are removed by filtration through nylon mesh.
The mixture of glands and cells is collected by centri-fugation at 200 x g and suspended in Buffer 1 containing1% bovine serum albumin (Miles Laboratories Ltd., Fraction V~. Finally the cells and glands are washed 3 times with Buffer 1 ana suspended in Buffer 2 lcontaining Eagles M~M
(500 ml.), Aprot~in (Sigma Chernical Co., 10 mg.) and HEPES (2-[4-(2-hydrQxyethyl)piperazin-l-yl]ethanesulphonic acid; 150 ~., 20 ml.) adjusted to pH 7.4 with NaOH;

- 18 ~ *~

150 ml. per 10 g. net weight of tissue]. The tissue suspension is stirred under an oxygen atmosphere at 32C.
for at least 1 hour before use. The tissue suspension is incubated with the test compound and aminopyrine (10 ~M) S labelled with C on the dimethylamino group (0.1 ~Ci/ml.) for 20 minutes. The uptake of the aminopyxine is tHen stimulated by addition of histamine and the phospho-diesterase inhibitor ICI 63197 (Eiochem.Soc.Special Publication 1, 1973, pp 127-132) to final concentrations of 10 5~. and 5 x 10 M. respectively. After 18 minutes the cells/glands are separated from the incubation medium by filtration of the suspension through glass microfibre filters. The cells~glands are quickly ( ~ 10 seconds) washed three times with ice-cold Buffer 1. The C14 aminopyrine retained by the tissue is measured on a scintillation counter and the degree of inhibition of uptake by the test cQmpound is calculated by reference to a control sample. The concentration of test compound giving 50% inhibition is then calculated graphically from a series of tests run at different concentrations.
All the compounds exemplified in this spec-ification were tested either on the guinea pig atrium test or on the aminopyrine test. All those tested on the guinea pig atrium test are active at or below a bath concentration of 10 ~M. and the more active compounds show complete inhibition of response at this concen-tration. All those tested on the aminopyrine test gave a 50~ inhibition of uptake of aminopyrine at or below a concentration of 3 ~M.
The inhibition of the secretion of gastric acid may be demonstrated in standard tests, for example by the ability of the compound of the formula I, when dosed intravenously, intragastrically or orally, to inhibit the secretion of acidic gastric juice in, for example, rats,or dogs pro~ided with gastric fistulae or denervated fundic pouches,and whose gastric secretion is stimulated by administration of a secretagogue, for example histamine, pentagastrin, bethanechol or food.
The test in rats is carried out as follows:-Female rats (200-230 g.) are anesthetized by intra~uscular administration of urethane (1.5 g/kg.) and the trachea cannulated. A soft tube is passed down the oesophagus into the stomach and secured by a tie in the neck region. A multi-orifice plastic tube (3 mm.
diameter) is passed into the antral region of the stomach, via an incision in the duodenum, and tied in place by ~leans of a ligature around the pylorus. Saline (9g./1. NaCl) is perfused through the stomach via the oesophageal cannula at a rate of 7 ml./minute and collected into beakers from the pyloric outlet over periods of 10 minutes.
Acid secretion is stLmulated by subcutaneous administration of the specific h-2 agonist dimaprit in a loading dose of 10 mg./kg. followed by an infusion of 30 mg./kg./hour.
~cid output is co~.puted by titration of the 10 minute samples to an end point of ph 6.4 with 20 mM. ~aOh. Wnen secretion has reached a plateau (three consecutive readings within 5~) the test compound is administered intravenously via a cannula placed in the left external jugular vein. Secretion is then measured for a furth~r 2 hour~. A stock solution of each test compound is prepared (10 mg./ml. in DMSO) and appropriate dilution made with saline to enable injection in a dose volume of 1 ml./kg. (DMSO <2%~-The test in dogs provided with chronic fistulae is carried out as follows:~
~ female pure bred beagle (9-12 kg.) naving a cnronic gastric fistula is fasted overnignt with water ad lib. During the experiment the dog is lightly restrained in a standing position. When studying the test compound by the intravenous route, the fistula is opened and, after ascertaining the absence of basal secretion over a period of 30 minutes, a continuous intravenous infusion of secretagogue (0.5 ~mol /kg/hour of histamine or 2~g./kg./hour pentagastrin) in saline - 20 ~

(15 ml./hour) is begun. Gastric acid samples are collected every 15 minutes. The volume of eac~l sample is measured and a 1 ml. aliquot is titrated to neutrality with lOOnM NaO~ to deter~ine acid concentrationO
Wnen a plateau of secretion is reached (1-2 nours), tne test compound is administered intravenously in saline and gastric acid samples are collected for a further 2-3 hours during which time the infusion of tne secretagogue continues uninterrupted.
~hen studying the test compound by the intragastric route, the aDsence of basal secretion over a period of 30 minutes is ascertained and the test compound, contained in 25 ml. of 0.5% w~v hydroxypropyl n~ethylcellulose and 0.1~ w~v 'Tween' 80 in water ~'Tween' is a Trade Mark~ is instilled into the stomacn through a fistula dosing plug. ~ne hour later, the fistula is reopened and intravenous infusio~ of a secretagoyue, as described abovel is immediately begun. Gastric acid samples are measured 2~ as described above and the approach of acid secretion to a plateau is compared to that of a control animal which is dosed intragastrically only with the dosing vehicle.
When studying the test compound by the oral route it is administered in a gelatin capsule with 15 ml. of water. One hour later, the fistula is opened and intravenous infusion of the secretagogue is immediately begun~ Gastric acid samples are measured as above and the approach of acid secretion to a plateau is compared to that of an undosed control animal.
Tne test in dogs provide~ with denervated funaic pouches is carried out as follows:-Male beagle dogs (14-22 kg.) are prepared with vagally denervated ~ouches of the fundic gland area by 35 the method of Rudick et al. (J.Surg.~es. 1967, 7 383.) The ani~lals are allowed 4-6 weeks to recover from surgery X ~
~ 21 -and a further period of 2-3 months prior to routine use, to allow for table training and standardization of secxetory responses. The dogs are starved for 23 hours beiore use (water ad lih) and during experiments they are lightly restrained in cloth slings. After rinsing tne poucn with warm water, histamine is infused subcuta~eously - at a rate of 10 ~g./minute. This dose of agonist produces a submaxLmal (60-90% of naximum~ increase in acid output in all dogs used. Pouch secretions are collected over 15 minute periods into graduated glass test tubes and the volume measured to the nearest 0.1 ml.
A 500 ~1 sample is diluted with 5 ml. of saline and titrated to p~ 7.0 with 100 mM~NaOH. Total acid output is computed from the product of acid concentration and ~olume of juice secreted. Compounds are administered intravenously (0.1 ml./kg.) via a cephalic vein or orally in a gelatin capsule when a secretory plateau t3 consecutive readings with~ 10%) has been attaine~. Secretion is measured for a period of 3 hours following administration of test co~x~nd.
The results obtained in the atrium and a~ino-pyrine tests are predictive of activity in the rat and dog tests.
No overt toxicity or side effects were noted during the rat or dog tests. The compounds 5-(4-[2-(2,2,2-trifluoroethyl)guanidino~pyrLmid-2-yl)valeramide, 5-(4-~2-(2l2,2-trifluoroethyl)guanidino~-1,2,3-triazol-2-yl)valeramide, 5-(6-L2-(2,2,3,3-tetrafluoropropyl)-guanidino~pyrid~2-yl)valeramide and 5~(3-~2-(2,2,2-tri-fluoroethyl)guanidino]pyrazol-l-yl)valeramide were administered intravenously to groups of two anaesthetised rats and four conscious mice at doses whicn were respectiYely ten times and one hundred times the dose, in mg.~kg., which produced an approximate 50% inhibition of gastric secretion in the anaesthetised rat. No toxic symptoms were noted in any of the dosed animals.

A number of compounds exemplified in this specification exhibit inhibition of acid secretion ~hich shows little or no decline from peak inhibition for several hours.
The N--methylcyanoguanidine group in known ~-2 receptor antagonists is potentially changeable into the - carcinogenic N-nitroso N-methylcyanoguanidine group in the mammalian body (Pool et al., To~icolo~y, 1975, 15, 69).
The correspondiIIg group in the compounds of the present invention, COl~R R4, is not potentially changeable into carcinogenic nitroso derivatives when R3 and R4 are hydrogen atoms.
~ ccording to a further feature of the invention there is provided a pharmaceutical composition which comprises a guanidine derivative of the invention in association with a non-toxic pharmaceutically-acceptable diluent or carrier.
The pha~naceutical composition may, for example, be in a form suitable for oral, rectal~ parenteral or topical administration, for which purposes it may be formulated by means known to the art into the form of, for ex~mple, tablets, capsules, aqueous or oily - solutions or suspension, emulsions, dispersible powders, suppositories, sterile injectable aqueous or oily solutions or suspensions, gels, creams, ointments or lotions.
In addition to the guanidine derivative of the formula I, the pharmaceutical compositior~ of the invention for oral, rectal or parenteral administration may also contain, or be co-administered with, one or more known drugs selected from antacids, for ~x~nple aluminium hydroxide - magnesium hydroxide mixtures;
antipepsin compounds, for example pepstatin; other histamine h-2 antagonistsl for example cimetidine or ranitidine; ulcer healing agents, for exaJnple carbenoxolone or bisI~uth salts; anti-inflammatory agents, for example - ~3 -ibuprofen, indomethacin, naproxen or aspirin prostaglandins, for example 16,16~dimethylpxostaglandin ~2i classical antihistamines (histamine ~-1 antaqonists), for example r,epyramine or diphenhydramine; antichol-S inergic agents, for example atropine ox propanthelinebromide; anxiolytic agents, for example diazepam, chlordiazepQxide or phenobarbital.
The pharmaceutical composition of the invention for topical administration may also contain, in addition to the guanidine derivative, one or more class-i~al anti-histamines (histamine H-l antagonists), for ex~mple mepyramine or diphenhydramine andjor one or more steroidal anti-inflammatory agents, for example fluocinolone or triamcinolone.
A topical formulation ~ay contain 1-10% w~
of the guanidine derivative of the invention, A
preferred pharmaceutical composition of the invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 5 mg. and 500 ~g. of the guanidine derivative, or one suitable for intravenousl sub~utaneous or intra-muscular injection, for example a sterile injectable containing between 0.1~ and 10~ wJw of the guanidine derivatiYe ~
The phannaceu~ical composition of the inYention will normally be administered to man for the treat~ent of peptic ulcers and other conditions caused or exacerbated by gastric acidity in the same general manner as that employed for cimetidine, due allowance being made in terms of dose levels for the potency ~nd duration of act~ of the g~udine derivative of the present invention relative to cirnetidine. Thus each patient will receive an oral dose of between 5 mg. and 500 mg.,and preferably between 10 mg. and 100 mg., 0c guanidine derivatiYe or an intravenous, subcutaneous or intra-muscular dose of between 0.5 mg. and 50 mg., and preferably between 2 mg. and 20 mg., of the guanidine derivative, the composition being administered 1 to 4 times, and preerably once, per day. The rectal dose will be approxLmately the same as the oxal dose. The composition may be administered less frequently when it contains an amount of guanidine derivative which is a multiple of the amount which is effective when given 1-4 times per day.
The invention is illustrated, but not limited, by the following Exampies. The n.m.r. spectra are quoted in ~ relatiYe to tetramethylsilane ( 6 = O) as internal standard (s = singlet, d = doublet, t = triplet, q =
quartet, m = ~ultiplet, br = broad~. The temperatures are in degrees Centigrade. The following contractions are used:~
HOAc - acetic acid DMF = dimethyl formamide ether = diethyl ether DMSO = dimethylsulphQxide MeOH - ~thanol EtOH = ethanol THF - tetrahydrofuran EtOAc - ethyl acetate Attention is drawn to the fact that 3-nitro-pyrazole ~Examples 10, 11 and 58~ and 4-nitrotriazole (Example 21) are both explosion haæards. In the Examples and thoughout the specification, the following abbreviations are used: C,H,N,O. etc. (The conventional chemical symbols for the elements unless otherwise designated).

-2~ æ~ 3~~

Example 1 A mixture of ethyl 4-[4-~2-[2,2,2-trifluoro-ethyl~guanidino)pyrimid - 2-ylthio]butyrate (0.18 g.) and a 33% w/v solution of methylamine in EtO~ (5 ml.) was stixred at room temperature for 4 days and then evaporated to dryn~ss. The residue was recrystalli~ed from EtQAc to give ~-methyl-4-[4-(2-[2,2,2-trifluoro-ethyliguanidino~pyrimid - 2-ylthio]butyramide (0.0~ g.), m.p. 153-155.
The ester used as starting material in the above process may be prepared as follows:-A mixture of 2-thiocytosine (0.64 g.), ethyl 4-bromobutyrate (1.07 g.) and 1,5-diazabicyclo[5,4,0]
undec-5-ene (0.84 g.) was stirred for 4 hours and then evaporated to dryness. The residue was treated with water and the mixture extracted with EtOAc, and the extract dried and evaporated to dryness to give a gum (1.9 g.~. The gum was dissolved in acetonitrile (5 ml.) the solution treated with 2,2,2-trifluoroethyl isothio-cyanate (1.1 g.) and the mixture heated at 70 for 72 hours with the addition of further portions of iso-thiocyanate (0.5 g.) at 24 and 48 hours. The mixture was cooled and the solid which crystallised was collected to give ethyl 4-~4-(3-[2,2,2-trifluoroethyl]thioureido)-pyrimid - 2-ylthio]butyrate, m.p. 104-106.
A mixture of ethyl 4-~4-(3-[2,2,2-trifluoro-ethylthioureido)pyrimid -2-ylthio]butyrate (0.25 g.), ~1~ (2 ml.), saturated ethanolic ammonia (5 ml.) and yellow mercuric oxide (0.2 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from ~tOAc ~ to glve ethyl 4-[4-(2-~2,2,2-tri-fluoroethyllguanidino)pyrimid - 2-ylthio]butyrate, m.p.
120-122.
Example 2 A mixture of ethyl 4-[4-(2-[2,2,2-trifluoro-ethyl]guanidino)pyrimid --2-ylthio]butyrate (0.2 g.), f~

ethanolamine (Q.5 ml.) and MeOh (5 ml.) ~as heated under reflux for 48 hours and then evaporated to dryness.
Water was added to the residue, and the mixture extracted with ~tOAc. The extract was dried and evaporated to dryness and the residue recrystallised from a small volume of EtOAc to give N-(2-hydroxyethyl)-4-[4-(2-~
- ~2,2,2-trifluoroethyl]guanidino)pyrimid - 2-ylthio]
butyramude (0.12 g.), m.p. 148-150.
Example 3 A mixture of ethyl 4~[4-(2-t2,2,2-trifluoro-ethyl]guanidino)pyrimid - 2- ylthio]butyrate (0~2 g.) t ethylenediamine (2 ml.) and MeOH (S ml.) was kept at room temperature for 18 hours and then heated under reflux for 4 hours. The solution was evaporated to dIyness, the residue treated with water, and the mixture extracted with EtOAc. The extract was dried and evaporated to dryness. The residue was dissolved in acetone and the solution added to a solution of maleic acid in acetone. The precipitate was collected to give 20 N-(2-aminoethyl) ~ 4-~4-(2-[2,2,2-trifluoroethyl3-guanidino)pyrimid - 2-ylthio]butyramide bis hydrogen maleate (0.22 g.), m.p. 144-148.
Example 4 By a similar process to that in Example 1, 25 using ethyl 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-pyrimid - 2-ylthio~valerate (prepared in an analogous manner to the butyrate used in Example 1) there was obtained N-methyl-5-~4-(2-[2,2,2-trifluoroethyl3guan-idino)pyrimid 2-ylthio]valeramide, m.p. 148-150.
Example 5 By a similar process to that described in Example 2 using ethyl 5-[4-(2-[2,2,2-trifluoroethyl3-guanidino3pyrimid-2-ylthio~valerate as starting material there was obtained N-(2-hydroxyethyl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid - 2-ylthio]valeramide hydrogen maleate, m,p. 179-181.

27 ~ 3 Example 6 A mixture of 4-[4-(2-r2,2,2-trifluoroethyl]-guanidino)pyrimid - 2-yltnio3butyronitrile (0.14 g.) and concentrated H2S04 was left at room temperature for 3 hours and then diluted ~ith crushed ice and water.
The solution was basified with lON aqueous NaOH and the mixture extracted three times with EtOAc. The combined extracts were dried and evaporated to dryness to give 4-~4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid - 2-ylthio~-butyramide tOo13 g.) which was characterised as thehydrogen maleate, m.p. 202-203 on recrystallisation from aqueous ~tOF..
The starting material for use in the above process may be prepared as follows:-4-Chlorobutyronitrile (0.23 g.) in ~t~F.
(2 ml.) was added to a solution of 2-thiocytosine (0025 g.) in 0.5N aqueous NaOH (5 ml.) and the mixture stirred for 18 hours. A further portion of 4-chloro-butyronitrile (0.23 g.) was added and the mixture stirred a further 24 hours. The solution was concentrated _ vacuo to 2 ml. and cooled and the crystalline precipitate collected to give 4-[ 4-amino_pyrimid - 2-ylthio]butyronitrile (0~3 g.), m p. 99-100.
A mixture of 4-[ 4-amino_pyrimid - 2-ylthio]
butyronitrile (0.25 g.), acetonitrile (3 ml.) and 2,2,2-trifluoroethyl isothiocyanate (O. 21 g.) was stirred at 70 for 72 hours and then evaporated to dryness. The residue was crystallised from a mixture of ether and petroleum ether (b.p. 60-80) to give 4-[4-(3-[2,2,2-trifluoro2thyl]thioureido)pyrimid - 2-ylthio]butyro-nitrile (0.37 g.), m.p. 125-126.
A mixture of 4-[4-(3-[2,2,2-trifluoroethyl]-thioureido)pyrimid - 2-ylthio]butyronitrile (0.32 g.), saturated ethanolic ammonia (20 ml.) and yellow mercuric oxide (0.5 y.~ was stirred at room temperature for 20 hours and then filtered and the filtrate evaporated to dryness. The residue was recrystallised from a mixture - 2a~ 2~
of acetone and petroluem ether (b.p. 60-80) to give 4~[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid ~ 2-yl-thio]butyronitrile (0.29 g.), m.p. 137.
Examples 7 and 8 3y a sirnilar process to that described in Example 6 and using the appropriate nitrile (prepared in an analogous manner to the butyronitrile described in Example 6) as starting material, there were obtained 5-[4-(2-[2,2,2-trifluoroethyl~guanidino)pyrimid - 2-10 ylthio~valeramide hydrogen maleate,m.p. 1~4-186 and 6-t4-(2-[2,2,2-trifluoroethyl~guanidino)pyrimid 2-ylthio]hexanoamide hydrogen maleate, m.p. 176-177.
Example ~ _ A mixture of 4-(4-[2-(2-methoxyethyl)guanidino]-pyrimid 2-ylthio~butyronitrile (0.16 g.) and concentrated sulphuric acid (2 ml.) was stirred at ambient temperature for 5 hours. The reaction mixture was then cooled in an ice-bath and basified by careful dropwise addition of concentrated aqueous a~nonia (s.g. 0.880). The resulting white precipitate was collected, washed with water and then cold EtO~.
The solid was dissolved in hot EtOX with maleic acid and the solution allowed to cool. There was thus obtained 4-(4-[2-(2-methoxyethyl)guanidino]pyrimid-2 2L ylthio)butyramide maleate (0.22 g.), rn.p. 194-195.
The starting material rray be obtained as follows:-To a stirred mixture of 4-1 4-amino_pyrimid 2-ylthio]butyronitrile (0.60 g.) and tetrahydrofuran q,~
- 2~ -(30 ml.) under argon at -78 was added n-butyl lithium (1.6 n,olar in hexa~e; 1.9 ml.). The reaction mixture was stirred for 0.5 hours at -78 and then 2-methoxy-ethylisothiocyanate (0.35 g.) in tetrahydrofuran (5 ml.) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirring was cont'inued for a further 64 hours. The reaction was poured into water and extracted (x 3) with EtOAc. The combined extracts were evaporated to dryness to give a crude solid which was purified by medium pressure chromatography on silica using CHC13/MeOH 9.5:0.25 v/v as eluant. The purified product ~0.25 g.~ was immediately added to a stirred mixture of ~tOh saturated with ammonia (10 ml.
and mercuric oxide (0.22 g.) and stirring was continued for 1.5 hours. The reaction mixture was filtered through diato~,~ceous earth, the filtrate evaporated and the residue purified by medium pressure chromatography on silica usin~ CHC13/MeOH/aqueous ammonia (s.g. 0.880) 9.5:0.6:0.05 ~/v,'v as eluant to give 4-(4-[2-(2-methox~-" ethyl~guanidino]pyrimid - 2-ylth;o)butyronitrile ~0.16 g.) as a semicr~sta~line solid which was used without further purification.
Example 10 5-[3-(2-[2,2,2-Trifluoroethyl]guanidino)-pyrazol-l-yl]valeronitrile (13 g.) was added over 10 minutes to concentrated sulphuric acid (65 ml.) with stirring. The resulting solution was kept at 20 for 18 ho~rs then diluted with i oe (300 ml.) and basified to pH 9 with 10.8 N sodium hydroxide. The mixtur~ was extracted with EtOAc (3 x 200 ml.) and the extract was dried (MgS04) and evaporated in vacuo to an oil which crystallised. The crude material was recrystallised from EtOAc to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-pyrazol-l-yl]valeramide, m.p. 130. The maleic acid 35 salt was prepared in acetone, m.p. 183-184.
The starting material may be prepared as follows:-3~

5odi~T hydride paste (6.16 g. of 61% w/w suspension in liquid paraffin) was added portionwise over 30 mir~utes to a solution of 3-nitropyrazole (17.4 g.) in dry DMF (150 ml.~ with external ice cooling to maintain 5 the temperature at 20-30 . The mixture was stirred for 45 minutes and to the almost clear solution was added 5-bromovaleronitrile (25 g.) over 30 minutes, at 25-30, and the mixture was stirred for 4 hours. Water (450 ml.~ and EtOAc (450 ml.) was added and the upper layer was separated, dried (MgS04) and evaporated in vacuo to an oil which was a mixture of 5-(3~nitro-pyrazol-l-yl)valeronitrile and 5-(5-nitropyrazol-1-yl)-valeronitrile. The oil was divided into two lS g.
portions which were fractionated on a silica column (3.5 cm diameter x 100 cm long) eluted at 2 ~tnDspheres by EtOAc/60-80 petrolllem ether (3:7 v/v). The 1:5 isomer was eluted first followed by the 1:3 isomer. The 5-(3-nitropyrazol-l-yl) valeronitrile had m.p. 32-33.
To a solution of 5-(3-nitropyrazol-1-yl)valero-nitrile (9.16 g.) in dry tetrahydrofuran (200 ml.) was added 59i w/w palladium on carbon (1.8 g.). The mixture was stirred at 20 under an atmosphere of hydrogen.
3.2 Litres of hydrogen were absorbed over 4 hours. The catalyst was filtered off and the filtrate was evaporated _ vacuo to give 5-(3-aminopyrazol-1-yl)valeronitrile as an oil.
To a solution of 5-(3-aminopyrazol-1-yl~-valeronitrile (7.0 g.) in acetonitrile (25 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6.02 g.).
After 15 minutes the solvent was evaporated in vacuo to give 5-(3- [3-(2,2,2-trifluoroethyl)thioureido]pyrazol-l-yl)valeronitrile as a white crystalline solid, m.p.
96-~8.
The above thiourea (12.5 g.) was dissolved in 8M ammonia in EtOE~ (120 ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at 20 for 30 3i~;~,~

minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give 5-~3-(2 [2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl~valero-nitrile as an oil. A sample of the oil was dissolved in acetone and 5 molecular equivalents of maleic acid was added. Ether was added to the resulting clear solution to produce the crystalline maleate, m.p. 123-125.
Alternatively, tilLi 5- l3-(2-L2,2,2-trirluoro-ethyl~guanidino)pyrazol-l yl~valeronitrile may be prepared by reaction of 3-aminopyrazole with 2,2,2-rifluoroetnylisothiocyanate, reaction of the resulting tniour~a With ~monia in the ~resence of n,ercuric oxide ~ld finally alkylation of the nitrogen atom in tne 1-position of the proauct, 3-[2-(2t2,2-trifluoroethyl3-Lj guanidinoipyrazolep witn 5-bromovaleronitrile.
Example 11 To a solution of 5-(3-[3-(2,2,2-trifluoroethyl~-thioureido]pyrazol-l-yl)valeramide (0.5 g.~ in 6M ~mxnia in ethyl alcohol (6 ml.) was added mercuric oxide (0.56 g.) 2~ over 5 minutes. The mixture was stirred for 1 hour and filtered. The filtrate was evaporated in vacuo to an oil which was dissolved in EtOAc. Addition of petroleum ether (b.p. 60-80) gave 5-[3-(2-t2,2,2-trifluoroethyl]-guanidino)pyrazol-~-yllvaleramide as a crystalline ~5 solid, m.p. 128-132.
The starting material may be obtained as follows:-A solution of 5-(3-nitropyrazol-1-yl)valero-nitrile (0.2 g.~ in ~centrated sulphuric aQd(1 ml.) was kept at 20 for 19 hours. The mixture was diluted with water (4 ml.), basified to pH 10 with 10.81~ sodium hydroxide and extracted with EtOAc (3 x 5 ml.). The extracts were dried (MgS04) and evaporated in ~acuo to a white solid which was recrystallised from ethanol to give 5-(3-nitropyrazol-l-yl)valeramide, m.p. 129-131.

A mixture of 5-(3-nitropyrazol-1-yl~valer-amide ~3.6 g.) ~nd 3% w/w palladium on carbon ~0.54 g.~
was stirred in isopropanol t20 ml. 3 under an atmosphere of hydrogen. The temperature was kept below 40 by external ice cooling. After 4 hours no more hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated in vacuo to give 5-(3-aminopyrazol-1-yl)-valexamide as an oil which crystallised. This product (2.5 g.) was stirred in a oe tonitrile (25 ml.) and 2,2,2-trifluoroethylisothiocyanate (2.17 g.) was added. After18 hours the mixture was filtered and the residue was washed with acetonitrile then ether to give 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1 yl)valer-amide, m.p. 172-174.
Exam~le 12 To a solution of 2,2,2-trifluoroethylcyanamide (0.65 g.) and 5-(3-aminopyrazol-1-yl)valeramide (0.87 g.) in EtO~, (10 ml.) was added concentrated hydrochloric acid (5 drops). The resulting mixture was heated under reflux for 5 hours. During this period drops of concen-trated hydrochloric acid were added perodically to maintain the pH at 4. Volatile material was evaporated in vacuo ~ld the residue was shaken with 2N ~ueous sodium ~ hydroxide (10 ml.) and EtOAc (35 ml.). The organic 25 layer was separated and the aqueous phase was re-extrac~ed with EtOAc (2 x 35 ml.). The combined ~xtracts were dried (MgS04) and maleic acid dissolved in acetone was added~to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-pyra201-l-yl]valeramide maleate, m.p. 180-182.
The 2,2,2-trifluoroethylcyanamide used as starting material may be obtained as follows:-Cyanogen bromide (1.06 g.) was dissolved in cold ether (5 ml.) and added to a solution of 2,2,2-trifluoroethylamine (1.98 g.) in cold ether (5 ml.).
3~ The mixture was allowed to warm to 20 over 30 minutes ~ 33 then filteredO The resi~ue was washed witn ether and tne combined filtraies were e~aporated in vacuo at 20 to give 2,2,2-txifluoroethylcyanamide as a mobile oil wnicn soliaifie~ on storage at -lS . Tne i. r. spectrum showe~ a band at 2~8~ cm (-Cl~). Tne n.m.r. spectr~n in a4 me hanol with tetramethylsilane as an internal-- standard ( ~ = O) haa tne following resonance~
3.~5 ~quartet).
Example 13 Tl~e process OI Example 1 was repeated~ using nydrazine in place of metnylamine, to o~tain 4-[~-(2-L2,2,2-trifluoroetnyliguan~ no)pyrimia-2-ylthio]-butyric acid hydrazide, m.p. 192-1~5.
~xamples 14-16 The process descriDed in ~xample 29 was repeated, using 4- L4- (2-L2~2,2-trifluoroetnylJguanidino)-pyrimi~-2-ylthioi~utyri_ acid an~ tne appropriate amines as starting materials. Tne following compounas were thus oDtained:-C~3C~
,)3- Col~H~

~xample -R

14 CF3CH~--CH~

16 -OCtl3 .

i~ e ~xample 1~ . maleate, m~p. 2~2-204 (yiela 50%).
~xam~le 15 : m.p. 17~-178 (yiel~ 47~).
~xample 16 : maleate, m. p. 161-163 (yield 15~).
The starting material ~lay ~e prepaxed as follows:--- A mixture of etnyl 4-~4-(2-~,2,2-trifluoro-etnylJyuanidino)pyrimi~-~-ylthiojbutyrate (1.03 g-1 and a solution of sodium nydroxide (0~13 g.) in water (10 ml.) was neated under reflux for 1 nour and then cooled~ The solution was acidified witn ~lacial ~OAc and the white solid whicn crystallised was collectea to give 4~[4-(2-l2~2~2-trifluoroethylJ~uaniaino)pyrilllid 2-ylthioJbutyric acid (0.75 g.),m.p. 234-236.
~xamples 17-20 The process of ~xam~le 10 was repeated, using tne appropriate starting materials, to obtain the following compoun~s.
RNI~ I
C=NJ~ (C~ Cot~

.
2~ ~xample R- m 17 CF3C~- 3 18 CF3C~2- 5 19C~F2CF2C~2- 4 20 CClF2C~2- 4 l~otes ~xam~le 17 : 1.2S maleate, rll.p. 158~159 (yield 36~).
~xample 18 : 1.5 maleat~, m.p. 130-131 ~yield 41~).
~xample 1~ : 2 maleate 0.5 H20, m.p. 93-9S (yield 58~).
~xample 20 : 1.25 maleate, m.p. 162-1~3 (yield B6%).
The starting materials may be prepared by' repeating the second, third, fourtn and fifth parts of ~xample 10 using, where appropriate, 4 bromobutyronitrile or 6 bromohexanonitrile in place of 5-bromovaleronitrile and using, where appropriate, 2,2,3,3-tetrafluoro-propylisothiocyanate or 2-chloro-2,2-difluoroethyliso-tniocyanate in place of 2,2,2-trifluoroethylisothio-cyanate.
Example 21 A solution of 5-[4-(2-[2,2,2-trifluoroethyl~-guanidino)-1,2,3-triazol-2-yl~valeronitrile (0.3~ g.) in concentrated sulphuric acid (1.0 ml.) was kept at room temperature for 5 hours. The mixture was poured into ice water (5 ml.~, basified with aqueous i~aOh, saturated with ~aCl and extracted with EtOAc~ Tne ~xtract was dried IMgS04) and evaporated to give a yellow gum. This gum was dissolved in a small volume of ~tOAc and treated with a solution of maleic acid (0.14 g.) in a small volume of acetone to give a solution from whicn the product crystallised. The pro~uct was filtered to give 0.33 g. of 5-[4-(2-[2,2,2-trifluoro-ethylguanidino) 1,2,3-triazol-2-yljvalerGmide maleate, m.p. 156-157.
The starting material may be obtained as follows:-A siirred solution of 4-nitro-1,2,3-triazole (23.0 g.) in dry DMF (135 ml.) was treated at room temperature with a dispersion of sodium hydride (4.8 g.) in mi~eral oil (4.8 g.). Tne mixture was stirred for 30 minutes and then treated with 5-bromo~aleronitrile t33DO g.). Tne rllixture was stirrea overnight at room temperature and then pourea into water. Trle product was extracted into EtOAc and purified ~y column chromatograpny on silica gel ~1 kg.) eluted with EtOAc/petroleum ether (b.p. 60-B0) (1:1 v/v) to give 22.3 g. of 5-(4-nitro-1,2,3-tria~ol-2-yl)valeronitrile as an oil.
~ suspension of palladium on charcoal (5~
w/w; 0~5 g.) in a solution of 5-(4-nitxo~1,2,3-triazol-2-yl)valer~nitrile (1.0 g.) in acetic acid (20 ml.) was stirred under one atmosphere of hydrogen until 420 ml. of hydrogen had been absorbed. The mixture was filtered and evaporated to give 0-85 g- of 5-14-arnino-1,2,3-triazol-2-yl)valeronitrile as an oil.
A solutiorl of 5-~4-~nino-1,2,3~triazol-2-yl)-valeronitrile (0.35 g.) and 2,2,2-trifluoroethyliso-thiocyanate (0.5 g.) in acetonitrile (5 ml.) was stirred at room temperature overnight. The mixture was evaporated and the residue recrystallised from toluene/petroleurn ether (b.p. 60-80~ to give 0.5 g.
Of 5-[4-(3-t2,2,2-trifluoroethyl~thioureiao)-1,2,3-triazol-2-ylJvaleronitrile, m.p. 86-88 after recrystal-iisation from toluene.
A stirred solution of 5-L4-~3-[2,2~2-trifluoro-etnylithioureido)-1,2,3-triazol-2-ylJvaleronitrile !o. ~5 g. ) in ~Nnoniacal ~t~h (6M; 10 ml.) was treated at roorn te~nperature with mercuric oxide (0.6 g.).
The mixture was stirred at room ternperature for 2 hours.
The mixture was filtered and evaporated to give 0.41 g.
of 5-~4-(2-[2,2,2-trifluoroethyliguanidino)-1,2,3-triazol-2-yl)valeronitrile.
Examples 22-24 Th~ process of Example 21 was repeated, using the appropriate starting materials, to obtain tne following compounds.

~7 C~ H2)p--Cc)~ ~

~xample R- P
_ _ . I
22 CF3C~- 3 23C~F~CF~C~2- 4 24CF3C~2- 5 _ _ Notes Example 22 : maleate, m.p. 159-161 (yiela 53%).
~xample 23 : maleate, m.p. 141-142 (yiela 58~).
.... .Example 24 : maleate, m.p. 146-147 (yield 49~).
The starting ~laterials may be prepared by .repeating the second, third, fourth and fifth parts of Example 21 using, where appropriate, 4-bromobutyro-nitrile or 6-bromohexanonitrile in place of 5-bromo-valeronitrile, and using, where appropriate, 2,2,3,3-tetrafluoropropylisothiocyanate in place of 2,2,2-trifluoroethylisothiocyanate.
Example 25 A mixture of 3-14-(3-[2,2,2-trifluoroethylj-thioùreido)-1,2,3-triazol-2-yl~cyclopentanecarboxamide (o.34 g.), mercuric oxide (0.4 g.) and nlethanolic an~onia (6~; 20 ml.) was stirred at room temperature for 3 hours.
The mixture was kept at room temperature overnight, filtered, and evaporated to give 0.27 g. of 3-14-(2-2~2~2-trifluoroethylJguanidino)-1~2~3-triazol-2-yl~-cyclopentanecar~oxamide. A sample in a small volume of ~tUAc was treated with an equivalent of maleic acid in a small volume of acetone to give, on addition of ether, - 3~

3-~4-(2-1~,2,2-trifluoroethyliguar.idino)-1,2,3-triazol-2-yl~cyclopenta~ecarboxamide maleate, m.p. 143-146~.
Tne starting material may be prepare~ as follo~Js :-A Mixture of 1,2,3-triazole ~3.5 g.), cyclo-pent-2-enone (5.0 g.), benzyltrimethylan~l,onium hydroxide (40% w/v solution in i~leOh; 2.0 ml.) and dioxan (20 rnl.) was stirrea at rooli~ ter,lperature overnight. Tne mixture was evaporated, treated with ~tOAc, washed twice with water and once with brine, dried (MgS04), and cvaporated to give unpurif ied 3- (1, 2,3~triazol-2-yl)cyclopent-anone as a pale yellow oil. Tne ~O~..r. spectrum of the product ~xhibited tne following resonances:- 7.62 (s, 2H~; 5.37 (br quintet, lh); 3.1-1.8 (m, 6~. (solvent CDC13) ~ mixture of urlpurified 3-(1,2,3-triazol-2-yl)-cyclo~entanone (0.5 g.), lithium alu~linium hyaride (o.S y.) and ether (2~ ml.) was stirred at room temperature overnight. The excess of lithium aluminium hyaride was uestroy-ea with aqueous l~aOh. 'l~he reaction mixture was filtered anu evaporatea to give 0.5 g. of unpurified 3-(1,2,~-triazol-2-yl)cyclopentanol as an oil.
A solution of unpurified 3-(1,~,3-triazol-2-yl)cyclopentanol (0.44 g.) in pyri~ine (5 ml.) was treated at 5 with toluene-~-sulphonyl chloride (1.1 g.).
The rllixture was kept at 5 overnight and then poured into water and extracted with ~t~Ac. The extract WdS washed witn water, a~ueous hCl ~2~) ard ~rine, and then dried (MgS04), and evaporatea to ~-ive 0.72 g. of unpurified 3-(1,2,3-triazol-2-yl)cyclopentyl toluene-p-sulphonate as an oil.
A mixture of unpurified 3-(1,2,3-triazol-2 yl)-c~clopentyl toluene-~-sulpnonate l~.7 ~ aCN (0.17 g.) a~ D~SO ~10 ml.) was stirred at 95 overnight. The mix~ure was poured i. ltO water and extracted witn ~tOAc.
The extract was washed with brine, driea (~ 04), alld evaporated to give 0.33 9. of unpurified 3-(1,2,3-triazol-2-yl)cyclopentanecarDonitrile as an oil.

- 39 ~

A mixture of unpurified 3-(1,2,3-triazol-2-yl)cyclopentanecarbonitrile (0.3 g~), concentrated sulphuric acid (2 ml.), and concentrated nitric acid (1 ml.) ~as kept at room temperature overnight. Tne initial reaction was exotnermic and required cooling.
The mixture was poured into water and extracted wit~
~tOAc. The extract was washed with brine, dried (l~gS04), and evaporated to give 0.26 g. of unpurifieu 3-(4-nitro-1,2,3-triazol-2-yl)cyclopentanecarboxylic acid.
A mixture of 3-(4-nitro-1,2,3-triazol-2-yl)-cyclopentanecarboxylic acid (0.3 g.) and thionyl chloride (2 ml.) was heated at 60 for 30 minutes. The mixture was evaporated under reduced pressure and then twice treated with toluene (10 ml.) and re-evaporated. Tne non-volatile residue was treated with ethanolic ar~lonia (6M; 10 ml.). Tne mixture was evaporated to give 0.25 g.
of unpurified 3-(4-nitro-1~2,3-triazol-2-yl)cyclo-p~ntanecarboxamiae. A sample purified by l,ledium pressure ~iquid chromatography on silica gel using ~tOAc as 2v eluant had m.p. 127-128.
A mixture of 3-(4-nitro-1,2,3-triazol-2-yl)-~yclopentanecarboxamide (o.28 g.), 5~ w/w palladium on charcoal (0.3 g.) and ~tOh (20 ml.) was treated at 50 with hydrazine hydrate (0.6 ml.). The reaction was kept at 50 for 15 minutes, filtered, and evaporated to give O.22 g. of unpurified 3-(4-~1ino-1,2,3-triazol-2-yl;cyclopentanecarboxamide as a white solid.
A mixture of 3-(4-amino-1,2,3-triazol-2-yl)-cycl~entanecarboxamide (0.215 g.), 2,2,2-trifluoro-ethylisothiocyanate (0.5 g.), acetonitrile (5 ml.), and DMF (1 ml.) was stirred at room temperature for 3 hours.
Tne mixture was evaporated, triturated with ~tOh and filtered to give 0.35 g. of solid 3-[4-(3-~2,2,2-tri-fluoroethylithloureiao)-1,2,3-triazol-2-yljcyclopentane-carboxamide which was used without further purification.

-40 ~ ~2 Example 26 __ A mixture of 3-14-(2-~2~2,2-triflucroethylj-guanidino)-1,2,3-triazol-2-yl~benzoic acid 10.2 g.), thionyl chloride ~2 ml.) and T~F (10 ml.~ was warmed for 10 minutes on a steam bath. The mixture was evap-orated under reaucea pressure, the residue redissolved in ThF ~10 ml.3 and re-evaporated under reduced pressure.
This re-evaporation procedure was repeated once more.
The resi~ue was aissolved in T~F (10 ml.) and poured into aqueous amnlonia-(s.g. 0.880; 20 ml.) to give a gummy precipitate. 'rhe precipitate was extracted into EtOAc.
The extract was dried (MgS04), concentrated to a small volume and treated with a solution of maleic acid (0.071 g.) in a small volume of acetone to give a precipitate of 0.146 g. of 3-[4-~2-~2,2,2-trifluoro-ethyliguanidino)-1,2,3-triazol-2-yl]benzamide, m.p. 199-~01.
The starting material may be prepared as ~ollows:-Nitromethane (61 g.) was added to a warm (45-50) solution of NaO~ (61 g.) in water (122 ml.) at such a rate that the temperature was maintained.
At the end of the addition the temperature was raised to 55 for 10 minutes and then allowed to fall back to 50. The mixture was chillea and neutralised to pH 7 with concentrated hydrochloric acid at ~ 10. The precipitatea product was redissolved by the addition of aqueous NaOH (12.5N; 40 ml.) to give a solution of the sodlum salt of methazonic acid.
A solution of NaN02 (36.2 g.) in water (300 ml.) was added during approximately 30 minutes to a suspension of 3-aminobenzoic acid (68.6 g.) in concentrated hydrochloric acid (126.3 ml.) and water (200 ml~) at 0-5. The mixture was filtered to give a solution of 3-carboxybenzenediazonium chloride.

The solution of the sodium salt of methazonic aci~ was treated at 10 with a cold t5) solution of 3-carboxybenzenediazonium chloriae A precipitate formed immediately ana was dissolved in aqueous NaO~ ~33% w/w;
100 r,~l.) to give a dark red solution. qne dark red solution was stirred and treated at 25 witn acetic' anhyaride (100 ~nl.). ~uring this tr~atment, aqueous ~aOh (33% w/w, 200 ml.) was added to keep the mixture basic. Tne reaction mixture was acidifed with concentrated hydrochloric acid and the precipitatea product was isolated by filtration to give 101.2 g of a light brown solid. ~ mixture of 23.5 g. of this solid, ~eOh (150 ml.~ ana concentrated sulphuric acid (0.5 ml.) was neated unaer reflux for 3 hours. The reaction mixture was neutralised with aqueous l~aOh (lN), concen-trated, and partitioned between ChC13 and brine. The Chcl3 phase was dried (MgS04) and evaporated to give 5.9 g. of a red oil that crystallised slowly. The solid was purified by medi~n pressure liquid chromatography on 2~ a silica gel column using ~tOAc as eluant to ~ive 5.3 g.
of a solid which was recrystallised twice from isopropanol to give 2.7 g. of methyl 3-(4-nitro-1,2,3-triazol-2-yl)-benzoate, m.p. 104-106.
A mixture of methyl 3-(4-nitro-1,2,3-triazol-2-yl)benzoate (1.0 g.), 5% w/w palladium on cnarcoal (0.5 g.
and ~OAc (100 ml.) was stirred under one atmosphere of hydrogen until 300 ml. of hydrogerl had been a~sorbea.
T`ne reaction was filtered and evaporated to give 0.91 g.
of methyl 3-(4-amino-1,2,3-triazol-2-yl)benzoate, r,l.p.
132-134 after recrystallisation from MeOh.
A warm mixture of methyl 3-(4-amino-1,2,3-triazol-2-yl)benzoate (o.44 g.) and acetoni~rile (5 ml.) was treated with 2,2,2-trifluoroethylisothiocyanate (0.34 g.), allowed to cool, and kept at room temperature for 21 hours. Tne reaction mixture was filtered, washed witn ether and petroleum etner (b.p. 60-80), and dried ~ ~2 ~ 3 ~3~

to give 0.63 g. of methyl 3-[4~(3-[2,2,2-trifluoroethylJ-thioureido)-1,2,3-triazol 2-yljbenzoate, m.p. 187-188.
A l~ixture of methyl 3-l4-~3-[2,2,2-trifluoro-ethyl~tnioureiao)-1,2,3-triazol~2-yl~benzoate (0.5 g.), S mercuric oxide (0.4 g.~ and ammoniacal ~tO~ 16M; 10 ml.) was stirred at room temperature for 2 hours. The mi'xture was treated witn mercuric oxide (0.1 y.) and stirred for another 2 hours. The mixture was filtered and evaporated to give 0.47 g. of methyl 3-[4-~2-[2,2,2-trifluoroethyl~guanidino)-1,2,3-triazol-2-yl~benzoate, m.p. 171-173 after recrystallisation from -~tOAc and petroleum ether (~.p. 60-80).
A mixture of methyl 3-[4-(2-[2,2,2-trifluoro-ethyl~guanidino)-1,2,3-triazol-2-ylJbenzoate (0.55 g.), ~tOh ~10 ml.) and aqueous NaOH (1l~; 1.7 ml.) was stirred at room temperature for 18 hours. The mixture was treated with aqueous NaOh (lN; 0.6 ml.) and kept at room temperature overnight. The mixture was diluted with aqueous ~aOh (lN), washed with ~tOAc, acidified to p~ 4, and extracted with EtOAc and T~F (2:1 v/v). Tne extract was dried (MgSO~) and evaporated to give 0.27 g. of 3-L4-(2-~2,2,2-trifluoroethyliguanidino)-1,2,3-triazol-2-ylibenzoic acid which was used without further purif-i~ation.
~xamr~e 27 ~ A mixture of methyl 3-[4-~2-[2,2,2-triflucro-e~lyl~guanidino~-1,2,3-triazol-2-yl~benzoate (0.12 g.), ~tOH (3 ml.) and hydrazine hydrate (1 ml.) was kept a~ rcom temperature overnignt. The reaction mixture was thrice both diluted with ~tO~ then evaporated to dryness. The residue was recrystallised from MeOh to give 0.03 g. of 3-~4-(2-~2,2,2-trifluoroethyl~guanidino)-1,2,3-triazol-2-yl)~enzoic acid hydrazide, m.p. 209-210 .
~xample 28 3j A mixture of methyl 3-L4-(?-L2~2/2-trifluor ethylJguanidino)-1,2,3-triaZ01-2-yl~benzoate ~0.2 g.) and ethanolamine ~5 ml.) was heated at 80 overnight.

. _ 43 ~ 3~ ~

Tne mixture was evaporated ana tne thic~ oily resi~ue was ~urlfied by cnrolliatograpny on silica gel using ~tOAc ana isopropanol ~o~l V~V) as eluant. l'he product was recr tailised from isopro~anol to give L~ -ny~roxyetnyl)-3~4-~-l2,~,2-tri~luoroetnyllguaniaino)-1,2,3-triazol-~-yllbenzamide, r,~.p. 171-173.
- E~ample 29 To a suspension of 4-~6~ ,2,2-trifluoro-ethyliguaniaino)pyrazin-2-yltniojbutyric acia (o.25 g~) in 'TnF ~10 m~ at O was aaaea triethylamine (0.082 g.), rollowe~ ~y etnyl cnloroformate (~.088 g.) and tne mixture ~as stirrea for 30 ~linutes. ~ solution of .~monia in ThF (~ r,~l.) was addea and the mixture stirred again for 30 minutes, tne temperature ~eing allv~e~ to rise to roonl temperature. Tne mixture wa~ evaporated _ vacuo, aqueous sodium bicarbonate (5 ml.~ was added ana tne mixture extracted witn ~tOAc (2 x ~5 ~1.).
After drying (~5gS04) tne solution was filtPrea ana evaporated ln vacuo to 4ive a pale yellow solid. 'l~nls 2V was æurified ~y meaiun pressure liquia cnro~atography on siliea eluted witn MeO~/Ch2C12 (1:1~ v/v) to give a solid. Tnis was dissolved in ~tOAc containing a trace of ~;tOh ana excess of a solution of maleic acid in EtOAc was aaded. The resulting precipitate was collectea 25 by filtration and recrystallised from ~tOh to give 4-~6-(2-l2,2,2-triIluoroetnyl]guani~ino)pyrazin-2-ylthioj-butyramide maleate, m.p. 171-172 t3~ yield).
Ine starting material may be prepared as IOllOWS:--To a solution of ~-amino-6-chloropyrazine (6 g.) in acetonitrile (50 ml.) wa~ addea 2,2,2-tri-fluoroetnylisotniocyanate (6 ml.) and tne nlixture heated unaer reflux on a steam bath for 6 hours. Tne mixture was allowed to cool, tne resulting soli~ filtered and recrystallised from toluene to give 2-chloro-6-(3-12,2,2-trifluoroetnylJtniourei~o)pyrazine.

To a solution of 2-cnloro-6-( ~l2,2,2-tri-fluoroetnylJtnioureiao)pyrazine (0.7 g.~ in alcoholic ~lui,onia (35 ml.) was aaaeu yellow mercuric oxide (0.65 g.) and tne Inixture was stirrea at room teI~lperature overnight.
5 Tne mixture was filterea and tne filtrate evaporatea in vacuo to ~ive a pale yellow solid. Iiecrystallisation~fron - toluene/petroleum e~ner (b.p. 6~ ) gave 2-cnloro-6-(2-12,2,2-trifluoroethyl~guanidino )pyrazine, m.p. 139-140~.
To a solution of soaium hydri~e (50% w/w dispersion in oil, 1.15 g.) was adaed 4-mercaptobutyric acid ~1.44 g.). ~-cnloro-6-(2-l2~2~2-trifluoroethylJ
guaniaino)pyrazine ~1.0 g.) was adaed ana tne mixture heatea unaex reflux on a steam bath overnight. Water was a~ded ana the mixture washed with ether. The aqueous phase was aciaified to ph 4 witn hyaro-cnloric acid to precipitate 4-16-(2 [2,2,2-trifluoro-etnyliguanidino~pyrazin-2-ylthioJbu*yric acid as a colourless solia, wnicn was collected ~y filtration, washed with water ana suc~ed dry. This material was used without further purification.
~xam~le 30 by a similar process to that described in ~xample 29, using ~niline instead of a~nonia, tnere was obtainea l~-phenyl-4-l6-(2-l2~2~2-trifluoroethylJ
guaniaino)pyrazin-2-ylthio~butyramiue, m.p. 165-167 (yield 28~).

Thionyl chloride (1 nil.) was aaaed dropwise to 5-l4` (2-[2,2,2-trifluoroethyliguanidino)pyrimia-2-ylJvaleric acia (0.3 g.) ana tne mixture heatea gently ~2~k~ ~2 on a steam ~ath or 5 minutes. ~xcess tnionyl chloriae was re~,loved ~y evaporation in vacuo anà tne resulting gum was covered witn C~l2C12 (5 ~ solution of aniline (0.105 g.) in CH2Cl~ (0.5 mi.) was addea, followea ~y aropwise aadition of triethylamine until Dasic. ~fter stirring at room temperature for 3~ minutes, t~le mixture was pourea into water, tl~e organic phase se~aratea and driea (MgS04). Filtration anà ~vaporation gave an oil whicn was dissolvea in a small volume of 1~ EtO~ an~ excess of a solution of maleic acia in ~tOAc added. Tne resulting precipitate was filtered~ washea with ht~l and recrystallised fron,FtOn to give N-phenyl-'~ 5-~4-(2-L2,2,2-trirluoroetnyligualliaino)pyrimia-2-yl~-valeramide maleate. 0.25 h~O, m~. 169-171 (yiela The starting material may be prepared as follows:-~ thyi 5-cyanovalerimiaate (75 g.) was stirred for 18 ~lours in ~eO~ (200 ml.) containiny ammonium cnloride (26.4 g.). The mixture was filtered and 2~ tne filtrate evaporated to dryness. lne residue was tnen neated under reflux in ~tOh (250 ml.) containing triethyl~rine (285 ml.) and 2-chloroacrylonitrile (106 g.). After 2 hours the ~.ixture ws coole~, adaed to water (1 1.) and tne ph aajustea to 4 witn ~OAc.
Tne aqueous mixture was treated witn charcoal, filtered and tne filtrate extrac~ed with EtOAc (300 ml.).
Tne aqueous layer was separated and the ph adjusted to ~ with a~ueous sodium nydroxide. Tne aqueous nlixture was extracted with tOAc (2 x 500 ml.). l'he comLined extracts were evaporate~ to dryness and the residue was recrystallised fror.l acetonitrile to give 16 g. of 5-(4-aminopyrimia-2-yl)valeronitrile.
A mixture of 5-(4-aminopyrimia-2-yl)valero-nitrile (30 g.) and 2,2,2-trifluoroetnylisothiocyanate (30 g.) in acetonitrile (50 ml.) was heated unaer reflux for 18 hours. Tne nlixture was evaporate~ to dryness ~6 and the resi~ue ~issolv~d saturat~d metnanolic ammonia.
Tne resulting solution was stirred ana mercuric oxiae (48 g.) adde~. ~fter 2 hours tne mixture was filtered tnrougrl aiatomaceous eartn and the filtrate evaporated to dryness. 'rne resid~e was triturated witn etner and the solid product filtered off to yive 39 g. of 5-[4-~2-12,2,2-trifluoroethylJguanidino)p~-rimi~-2-yl~valeronitrile.
To 5-[4-(2-~2,2,2-trifluoroethylJguanidino)-1~ pyrimid-2-ylivaleronitrile {2 g.~ was added concentrated H~ ~1.), and the rnixture was heated on a steam batn for 1.75 hours. After cooling and evaporation _ vacuo, the residue was dissolved in water and brought to p~ 5 witn aqueous sodium carbonate solution.
Tne resulting precipitate was filtered, washed with water, then ~t~X and dried at 7~ under vacuum to give 1.9 g. of 5-[4-(2-l2,2,2-trifluoroethyliyuanidino)-pyrir,lid-2-yl)valeric acid ~-hich was u~d without further purification.
~xarn~les 32-36 The process OI ExaIIlple 31 ~as repeatea,using tne appropriate starting ~naterials, to give the following compounds.

~ C= ~ ~(cH?~4--C~ R

~7 _ Example -R

32 ~t-~

33 ~ (C~3>~

3~ ~

3~ - ~H ~ C~C~3 .

LJotes ~xample 32 : maleate, m.p. 165-166 (yield 66%) ~xample 33 : maleate, m.p. 194 136~ (yield 25%) ~xample 34 : 2 maleate, m.p. 162-163 (yield 45%) ~xample 35 : 2.5 maleate. lH20, m.p. 165-168 Example 36 : maleate. 0.5h20, m.p. 187-1~9 (yiel~ 10%).
~xarnple 37 To a suspension of 5-14-(2-l2,2,2-trifluoro-etnyliguanidino)pyrimid-2-yljvaleric acia (0.25 g.) in frèshly distilled ThF (10 ml.) was addea trietnylamine (0.093 g.) witn ice cooling. A~ter stirring 15 minutes, ethyl cnloroformate (0.095 g.) was aaded dropwise and stirred 30 minutes at 0. Furtner triethylamine (0.093 g.) was added, followea ~y 2,2,2-trifluoroetnyl-ar.,ine hydrochloride (0.124 g.), ana the mixture was stirred at 0 for 30 nlinutes, then allowed to come to room temperature. After evaporation in vacuo, aqueous ~o~r~ 2~

so~ium car~onate solution was added and the mixture extracte~ witn ~tO~c. The extract was ~ried (MgS04) filtereu and evaporated in vacuo to give an oil wnicn was aissolved in a small volume of ~t~Ac and excess of a solution of maleic acid in LtOAc added. Addition of ether, with scratching, causea a colourless solid to precipitate. Tnis was collected and recrystallised from ~iOAc to give 1~(2,2,2-trifluoroethyl)-5-~4-(2-[2,2,2-trifluoroethyliguanidino)pyrirliu-2-ylivaleronitrile maleate. 0.25h20, m.p. 135-140.
~,~
By a similar procedure to that described in ~xanlple 37, using 3-aminopyridazine in place of 2,2,2-trifluoroethylamine, tnere was obtained N (pyridazin-3-yl)-5-[4-(2-l2,2,2-trifluoroethylJguanidino)pyrimid-2-ylJvaleramide maleate, m.p. 160-163 (yield 17~.
Txample 3~
A mixture of 5-~4-(2-[2,2,2-trifluoroetnyl]-g-uanidino)pyrimid-2-yl~valeronitrile hydrogen maleate, prepared as described in Example 31,(0.45 g.) and concentrated sulphuric acid ( 4 ml.) was stirred at room temperature for 4 hours. The mixture was then added to ice ( 15 g.) and the ph aajusted to 9 with aqueous sodium hydroxiae. The mixture was then evaporated to dryness and tne solid residue extracted with a mixture of ~ieOh and cnloroform (1:20 v/v, 150 ml.). The extract was filtereu and evaporated to dryness. Tie residue was treated with maleic acid in acetone to give 0.15 g. of 5-~4-(2-12,2,2-trifluoroethyl]guaniaino)pyrir,id-2-yl~-- 3~ valerasnide hydrogen snaleate. 5~2~ hl.p. 182-185.
~xample 4~
~y a similar proceaure to that described in ~xample 39, using the appropriate starting material, there was o~tained 6-[4-(2-[2,2,2-trifluoroethyli-guanidino)pyrimiG-2-ylihexanoamider m.p. 179-181 ~yield 32~).
i q 9 ~ k~3~

The starting material may be prepared by repeating the secona and third parts of Example 31, using ethyl 6-cyanohexan~,idate in place of ethyl 5-cyanovalerimidate.
xample 41 A solution of 3-14-(2-12,2,2-trifluoroeth~lJ-guanidino)pyrimid-2-ylthio~propanethiol hydroyen maleate (147 mg.~ and sodium methoxide (70 mg~ in MeOh was treated with 2-iodoacetamide (123 mg.) and the solution stirred at room temperature for 24 hours and then evaporated to dryness~ The residue was partitioned between water and EtOAc, and the ~tOAc phase was dried ana evaporated ~o dryness. The resiaue was purifieci by preparative tlc on silica gel using EtOAc/l~eOh/concen-15 trated aqueous ammonia (s.g. 0.8~0) 6:1:0.5 v/v/v as develop-ing solvent to give 2- L 3-(4 [2-(2,2,2-trifluoroethyl)-guanidinoipyrimid-2-ylthio)propylthioiacetamide as a gum (50 mg.) which was crystallised as the hydrogen maleate salt (m.p. 168-170) from ~tOAc.
Tile starting material may be obtained as follows:-A mixture of sodium methoxide (81 mg.), ~eO~
(10 ml.) 1,3~propanedithiol (1 ml.) and 4-[2-(2,2,2-trifluoroethyl)guanidinoj-2-methanesulphinylpyrimidine 25 (280 mg.) ~European patent publication No.30092) was stirred at room tem~erature for 2 hours and then evaporated to dryness. The residue was partitioned between aqueous 2W ~Cl and ether, and the aqueous phase was Lasified with aqueous lON NaO~ and extracted with htOAc. Tne EtOAc extI-act was dried ancl evaporated to dryness and the residue crystallisecl as the hydrogen maleate from acetone to give 3-[4 (2-[2,2,2-trifluoroetnyl~guanidino)-pyrimid-2-ylthioipropanethiol hyarogen maleate (260 mg.), m.p. 153-155.

Exam~le 42 A mixture of 5-[4-(2-~2,2,2-trifluoroethylJ-guanidino)pyr~mi~-2-yloxylvaleronitrile (0.5 g.) ana concentrateQ sulpnuric aci~ (3 ml.) was warn~ed until solution was obtaineal then stirred 2 hours at room temperature. The mixture was poured into water and basified with potassium carbonate. ~xtraction with Et~Ac gave a yellow gum which was converted in acetone to the maleate of 5-[4-(2-12,2,2-trifluoroethyljguanidino)-pyrimid-2-yloxyJvaleramide (0.38 g.), m.p. 192-193 (54~)-The starting material may be prepared as follows:-4-Cyano~utanol (10 g.) was added to so~ium hydride (2.75 g.) in t-butano~ (95 ml.) and the solution warmed to 40 . 4-[2-(2,2,2-Trifluoroetnyl)guanidii;oJ- 2-methylsulphinylpyrimidine (11.24 g.) was added over 10 minutes and the solution kept at 40 for 2 hours then at room temperature for 18 hours. The solvent was remove~
2~ un~er vacuum and the residue washe~ with water, then ether to give 5-[4-(2-[2,2,2-trifluoroethyliguanidino)-pyrimid-2-yloxyivaleronitrile (8.5 g~, m.p. 134-136.
~xamples 43-45 The process of Example 42 was repeated, using the appropriate starting materials, to give the following compounds.

~NH
~,L o- (C~z~ 3--C C:~ H ~ ~le~t~

$~ ~

~xample R-43 CClF2C~-44 C~F~CF~Ch2-CF3Ch~-Notes ~xample 43 : m.p. 149~153 ~xample 44 : m.p. 161-162 ~yield 38~) ~xam~le 45 : IQ.p. 189-191 (yield 69~).
The starting materials for the above process may be prepared by repeating the second part of Example 42 using 3-cyanopropanol in place of 4-cyano-butanol and using, where appropriate, 2-rethylsulphinyl-4-[2-(2-chloro-2,2-difluoroethyl)guanidinojpyrimidine or 2-methylsulphinyl-4-12-(2,2,3,3-tetrafluoropropyl)-gua;lidinoJpyrimidine in place of 2-methylsulphinyl-4-L2-(2/2,2-trifluoroethyl)guanidino]pyrimidine. Tnese two pyrimidine derivat.ives may be preparec by repeating tne second, third and fourth parts of ~xample 34 in European patent puolication No.30092 using 2-chloro-2,2-~ifluoroethylisothiocyanate or 2,2,3,3-tetrafluoro-propylisothiocyanate respectively in place of 2,2,2-trifluoroethylisothiocyanate.
Example 46 A solution of 3-[4-(2-l2,2,2-trifluoroethylj-guanidino)pyrinlid-2-ylmethylthioJpropionitrile (850 mg.) in concentrated sulphuric acid (4 ml.) was kept at 20 for 16 hours then addea dropwise to saturated aqueous sodium carbonate. Tne mixture was extracted with EtOAc (3 x 20 mlO) and the extract driea ~MgS04) and evaporated in vacuo to give 3-[4-~2-12,2,2-trifluoroethyljguanidino)-pyrimid-2-ylmethylthioipropionamide as an oil. The maleic aciu salt was prepared in acetone (yield 72~ mg;
~0%), m.p. 168-169 (decomp.).
The starting material may be prepared as ~ollows:-2-Chloroacrylonitrile (3~ ml.) was a~ded in portions over 15 minutes to a solution of chloroacet-amidine hydrochloride (55 g.) an~ trietnylamine (120 ml.) in ~tOh (250 ml.) cooled to 10 . The temperature was allowed to rise to 40 over 1 hour. r~he mixture was coole~ and filtered and tne resulting solutiQn-evaporated in vacuo. The residue was taken up in EtOAc (600 ml.) from which a tar precipitated. The solution was treated with decolourising carbon, filterea and evaporated to give 4-amino-2-chloro~ethylpyrimidine as a ~rown solid.
The above pyrimi~ine ~1.4 g.) ancl thiourea (0.8 g.) in EtO~ (40 ml.) were neated under reflux for 20 minutes, a crystalline precipitate being formed. On cooling s-L4~aminopyriJnid-2-ylmethyl)isothiourea nyaro-chloride was isolated ~y filtration.
The above isothiourea (2 g.) was added to a solution of potassium hydroxide (1.1 g.) in water (20 ml.) and the solution stirred for 2 hours under nitrogen.
Acrylonitrile (1 ml.) was then added and the mixture vigorously stirred for 30 minutes. 'rhe solution was extracted with EtOAc, the extract driecl (~gS04) and evaporatecl in vacuo to give 3-14-aminopyrimid-2-ylmethyl-thioJpropionitrile as a gum which solidified on standing, m.p. 106-9.
To a solution of 3-(4-aminopyrimid-2-ylmethyl-thio)propionitrile (1.7 g.) in acetonitrile (40 ml.) was aaded 2,2,2-trifluoroethylisothiocyanate (2 ml.) ana the solution heatea under reflux for 17 hours. The acetonitrile was evaporated in vacuo ana the residue dissolved in LtOAc, treated with decolourising carbon, filterea and evaporated to give 3-[4-(3-[2,2,2-trifluoro-ethyl~thioureido)pyrimid-2-ylmethylthioipropionitrile as an orange solid, m.p. 108-110.

r 3 ~9~

The above thiourea (1 g.) in D~ (10 ml.) and 8M ammonia in XtOh (10 ml.) was treated with mercuric oxide (3 g.). The mixture was stirred for 40 minutes, diluted with EtOAc/water 1:1 v/v ~100 ml.) and filtered through diatomaceous earth. The rtOAc extract was dried (llgS04 ) and evaporated in vacuo to give 3-~4-(2-[2,2;2-- trifluoroethyliguanidino)pyrimid-2-ylmetnylthio~propio-nitrile as an oil, which was used without further purification.
Example 47 The process aescribed in Example 46 was repeated, using 4-[4-(2-[2,2,2-trifluoroethyl~yuanidino)-pyrimid-2-ylmethylthioibutyronitrile,to give 4-[4-(2-L2,2,2-trifluoroethyl~guanidino)pyrimid-2-ylmethylthioj-15 butyramidet m.p. 126-128 (yiela 45%).
The starting material may be prepared ~y repeating the fourth, fifth and sixth parts of Example 46 using 4-bromobutyronitrile in place of acrylonitrile.
Example 48 A solution of trans-6-[4-(2-i2,2,2-trifluoro-etnyl~guanidino~yyrimid-2-yl~llex-5-enenitrile (400 mg.) ir- concentrated sulphuric acid (2 ml.) was kept at 20 for 18 hours then added dropwise to saturated aqueous sodium carbonate. The mixture was extracted wit~. EtOAc 25 (2 x 15 ml.) and the extract dried (MgS04) and evaporated in vacuo to give trans-6-[4-(2-[2,2,2-trifluoroethyl~-guanidino)pyrimid-2-yl]hex-5-enamide as an oil. The maleic acid salt was prepared in acetor,e (yield 205 mg;
36%),m p. 177-179.
rl~he starting material may ~e prepared as follows:-To a solution of thiophenol (50 ml.) in 2.5M
aqueous so~ium hydroxiae (400 ml.) stirred under nitrogen at 20 was added chloroacetamidine hydrochloride (63 g.) in water (250 ml.). Tne precipitated solid was collected, pressed dry, suspenaed in EtOAc and the EtOAc evaporated.

The solid was resuspended in ~tOAc, a saturated solution of hydrochloric acid in EtOAc added and the mixture stirred for 30 minutes. Tne hydrochloride salt of phenylthio-acetamidine was collected, washed with ether and used directly.
Phenylthioacetamidine hydrochloride (10 g:), 2-chloroacrylonitrile (8.75 g.~ t triethylamine (27.5 ml.) and EtOH (75 ml.) were heated under reflu~ together for 4 hours. The solution was evaporated in vacuo and the residue partitioned between ~tOAc and lM aqueous hydrochloric acid. The aqueous extract was basified and extracted with EtOAc (3 x 100 ml.), dried (MgS04) and evaporated in vacuo to give a red oil containing 4-amino-2-phenylthiomethylpyrLmidine.
The crude 4-amino-2-phenylthiomethylpyrimidine (15 g.) in MeOh (150 ml.) and water (100 ~1.) at 60 was treated over 15 minutes with sodium metaperiodate (20 g.) in wa er (100 ml.). Tne MeOh was evaporated ln vacuo and the clear aqueous solution decanted from the red gum which precipitated. 4-Amino-2-phenylsul-phinylmethylpyrimidine crystallised from the aqueous solution as a white solid, m.p. 202-204. Recrystallisation rom ~tOH/ether gave an analytical sample, m.p. 207-208.
To a solution of po~assium t-butoxide (0.88 g.) in DMF (30 ml.) stirred at 0 under nitrogen was added 4-amino-2-phenylsulphinylmethylpyrimidine (1.84 g.).
~he solution was stirred for 10 minutes and 5-bromo-valeronitrile (1.3 g~) in DME (5 ml.) added over 5 3C ~inutes. The mixture was stirred for 30 minutes at 0, poured into water (150 ml.) and extracted with EtOAc (4 x lS ml.) and the extract dried (MgS04) and evaporated in vacuo to give a clear gum (1.7 g.). The gum was heated in toluene (40 ml.) at reflux for 30 minutes during which time it dissolved. The toluene was evaporated in vacuo and the residue partitioned between _ 55 ~

C~2C12 and lM aqueous nydrochloric acid. Tne aqueous layer was basifiea with 4M aqueous soaiun~ilydroxiae and extracted witn C~2Cl~ (3 x 15 ml.3, the extract dried (Mg504) ana evaporated in vacuo to give a clear gun, (~00 nlg.j. l'o this gum (900 mg.) in acetonitrile (20 ml.) was added 2,2,2-trifluoroethylisothiocyanate (~0~ mg.) and the solution neated under reflux for 19 hours. The acetonitrile was evaporated in vacuo ana trans-6-[4-(:~-12,2,2-trifluoroetnylitnioureido)pyrimi~
1~ ~-ylJnex-5-enenitrile was isola.ed from the mixture ~y meaiw,l pressure cnromatography on silica using ~tOAc/
cyclohexane 3:7 v/v as eluant.
The aDove thiourea (350 ug.) was dissolvea in DMF (8 r.l.) and 8M amn~onia in EtOX (4 ml.).
liercuric oxide (1 g.) was added and the mixture stirred for 40 n,inutes, then poured into water/~tOAc 1:1 (loo ml.) and tne resulting mixture filtered through diatomaceous eartn. Tne ~tOAc extract was driea (~iy~04) and evaporate~
in vacu to give trans-6-[4-(2-[2,2,2-trifluoroetnylj-guaniaino)pyrimid-2-ylihex-5-enenitrile as a gum which was used without further purification.
hxample 49 - ~lethyl 3-[2~(2-12,2,2-trifluoroethyljguanidino)-thiazol-4-ylmethylthioJpropiOnate (0.5 g.) in EtO~
(20 ml.) was treated with 33~ w/v etnanolic n,ethylamine (7 ml.) and stirred i-or 18 hours at room temperature.
Tne solution was evaporated and the residue crystallised fro!~ aqueous Et~h to give ii-lletnyl-3-l2-(2-[2,2,2-tri-fluoroèthylJguanidino)thiazol-4-ylmethylthiolpropionamiae 30 (0.35 g.), m.p. 152-154 (73%).
'l'ne starting material r;~ay ~e prepared as follows:-~ r,li~ture of 2-[2,2,2-trifluoroethyljguanidino-4-chloromethylthiazole hyarochloriue (4.6 g.) in ~tOh (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5 was tr~ated dropwise with aqueous sodium hydroxide 5G ~ 3~

(1.8 g. in 15 ml. of water) over 10 minutes. Tne resulting solution was allowea to reacn roorn temperature and was stirred for 1 hour~ It was tnen poured into water and tne precipitate filtered and crystallised from ~t~ to give meth~l 3-l2-(?-l2,2,2-trifluoroethylJ-suanidino)thiazol-4-ylmethylthio]pro~ionate (1.93 S) m p. Y6-9~
~ample 50 Tne process of Exarn~le 49 was repeated, using tne appropriate starting materials, to give 3-(2-12-(2,2,2-trifluoroethyl~guanidino~thiazol-4-yl)pro~ionic acid hydraziae, m.pO 125-126 (yield 69%).
~`xam~le 51 A mixture of methyl 5- L 2-(2-[2,2,2-trifluoro-ethyl~yuanidino)thiazol-4-yljvalerate (0.4 g.) and etnanolic r,ethylamine (33~ w/v, 60 Lll.) was allowed to stand at roolll ter.lperature for 2 days. Tne l"ixture was then evaporated to dryness and the residue recrystal-~;sed from ~tOAc/ether to give N-l.lethyl-5-l2-(2-~2,2,2-2~ trirluoroethyliguani~ino)thiazol-4-ylJvaleramide (yield 85~), ~.p. 122-1~6 Tne starting material may be prepared as follows:-To a solution of methyl 7-chloro-5-oxoheptan-oate (2.0 g.) in hot EtO-~ (20 ml.) was aaded a solution of 2,2,2-trifluoroethylamidinothiourea (2.1 g.) in hot EtOn (20 ml.). Tne resulting mixture was heated under reflux for 1 hour. The ~,ixture was then evaporated to dryness and the residue partitioned between ether (20 ~ll.) and water (60 ml.). The a4ueous layer was separate~ and basified witn souium bicarbonate and e~tracted witn EtOAc. The ~tOAc solution was evaporated to dryness and the residue crystallised from ~tOAc/
ether containing a small amount of acetone to give methyl 5-L2-(2-[2,2,2-trifluoroethyl~guaniQino)thiazol-4-ylJ-valerate whicn was used without further purification.

~L2~3~3.~ t Exanlple 52 The process of ~xample 51 was repeated, using the appropriate starting material, to give N-methyl 4-[2-(2-[2,2~2-trifluoroethyl~guanidino)thiazol-4~ylJ-butyramide. Requires C, 47.1%; h, 6.9%; N, 26.8%.
Found C, 47.0%; ~, 6~7%; N, ~6.8~.
The starting material may be prepared by repeating the second part of Example 51 using methyl 6-chloro-5-oxohexanoate in place of metnyl 7-chloro-6-oxoheptanoate to give methyl 4-[2-12-12,2,2-tri-fluoroethyliguanidino)thiazol-4-yl~butanoate.
~xample 53 A solution of methyl 3-~2-(2-L2,2,2-trifluoro-ethyliguanidino)thiazol-4-yl~cyclopentanecarboxylate ~0.25 g.) in ethanolic methylamine (33% w/v, 50 ml.) was allowed to stand at room temperature for 5 days.
Tne solution was then evaporated to dryness and the residue in acetone treated with maleic acid to give N-methyl-3-[2-(2-[2,2,2-trifluoroethyl~guanidino)tniazol-4-yl~cyclopentanecarboxamide hydrogen maleate (yield 63~),m.p. 156-15B.
The starting material may be prepared as follows:-A mixture of cyclopentane-1,3-dicar~oxylic acia mono methyl ester (18.6 g.) and thionyl chloride (30 ml.) was allowed to stand at room temperature for 3 hours. TAe mixture was then evaporated to dryness and the residue twice evaporated to dryness from a toluene solution. The residue was added to an excess of diazomethane solution in ether and the mixture allowed to stand at room temperature for 18 hours and then evaporated to dryness. The residue was dissolved in acetone (100 ml.) and concentrated hydro-cnloric acid was added slowly until evolution of nitrogen ceased. The resulting r,lixture was evaporated to low bulk and partitionea between ~tOAc and aqueous sodium bicar~onate. The EtOAc layer was separated, dried anà evaporatea to dryness to give methyl 3-12-- 53 ~ ~2~`3~

chloro-l-oxoethyl~cyclopentanecarboxylate as a brown oil (16 g.~.
A solution of this material (3.0 g.~ in EtOh (20 ml.) was added to a solution of 2,2,2-trifluoro-ethylamidinothiourea (2.8 g.) in EtO~ (20 ml.). Themixture was heated under reflux for 2 hours and then evaporated to dryness. The r~sidue was partitioned ~etween water ~40 ml.) and EtOAc (60 ml.). The aqueous layer was basified with sodium bicarbonate and the precipitate extracted into EtOAc. This was evaporated to dryness and the residue obtained purified by preparative thin layer chromatography using ChC13/
MeOH/aqueous ammonia (s.g. 0.880) 90:10:0.1 v/v/v as eluant. The appropriate band was isolated to give methyl 3-~2-(2-~2,2,2-trifluoroethyliguanidino)thiazol-4-yl~-cyclopentanecarboxylate (0.64 g.) as a g~l which was used without furthur purification.
hxample 54 A solution of crude methyl 3-L2-(2-[2,2,2-2~ trifluoroethylJguanidino)thiaZol-4-ylibenzoate hydro-chloride (1 g.) in ethanolic methylamine (33% w/v, 20 ml.) was allowed to stand at room temperature for 4 days~ The mixture was then evaporated to dryness and the residue triturated with water to give 0.16 g. of N-methyl-3-[2-(2-[2,2,2-trifluoroethyl~guanidino)~
thiazol-4-yl~benzamide (yield 20%). The n.~r.
spectrum in d6DMSO included the following resonances:-~.8 (d, 3~; 4.1 (m, 2H); 7.3 (s, lH); 7.0-8.4 ~complex, 7~)-The starting material may be prepared as follows:-A solution of 3-cyanophenacyl chloride (3.6 g.) in warm EtO~ (30 ml.) was added to a solution of 2,2,2-trifluoroethylamidinothiourea (4.0 g.) in EtOH (30 ml.).
The mixture was then heated under reflux for 1 hour and evaporated to low volume. On cooling this solution ~eposited 3-[2-(2-[2,2,2-trifluoroethyliguanidino)-thia~ol-4-ylJkenzonitrile hydxochloride (4~4 g.). The n.~,.r. in d6DMSO included the following resonanceS:-4.4 (m, 2H); 7.5-9~2 (complex, ~H).
The above material (4~3 g.) was heated under reflux in a mixture of ~OAC (30 ml.) and concentrated ayueous ~Cl (30 ml.) for 2 hours. The solution was then evaporated to dryness and the residue dissolved in MeOH (100 ml.). To this was added thionyl chloride (20 ml.) dropwise. The solution was then evaporated to dryness to give crude methyl 3-[2-(2-~2,2,2-tri-fluoroethyl~guanidino~thiazol-4-yl~benzoate hydro-chloride which was used without further purification.

A solution of 5-[3-(2-~2,2,2-trifluoroethyl~-guanidino)-1,2,4-triazol l-ylivaleronitrile (0.15 g.) in concentrated sulphuric acid (3 ml.) was stirred for 1.5 hours at room temperature then poured onto ice and basified with concentrated aqueous an~onia. Extraction with EtOAc gave 0.12 g. of a white solid which was triturated with ether to give 5-[3-(2-[2,2,2-trifluoro-ethyliguanidino)-1,2,4-tria~ol-1-yl~valeramide (0.085 g., 54%), m.p. 162-164 The starting material may be prepared as follows:-3-Amino-1,2,4-triazole (4.2 g.) was added to a solution of sodium methoxide in MeO~ ~1.2 g. sodium i~ 30 ml. MeO~) and the solution stirred for 0.5 hours at room temperature. 5-~romovaleronitrile (8.1 g.) was added and the solution heated under reflux for 12 hours. The solution was evaporated and the residue partitioned between water and EtOAc. The extracts were washed with brine, dried over M~S04 and evaporated to give a pale yellow oil (6.5 g.) which was purified by medium pressure liquid chromatography using EtOAc/MeOh 6:1 v/v as eluant. The colourless oil obtained was used without characterisation for the following reaction.

k ~ .f ;''~t _ 6~ -The crude 1--(4-cyanobutyl)-3-amino-1,2,4-triazole (5 45 g.) in acetonitrile (80 ml.) was treated with 2,2,2-trifluoroethylisothiocyanate [4.4 g.) and the solution heated under reflux for 3.5 hours. ~vaporation gave a white stic~y solid which was triturated with ether/E.tO~ to give 5-(3-L3-(2,2,2-trifluoroethyl)-thioureido~-1,2,4-triazol-1-yl)valeronitrile (~04 g.) as a wnite solid, m.p. 136-138.
This nitrile (3.6 g.~ in MeOn (80 ml.) and acetonitrile (5 ml.) was treated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.). After stirring for 1.5 hours the black suspension was filtered through diatomaceous earth and the filtrates evaporated to give a white solid. The solid was washed with ether and filtered to give 5-[3-(2-[2,2,2-trifluoroethyljguanidino~-1,2,4-triazol-1-yl3valeronitrile (2.87 gn) as a white solid, m.p. 200-201 ater recrystallisation from LtO~.
Example 56 A solution of 5-l4-(2- L 2,2,2-trifluoroethyl,-guanidino)-1,3,5-triazin-2-ylthio~valeronitrile (0.25 g.
in concentrated sulphuric acid (1 ml.) was kept at room tem~erature for 4 hours. The reaction mixture was ailuted with an equal volume of ice, basified with ayueous NaOH and then filtered to give a white solid. This solid was dissolved in a small volume of ~tOh and aceto~le and treated with a solution of maleic acid (0.09 g.) in a small volume of acetone. The mixture was left at room tem~erature overnight and then filtered to give 0.15 ~. of 5-~4-(2-[2,2,2 trifluoroethyl~guanidino)-1,3,5-triazin 2-yl~hio]valeramide maleate, m.p. 166-168 after recrystallisation from ~tOIlA
The starting material may ~e prepared as follows:-~ stirred mixture of 2-mercapto-4-amino-1,3,5-triazine (5.1 g.), 10% w/v aqueous NaO~ (16 ml.) and 5-bromovaleronitrile was kept at room temperature for - 61 - , 3 nours~ Tne mL~ture was filtered to separate a first crop or ~rodurt. The filtrate was kept at room temperature overniyht and refiltered to yield another crop of product.
These crops were washed with ether and recrystallised from LtO~ to give 6.7 g. of 5 (4-amino-1,3,5-triazin-2-ylthio~valeronitrile, m.p. 123-125.
A stirred mixture of 5-(4-amino-1,3,5-triazin-2-ylth`io)valeronitrile (0.9 g.) and THF (30 ml.) was kept under argon at -60 and treated with a solution of n-butyllithium in hexane (1.6M; 3.1 ml.). The mixture was stirred at -60 for 30 minutes and then treated with 2,2,2-trifluoroetnylisothiocyanate (007 g.). The mixture was allowe~ to warm to room tempexature and stirred overniyht. The mixture was ~cured into water and acidified with a sMall volu~e of concentrated hydrochloric acid.
The aqueous and organic phases were separated. The aqueous phase was extracted with EtOAc and the extract was coMLined with the organic phase frolll the reaction mixtur~. The combination was dried (My~04) and evaporated to give a sticky solid that was triturated with petrole~
etner (b.p. 40-60 ) and EtOAc and filtered to give 1.0 g.
of 5-[4-(3-~2,2,2-trifluoroethylithioureido)-1,3,5-triazin-2-ylthio~valeronitrile, m.pO 136-137 after recrystallisation from EtOh.
~ stirred suspension of 5-[4-(3-[2,2,2-tri-fluoroethylithioureido~-1,3,5-triazin-2-ylthiO~valero-nitrile (2.~ g.) i~ ammoniacal ~tO~ (6M; 40 ml.) was treated at room temperature with mercuric oxide (2.0 g.).
After about 1 hour the mi~;ture was diluted with Dr~ (20 ml.).
The mixture was kept at room temperature overnight, filtered, and evaporated. The non-volatile residue was dissolve~ i~ Dl~F (40 ml.) and a~loniacal ~tO~ (6M; 20 ml.) ana treatea at room temperature with l,lerCUriC oxide (1 g.). The mixture was stirred for 4 hours and then filtered. The filtrate was evaporated to dryness, In redissolVed~LtOH and saturated ~;ith h2S gas. Tne mixture was filtered/ evaporated to dryness, redissolved in EtOAc (15 ml.), refiltered, treated with ,r r~
~ 62 a solution of maleic acid (0.66 g.) in a small volume of acetone, and then diluted with petroleum ether ~b.p.
60-80 ) to giYe a solution from which the product gradually precipitated. The precipitate was filtered, washed with a small volume of cold acetone and then with ~etroleum ~ther (b.p. 6~-80) to give 1.6 9. of 5-~4-~2-L2,2,2-trifluoroethyliguanidino)-1,3,5-triazin-2-ylthio3valeronitrile maleate, m.p. 155-156 after recrystallisation from EtO~.
Exa~ple 57 o a solution of 4-(2~[3-(2~[2,2,2-trifluoro-ethyl] guanidir.o~ pyrazol-l-yl] ethoxymethyl~ber.zs~ e ~650 mg.~ in MeO~ C5 ml.l was ~dded hydrogen peroxide (30%, 100 volume~ ~2 ~1.~ followed by N aqueous NaO~
~1 ml.). The mixture was then stirred at room te~lperature for 2.25 hours. The sol~ent was then evaporated in acuo to give a yellow gum C700 mg.). This gum was purified by medium pressure chrQmatography using EtOAc/
EtOH~triethylamlne 96;3;1 v/Y~Y as eluant to give 4-(2-[3-(2-[2,2,2-trifluoroethyl~uanidino~pyrazol-1-yljethoxymethyl)benzamide (210 mg.; 31~ having the following n.m.r. in d6DMSO:- 7.5 ~m, 4~); 7.5 (d, lH);
5.8 (d, lH); 5.0 (s, 2H); 4.0 (m, 4H); 3.7 (m, 2H).
The starting mat~rial may be prepared as follows:-2-~ydroxyethylhyarazine (7.6 g.) was added slowly to a solution of potassium carbonate (13.8 g.) in water (40 ml.). The mixture was cooled to 0, then 2-chloroacrylonitrile (8.75 g.) was added slowly with ~igorous stirring. ~tirring was continued for a furtner 17 hours and the mixture was then continuously extracted witn ~tOAc for 20 hours. On evaporation of the solvent, 3-amino-1-(2-hydroxyethyl)pyrazole ~as obtainea, (7.7 g.; 60~), b.p. 170/0.5mm.
A solution of 2,2,2-trifluoroethylisothio-cyanate (13.8 g.) and 3-amino-1-(2-hydroxyethyl)pyrazole 3~
-- 63 - , (12.5 g.) in acetonitrile dried over 4A molecular sieve (30 ml.) was stirred at room temperature for 4 hours.
A preci~itate formed after 30 minutes. Filtration gave 1 (2-hydroxyethyl)-3-13-(2,2,2-trifluoroethyl3thio-ureidoipyrazole (12.1 g.; 46~), m.p. 145-146.
To a solution of 1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido~pyrazolP ~20.0 g.~ in 5~
ammonia in ~tOH solution (700 ~.1.) was added yellow mercuric oxide (64.8 g.) with stirring. Stirring was continued for a period of 2 hours. The mixture was filtered through diat~maceous earth and the solvent then evaporated to dryness in vacuo. The residual oil was triturated with ether to give l-(2-hydroxyethyl)-3-E2-(2,2,2-trifluoroetllyl)guanidino~pyrazole (18.5 g.;
99%), m.p. 82 .
~ r.lixture of 1-(2-hydroxyethyl)-3-12-(2,2,2-trifluoroethyl)guanidino~pyrazole (2.51 g.) and p-cyanobenzyl bromide (1.96 g.) was heated at 140 for 10 minutes. The melt, on cooling, was dissolved in MeO~ (5 ml.~ and purified ~y chro~atography on silica gel using EtOAc/~tOH/triethylamine 9:1:1 v/v/v as eluant to give 4-~2-[3-~2-~2,2,2-trifluoroethyl]guanidino)pyrazol-l-yl]ethoxymethyl)benzonitrile (700 mg.~ 19%).
25 Exam~le 58 To a solution of 4-(3-13-(2,2,2-trifluoro-ethyl)thioureidoipyrazol-l-ylmethyl)benzamide (180 mg.) in EtO~ saturated with ammonia (5 ml.) was added yellow m~rcuric oxiàe (380 mg.). The mixture was stirred at room temperature for 17 hours. The mixture was centrifuged, then the supernatant liquor was evaporated ln vacuo to give 4-[3-(2-[2,2,2-trifluoroethyl~guanidino)-pyrazol-l-ylmethyl~benzamide, m.p. 192 (from ~tO~I/
petroleum ether (D.p. 60-80) ) .
The starting material may be prepared as follows:-- 64 ~ 2 Sodium hydride paste (61% w/w dispersiGn in oil, 70 mg.) was added to a solution of 3-nitropyrazole ~200 mg.~ in dry DMF (2.5 ml.) with stirring. When effervescence had ceased, 4-chloromethylbenzamide (300 mg.) was added. The mixture was stirred at room temperature for 2 days, then diluted with water (20'ml.).
The precipitated 4-[3-nitropyrazol-1-ylmethyl~benzamide ~300 mg.),m.p. 200-201, was collected by filtration.
A solution of the above nitro amide (100 mg.) in dry DMF was hydrogenated at room temperature and at atmospheric pressure using 5% w/w palladium on carbon (10 mg.) as catalyst. Filtration and subsequent evaporation in vacuo of the filtrate gave 4-[3-amino-pyrazol-l-ylmethyl]benzamide.
A mixture of the above amine (250 mg.) and 2,2,2-trifluoroethylisothiocyanate (0.16 g.) in aceto-nitrile (1 ml.) was stirred at room temperature for 3 hours. The precipitated solid was filtered off to give 4-(3-[3-(2,2,2-trifluoroethyl)thioureidolpyrazol-l-ylmethyl)benzamide (180 mg.), m.p. 205-206.
Example 59 A solution of 4-[6-(~-[2,2,2-trifluoroethyl~-guanidino)pyrid-2-ylthioibutyric acid (84 mg.) and triethylamine (0.2 ml.) in DMF (5 ml.) was stirred at 0 while isobutylchloroformate (68 mg) was added. The solution was kept at 0 for 0.5 hours, treated with a saturated solution of ammonia in EtO~ (1 ml.) and then stirrea at room temperature for 18 hours. The solution was èvaporated to dryness and the residue partitioned between N aqueous ~Cl and EtOAc. The aqueous phase was basifiea with lON aqueous NaO~ and extracted with EtOAc, and the extract was aried and e~aporated to dryness to give 4-[6-(2-[2,2,2-trifluoroethyl~guanidino)pyrid-2-ylthio~butyramide (60 mg.) which was crystallised as the hydrogen maleate salt from acetone, m.p. 138-141.
The startins material r~ay be prepared as follows:

3. .~ ~ ~a - 65 _ ~ mixture of 4-mercaptobutyric acid (0.72 g.) a 50% w/w dispersion of sodium hydride in mineral oil (o.58 g.) and 2-ethoxyethanol (5 ml.) was treated with 2-amino-6-bromopyridine (0.35 g.) and the mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between water'and EtOAc and the aqueous phase was neutralised with HOAc.
The precipitated yellow solid was collected to give 4-~6-aminopyrid-2-ylthio)butyric acid (0.27 g.) which was used witnout further purification.
A mixture of 4-(6-aminopyrid-2-ylthio~butyric acid (0.21 g.), DMF (3 ml.) and 2,2,2-trifluoroethyl-isothiocyanate (0.15 g.) was left at room temperature for 18 hours and then evaporated to dryness. A solution of the residue in methanolic ammonia was treated with yellow mercuric oxide (0.43 g.) and the mixture stirred at room temperature for 1 hour. The mixture was filtered and the filtrate evaporated to dryness and the residue treated with 2N aqueous NaOH (5 ml.) and then filtered.
The filtrate was acidified with HOAc and the precipitate collected to give 9-[6-(2-[2,2,2-trifluoroethyl~guanidino)-pyrid-2-ylthio~butyric acid (0.17 g.) which was used without further purification.
~xample 60 The process of Example 59 was repeated,using the appropriate starting material, to give 5-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio~valer-amide maleate, m~p. 138-139 (yield 69~).
The starting material may be prepared by repeating the second and third parts of Example 59 using 5-mercaptovaleric acid in place of 4-mercaptobutyric acid to give 5-l6-(2-[2,2,2-trifluoroethyl~guanidino~-pyrid-2-ylthio~valeric acid.
Example 61 A solution of 4-[6-(2-[2,2,2-trifluoroethyl]-guanidino)pyrid-2-yloxy~butyronitrile (0.2 g.) in 6~

concentrated sulpnuric acid was kept at room temperature for 6 hours and then diluted with water and basified with lOI~ a~ueous NaO~. The solution was extracted three t~aes with EtOAc, and the combined extracts dried and evaporated to dryness. A solution of the residue in acetone was added to a solution of maleic acid in acetone, and the crystalline precipitate was collected to give 4-16-(2-12,2,2-trifluoroethyliguanidino)pyrid-2-yloxyJbutyramiae hydrogen maleate (0.14 g.~, m.p.

The nitriie used as starting material may be prepared as follows:-A ~ixture of 4-hydroxybutyronitrile (0.85 g.), a 50% w/w dispersion of sodium hydriae in mineral oil (0.48 g.) and sulpholane (5 ml.) was stirred at room temperature for 1 hour. The mixture was treated with 2-amino-6-bromopyridine (0.87 g~) and the mixture heated with stirring at 130 for 18 hours. The cooled mixture was diluted with water (20 ml.), acidified with concentrated a~ueous ~Cl and washed with ether. The aqueous phase was basified with lOI~ aqueous NaO~, extracted three tir~s with EtOAc and the combined extracts dried and evaporated to dryness.
A solution of the residue in acetonitrile (5 ml.) was treated with 2,2,2-trifluoroetnylisothio-cyanate, and the solution heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred w,th 2N aqueous hCl (20 ml.) and ether (20 ml.) and the insoluble n;aterial collected.
'~'he solid was aissolved in methanolic ammonia solution, and the solutiorl treated with yellow mercuric oxide (2 g.) and then stirred at rooll, temperature for 18 hours. The mixture was filtered and the filtrate evaporated to dryness to give 4-[6-~2-[2,2,2-trifluoro-ethyl~guanidino)pyrid-2-yloxy~utyrorlitrile (1.0 g.) which was used without further purification.

~am~le_62 In a similar manner to the process described in Example 61, using 4-~2-(2-12,2,3,3-tetrafluoropropyl~-guanidino)pyrid-6-ylthio~butyronitrile as starting material, there was obtained 4~12-(2-[2,2,3,3 tetra-fluoropropyl~guanidino)pyrid-6-ylthio~butyramide maleate, m p. 173-174 (yield 58~).
The above nitrile may be prepared in an analogous manner to the butyric acid described in Example 59, using 4-mercaptobutyronitrile in place OI 4-mercapto-butyric acid and 2,2,3,3-tetrafluoropropylisothio-cyanate in place of 2,2,2-trifluoroethylisothiocyanate.
Example 63 A mixture of 5-(3-aminop~-razol-1-yl~valeramide (1~.2 mg.) and ~2,2,2-trifluoroethyl)-S-methylisothiourea hydroiodide (51 mg.) was heated at 100 for 20 minutes. Preparative high pressure liquid chromatography on silica gel, ucing CHC13/MeOH/ammonia ~s.g. 0.880) 8:2:0.5 v/v/v as eluant gave 5-~3-(2-[2,2,2-i-rifluoroethyliguanidino)pyrazol-l-yl~valeramide~ m.p.
129-130 (40~).
The isothiourea used as startinq material may be prepared as follows:-A solution of ammonium thiocyanate (9.12 g.), and 2,2,2-trifluoroethylamine hydrochloride (13.6 g.) in water (50 ml.) was heated at 100 for 20 hours. I~ater (50 ml.) was added and the mixture reheated to redissolve the solid. On cooling crystals of 2,2,2-trifluoro-ethylthio~rea hydrate, m.p. 154-156 (52.4~),were precipitated.
A solution of 2,2,2-trifluoroethylthiourea (8.0 g.) and methyl iodide (3.5 g.) in ~tOH (40 ml.) was heated under refl~ for 70 minutes, then evaporated to dryness in vacuo. The residue was triturated with ether to give 2,2,2-trifluoroethyl-S-methylisothiourea hydro-iodide,m.p. 154-156 (90%).

E~ Ele 64 A tablet containing 50 mg. of 5-[3-(2-~2,2,3,3-tetrafluoropropyl~guanidino)pyrazol-l-yl~valeramide may be prepared using ingredients in the following proportions:-(a) Tablet Core. mg./tablet Active agent 50 Lactose 218.5 Calcium carb~xymethylcellulose 22.5 Polyvinylpyrrolidcne 6.0 Magnesium stearate 3.0 (b) Tablet Coat mg.~tablet Hydro~ypropylmethylcellulose 4.5 Polyethylene glycol 0.9 Titanium dioxide 1.35 The active agentr lactose and calcium carboxy-methylcellulose are mixed. An aqueous solution of poly-vinylpyrrolidone is added, and the mass is then mixed until it is suitable for granulation. The ~ass is then granulated and dried. The magnesium stearate is blended 2C~ with the dried granules and the resulting mixture is compressed into tablets. The tablets are film-coated using an aqueous or solvent suspension of hydroxypropyl-methylcellulose, polyethylene glycol and titanium dioxide.

Claims (2)

1. A process for the manufacture of a heterocyclic derivative of formula V:

V

in which R1 and R2, which may be the same or different, are hydrogen atoms or branched or unbranched 1-10C alkyl, 3-8C
cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl, cycloalkyl or cycloalkylalkyl radical being optionally substituted by one or more halogen atoms selected from fluorine, chlorine and bromine atoms, provided that at least one of R1 and R2 is a halogen-substituted alkyl, halogen-substituted cycloalkyl or halogen-substituted cycloalkylalkyl radical and provided there is no halogen-substituent on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radical which is directly attached to the nitrogen atom, or -R2 is a hydrogen atom and -R1 is a radical of the formula 11:-in which W is an unbranched 2-6C alkylene chain which is optionally substituted by one or two 1-4C alkyl radicals, E
is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical, or a radical of the formula NR6 in which R6 is a hydrogen atom or a 1-6C alkyl radical, R5 is a hydrogen atom or an unbranched 1-6C alkyl radical which is option-ally substituted by one or two 1-4C alkyl radicals, or R5 and R6 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring;

in ring X the dotted line is a double bond on one side of the nitrogen atom N and Z is a carbon or nitrogen atom such that ring X is a 5- or 6- membered aromatic heterocyclic ring which contains at least one nitrogen atom and may optionally contain one or two additional hetero atoms selected from oxygen, nitrogen and sulphur atoms, which heterocyclic ring may, where possible, carry one or two optional substituents, the optional substituents on ring X
being selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, trifluoromethyl, hydroxy and amino radicals;
A is a phenylene or 5-7C cycloalkylene radical or a 1-8C
alkylene chain which is optionally substituted by one or two 1-3C alkyl radicals and into which is optionally inserted, as part of the backbone of the chain, one or two groups selected from oxygen and sulphur atoms and NH, 1-6C
N-alkyl, cis and trans vinylene, ethynylene, phenylene and 5-7C cycloalkylene radicals, provided that the shortest link between ring X and CN is of at least 3 atoms, pro-vided that when an optional insertion is made in chain A
which results in the inserted group being directly attached to CN the inserted group is other than an oxygen or sulphur atom or an NH or N-alkyl radical, and provided that no two insertions selected from oxygen and sulphur atoms and NH and N-alkyl radicals are directly attached one to the other, which comprises:
(a) for those compounds in which ring X is a thiazole ring and A contains no inserted group or the inserted group is phenylene , reaction of a compound of formula XIII:

XIII

With a compound of formula (G):

(G) in which Hal is a chlorine or bromine atom and R8 is a hydrogen atom or the optional substituent on the thiazole ring; and (b) for those compounds in which R2 is H, reaction of a compound of the formula (H):

(H) with an isothiocyanate of the formula R1-N=C=S, followed by treatment of the resulting thiourea (J) (J) with ammonia in the presence of mercuric oxide.

2. A compound of the formula V:- V

in which R1, R2, A and ring X are as defined in Claim 1, whenever produced by the process of Claim 1.