This invention relates to new therapeutically useful thioforma ide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

The thioformamide derivatives of the present invention are those compounds of formula (I), hereinafter depicted wherein:- R represents an alkyl group;

A represents a phenyl group which is optionally substituted, by one or more substituentε selected from, for example, halogen atoms and cyano, nitro, trifluoromethyl, carbamoyl, carboxyl, alkoxycarbonyl and alkylsulphonyl groups or, preferably, a heterocyclyl group, preferably selected from quinolin-3-yl, isoquinolin-4-yl, pyridazin-4-yl, pyrimidin-5-yl, pyraeiή-3-yl, indol-3-yl, thiazol-5-yl, and, more especially, pyridyl, e.g. pyrid-3-yl or pyrid-4-yl, optionally substituted by an alkyl or alkoxy group, or by a halogen atom; Y represents a direct bond or an ethylene or, preferably, ethylen group; and either:

1 2

(1) R represents hydrogen and R represents: 1) a group of formula -CXNHR , wherein R ³ is an alkyl group and X is a group of formula ^NSO-R ,

4 wherein R is alkyl or phenyl; or

ii) a group of formula -S0 ₂ , wherein R represents;- a) a naphthyl or phenyl group optionally substituted by one or more halogen atoms, hydroxy, alkoxy, C- g cycloalkoxy, alkyl, C.. ₄ alkenyl, cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, alkanoyla ino, dialkanoyla ino, benzoylamino, carbamoyl, N-(optionally hydroxyalkyl)carbamoyl or N,N-di(optionally hydroxyalkyl)carbamoyl groups, or amino or carbamoyl groups N,N-disubstituted by a C, ₆ alkylene chain one or more of whose methylene groups may have been replaced by an oxygen or sulphur atom or by an imino or alkylimino group; b) a pyridyl or thienyl group; or c) an alkyl group optionally substituted by one or more halogen atoms, phenyl, naphthyl, pyridyl, hydroxy, alkoxy, c ₃ _ ₆ cycloalkoxy, alkyl, C _2-4 alkenyl, cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino-, dialkylamino, alkoxycarbonylamino, alkanoylamino, dialkanoylamino, benzoylamino, carbamoyl, N-(optionally hydroxyalkyl)- carbamoyl or N,N-d (optionally hydroxyalkyl)carbamoyl groups, or amino or carbamoyl groups N,N-disubstituted by a C ₃ _ ₆ alkylene chain, one or more of whose

methylene groups may have been replaced by an oxygen or sulphur atom or an i ino or alkylimino group;

1 2

(2) R and R both independently represent a group of formula -S0~R , as defined above; or

1 2

(3) R and R' together with the nitrogen to which they are attached from a group of formula (IA) q wherein each group R is independently hydrogen or alkyl and Q is oxygen, sulphur or a group of formula o e R or (CR,) , wherein n is 0, 1 or 2/ wherein all alkyl groups and moieties, including those in alkoxy, alkoxycarbonyl and lkanoyl groups, are straight-chain or branched, and, unless otherwise specified, contain one to about six carbon atoms; and salts thereof.

Particularly important classes of compounds of formula (I) exhibit one of more of the following features: i) R represents a methyl or ethyl group; ii) A represents a pyrid-3-yl or pyrid-4~yl group; lii) V represents a methylene group; iv) ^ represents a hydrogen a'.om; v) R represents a methyl group; vi) R represents a methyl or phenyl group; vii) R ⁵ represents:

a) a phenyl or naphthyl (especially 1-naphthyl) group optionally substituted by one or more halogen (especially fluorine or chlorine) atoms or nitro, cyano, alkoxy (especially ethoxy) or dialkylamino (especially dimethyla ino) groups; b) a pyrid-3-yl or thien-2-yl group; or c) an alkyl group of up to 4 carbon atoms; and/or viii) the group of formula (IA) is a 3,5-dioxo- orpholino group; the other symbols being as hereinbefore defined, and their pharmaceutically acceptable salts.

The presence of an exocyclic a inoethyl group on the ring creates an iso eric centre in the molecule which in association with the adjacent asymmetric ring carbon atom leads to 4 stereoisomers which, optionally, can be separated into 2 raccmic pairs. The raeemic pair and enantiomers in which the -(CH ₂ ) ₂ NR ^l R ² and -CSNHR groups are in the trans relationship are preferred. In certain cases the substituents A, R, R ¹

5 and R can also contribute to stereoisomeris . All such forms are embraced by the present invention.

Particularly important, compounds of the present invention include the following:* 1H (±)-trans-2- ⁽ N-mcthyl-N'-benzencsulphonylimino- ureido)ethyl-N-methyl-l-(3-pyridyl)cyclohexane

carbothioamide II ( )-trans-2-(N-methyl-N'-methanesulphonylimino- υreido)ethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide 1J (i)-trans-2-benzenesulphonylaminoethyl-N-methyl-

1-(3-pyridyl)cyclohexane carbothioamide IK i t )-trans-2-methanesulphonylarainoethyl-N-methyl- (3-pyridyl)cyclohexane carbothioamide 1 )-trans-2-( - luorobenzenesulphonyl)amino- ethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide 1M (±)-trans-2-( -nitroben2enesulphonyl)amino- ethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide IN (±)-trans-2-(4-chlorobcnzcnesulphonyl)amino- etbyl-N-methyl-l-(3-ρyridyl)cyclohexane carbothioamide 10 (±)-trans-2-(4- ethoxybenzenesulphonyl)amino- ethy1-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide IP (±)-trans-2-(2-thiophenesulphonylJaminoothyl-

N-methyl-1-(3-pyridyl)cyclohexano carbothioamide 10 (±)-trans-2-(3-pyridinesulphonyl)aminoethyl-N- methyl-1-(3-pyridyl)cyclohexane ca bothioamide

R (4)-trans-2-(3,4-difluorobenzenesulphonyl)amino- ethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide IS (±)-trans-2-(5-dimethylamino-1-naphthalene- sulphonyl)aminoethyl-N-methyl-l-(3-pyridyl)- cyclohexane carbothioamide IT (±)-trans-2-(3 ,5-dioxomorpholino)ethyl-N- methyl-1-(3-pyridyl)cyclohexane carbothioamide

2A (±)-trans-2-(propylsulphonyl)aminoethyl-N- methyl-l-(3-pyr dyl)cyclohexane carbothioamide 2B it )-trans-2-(isopropylsu3phonyl)aminoetbyl-N- methyl-1-(3-pyridyl)cyclohexane carbothioamide 2C (4)-trans-2-(butylεulphonyl)aminoethyl-N- methyl-1-(3-pyridyl)cyclohexane carbothioamide 2D (±)-trans-2-(2-fluorobcnzenesulphonyl)amino- ethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide 2E (±)-trans-2-(3-cyanobenzenesulphonyl) minoethyl-

N-methyl-l-(3-pyridyl)cyclohexane carbothioamide 2F (±)-trans-2-(bcnzenosulphonyl)aminoethyl-N- ethyl-l-(3-pyridyl)cyclohexane carbothioamide G (4)-trans-2-(isopropylsulphonyl)aminoethyl-N- ethyl-l-(3-pyridyl)cyclohexane carbothioamide

H (±)-trans-2-( -fluorobenzenesulphonyl)amino- ethyl-N-ethyl-l-(3-pyridyl)cyclohexane carbothioamide 1 (t)-trans-2-(3-pyridinesulphonylaminoethyl-N- ethyl-1-(3-pyridyl)cyclohexane carbothioamide 2J (-)-trans-2-(3-pyridinesulphonyl)aminoethyl-N- methyl-1-(3-ρyridyl)cyclohexane carbothioamide 2K (-)-trans-2-( - luorobenzenesulphonyl)amino- e hyl-N-methy1-1-(3-pyridyl)cyclohexane carbothioamide 2L (-)-trans-2-(isopropylsulphonyl)aminoethyl-N- methyl-1-(3-pyridyl)cyclohexane carbothioamide 2M ( )-trans-2-(isopropylsulphonyl) minoethyl-N- ethy1-1-(4-pyridyl)eyelohexane carbothioamide as well as their stereoisomeric forms and pharmaceutically acceptable salts thereof.

Letters IK to IT and 2A to 2M are allocated to compounds for ease of reference in other parts of the specification.

Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by tests which are believed to correlate to pharmacological activity in humans and other animals.

For example, the compounds have valuable pharmacological properties, in particular properties

which are indicative of utility in the treatment and/or prophylaxis of disorders associated with:-

(1) vascular smooth muscle contraction including hypertension and other cardiovascular disorders such as congestive heart failure, and conditions associated with tissue ischacmia such as angina, peripheral vascular disease and cerebrovascular disease;

(2) respiratory smooth muscle contraction including reversible airways obstruction and asthma;

(3) contraction of smooth muscle of gastro¬ intestinal tract, urinary bladder and uterus, including peptic ulcers, irritable bowel syndrome and diverticular disease; irritable bladder syndrome; and premature labour.

For example, compounds of general formula (I) were submitted to:- Vaso-relaxant Activity Tests.

The test methods used were adapted from those described by Winslow et al [Eur.J.Pharmacol. , 131, 219-228 (1986)] and Karaki [J.Pharmacol. Methods, 18^ 1-21 (1987)] for differentiating vaso-relaxan activity.

Test A: Activity against contractions Induced by low K concentrations in the isolated rat aorta Thoracic aorta was removed from rats and transverse strips, denuded of endothelium, were suspended in a bath containing Krebs solution. The tension was recorded and a contraction induced by addition of 20mM K ⁴ (potassium ion) to the bathing solution. The test compound was added to the bath as a solution in increasing cumulative concentration. The concentration in the bathing solution of the test compound which reduced the K ⁺ -induced contraction by 90% was determined and expressed in μM as the effective concentration (EC ₉₀ ), given in Table 1.

Table 1

Test B: Activity against contractions induced by high K* concentrations in Isolated rat aorta

The test method was as in Test A with the exception that contractions were induced by addition of 60mM K ⁺ to the bathing solution. The cumulative addition of the solutions of the test compound was conducted and the concentration in the bath reducing the K -induced contraction by 90% was found and expressed as the EC _9Q . For each compound tested it was greater than 3 μM.

The compounds of general formula (1) can be prepared by the application and adaptation of known methods, for example as hereinafter identified.

By the term "known methods" as used in this specification is meant methods heretofore used or described in the literature.

According to a feature of the present invention, compounds of formula (I), wherein is hydrogen and R ² is a group of formula -C(*NS0 ₂ R )NHR , as hereinbefore defined, are prepared by the reaction of compounds of formula (V), hereinafter depicted, wherein R, Y, A and R are as hereinbefore defined, with a compound of general formula:-

R ³ NH. (VI)

3 wherein R is as hereinbefore defined. The reaction is carried out in a inert organic solvent e.g. ethanol at a temperature of from 0 ^# C to 80 C, preferably at reflux.

According to a further feature of the invention compounds of formula (I), wherein R, A and Y are as

1 2 hereinbefore defined and one or both of R and R represents a group -SO ₅ 1 as hereinbefore defined, are βynthesiβed from compounds of formula (I) wherein one

1 2 of R and R is hydrogen, or from a compound of formula

(II),. wherein Y, A and R are as hereinbefore defined, by reaction with a compound of formula:

R ⁵ S0 ₂ C1 (VIII) wherein R is as hereinbefore defined, in the presence of an anhydrous inert organic solvent e.g. dichloro ethane or tetrahydrofuran. The reaction is effected, optionally in the presence of an acid acceptor, for example a tertiary a ine, e.g. triethyla ine, or an inorganic base, e.g. sodium bicarbonate, at a temperature of from -30 ^# C to +30 ^# C

According to a further feature of the invention,

1 2 compounds of formula (I), wherein *nd form part of a ring of formula (IA) and R, A and Y are as hereinbefore defined, are synthesised from compounds of formula (II), wherein Y, A and R are as hereinbefore defined, by reaction with a compound of formula (IX)

wherein Q and R are as hereinbefore defined. The reaction is preferentially carried out in an inert organic solvent e.g. toluene, at reflux, in the presence of 1,2-dichlorobenzene to aid solubility.

The intermediate compounds and the starting materials may be prepared by the application or adaptation of known methods, for example as indicated in the following Examples and Reference Examples.

For example, compounds of formula (V) can be synthesised from compounds of formula (II), hereinafter depicted, wherein Y, A and R are as hereinbefore defined, by reaction with a compound of formula:

(CH ₃ S) ₂ C«NS0 ₂ R ⁴ (VII) wherein R is as hereinbefore defined. The reaction is carried out in a inert organic solvent e.g. ethanol at a temperature of from 0 ^# C to 80 ^β C

Compounds of formula (II), wherein A, Y and R are as hereinbefore defined, can be prepared from the corresponding compounds of formula (X), hereinafter depicted, wherein A, Y and R are as hereinbefore defined, by reduction with a complex metal reducing agent, such as an aluminium hydride (e.g. lithium aluminium hydride) in a dry organic solvent, such as an ether (e.g. tetrahydrofuran) at elevated temperature, preferably from 40 to 80 ^β C.

Compounds of formula (X), wherein A, Y and R are as hereinbefore defined, may be prepared by the reduction of the corresponding compounds of general formula (XI), with a complex metal reducing agent, such as an aluminium hydride (e.g. lithium aluminium hydride) in a dry inert organic solvent, such as an ether (e.g. tetrahydrofuran) at room temperature.

This reaction preferentially gives the reduced product (X) in which the -CSNHR group bears a trans relationship to the -Cϊ? ₂ CN group.

The compounds of formula (XI), wherein Y, A and R are as hereinbefore defined, may be prepared by the reaction of a compound of general formula (XII), hereinafter depicted, wherein A, Y and R are as hereinbefore defined, with a compound of general formula:

(R ⁶ 0) ₂ P(O)CH ₂ CN (XIII) wherein R represents an alkyl group of 1 to 4 carbon atoms, preferably a methyl or ethyl group. The reaction is generally carried out in the presence of a base, preferably sodium hydride, in an ethereal solvent (e.g. tetrahydrofuran) and preferably at a temperature of from 20 ^» C to 100 ^# C.

Compounds of general formula (XII), wherein A, Y and R are as hereinbefore defined may be prepared by the reaction of a compound of general formula (XIV) ,

hereinafter depicted, wherein A and Y are as hereinbefore defined, with a compound.of the general formula:

R-N=C*S (XV) wherein R is as hereinbefore defined. The reaction is generally carried out in an anhydrous inert organic solvent such as tetrahydrofuran, dimethylforma ide or hexa ethylphosphoramide, or a mixture of these solvents, at a temperature from -80°C to +S0'C, in the presence of an inorganic base such as potassium tert.-butoxide, or an organo-lithium derivative such as n-butyllithium, or of sodium hydride.

Compounds of formula (XIV), wherein A is as hereinbefore defined and Y is a methylene or ethylene group, can be made via a dehydrobromination/rearrange- mcnt reaction of compounds of formula (XVIII), hereinafter depicted, wherein A is as defined above and Y ¹ is methylene or ethylene. This may be initiated by a bromide extracting agent such as a silver salt (e.g. silver pcrchlorate) and carried out in an inert anhydrous solvent (for example an ether such as tetrahydrofuran).

Compounds of formula (XVIII), wherein A and Y ¹ are as defined above, can be made by the addition of hypobromous acid across the double bond of compounds of formula (XIX), hereinafter depicted, wherein A and Y ¹

are as defined above. This may be done by reaction with a brominating agent (e.g. l,3-dibromo-5,5- dim thylhydantoin) in an aqueous acidic medium, optionally in the presence of a cosolvent.

Compounds of formula (XIX), wherein A and Y are as defined above, can be made via a coupling reaction between a compound of formula (XX), hereinafter depicted, (typically made in situ by the reaction of a compound of formula (XXI), hereinafter depicted,

1 β wherein is as defined above and R and Z are conventional groups present in a Wittig reagent and its phosphonium salt precursor [e.g. phenyl and bromine respectively] with a strong base, such as potassium t-butoxide, in an anhydrous solvent, such as tetrahydrofuran, preferably under an inert atmosphere) and a compound of formula:

A - CHO (XXII) wherein A is as defined above.

Alternatively, compounds of formula (XIV), wherein A and Y are as hereinbefore defined, can be made from compounds of formula (XXIII), wherein A and Y are as defined above. This is typically carried out in the presence of a strongly acidic agent (e.g. phosphorus pentoxide or sulphuric acid), optionally in a solvent (such as toluene) and at elevated temperature.

Compounds of formula (XXIII) can be made by reaction of a compound of formula:

A - Hal (XXV) wherein A is as defined above and Hal is a halogen, preferably bromine or chlorine atom, in the presence of a strong base, such as an alkyl lithium (e.g. butyl- lithium), with a compound of formula (XXIV), wherein Y is as defined above, in an inert solvent such as an ether (e.g. diethyl ether) or a hydrocarbon (e.g. toluene).

_*

Alternatively, compounds of general formula (XII), wherein A and Y are as hereinbefore defined and R is methyl, can be prepared from compounds of general formula (XVI), wherein A and Y are as defined above and

7

R is an alkyl group of 1 to 4 carbon atoms or a benzyl or carboxymethyl radical, by reaction with methyla ine. The reaction is generally carried out with an excess of amine, without a solvent or in an inert organic solvent such as an ether (e.g tetrahydrofuran) an aromatic hydrocarbon or an alcohol or a mixture of these solvents at a temperature from room temperature to 130*C, optionally under pressure, and the amine may be added in an alcoholic solution, preferably ethanol.

It may be advantageous for the thiol formed during the reaction to be fixed in the form of a heavy

- 16 - metal salt using a thiol acceptor such as mercuric chloride.

7

Compounds of formula (XVI), wherein Y, A and R are as hereinbefore defined may be prepared by the reaction of compounds of ormula (XIV) , wherein Y and A are as hereinbefore defined, with carbon disulphide followed by reaction with a compound of formula:

R ⁷ - X (XVII)

7 wherein R is as hereinbefore defined and X is halogen, preferably chlorine, bromine or iodine, or a readily displaceable ester group such as methanesulphonyloxy or 4-toluenesulphonyloxy. The reaction is generally carried out in an anhydrous inert organic solvent such as tetrahydrofuran, to which hexa ethylphosphoramide may be added, at a temperature from -80 ^β C to +50 ^# c in the presence of an organic base such as potassium tcrt.-butoxide , or an organo-lithium derivative such as butyllithiu , or sodium hydride.

By the term "pharmaceutically acceptable salts" as used in this specification is meant salts the anions or cations of which are relatively innocuous to the animal organism when used in therapeutic doses so the the beneficial pharmaceutical properties of the parent compounds of general formula (I) capable of forming salts are not vitiated by side-effects ascribable to those anions or cations.

It is to be understood that, where in this specification reference is made to compounds of formula (I), it is intended to refer also, where the context so permits, to their pharmaceutically acceptable salts.

Suitable acid addition salts for use in pharmaceuticals may by selected from salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleatcs, methylene-bis-β-hydroxynaphthoates, gentiβates and di-p-toluoyltartrates.

Suitable salts with bases include alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium), ammonium and amine (e.g. dlethanolamine, triethanolamine, octylamine, morpholine and dioctylmcnlhylamine) salts.

As well as being useful in themselves as active compounds, salts of the compounds of general formula (I) capable of forming salts with acids or bases are useful for the purposes of purification of the parent compounds of general formula (I), for example by exploitation of the solubility differences between the- salts and the parent compounds, by techniques well known to those skilled in the art.

The thioformamide derivatives of general formula (I) obtained by the aforedescribed processes can be purified by the usual physical methods, in particular crystallisation and chromatography, especially to resolve mixtures of enantiomerε using a chiral column.

g _r (xπn) ⁰ ~ ^* (xix)

The following Examples and Reference Examples illustrate the preparation of compounds according to the present invention and their intermediates.

All N.M.R spectra were recorded at 200MHz. The chemical shifts are expressed in ppm relative to tetramethylεilane. Abbreviations in the text are as follows: s ■ singlet, d = doublet, t s triplet, q = quartet, dd = doublet of doublets, ddd * doublet of doublets of doublets, dt = doublet of triplets, dq = doublet of quartets, m - ultiplet, c « unresolved complex peak, br * broad signal.

The expression "m/z" indicates the peak assigned to the molecular ion in the mass spectrum.

EXAMPLE 1 Compound 1H

To a solution of ( ± )-trans-2-(2-(N-benzene- sulphonyl-S-methylisothioureido)ethyl)-N-methyl-1-(3- pyridyl)cyclohexane carbothioamide (280mg, 0.57mmol) in ethanol (5ml) was added a 33% ethanolic solution of methylamine (1ml) and the mixture heated at reflux for 6hr, cooled and concentrated in vacuo to give a pale yellow oil. The oil was purified by flash chromatography over silica gel using ethyl acetate / methanol (9:1) as eluent to give (i)-trans-2-(N-methvl- N'-bcnzenesulphonyliminoureido)ethyl-N-methyl-1-(3-

pyridyl)cyclohexane carbothioamide (lOOmg), as a white solid, m.p 163-164 C;

(N.M.R.(CDC1 ₃ ): 1.0-1.6 (m,5H), 1.6 (m,lH), 1.8-2.0 (m,2H), 2.8 (t, 3H), 2.9-3.0 (m,2H), 3.05(t, 3H), 3.1-3.2 (m, 2H), 7.2 (q, 1H), 7.4 ( , 3H), 7.8 (d, 3H), 8.4 (d, 1H), 8.6 (d,lR), 6.6 (br s, IK)

Found C, 57.7; H,6.6; N, 14.4; S, 13.3% 23 ^H 31 ^N 5°2 ^S 2 ^re « ^{uires c} ' ^58»3 * -~t - * - • N, 14.8; S, 13.5%].

EXAMPLE 2

Compound II

To a solution of ( t)-_trans-2-(2-(N-methane- sulphonyl-S-methylisothioureido)ethyl)-N-methyl-l-(3- pyridyl)cyclohexane carbothioamide (220mg, 0.5 mmol) in ethanol (5ml) was added a 33% solution of methylamine in ethanol (1ml) and the solution heated at reflux for 5hr. After cooling, the solution was concentrated in vacuo to give a light brown oil. The oil was purified by flash chromatography over silica gel using ethyl acetate / methanol (95:5) as eluent to give (∑)-trans- 2-(N-mcthyl-N'-methanesulphonyliminoureido)ethyl-N- methyl-1-(3-pyridyl)-cyclohexane carbothioamide (lOOmg), .pt 125-126 ^» C;

(N.M.R. (CDC1 ₃ ): 1.3-1.7 (m,7H), 1.75 (m, 1H), 2.15 (m, 1H), 2.6 (m, 1H), 2.9(d, 3H)-, 2.95 (m,lH), 2.96 (s, 3H), 3.1 (d, 3H), 3.25 (m,2H), 7.33 (q, 1H), 7.4 (br s, 1H), 7.8(dt, 1H), 8.55 (dd, 1H), 8.65 (d, 1H)

Found:- C, 51.4; H, 7.2; N, 16.65; S, 15.25%

^C 18 ^H 29 ^N 5°2 ^S 2 ^, ^ ^H 2° ^re ? ^uirβS! ~ ^c * 52.5; H,7.1; N, 17.0; S, 15.6%].

EXAMPLE 3 Compounds 1J to IS

To a solution of ( t)-trans-2-aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide (0.5g, l.δmmol) in dichloromethane (10ml) at 0*C was added, with stirring, triethylamine (0.25ml, l.δmmol) and then benzenesulphonyl chloride (0.22ml, l.βmmol). After stirring for Ihr at 0 ^β C, the solution was allowed to warm slowly to room temperature and stirred for a further lhr. The solution was treated with water (30ml) and dichloromethane (30ml). The organic layer was collected, washed with water, dried (MgSO,) and concentrated in vacuo to give an orange solid. The residue was subjected to flash chromatography over silica gel using methanol / ethyl acetate (5:95) as eluent, to gfive (±)-trans-2-benzenesulphonylamino- ethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide (130mg), .pt 109-110 ^e C;

(N.M.R.(CDC1 ₃ ): 1.25-1.55 (m, 6H), 1.8(m,lH), 2.1-2.2 (m,2H), 2.5, (m, IH), 2.8 ( , 2H), 3.0 ( , IH), 3.1(d, 3H), 4.9 (br t, IH), 7.2 (br s, IH), 7.3(q, IH), 7.5-7.6 (m, 3H), 7.8 (dt, IH), 7.85(d,2H), 8.5 (dd, IH), 8.6 (d, IH)

Found:- C, 60.3; H, 6.76; K, 9.8%

^C 21 27 ^N 3°2 ^S 2 ^re 9 ^uireε: " ^c » 60.4; H, 6.5; N, 10.1%].

By proceeding in a similar manner but replacing the benzenesulphonyl chloride with the appropriate sulphonyl chloride, there were prepared: i)(±)-trans-2-methanesulphonylaminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.pt 90 ^β C;

[N.M.R. (CDC1 ₃ ): 1.3-1.4(m,lH), 1.4-1.7(m,6H) , 1.9-2.05(m, IH), 2.1-2.2(m,lH) 2.6-2.7(m,lH) , 2.9(s, 3H), 3.0-3.1 ( , 2H), 3.1(d, 3H) , 3.2(m, IH) , 4.8 (br t, IH), 7.3.(q, 1H),7.5 (br s, IH), 7.85 (dt, IH), 8.5 (dd, IH), 8.65 (d, IH)

Found C, 53.6; H, 7.2; N, 11.1; S, 17.0%

^C 16 ^H 25 ^N 3°2 ^S 2 - ^" -V-ir*' - - C, 54.0 ; H, 7.1 ; N, 11.6 ; S, 16.0%] ; ii ) ( i ) -trans- 2- ( 4 - luorobenzenesulphonyl ) - ajτιinoethyl-N-methγl-1- ( 3-pyridγl )cγclohexane carbothioamide, m.pt. 64-66*C;

- 26 -

[N.M.R. (CDC1 ₃ ): 1.2-1.9(m,7H) , 2.1 (m,lH), 2.55 (m,lH), 2.7-3.0 (m, 4H) , 3.1(d, 3H), 5.2 (br t, IH), 7.1-7.3 (m, 3H), 7.4 (br s, IH), 7.7-7.9 (m, 3H) 8.4 (dd, IH), 8.6 (d, IH)

Found:- C, 57.9; H, 6.3; N, 9.1; S, 14.2% 21 ^H 26 ^FN 3°2 ^S 2 ^re 3 ^uireε:* -ι 57.9; H, 6.0: N, 9.65; S, 14.7%]; iii) (i)-tranε-2-(4-nitrobenzenesulphonyl)- aminoethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.pt 108-109*C

IN.M.R.(CDC1 ₃ ): 1.2-1.9(m,8H) , 2.0-2.2 ( , IH) , 2.4-2.6 ( , IH), 2.7-3.0 (m, 3H), 3.1 (d,3H), 5.8 (br t, IH), 7.2-7.4 ( , 2H) , 7.8 (d,lH), 8.0 (d, 2H) , 8.4 (dd, 3H), 8.6(d, IH)

Found:- C, 54,2; H, 5.6; N, 11.8; S, 13.8%

^C 21 ^H 26 ^N 4°4 ^S 2 ^re< 2 ^uire s:- C, 54.3; H, 5.7; N, 12.1; S, 13.9%]; iv) ( ± )-trans-2- ( 4-chlorobenzenesulphonyl ) - aminoethyl-N-mcthyl-l- ⁽ 3 -pyridyl) cyclohexane carbothioamide, pt 106-107 ^# C;

(N.M.R. (CDC1 ₃ ): 1.3-1.6 ( , 7H), 1.8 (m,lH), 2.1-2.2(m,lH), 2.5-2.55(m,lH) , 2.75-2.9(m, 2H), 2.95-3.05(m, IH), 3.1 (d, 3H), 5.1 (br 8, lH),7.25(br s, IH), 7.3 (q, IH), 7.5(d, 2H), 7.8 (m, 3H) , 8.5 (dd, IH), 6.65 (d, IH)

Found: - C, 55.3; H, 5.8; N, 9.2; 5, 13.9%

^C 21 ^H 26 ^ClN 3°2 ^S 2 ^re 9 ^uiress " ^c » 55.8; H, 5.8; , 9.3; S, 14.2%]; v) (i)-trans-2-(4-methoxybenzenesulphonyl)- aminoethyl-N-methyl-1-(3-pyridylJcyclohexane carbothioamide, m.pt 95-96*C;

(N.M.R. (CDC1 ₃ ): 1.25-1.6 (m,7H), 1.8 (m,lH), 2.05-2.15(m, IH), 2.52-2.6(m, IH), 2.8-2,9 ( , 2H), 2.9-3.0(m, IH), 3.1 (d, 3H), 3.9 (s, 3H),4.85 (br t, IH), 7.0(d, 2H), 7.25-7.35 (m, 3H), 7.8(d, 2H), 8.5 (dd, IH), 8.6 (d, IH)

Found:- C, 59.5; H, 6.7; N, 9.5; S, 14.0%

^C 22 ^H 29 ^N 3°3 ^S 2 ^re< 2 ^uires: " ^c » 59.0; H, 6.5; N, 9.4: S, 14.3%]; vi) (±)-trans-2-(2-thiophenesulphonyl)a ino- ethyl-N-methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.pt 96-98 ^β C;

[N.M.R.(CDC1 ₃ ): 1.3-1.6 (m,7H), 1.8-1.9(m, IH), 2.1-2.15 (m, IH), 2.5-2.6 (m, IH), 2.8-2.9 ( , IH), 2.9-3.0 (m, IH), 3.0-3.1 (m, IH), 3.1(d, 3H), 5.15 (br t, IH), 7.1 (dd, IH), 7.3 (q, IH), 7.32 (br β, IH), 7.6 ( , 2H), 7.8 (dt, IH), 8.5 (dd, IH), 8.65 (dd)

Found:- C, 53.6; H, 5.9; N, 9.6% 19 ^H 25 ^N 3°2 ^S 3 ^re< ϊ ^uires: " - ' 53.9; H, 5.95; N, 9.9%];

vii) (±)-trans-2-(3-pyridinesulphonyl)amino- ethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide, m.pt 101-102 ^β C;

[N.M.R. (CDC1 ₃ ): 1.3-1.6 (m, 7H), 1.8-1.9(m, IH), 2.1-2.15 (m, IH) , 2.5-2.6 (m, IH), 2.8-2.9 (m, 2H), 3.05(m, IH) , 3.1(d, 3H) , 5.9(br t, IH), 7.3 (q, IH), 7.45 (q, IH), 7.5 (br β, IH), 7.8 (dt, IH), 8.15 (dt, IH), 6.4 (dd, IH), 8.6(d, IH), 8.8(dd, IH), 9.0 (d, IH)

Found C, 55.9; H, 6.3; N, 13.1%

^C 20 ^H 26 ^N 4°2 ^S 2'^ ^H 2° 'W* ^1® * - ^c * 56.1; H, 6.36; N, 13.1%]; viii) (1)-trans-2-(3,4-difluorobenzene- sulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide, m.pt. 90-91*C;

[N.M.R. (CDC1 ₃ ): 1.2-1.6 ( , 6H), 1.6-2.0(m, 3H), 2.0-2.2(m, IH), 2.4-2.6 ( , IH), 2.7-3.1 ( , 2H), 3.1 (d, 3H), 5.5 (t, IH), 7.2-7.4 (m, 2H), 7.6-7.8 (m, 2H), 8.45 (dd, IH), 8.6(d, IH)

Found:- C, 55.6; H, 5.6; N, 9.0; S, 14.5%

^C 21 ^H 25 ^F 2 ^K 3°2 ^S 2 ^re< ϊ ^{uires j} " C, 55.6; H, 5.6; N, 9.3; S, 14.1%] ; and ix) ( ± ) -trans-2- ( 5-dimethylamino-l-naphthalene- sulphonyl ) aminoethyl-N-methyl-1- ( 3-ρyridyl ) cyclohexane carbothioamide, m.pt 125-126 ^f C

[N.M.R. (CDCΪ ₃ ): 1.0-1.4 On, 6H), 1.4-1.6 (m, 2H), 1.9-2.1 ( , IH), 2.3-2.5 (m, IH), 2.6-2.8 (m, 2H), 2.65 (β, 6H), 2.9 ( , IH), 3.1 (d, IH), 5.2 (br t, IH), 7.1- 7.3 ( , 4H), 7.4-7.7 ( , 3H), 8.2-8.4 (dd, 2H), 8.4-8.5 ( , 2H)

Found:- C, 60.3; H, 6.7; N, 9.8%

^C 27 ^H 34 ^N 4°2 ^S 2 ^re ? ^u i ^re8: " ^c # 63.5; H, 6.7; N, 11.0%].

EXAMPLE 4 Compound IT

To a solution of (±)-trans-2-aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide (lg, 3.6mmol) in toluene (20ml) and 1,2-dichlorobenzene (5ml) was added 90% diglycollic anhydride (928mg, 7.2mmol) and the solution heated at reflux for 3hr. After this time the mixture was cooled and the liquors decanted from the black tar and concentrated in vacuo to give a pale yellow oil. The oil was subjected to flash chromatography over silica gel using methanol / ethyl acetate (5:95) as eluent to give (i)-trans-2- (3,5-dioxomorpholino)ethyl-N-methyl-l-(3-pyridyl)- cyclohexane carbothioamide (290mg), as a cream solid, m.pt 181-183 ⁴ C

[N.M.R. (CDC1 ₃ ) :1.4-1.6 (m, 8H) , 2.0-2.2 (m, 2H) , 2.6-2.7 (m, IH) , 3.1(d, 3H) ,3.7 (m, IH) , 3.8 (m, IH) , 4.35 (s, 4H) , 7.3 (br s, IH) , 7.4 (q, IH) , 7.95 (d, IH) , 6.55 (dd, IH) , 8.6 (d, IH)

Found:- C, 60.2; H, 6.6; N, 11.1; S, 7.3%

^C 19 ^H 25 ^N 3°3 ^{S re} 3 ^u i ^rβs * ^c » 60.8; H, 6,7; N, 11.2; S, 8.5%].

EXAMPLE 5 Compounds 2A to 2M

By carrying out processes similar to those described herein, more especially in the Examples and Reference Examples, there were prepared the following compounds:-

( t )-trans-2-(propylsulphonyl)aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 81-83°C, in the form of a foam;

• -)*trans-2-(isopropylsulphonyl)aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, .p. 104-106 _* ^» C;

( ± ) -trans-2- (butylsulphonyl ) minoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 82-84 ^β C, in the form of a foam;

( i ) -trans-2- ( 2-f luorobenzenesulphonyl ) amino-

- 33 - ethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide, m.p. 105-112*C, in the form of a foam;

(4)-trans-2-(3-cyanobenzenesulphonyl)aminoethyl- N-methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 85-90 ^# C, in the form of a foam,-

(4)-trans-2-(benzenesulphonyl)a inoethyl-N- ethyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 79-80 ^β C, in the form of a foam;

(±)-trans-2-(isopropylsulphonyl)aminoethyl-N- ethyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 64-65 C, in the form of a foam;

(4)-trans-2-( -fluorobenzenesulphonyl)a ino- ethyl-N-ethyl-1-(3-pyridyl)cyclohexane carbothioamide, m.p. 61-83*C in the form of a foam;

(4)-trans-2-(3-pyridinesulρhonylaminoeth l-N- ethyl-l-(3-ρyridyl)cyclohexane carbothioamide, m.p. 58-60 ^# C, in the form of a foam;

(-)-trans-2-(3-pyridinesulphonyl)aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 98-99 ^β C, [α] * -26 ^β ;

■-)-trans-2-(4-fluorobenzenesulphonyl)amino- ethyl-N-methyl-J-O-pyridyl)cyclohexane carbothioamide, m.p. 64-65 ^# C, in the form of a foam, [αJ ^D ■ -20.6';

(-)-trans-2-(isopropylsulphonyl)aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide, m.p. 90-91*C, in the form of a foam; and

⁽ i ⁾ -trans-2 - ⁽ isopropylsulphonyl ) aminoethyl-N- methyl-l- ⁽ 4-pyridyl ⁾ cyclohexane carbothioamide as a hite solid, m.p. 146-147»c

REFERENCE EXAMPLE 1 To a solution of (4)-trans-2-aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide (500mg, 1.8mmol) in ethanol (10ml) was added, with stirring, dithiomethyl bcnzenesulphonyliminocarbonate (470mg, l.δmmol) and the mixture heated at reflux for 8hr, cooled and concentrated in vacuo to give a brown oil. The oil was purified by flash chromatography over silica gel using ethyl acetate / methanol (95:5) as eluent to give a pale yellow oil which was triturated with ether to give (4)-trans-2-(2-(N-benzenesulohonvl- S-methylisothioureido)ethyl)-N-methyl-1-(3-pyridyl)- cyclohexane carbothioamide (280mg), as a white solid

[N.M.R. (CDC1 ): 1.0-1.8 (m, 8H), 2.0-2.2 (m, 2H), 2.3 (s, 3H), 2.6 (m, IH), 3.1(d, 3H), 3.2-3.3 (m, 2H), 7.2 (m, 2H), 7.4- 7.5 (m, 3H) , 7.8-8.0 (dd, 2H), 8.5 (d, IH), 8.6(d, IH), 8.1 (br s, IH)

Found:- C, 55.9; H, 6.2; N, 11.2; S, 18.5%

^C 23 ^H 30 ^N 4°2 ^S 3 ^re S ^u * ^reS! " ' 56.3; H, 6.2; N, 11.4; S, 19.6%].

REFERENCE EXAMPLE 2

To a solution of ( )-trans- -aminoethyl-N- methyl-l-(3-pyridyl)cyclohexane carbothioamide (SOOmg, l.δmmol) in ethanol (10ml) was added, with stirring, dithiomethyl ethanesulphonyliminocarbonate (360mg, l.βm ol) and the mixture heated at reflux for Bhr,

cooled and concentrated in vacuo to an oil. The oil was purified by flash chromatography over silica gel using ethyl acetate / methanol (95:5) as eluent to give (t)-trans-2-(2-N-methanesulphonyl-S-methvl- isothioureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide (220mg), as a white solid, m. pt 74-75*C

[N.M.R.(CDC1 ₃ ): 1.3-1.8 (m, 7H), 2.0-2.2 (m, 2H), 2.4 (s, 3H), 2.6(m, IH), 3.0 (β, 3H), 3.05(m, IH), 3.15 (d, 3H), 3.25 (m, 2H), 7.3 (q, IH), 7.4 (br s, IH), 7.8 (br β, IH), 7.9 (d, IH), 8.5 (d, IH), 8.6 (d, IH)

Found:- C, 49.9; H, 6.5; N, 12.6; S, 20.7%

^C 18 ^H 28 ^N 4°2 ^S 3 ^ze( --- ^τes - " ^c » 50.4; H, 6.6 ^; N, 13.1; S, 22.4%].

REFERENCE EXAMPLE 3

A solution of (4)-trans-2-cyanomcthvl-N-methyl- l-(pyrid-3-yl)cyclohexane carbothioamide (3g, lO.β mol) in dry tetrahydrofuran (30ml) was added dropwisc at room temperature under argon to a stirred suspension of lithium aluminium hydride (1.25g, 33mmol) in dry tetrahydrofuran (75ml). After the addition, the mixture was stirred e reflux for lhr, cooled and treated with Rochelle salt solution (20ml) and ethyl acetate (50ml). The layers were separated and the aqueous was extracted with ethyl acetate (30ml). The combined extracts were washed with water, dried (MgSO )

and concentrated in vacuo to give a yellow oil which was triturated with ether to give (4)-trans-2-(2- a inoethyl)-N-roethyl-1-(pyrid-3-yl)cyclohexane carbothioamide (2g) as a yellow solid;

[N.M.R. (CDC1 ₃ ): 1.0-1.1 (m, IH), 1.4-1.8 ( , 4H), 2.0 ( , IH), 2.1 (m, IH), 2.5 (m, 2H), 2.7 (m, 4H), 3.1 (d, 3H), 3.15-3.3 (m, 2H), 7.25 (g, IH], 7.9 (dt, IH), 8.4 (dd, IH), 8.7 (d, IH)].

REFERENCE EXAMPLE 4

A suspension of lithium aluminium hydride (135mg, 3.5 mmol) at room temperature in dry tetrahydrofuran (20ml) was treated drop ise with a dry tetrahydrofuran solution (10ml) of 2-cyanomethylene- N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamide (960mg, 3.54mmol). The mixture was stirred at room temperature for lOmins. Water (5ml) was added dropwiεe followed by ethyl acetate (50ml). The mixture was washed with an aqueous solution of Roehelle salt (50ml) and the separated organic extract dried over magnesium sulphate. Concentration in vacuo yielded a yellow gum which was purified by flash chromatography over silica gel, eluting with ethyl aeetate to yield a pale yellow gum (610mg, 2.23mmol). Trituration with ether / hexane yielded (i)-trans-2-cyanomethyl-N-raethyl-l-(pyrid- 3-yl)cyclohexane carbothioamide (6lCmg, 2.23mmol), as a white solid, m.p. 177-178'C;

[N.M.R. (CDC1 ₃ ) : 1.38-2.6 (c, 10H) , 3.06-3.14 (d, 3H) , 3.64-3.80 (m, IH) , 7.28-7.36 (m, IH) , 7.48-7.68 (br s, IH) , 7.72-8.00 (m, IH) , 8.52-8.60 (m, IH)

Found:- C, 65.5; H, 6.9; K 15.1%

Calculated for C, 65.9; H, 7.0; N, 15.4% m/z « 274].

REFERENCE EXAMPLE 5

A solution of diethyl cyanomethylphosphonate (215mg, 1.2mmol) at room temperature in dry tetrahydrofuran (20ml) was treated with a 60% oil dispersion of sodium hydride (40mg, lmmol). After 15 mins at room temperature (i)-N-methyl-2-oxo-l- (pyrid-3-yl)cyclohexane carbothioamide (245mg, lmmol) was added and the resulting solution stirred for 3 hours at room temperature. Ethyl acetate (50ml) and then water (50ml) were added to the reaction mixture. The layers were separated and the organics washed with water (50ml). The organic extract was dried over magnesium sulphate and concentrated in vacuo to give a crude gum. Purification by flash chromatography, eluting with a 1:1 (v/v) mixture of ethyl acetate / hexane gave (i)-2-cyanomethylene-N-methyl-l-

(pyrid-3-yl)cyclohexane carbothioamide as a colourless gum (190mg, 0.7mmol). Trituration with ether yielded a white solid (190mg, 0.7mmol), m.p. 182-183*C;

[N.M.R. (CDC1 ₃ ): 1.47-1.78 (c, 2H), 1.78-2.00 (c, 2H), 2.20-2.38 (m, IH), 2.46-2.64 (m, IH), 2.62-2.96 (m, IH), 3.06-3.24 (m, IH), 3.22-3.26 (d, 3H), 3.94 (s, IH), 7.26-7.36 (m, IH), 7.48-7.64 (m, 2H), 8.48-8.52 (m, IH), 8.52-8.58 (m, IH)

Found:- C, 66.6; H, 6.3; N, 15.7%

Calculated for C ₁₅ H _1? N ₃ S - C, 66.4; H, 6.3; N, 15.5% m/z = 271).

REFERENCE EXAMPLE 6

A vigorously stirred solution of (4)-2- (pyrid-3-yl)cyclohexanone (5.5g, 30mmol) in anhydrous tetrahydrofuran (50ml) under argon at -15 ^β C was treated with potassium t-butoxide (3.36g, 30mmol).

After 60 minutes at 0 ^Φ C, a solution of methyl isothiocyanate (2.4 g, 33 mmol) in anhydrous tetrahydrofuran (10ml) was added during 5 minutes. After 2.5 hours at 0*C the solution was warmed to 20*C and then poured into a saturated aqueous brine solution (250ml). The mixture was extracted with ethyl acetate (50ml) and then with chloroform (3 x 50 ml). The combined organic extracts were dried over sodium sulphate and the concentrated in vacuo (30 ^» C; 14 ramHg).

The crude product was recrystalϋβed from methanol to give (4)-N-meth l-2-oxo-l-.(pyrid-3-yl)- cyclohexane carbothioamide (4.8 g, 19 mmol), m.p. 188-190«C;

[N.M.R. (CDC1 ₃ ): 1.62-2.06 (m, 4H) , 2.42-2.60 (m, 2H), 2.60-2.82 (m, IH], 2.84-3.06 (m, IH) , 3.16-3.2 (d, 3H), 7.24-7.34 (ddd, IH), 7.6-7.68 (ddd, IH), 8.43-8.47 (d, IH), 8.48-8.54 (dd, IH) , 8.9-9.2 (br s, IH)

Found:- C, 62.9; H, 6.6; N, 11.3; 5, 13.1%

Calculated for C, ₃ H,gN ₂ OS - C 62.9; H, 6.5; N, 11.3; S, 12.9%].

REFERENCE EXAMPLE 7

A solution of (4)-trans-1-[(pyrid-3-yl)- bromomethyl]cyclopentanol (10.24 g, 40mmol) in anhydrous tetrahydrofuran (500 ml) at 0 ⁹ C was treated, dropwise during 30 minutes, with a solution of silver perchlo ate (9.9 g, 48 mmol) in anhydrous tetrahydrofuran (50 ml). After 60 minutes at 0 ^# C the mixture was poured into a mixture of saturated aqueous brine solution (500 ml) and 10% w/v aqueous sodium bicarbonate solution (500 ml). The resulting mixture was filtered and then extracted with ethyl acetate ( 2 x 500 ml). The combined organic extracts were washed with brine and then dried over sodium sulphate. Concentration in vacuo (30*C; 14 mmHg) afforded a crude

oil which was recrystallised from cyclohexane (120 ml) to give (i)-2 (pyrid-3-yl)-cyclohexan©ne (6.7 g, 38 mmol), m.p. 78-80*C;

[N.M.R. (CDCl ₃ )z 1.72-2.12 (m, 4H), 2.12-2.40 ( , 2H), 2.40-2.64 (m, 2H), 3.56-3.72 (dd, IH), 7.22-7.32 (m, IH), 7.44-7.54 (ddd, IH), 8.34-8.42 (dd, IH), 8.46-8.54 (dd, IH)].

REFERENCE EXAMPLE 8

A solution of 3-cyclopentylidenemethylpyridine (62.2 g, 0.39 mol) in acetone (600 ml) and water (100 ml) was treated with a solution of concentrated sulphuric acid (18.9 g, 0»19mol) in water (100 ml) at 5°C. The ice-cold solution was treated with l,3-dibromo-5,5-dimethylhydantoin (55 g, 0.19 mol) during 20 minutes. After 3.5 hours at 0*C the mixture was treated with sodium bicarbonate (33.6 g, 0.4 mol) followed by water (2 1) and then extracted with ethyl acetate (2 x 500 ml). The organic phase was removed and washed with 10% w/v aqueous sodium bicarbonate solution (500 ml) followed by water (200 ml) and brine (200 ml). The crude extract was dried over sodium sulphate and then filtered through a column of flash silica gel (10 cm x 2.4 cm diameter). After concentration in vacuo (20*C; 14 mmHg) the dark oil crystallised on standing to give (4)-trans-l-

- 42 -

[(pyrid-3-yl)bremometh lJcyclopβntanol (56 g, 0.22 mol) m.p. 92-94 ^# C;

[N.M.R. (CDC1 ₃ ) 1.36-2.06 (c, 8H), 2.32-2. 6(br s, IH), 5.02 (8, IH), 7.24-7.34 (ddd, IH), 8.0-8.1

(ddd, IH), 8.52-8.56 (dd, IH), 8.62-8.66 (d, IH) Found:-C, 51.9; H, 5.6; Br, 30.6; N, 5.5% Calculated for C^H^BrNOr-C, 51.6; K, 5.5;

Br, 31.2; N, 5.5%].

REFERENCE EXAMPLE 9

A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran C1000ml) at 2*C was treated with vigorous stirring under an atmosphere of argon, with potassium t-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5*C for 80 minutes and then treated with pyridine-3-carbaldehyde (56.9 g, 0.55 mol) during a period of 20 minutes. The reaction mixture was stirred at 0*C for 2 hours and then at 20*C for 18 hours. The tetrahydrofuran was removed in vacuo (30*C; 14 mmHg) and the residue extracted with.pentane (2 x 500 ml). After treatment with decolourising charcoal (5g), the mixture was filtered through a plug of flash silica gel (Merck 70-230 mesh; 13cm x 2cm diameter). The filtrate was concentrated in vacuo (30 C, 14mmHg; then 20*C, O.OlmmHg) to afford 3-cyclopenty idenemeth lpyridine

(54g, 0.34mol) as en orange oil which was used without further purification;

[N.M.R. (CPCl ₃ )x 1.6-1.95 (m, 4H), 2.4-2.65 (m, 4H), 6.26-6.34 ( , IH), 7.16-7.25 (ddd, IH), 7.56-7.65 (ddd, IH), 8.52-8.52 (d, IH)].

REFERENCE EXAMPLE 10

A 4:1 mixture of ( )-eis/trans-2-methoχy- l-(pyrid-3-yl)cyclohexanol (2g, lOmmol), toluene and phosphorus pentoxide (3.4g, 24mmol) was heated at reflux for 5 hours. The mixture was then filtered and the precipitate partitioned between 2M sodium hydroxide solution (80ml) and diethyl ether (25ml). The aqueous layer was extracted with ether (3x25ml) and the combined organic extracts were dried over sodium sulphate. Concentration £n vacuo afforded a crude oil which was purified by flash chromatography to give 2-(pyrid-3-yl)cyclohexanone (0.7g, 4mmol).

REFERENCE EXAMPLE 11

To a solution of 2.5M n-butyllithium in hexane (13.2ml, 33mmol) at -78 ^V C was added diethyl ether (15ml) followed by a solution of 3-bromopyridine (4.7g, 0mmol) in ether (90ml) over a period of 10 minutes. After 1 hour at -78 ^» C a solution of (4)-2-metboxy- cyclohexanone (3.84g, 3 mmol) in ether (20ml) was added dropwise during 10 minutes. After 2 hours at -78 *c and 30 minutes at 0*C the reaction mixture was warmed to

20*c and then poured onto ice (150g). The mixture was extracted with ether (2x50ml) and then the combined organic extracts were extracted with IN hydrochloric acid (50ml). This aqueous extract was washed with ether (20ml) and then treated with 2M sodium hydroxide solution (25ml) and extracted with ether (3x100ml). The organic extracts ware combined, washed with brine then dried over anhydrous sodium sulphate. Concentration in vacuo afforded (±)-2-methoxy-l- (pyrid-3-yl)cyclohexanol (5.0g, 24mmol) as a 4:1 mixture of cis and trans iso ers;

[N.M.R. (CDC1 ₃ ): 1.2-2.14 (O, 2.24-2.44 (m), 2.90-3.28 (c), 3.48-3.60 ( ), 7.18-7.30 (m), 7.78-7.96 (m), 8.40-8.48 (m), 8.62-8.72 ( ), 8.78-8.82 (m)].

- 45 -

The present invention includes within its scope pharmaceutical compositions which comprise a compound of general formula (Z) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or coating, in clinical practice the compounds of the present invention may be administered rectally, but are preferably administered parenteraliy, by inhalation if appropriate, or, more preferably, orally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.

The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearata.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting, and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also

52

- 46 • include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-or anic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive and inject ble organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Compositions for inhalation may be sterile aqueous solutions which are then nebulised or dry powders formulated in accordance with known methods.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing one or more of the

- 47 - compounds of formula (I) or a pharmaceutically acceptable salt thereof.

The percentage of active Ingredient in the composition of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. Tha dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration, the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably from about 0.01 to about 5, g/kg body weight per day by oral administration. By inhalation, either as a nebulised solution or as a formulated dry powder, the preferred daily dosage is from about 0.001 to about 5, preferably from about 0.01 to about 0.5, mg/kg body weight.

The following Example illustrates pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE

No. 2 size gelatin capsules each containing -

- 48 -

(4)-trans-2-benrenesulphonylaminoethyl-N-methyl-

1-(3-pyridyl)cyclohexane carbothioamide 20mg lactose lOOmg starch 60mg dextrin • 40mg magnesium stearate lmg were prepared in accordance with the usual procedure .