GB2213816A

GB2213816A - Urea and carbamic acid derivitives of n-containing heterocylic compounds

Info

Publication number: GB2213816A
Application number: GB8829164A
Authority: GB
Inventors: Terence James Ward; Janet Christine White
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1987-12-24
Filing date: 1988-12-14
Publication date: 1989-08-23
Anticipated expiration: 2008-12-14
Also published as: US4983600A; FI95031B; DE3850255D1; EP0323077B1; ES2051867T3; PH27437A; CA1334095C; IE63474B1; KR970009588B1; EP0361629B1; IE883661L; DK82793A; PT89286A; FI95031C; US5106843A; JP2588265B2; ATE107304T1; IL88644A; AU611976B2; EP0361629A3

Abstract

Heterocyclic urea and carbamate cpds. of formula A-X-NH-CW-Y-B (I) and pharmaceutically acceptable acid addn. salts are new where A is aromatic gp. of formula (A1)-(A4). R1 is H or one or more of lower alkyl, lower alkoxy, OH, halogen, lower haloalkyl, NH2, NO2, carboxamido, phenyl(lower) alkoxy (where phenyl is opt. substd. by lower alkyl, lower alkoxy or halogen substit(s).), acylamino or mono- or di-lower slkylamino, Z1-Z2 are CH2-CH, NR2-CH, 0-CH, -S-CH, CH2-N, O-N, S-N, NR2-N, CH-NR2 or N-NR2, R2 is H, lower alkyl or phenyl or phenyl(lower)alkyl where phenyl is opt. substd. by lower alkyl, lower alkoxy or halogen substit(s).; Z2-Z4 are CH:CH, O-CH2 or N:CH, Z5 is N or CH, Z6 is O, S or NH; X is a bond or -CO-, W is O or S, Y is NH or O, B is satd. azacyclic ring of formula (B1-(B5) or N-oxide of (B2), n is 2, 3 or 4, R3 is H or lower alkyl, m is 1, 2 or 3, p is 0, 1 or 2 and R4, R5 are H or lower alkyl, with the proviso that when X is bond, A is (A3) or (A4) and W is O, then (A3) or (A4) does not contain a substit. ortho to the -X-NH-Cw-Y-B side chain.

Description

H-390/396 -1 2213816 Heterocyclic Compounds H-390/396 This invention

relates to heterocyclic compounds In particular the invention relates to novel aryl or aroyl ureas or carbamic acid derivatives, and the corresponding thio analogues, to processes for their preparation, to their use and to pharmaceutical compositions containing them The novel compounds of the invention are useful as antagonists of specific 5-hydroxytryptamine ( 5-HT) receptors as explained hereinbelow Certain related aryl ureas and carbamic acid derivatives are disclosed in European Patent Applications 235878 and 255297.

The novel heterocyclic compounds of the present invention are those of the general formula A-X-NHCW-Y-B (I) and the pharmaceutically acceptable acid addition salts thereof In this formula A represents an aromatic radical of the formula z 1 (a) (b), R 1 O Z z z 6 (c) or (d) where the free valence is attached to either fused ring of formula (a) or (b), H-390/396 R 1 represents hydrogen or one or more (eg 1 to 3) same or different substituents selected from lower alkyl, lower alkoxy lsuch as loweralkyloxy (eg methoxy, ethoxy, propoxy or butoxy), cyclo(lower)alkyloxy, cyclo(lower)alkyl-loweralkyloxy (eg cyclopropylmethoxy), (lower)alkenyl(lower)alkyloxy (eg allyloxy) and halo(lower)alkyloxyl, hydroxy, halogen (eg chlorine), halo(lower)alkyl (eg trifluoromethyl), amino, nitro, carboxamido, phenyl(lower)alkyloxy (in which the phenyl group may be optionally substituted by one or more lower alkyl, loweralkyloxy or halo substituents), (lower)alkylamino, di(lower)alkylamino or acylamino leg (lower) alkanoylamino or halo(lower) alkanoylaminol Z -Z represents CH 2-CH, NR -CH, O-CH, S-CH, CH 2-N, 2 2 2 2 2 2 O-N, S-N, NR 2-N, CH-NR or N-NR, lwhere R is hydrogen, (lower)alkyl, or phenyl or phenyl(lower)alkyl in which the phenyl groups may optionally be substituted by one or more lower alkyl, lower alkyloxy or halo substituentsl Z 3-Z 4 represents CH=CH, O-CH 2 or N=CH Z 5 represents N or CH z 6 represents 0, S or NH X represents a direct bond or CO, W represents oxygen or sulphur, Y represents NH or 0, H-390/396 B represents a saturated formula azacyclic ring of the (II) where N is 2,3 or 4 and R is hydrogen, or (lower)alkyl, or N (CH 2)2 H 2 2 (III) or the N-oxide thereof or (IV) where m is 1, 2 or 3 and R 3 has the meaning given above or (CH 2)p \ where p is 0, 1 or 2 or N-R 4 N-R 5 (VI) where R 4 and R 5 are each hydrogen or lower alkyl with the proviso that when X is a direct bond, A represents a group of formula (c) or (d) and W H-390/396 represents oxygen, then the ring (c) or (d) does not contain a substituent ortho to the -X-NHCW-Y-B side chain.

The term "lower as used herein means that the radical referred to contains up to 6 carbon atoms The radical preferably contains up to 4 carbon atoms For example, a lower alkyl group may be straight chain or branched and may be methyl, ethyl, propyl or butyl.

Preferably X represents CO.

When A represents a radical of formula (c) above, the radical preferably has the formula R 9 6 R 8 'N 6 (XIV) R 7 where R 6 to R 9 are independently hydrogen or a substituent R as defined above Particularly preferred meanings are those in which R 6 is lower alkoxy (eg methoxy) and R R and R are hydrogen and those in which R 6 is lower alkyloxy (eg methoxy) or cyclo(lower)alkyl(lower)alkyloxy (eg cyclopropylmethoxy), R 7 is hydrogen, R 8 is amino or lower alkylamino and R 9 is halo (eg chloro) Other preferred meanings are those in which R 7 and R 9 are chloro and R 6 and R 8 are hydrogen.

In the radical B of formula (II), preferably N is 2 and R 3 is lower-alkyl, preferably methyl The radical in which N is 2 and R 3 is methyl is known as tropan-3-yl, otherwise 8-methyl-8-azabicyclol 3 2 1 loctan-3-yl.

The radical of formula (III) is known as quinuclidinyl, otherwise 1-azabicyclol 2 2 2 loctan-3-yl.

H-390/396 In the radical of formula (IV), preferably m is 2, and 153 is preferably C 1 4-alkyl, particularly methyl, In the radical of formula (V), p is preferably 1.

The compounds of the invention may contain one or more asymmetric carbon atoms so that the compounds can exist in different stereoisomeric forms The compounds can, for example, exist as racemates or optically active forms The optically active forms can be obtained by resolution of the racemates or by using an optically active form of the starting material in the processes described hereinafter Furthermore radicals such as those of formulae (II) and (IV) can exist in two different configurations corresponding to the endo configuration as in tropine and the exo configuration as in pseudotropine The endo configuration is preferred.

The compounds of the invention are aryl or aroyl ureas or carbamic acid derivatives (or their corresponding thio analogues) and may be prepared by methods known for the preparations of urea and carbamic acid derivatives (and thio analogues).

A first general process for preparing the compounds of the-invention comprises reacting an isocyanate or isothiocyanate of formula (VII) A-X-NCW (VII) (where A, W and X are as defined above) with an amine or alcohol of formula (VIII) H-390/396 B-YH (VIII) (where B and Y are as defined above).

Such a reaction may, for example, be effected at room temperature in an organic solvent.

Compounds of the invention in which Y represents NH may be prepared by an alternative process in which a compound of general formula (IX) A-X-NHCWNH 2 (IX) (where A, W and X are as defined above) is reacted with an amine of general formula B-NH 2 (X) (where B is as defined above) This process may be performed in the absence of a solvent but is usually carried out by heating the reactants in the presence of a suitable inert organic solvent, for example toluene, pyridine, xylene, chlorobenzene, dimethylformamide or dioxan Pyridine is the preferred solvent Often it is convenient to reflux the reactants in the solvent.

Compounds of the invention in which X represents CO may be prepared by acylating a compound of formula NH 2 CWY-B (XI) (where Y, W and B are as defined above) with an acylating agent containing the group A-CO (where A is as defined above) Examples of acylating agents are reactive derivatives of acids of formula ACOOH such as H-390/396 the acid halides (e g the acid chloride) and the anhydride.

Compounds of the invention in which X represents a direct bond and Y is NH may be prepared by reacting an isocyanate or isothiocyanate of formula B-NCW (XII) (where B and W are as defined above) with an amine of formula A-NH 2 (XIII) (where A is as defined above).

The compounds of the invention in which B represents the N-oxide of the radical (III) may be prepared by oxidising a compound in which B represents the radical (III) with, for example, hydrogen peroxide or a peracid.

If in any of the above processes a reactant contains groups that would be affected under the reaction conditions employed for the reaction the group may be protected and the protecting group subsequently removed.

The starting materials for the above processes are either described in the literature or may be prepared by methods known for analogous compounds.

If in the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt Conversely, if the product of H-390/396 the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methane- sulphonic, p-toluenesulphonic, oxalic and succinic acids.

The compounds of the present invention possess pharmacological activity In particular they antagonise specific 5-hydroxytryptamine ( 5-HT) receptors in warm blooded animals Specifically the compounds possess 5-HT 3 antagonistic activity and hence are of value in conditions where antagonism of 5-HT 3 receptors is desirable 5-HT 3-antagonists are also termed "antagonists of neuronal" 5-hydroxy- tryptamine receptors" and "serotonin ( 5-hydroxy- tryptamine) M-receptor antagonists" Such compounds have been described as being useful inter alia in the treatment of migraine, emesis, anxiety, gastro- intestinal disorders and as anti-psychotics.

The compounds of the invention are tested for 5-HT 3 antagonistic activity in the isolated right atrium of the rabbit heart based upon the method of Fozard J R, Naunyn-Schmiedeberg's Arch Pharmacol, 1984, 326, 36-44 This procedure relies upon the ability of 5-HT to stimulate 5-HT 3 receptors present on sympathetic nerve terminals in the heart, causing H-390/396 -1 O release of noradrenaline which evokes an increase in the spontaneous rate of beating The antagonist potency is expressed as -log IC 50 (where IC 50 is the concentration of antagonist which reduces the chronotropic response to 10-5 M 5-HT by 50 %) When tested by this procedure N-( 1-azabicyclol 2 2 2 l- octan-3-yl)-N -( 3,5-dichlorophenyl)urea and N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll-2- methoxybenzamide representative compounds of this invention, had, respectively, -log IC 50 of 8 3 and 8.67 The (S)-enantiomer of the former compound had -log IC 50 of 9 3.

The compounds of the invention are tested for potential anxiolytic activity by a test procedure measuring mouse exploratory activity in a two-compartment light/dark box based upon the procedure of B Costall et al, Neuropharmacoloav, 1987, 26, 195-200 and J N Crawley et al, Pharmac Biochem Behav, 1980, 13, 167-170 The test involves observing groups of mice placed in an open topped box, one third of which is painted black and illuminated under a dim red light and partitioned from the remainder of the box which is painted white and brightly illuminated Access between the two sections is via an opening in the centre of the partition The groups of mice are treated with vehicle or test compound and various behavioural parameters of the animals are measured including the number of exploratory rearings made by the mice in each section and the number of times the mice cross lines marked on the floor of each section For each treatment group the mean number of line crossings and rears in each section of the box are calculated Differences between drug-treated groups and vehicle-treated controls are compared using Student's unpaired t-test Standard Z H-390/396 -1 1- anxiotic agents significantly increase locomotion and rearing in the light section Test compounds are considered to be active if they induce a similar set of changes and, in particular, if they produce a significant (p < 0 05) increase in rearing activity in the light section of the box Results for compoundsof the invention and a standard anxiolytic agent are given below:

Compound % Change Relative to Controls (dose mg/kg s c) Line Crossings Rears Ex.1 ( 0 1) + 40 %/o + 85 % Ex.5 ( 0 1) + 20 % + 73 % Ex.12 ( 1 0) + 42 %, + 75 %/O- Ex.13 ( 0 1) + 69 %/, + 90 % O Io Chlordiazepoxide ( 2 0) + 42 % + 77 % P < 0 05 P < 0 01 P < 0 001 (Student's unpaired t-test relative to vehicle treated controls) The invention further provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for use in antagonising 5-HT 3 receptors in a mammal.

In a further aspect the invention provides the use of a compound of the invention for the treatment of migraine, emesis, anxiety, gastro-intestinal disorders or psychotic disorders The invention also provides a method for the treatment of migraine, emesis, anxiety, gastro-intestinal disorders or psychotic disorders which comprises administering to a warm blooded animal in need thereof, an effective amount of the compound of the invention.

H-390 / 396 For certain of the above mentioned conditions it is clear that the compounds may be used prophylactically as well as for the alleviation of acute symptoms.

References herein to -treatment" or the like are to be understood to include such prophylactic treatment, as well as treatment of the acute conditions.

The anti-emetic properties of the compounds are particularly advantageous in the treatment of nausea and vomiting associated with cancer chemotherapeutic agents and radiation therapy The compounds are therefore of use in the treatment of cancer by chemotherapeutic agents (cytotoxic or cytostatic agents such as cisplatin, doxorubicin and cyclophosphamide) as well as irradiation Accordingly, the invention also provides a product containing a cancer chemotherapeutic agent and a compound of the invention as a combined preparation for simultaneous, separate or sequential use in cancer therapy.

In a further aspect the invention provides a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable carrier Any suitable carrier known in the art can be used to prepare the pharmaceutical composition In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e g hard and soft gelatin capsules),suppositories and pessaries A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating H-390/396 -1 3- agents; it can also be an encapsulating material In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired The powders and tablets preferably contain up to 99 %, e g from 0 03 to 99 %, preferably 1 to 80 % of the active ingredient Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

The term 'composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions The active ingredients, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.

Suitable examples of liquid carriers for oral and parenteral administration include water (particularly H-390/396 containing additives as above e g cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e g glycerol and glycols) and their derivatives, and oils (e g fractionated coconut oil and arachis oil) For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection Sterile solutions can also be administered intravenously When the compound is orally active it can be administered orally either in liquid or solid composition form.

The compounds of the invention can also be administered by the nasal route When formulated for nasal administration the compositions may comprise a compound of the invention in a liquid carrier; such compositions may be administered for example in the form of a spray or as drops The liquid carrier may be water (which may contain further components to provide the desired isotonicity and viscosity of the composition) The composition may also contain additional excipients such as preservatives, surface active agents and the like.

The compositions may be contained in a nasal applicator that enables the composition to be administered as drugs or as a spray For administration from an aerosol container the composition should also include a propellant.

H-390/396 -1 5- Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0 5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.

The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention.

H-390/396 EXAMPLE l

N-( 1-azabicyclol 2 2 2 loctan-3-yl- N'-( 3,5-dichlorophenyl)urea A solution of 3,5-dichlorophenyl isocyanate ( 1 88 g, 10 -5 mmol) in toluene ( 20 ml) was added at 0 to 1-azabicyclol 2 2 2 loctan-3-amine ( 3-aminoquinuclidine) ( 1.26 g, 10 mmol) in THF ( 40 ml) The mixture was stirred at room temperature overnight and evaporated to dryness The residue was partitioned between ether and dilute hydrochloric acid The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate The dried (Na 2 SO 4)ethyl acetate phase was evaporated and the residue ( 1 64 g) converted to the 1:1 oxalate, quarter hydrate, mp 208-209 C (dec).

EXAMPLE 2

N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll -3,5-dichlorobenzamide 3-Aminoquinuclidine ( 1 26 g, 10 mmol) and 3,5-dichlorobenzoylurea ( 2 2 g, 9 44 mmol) in pyridine ( 15 ml) were stirred and refluxed overnight under nitrogen, filtered hot and allowed to cool to room temperature The precipitated solid was collected, washed with ethyl acetate and dried to give the title compound ( 0 93 g) which was converted to the hydrochloride, monohydrate mp 253-254 C.

H-390/396 EXAMPLE 3 (Endo)-N-( 3,5-dichlorobenzoyl)-O-( 8-methyl-8azabicyclol 3 2 1 loct-3-yl)carbamate Tropine ( 1 g, 7 09 mmol) was dissolved in dichloromethane ( 10 ml) then treated with 3,5-dichlorobenzoyl isocyanate ( 1 6 g, 7 34 mmol) in dichloromethane ( 8 ml) to give a clear solution, which was left overnight under nitrogen Methanol was added, the solution was evaporated, and the residue triturated with ether to give product,1 62 g This was triturated in refluxing acetonitrile ( 40 ml) for about 30 mins, collected and dried to give 0 32 g, containing 1/6 mole acetonitrile mp 175-177 C.

EXAMPLE 4

N-( 3,5-dichlorophenyl)-N'-( 1,2-diethylpyrazolidin- 4-yl)urea.

A solution of 4-amino-1,2-diethylpyrazolidine ( 1 26 g, 8.8 mmol) in anhydrous toluene ( 5 ml) was added to a solution of 3,5-dichlorophenyl isocyanate ( 1 71 g, 9 1 mmol) in dry toluene ( 20 ml) and the mixture stirred overnight The precipitated solid was collected, washed with toluene and dried to give the title compound, 1 94 g This was converted to the 1:1 maleate, mp 165-167 C.

H-390/396 EXAMPLE 5

N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-2-methoxybenzamide (a) 2-Methoxybenzoyl isocynanate 2-Methoxybenzamide ( 2 27 g, 15 04 mminol) and oxalyl chloride ( 2 4 g, 18 9 mmol) were heated together in 1,2-dichloroethane ( 40 ml) for 16 h at reflux The resulting solution was concentrated under reduced pressure to a residue which was re-evaporated with toluene to give the crude acyl isocyanate as an oil ( 2.94 g).

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-methoxybenzamide This compound was prepared by the procedure of example 1, using 3-aminoquinuclidine ( 0 63 g, 5 mmol) and 2-methoxybenzoyl isocyanate ( 1 0 g, 5 mmol), giving crude title product ( 1 6 g) which was purified as its 1:1 fumarate mp 187-188 C ( 0 79 g) H-390/396 EXAMPLE 6

N-(Azabicyclol 2 2 2 loctan-3-yl)-N'- ( 3,5-dichlorophenyl)thiourea Thiophosgene ( 1 0 ml, 1 51 g, 13 13 mmol) was suspended in water ( 10 ml) and stirred vigorously while 3,5-dichloroaniline ( 1 62 g, 10 mmol) in chloroform ( 8 ml) was added over 1 min Triethylamine ( 1 4 g, 13 86 mmol) was added and stirring was continued for 30 min.

The aqueous phase was discarded and the chloroform retained.

3-Aminoquinuclidine dihydrochloride ( 1 99 g, 10 mmol) was dissolved in water ( 2 ml) and treated with sodium hydroxide pellets until the p H was 9 This solution was then added to the above chloroform solution and the two stirred together overnight.

The aqueous phase was extracted 3 times with chloroform The combined organic phases were washed once with water An insoluble oil was separated The chloroform solution was dried (Na 2504)and evaporated, and the residue combined with the insoluble oil This material was triturated with dichloromethane for 3 h to give the title product, 2 09 g, mp 137-140 C, as hydrochloride containing 0 5 mole of dichloromethane not removable by drying.

H-390/396 EXAMPLE 7

Endo-N-( 3,5-dichlorophenyl)-N'-( 8-methyl-8- azabicyclol 3 2 1 loctan-3-yl)urea The above compound was prepared, following the procedure of Example 1, from 3,5- dichlorophenylisocyanate ( 0 94 g, 5 mmol) and (endo)-8-methyl-8-azabicyclol 3 2 1 loctan-3-amine ( 3-aminotropane) ( 0 70 g, 5 mmol) The product was isolated as the 1:1 maleate ( 0 58 g), mp 208-210 C.

EXAMPLE 8

N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N'-( 3- trifluoromethylphenyl)urea The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 63 g, 5 mmol) and 3-trifluoromethylphenyl isocyanate ( 0.94 g, 5 mmol) The product was isolated as the hydrochloride ( 1 02 g), mp 245-247 C.

EXAMPLE 9

N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N'- ( 4-chlorophenyl)urea The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0.63 g, 5 mmol) and 4-chlorophenyl isocyanate ( 0.768 g, 5 mmol) The product was purified as the 1:1 maleate ( 1 23 g), mp 182-183 C (dec).

H-390/396 EXAMPLE 10

N-(l-Azabicyclol 2 2 2 loctan-3-yl)-N - ( 1-methyl-i H-indol-3-yl)urea The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0.96 g, 7 62 mmol) and 1-methyl-3-isocyanatoindole (prepared from 1 5 g, 7 5 mmol, 1-methylindole-3-carbonyl azide which was prepared by reacting 1-methylindole-3-carboxylic acid with diphenylphosphoryl azide) The product was isolated as the 1:1 oxalate ( 0 32 g), one-third 2-propanol, mp (double) 120-124 C, 130-132 C.

EXAMPLE 11

N-(l-Azabicyclol 2 2 2 loctan-3-yl)-N'-( 2- benzothienyl)urea The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0.53 g, 4 21 mmol) and 2-isocyanatobenzothiophene ( 0.73 g, 4 17 mmol) The product was isolated as the 1:1 oxalate( O 18 g), quarter hydrate, mp 204-206 C.

H-390/396 EXAMPLE 12 (S)-(-)-N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N'-( 3,5- dichlorophenyl)urea (a) ( 3 S)-3-l(S)-a-methylbenzylaminolquinuclidine A mixture of 3-quinuclidinone hydrochloride ( 80 5 g, 0 5 mol), (S)-a-methylbenzylamine ( 180 g, 1 49 mol), sodium cyanoborohydride ( 31 g, 0 5 mol).

3 A molecular sieve ( 75 g), methanol ( 750 ml), and enough gaseous hydrogen chloride to give a p H of approx 6 was stirred in ice for 1 h, then at room temperature overnight, with addition of hydrogen chloride as necessary to maintain p H 6 The mixture was filtered and the filtrate evaporated The residue was dissolved in water, basified with potassium hydroxide, and extracted with ethyl acetate The ethyl acetate extracts were dried (Na 2 SO 4), evaporated and distilled.

2 4 evprtdaddsil.

The product fraction, bp 138-142 C ( 2 mbar) was fractionally crystallised as its hydrochloride to give the title compound ( 29 22 g), mp 238-242 C (phase change 193-200 C).

(b) (S)-(-)-3-aminoquinuclidine ( 3 S)-3-l(S)-a-methylbenzylaminolquinuclidine hydrochloride ( 24 38 g, 91 5 mmol) in water ( 80 ml) and glacial acetic acid ( 130 ml) was hydrogenated over 10 % Pd/C ( 1 2 g) at 50 C and 40 psi 2 5 (about 2 7 x 105 Pa) The mixture was filtered, the filtrate treated with concentrated hydrochloric acid ( 10 ml) and evaporated The residue was triturated with isopropanol to give the title compound dihydrochloride ( 16 6 g) A second crop ( 0 5 g) of H-390/396 dihydrobromide salt, mp 273-280 C (phase change > 240 C) lalD 5 = 16 o(C= 1, H 20) was obtained from the isopropanol mother-liquors by treating with excess hydrogen bromide and concentrating to low volume until crystallisation occurred.

(c) (S)-(-)-N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N'- ( 3,5-dichlorophenyl)urea The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine ( 1 98 g, 15 71 mmol) and 3,5-dichlorophenyl isocyanate ( 2.96 g, 15 74 mmol) to give the title compound ( 0 95 26 g), mp 200-201 'C, lal = -21 (C= 1, CHC 13.

D 3 EXAMPLE 13 (R)-(+)-N-( 1-Azabicyclol 2 2 2 loctan-3-yl) -N'-( 3,5-dichlorophenyl)urea (a) ( 3 R)-3-l(S)-a-methylbenzylaminolquinuclidine The above compound was obtained from the mother-liquors of the ( 3 S)-3-l(S)-a- methylbenzylaminolquinuclidine hydrochloride, the preparation of which is given in example 12 a, by fractional crystallisation as the 1:1 di-p-toluoyl-L-tartrate ( 44 8 g), mp 172-174 C.

H-390/396 (b) (R)-(+)-3-aminoquinuclidine ( 3 R)-3-l(S)-a-methylbenzylaminolquinuclidine di-p-toluoyl-L-tartrate ( 39 7 g, 62 6 mmol) was partitioned between ether ( 200 ml) and 5 M aqueous potassium hydroxide ( 50 ml) The aqueous phase was extracted again with ether, the combined ethereal phases dried (Na 2 SO 4) and evaporated The residue was hydrogenated in glacial acetic acid ( 130 ml) over 10 % Pd/C ( 1 1 g) at 50 C and 45 psi (about 3 1 x 10 Pa).

The mixture was worked-up as in example 12 b to give the title compound dihydrochloride ( 10 1 g), lal 5 = + 16 5 D (C= 1, H 20) with a second crop of dihydrobromide ( 0 5 g), mp 284-285 C (phase change > 230 C).

(c) (R)-(+)-N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N- ( 3,5-dichlorophenyl)urea The above compound was prepared, following the procedure of Example 1, from (R)-3-aminoquinuclidine ( 1.26 g, 10 mmol) and 3,5-dichlorophenyl isocyanate ( 1.88 g, O 10 mmol) to give the title compound quarter hydrate ( 1 35 g), mp 190-194 C (forms a gum at 180-183 C), lal 23 = + 23 (C= 1, CHC 1 13).

D 3 H-390/396 EXAMPLE 14

N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-3-trifluoromethylbenzamide (a) N-Trifluoromethylbenzoylurea A mixture of 3-trifluoromethylbenzoic acid ( 10 g, 52 6 mmol) and thionyl chloride ( 15 ml) was heated under reflux for 0 75 h The excess thionyl chloride was evaporated, urea ( 10 g, 167 mmol) was added to the residue, and the mixture heated at 100-110 C for 1 5 h The solid was extracted under reflux with water ( 20 ml), cooled, basified with sodium bicarbonate, the solid collected and recrystallised from aqueous acetic acid to give product ( 8 g), mp 191-193 C.

(b) N-lllH-azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-3-trifluoromethylbenzamide The above compound was preparedfrom 3-amino quinuclidine dihydrochloride ( 1 0 g, 5 mmol), 3-trifluoromethylbenzoylurea ( 1 16 g, 5 mmol) and diisopropylethylamine ( 1 29 g, 10 mmol) in pyridine ( 20 ml), by refluxing under nitrogen overnight The solvent was evaporated and the residue worked-up as in Example 1 The product ( 1 18 g) was converted to oxalate salt, mp 197-200 C.

H-390/396 EXAMPLE 15

N-lll 1-azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-4-methoxybenzamide The above compound was prepared, following the procedure of Example 14 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 4-methoxybenzoylurea ( 0.97 g, 5 mmol) and di-isopropylethylamine ( 1 29 g, 10 mmol) in pyridine ( 20 ml) The product ( 1 12 g) was converted to 1:1 maleate half hydrate, mp 166-168 C.

EXAMPLE 16

N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminol)carbonyll naphthalene-2-carboxamide (a) 2-Naphthoylurea The above compound was prepared, following the procedure of Example 14 a from 2-napthoic acid ( 8 2 g, 47.7 mmol), thionyl chloride ( 40 ml) and urea ( 10 g, 167 mmol) to give the title compound ( 7 1 g), mp 207-208 C.

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminol carbonyllnaphthalene-2-carboxamide The above compound was prepared, following the procedure of Example 14 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 2-naphthoylurea ( 1 07 g, 5 mmol) and di-isopropylethylamine ( 1 29 g, 5 mmol) in pyridine ( 20 ml) The title compound was isolated as hydrochloride half hydrate ( 1 39 g), mp 271-273 'C (dec).

H-390/396 EXAMPLE 17

N-lll 1-Azabicyclol 22 22 loctan-3-yllaminol carbonyll-2-furancarboxamide The above compound was prepared, following the procedure of Example 14 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 2-furoylurea ( 0 77 g, mmol), and diisopropylethylamine ( 1 3 g, 10 mmol) in pyridine ( 20 ml) The product ( 0 58 g) was converted to the 1:1 succinate mp 156-159 C.

EXAMPLE 18

N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll -2,6-dimethylbenzamide (a) 2,6-Dimethylbenzoylurea The above compound was prepared, following the procedure of Example 14 a, from 2,6-dimethylbenzoic acid ( 10 g, 66 7 mmol), thionyl chloride ( 15 ml) and urea ( 10 g, 168 mmol) to give the title compound ( 8 9 g), mp 210-213 C.

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2,6-dimethylbenzamide The above compound was prepared, following the procedure of Example 14 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 2,6-dimethylbenzoylurea ( 0 96 g, 5 mmol) and diisopropylethylamine ( 1 3 g, 10 mmol) in pyridine ( 20 ml) by refluxing for 4 days The product was recrystallised from acetonitrile to give the title compound quarter hydrate ( 0 54 g), mp 230-231 C.

H-390/396 EXAMPLE 19

N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-2-thiophenecarboxamide The above compound was prepared, following the procedure of Example 14 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 2-thienoylurea ( 0 85 g, 5 mmol) and diisopropylethylamine ( 1 3 g, 10 mmol) in pyridine ( 20 ml) The product ( 0 79 g) was converted to hydrochloride half hydrate, mp 232-233 C.

EXAMPLE 20

N-lll 1-Azabicyclol 2 2 2 loctan-3-yl 3 aminol carbonyll-2-fluorobenzamide (a) 2-Fluorobenzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-fluorobenzamide ( 0 97 g, 6 98 mmol) and oxalyl chloride ( 1 08 g, 8 36 mmol) in 1,2-dichloroethane ( 20 ml) to give crude product ( 1.3 g).

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-fluorobenzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 63 g, 5 mmol) and crude 2-fluorobenzoyl isocyanate ( 1 3 g, ca 7 mmol) The product ( 1 35 g) was converted to the 1:1 succinate, mp 187-188 C.

H-390/396 EXAMPLE 21

N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-ethoxybenzamide (a) 2-Ethoxybenzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-ethoxybenzamide ( 1 15 g, 6 97 mmol) and oxalyl chloride ( 1 08 g, 8 36 mmol) in 1,2-dichloroethane ( 20 ml) to give crude product ( 1.59 g).

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-ethoxybenzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 63 g, 5 mmol) and crude 2-ethoxybenzoyl isocyanate ( 1 59 g, ca 7 mmol) The product ( 1 77 g) was converted to the 1:1 fumarate, mp 198-199 C.

H-390/396 EXAMPLE 22

N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-isopropoxybenzamide (a) 2-Isopropoxybenzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-isopropoxybenzamide ( 0.44 g, 2 46 mmol) and oxalyl chloride ( 0 38 g, 2 97 mmol) in 1,2-dichloroethane ( 10 ml) to give crude product ( 0 58 g).

(b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-isopropoxybenzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 31 g, 2 46 mmol) and crude 2-isopropoxybenzoyl isocyanate ( 0 58 g, ca 2 5 mmol) The product ( 0 51 g) was converted to the 1:1 fumarate, mp 171-175 C.

EXAMPLE 23

2-Allyloxy-N-lll 1-Azabicyclol 2 2 2 l octan-3-yllaminolcarbonyllbenzamide (a) 2-Allyloxybenzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-allyloxybenzamide ( 0 39 g, 2 2 mmol) and oxalyl chloride ( 0 35 g, 2 74 mmol) in 1.2-dichloroethane ( 10 ml) to give crude product ( 0 53 g).

H-390/396 (b) 2-Allyloxy-N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyllbenzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 28 g, 2 2 mmol) and 2-allyloxybenzoyl isocyanate ( 0 53 g, ca 2 2 mmol) The product ( 0 61 g) was converted to the 1:1 fumarate.

EXAMPLE 24

N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-pyridinecarboxamide (a) 2-Pyridoylurea A mixture of sodium ( 0 23 g, 10 mmol), urea ( 0 8 g, 13.3 mmol) and liquid ammonia ( 40 ml) was stirred until the blue colour was discharged, then ethyl 2-pyridinecarboxylic acid ( 2 85 g, 18 8 mmol) was added all at once After I h the ammonia was evaporated and the residue triturated with water to give the above compound, mp 183-185 C.

(b) N-lll 1-Azabicyclol 2 2 2 l-3-yllaminol carbonyll-2-pyridinecarboxamide The above compound was prepared, following the procedure of Example i 4 b, from 3-aminoquinuclidine dihydrochloride ( 1 0 g, 5 mmol), 2-pyridoylurea ( 0 82 g, 5 mmol) and di-isopropylethylamine ( 1 3 g, 10 mmol) in pyridine ( 20 ml) by refluxing for 4 days The pyridine was evaporated and the residue partitioned H-390/396 between ether and 10 % aqueous w/v citric acid The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound ( 0 60 g) which was converted to the 1:1 fumarate, mp 202-203 C.

EXAMPLE 25

Endo-N-lll 8-methyl-8-azabicyclol 3 2 1 loctan-3-yll aminolcarbonyll-2-methoxybenzamide The above compound was prepared, following the procedure of Example 1, from endo-3-aminotropane ( 0.70 g, 5 mmol) and 2-methoxybenzoyl isocyanate ( 1.0 g, 5 mmol) The product ( 2 1 g, crude) was converted to hydrochloride ( 0 65 g).

EXAMPLE 26

N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-methylbenzamide (a) 2-Methylbenzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-methylbenzamide ( 0 95 g, 7 mmol) and oxalyl chloride ( 1 08 g, 8 36 mmol) in 1,2-dichloroethane ( 20 ml) to give crude product ( 1 35 g).

H-390/396 (b) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-methylbenzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( O 63 g, 5 mmol) and crude 2-methylbenzoyl isocyanate ( 1 35 g, ca 7 mmol) The product ( 1 23 g) was converted to the 1:1 fumarate, mp 216-217 C.

EXAMPLE 27

N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-((cyclopropyl)methoxy)benzamide (a) 2-((Cyclopropyl)methoxy)benzamide 2-Hydroxybenzamide ( 5 17 g, 37 74 mmol) and sodium hydroxide ( 1 5 g, 37 5 mmol) in ethanol ( 20 ml) were refluxed for 1 h to give a clear solution.

(Bromomethyl)cyclopropane ( 5 09 g, 37 7 mmol) was added and the mixture refluxed for 36 h The solvent was evaporated and the residue triturated thoroughly with ether and water to give the above compound ( 4 37 g).

(b) 2-((Cyclopropyl)methoxy)benzoyl isocyanate The above compound was prepared, following the procedure of Example 5 a, from 2-((cyclopropyl)methoxy)benzamide ( 0 95 g, 5 mmol) and oxalyl chloride ( 0 79 g, 6 2 mmol) in 1,2-dichloroethane ( 20 ml) to give the crude product ( 1 4 g).

H-390/396 (c) N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-((cyclopropyl)methoxy)benzamide The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine ( 0 63 g, 5 mmol) and crude 2-((cyclopropyl)methoxy)benzamide ( 1.4 g, ca 5 mmol) The product was converted to the 1:1 oxalate, half hydrate mp 128-131 C.

EXAMPLE 28 (S)-N-l l l 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-methoxybenzamide The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine ( 0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate ( 1 26 g, 7 mmol) The product ( 1 44 g) was converted to the 1:1 fumarate, mp 158-159 C (dec).

EXAMPLE 29 (R)-N-lll 1-Azabicyclol 2 2 2 loctan-3-yll aminolcarbonyll-2-methoxybenzamide The above compound was prepared, following the procedure of Example 1, from (R)-3-aminoquinuclidine ( 0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate ( 1 33 g, 7 5 mmol) The product ( 1 49 g) 'was converted to the 1:1 fumarate, mp 158-159 C (dec).

A' H-390/396 EXAMPLE 30 (Endo)-O-l 8-Methyl-8-azabicyclol 3 2 1 loctan-3-yll- N-( 3,5-dichlorophenyl)carbamate Tropine ( 1 0 g, 7 04 mmol) was added to 3,5-dichlorophenyl isocyanate ( 1 32 g, 7 02 mmol) in dichloromethane ( 20 ml) at room temperature under nitrogen The reaction mixture was stirred for 20 h, the solid collected and partitioned between ether and dilute hydrochloric acid The insoluble solid was collected and washed with dilute hydrochloric acid then ether to give the above compound as its hydrochloride ( 0.73 g), mp 288-294 C (dec).

H-390/396-fl

Claims

1 A heterocyclic compound of the general formula A-X-NHCW-Y-B (I) or a pharmaceutically acceptable acid addition salt thereof where A represents an aromatic radical of the formula R 1 O z 2 z, (a) R 1 c) z cc) R I 004 (b), R O or (d) lwhere the free valence is attached to either fused ring of formula (a) or (b)l RI represents hydrogen or one or more same or different substituents selected from lower alkyl, lower alkoxy, hydroxy, halogen, halo(lower)alkyl, amino, nitro, carboxamido, phenyl(lower)alkyloxy (in which the phenyl group may be optionally substituted by one or more lower alkyl, loweralkyloxy or halo substituents), (lower)alkylamino, di(lower)alkylamino or acylamino H-390/396-fl 1 2 2 Z -z represents CH 2-CH, NR -CH, O-CH, S-CH, CH 2-N, O-N, S-N, NR -N, CH-NR or N-NR, lwhere R 2 is hydrogen, (lower)alkyl or phenyl or phenyl(lower)alkyl in which the phenyl groups may optionally be substituted by one or more lower alkyl, lower alkyloxy or halo substituentsl Z 3 _Z 4 represents CH=CH, O-CH 2 or N=CH Z represents N or CH z 6 represents 0, S or NH X represents a direct bond or CO, W represents oxygen or sulphur, Y represents NH or 0, B represents a saturated azacyclic ring of the formula X 3 (OCH 2 N-R (II) where N is 2,3 or 4 and R 3 is hydrogen, or (lower)alkyl, or (H 2)2 (III) or the N-oxide thereof or (IV) -R 3 H-390/396-fl where m is 1, 2 or 3 and R has the meaning given above or (CH-)n (V) / where p is 0, 1 or 2 or / N-R (VI) R 5 where R 4 and R 5 are each hydrogen or lower alkyl with the proviso that when X is a direct bond, A represents a group of formula (c) or (d) and W represents oxygen, then the ring (c) or (d) does not contain a substituent ortho to the -X-NHCW-Y-B side chain.

2 A compound as claimed in claim 1

3 A compound as claimed in claim 1 of the formula R 8 in which X is CO.

or 2 in which A is (XIV) where R 6 to R 9 are independently hydrogen or a substituent R 1 as defined in claim 1.

4 A compound as claimed in claim 3 in which R 6 is lower alkoxy and R 7, R 8 and R 9 are hydrogen or R 6 is lower alkyloxy or cyclo(lower)alkyl(lower)alkyloxy, H-390/396-fl ( -39- R 7 is hydrogen, R is amino or loweralkylamino and R 9 is halo or R and R are chloro and R and R are hydrogen.

A compound as claimed in any one of the preceding claims wherein B is tropan-3-yl or quinuclidin-3-yl.

6 A compound as claimed in claim 1 in which A represents a radical of formula (a) or (b) where R is hydrogen or a single halo(lower)alkyl, lower alkoxy, lower alkyl, amino, (lower)alkylamino, di(lower)alkylamino or (lower)alkanoylamino substituent or A represents a radical of formula (c) in which Z 5 represents CH and R represents hydrogen or one or more same or different substituents selected from lower alkyl, lower alkoxy, hydroxy, halogen, halo(lower)alkyl, amino, nitro, carboxamido(lower)alkylamino, di(lower)alkylamino or (lower)alkanoylamino.

7 N-( 1-Azabicyclol 2 2 2 loctan-3-yl)-N'-( 3,5- dichlorophenyl)urea or a pharmaceutically acceptable salt thereof.

8 N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll2-methoxybenzamide or a pharmaceutically acceptable salt thereof.

9 N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll3,5-dichlorobenzamide, (endo)-N-( 3,5-dichorobenzoyl)-O-( 8-methyl-8azabicyclol 3 2 1 loct-3-yl)carbamate or N-( 3,5-dichlorophenyl)-N'-( 1,2-diethylpyrazolidin-4 -yl)urea or a pharmaceutically acceptable salt thereof.

H-390/396-fl N-(Azabicyclol 2 2 2 loctan-3-yl-N'-( 3,5dichlorophenyl)thiourea, (endo)-N-( 3,5-dichlorophenyl)-N'-( 8-methyl-8azabicyclol 3 2 11 octan-3-yl)urea, N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'- ( 3-trifluoromethylphenyl)urea, N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'- ( 4-chlorophenyl)urea, N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'-( 1-methyl- 1 H-indol-3-yl)urea, N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'- ( 2-benzothienyl)urea, (S)-(-)-N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'- ( 3,5-dichlorophenyl)urea, (R)-(+)-N-( 1-azabicyclol 2 2 2 loctan-3-yl)-N'- ( 3,5-dichlorophenyl)urea, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 3-trifluoromethylbenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-4-methoxybenzamide or N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll naphthalene-2-carboxamide or a pharmaceutically acceptable salt thereof.

11 N-lll 1-Azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll2-furancarboxamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll2,6-dimethylbenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-thiophenecarboxamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-fluorobenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-ethoxybenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-isopropoxybenzamide, H-390/396-fl 2-allyloxy-N-lll 1-azabicyclol 2 2 2 loctan-3-yll amino carbonyllbenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll2-pyridinecarboxamide, (endo)-N-lll 8-methyl-8-azabicyclol 3 2 1 loctan-3-yll aminolcarbonyll-2-methoxybenzamide, N-lllE-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-methylbenzamide, N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminolcarbonyll- 2-((cyclopropyl)methoxy)benzamide, (S)-N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-2-methoxybenzamide, (R)-N-lll 1-azabicyclol 2 2 2 loctan-3-yllaminol carbonyll-2-methoxybenzamide or (endo)-O-l 8-methyl-8-azabicyclol 3 2 11 octan-3-yll- N-( 3,5-dichlorophenyl)carbamate or a pharmaceutically acceptable salt thereof.

12 A process for preparing a compound as claimed in claim 1 which comprises (a) reacting an isocyanate or isothiocyanate of formula (VII) A-X-NCW (VII) (where A, W and X are as defined in claim 1) with an amine or alcohol of formula (VIII) B-YH (VIII) (where B and Y are as defined in claim 1) or (b) a compound of general formula (IX) A-X-NHCWNH 2 (IX) H-390/396-fl (where A, W and X are as defined in claim 1) with an amine of general formula B-NH 2 (X) (where B is as defined in claim 1) to give a compound of formula (I) in which Y represents NH or (c) acylating a compound of formula NH 2 CWY-B (XI) (where Y, W and B are as defined in claim 1) with an acylating agent containing the group A-CO- (where A is as defined in claim 1) to give a compound of formula (I) in which X represents CO or (d) reacting an isocyanate or isothiocyanate of formula B-NCW (XII) (where B and W are as defined in claim 1) with an amine of formula A-NH 2 (XIII) (where A is as defined in claim 1) to give a compound of formula (I) in which X represents a direct bond and Y is NH or (e) oxidising a compound of formula (I) in which B represents the radical (III) to give a compound of formula (I) in which B represents the N-oxide of the radical (III) or H-390/396-fl (f) converting a base of formula (I) into a pharmaceutically acceptable acid addition salt thereof, or (g) resolving a racemic compound of formula (I) into an optical isomer thereof.

13 A process for preparing a compound claimed in claim I substantially as hereinbefore described with reference to any one of Examples I to 4.

14 A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to any one of Examples 5 to 16.

A process for preparing a compound claimed in claim I substantially or hereinbefore described with reference to any one of Examples 17 to 30.

16 A compound as claimed in claim 1 whenever prepared by the process claimed in any one of claims 12 to 15.

17 A pharmaceutical composition comprising a compound as claimed in any one of claims I to 11 and 16 in association with a pharmaceutically acceptable carrier.

18 A pharmaceutical composition as claimed in claim 17 in the form of a spray or as drops for nasal administration.

H-390/396-fl 19 A product containing a compound as claimed in any one of claims 1 to 11 and 16 and a cancer chemotherapeutic agent as a combined preparation for simultaneous, separate or sequential use in cancer therapy.

Published 1989 at The Patent Office, State House, 6671 High Holborn, London WC 1 R 4 TP Further copies maybe obtalned from The Patent Office.

8 ale O Brancb, St Mare Cray OJ'oingon went BE 5,P D Printed by Multiplex techlniques Itd, St Mary Cray, Kent, Con 1/87