GB2182935A

GB2182935A - Quinoline derivatives

Info

Publication number: GB2182935A
Application number: GB08627302A
Authority: GB
Inventors: John Leheup Archibald; Terence James Ward
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1985-11-15
Filing date: 1986-11-14
Publication date: 1987-05-28
Also published as: ATE72814T1; DE3684009D1; HU197738B; EP0234098B1; FI864642A0; PT83716B; IE59660B1; AU6505986A; ZA868556B; IL80642A; KR870004962A; CA1285945C; FI85700C; GB8627302D0; FI864642A; PT83716A; JPS62149674A; IL80642A0; EP0234098A1; ES2041644T3

Abstract

The invention relates to compounds of formulaor a salt thereof, wherein =X- is =CH- or =N-, R and R<sup>1</sup> independently represent hydrogen, halogen or lower alkoxy and R<sup>2</sup> is hydrogen or a substituent selected from halogen, lower alkyl, lower alkoxy or halolower alkyl which compounds exhibit psychotropic activity and are useful as anti-depressants.

Description

1 GB 2 182 935 A 1

SPECIFICATION

Heterocyclic compounds This i nvention relates to heterocyclic corn pou nds, more pa rticu larly piperidi ne derivatives, to processes for preparing them and to pharmaceutical compositions containing them.

In our UK Patent Publication No. 2073176B there are described and claimed a class of piperidine derivatives which exhibit psychotropic activity in standard pharmacological test procedures and are potentially useful as anti-depressants. In general the compounds are specific inhibitors of 5hydroxytryptamine re-uptakein vitro 1() and in vivo, and therefore are also useful in any othertherapeutic applications where such pharmacological 10 specificity is beneficial. The piperidine derivatives of UK Patent Publication 2073176B have the formula (11) 9_ 2 1 v 3 Ar-Y-CHR (CHR) n -NS.)-NR CXN-ZR (II) and acid addition and quaternary ammonium salts thereof, wherein the dotted line represents an optional 20 bond, Ar represents a ring system of formula R 5 4C 6 R Q R 25 in which Q is 0, S, -CR 7 = CR"-, -N =CR"- and -N =-;R', R' and R', and R' and Wwhen present, each represent hydrogen or a substituent selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, N02, NH2, halo loweralkyl, hydroxyloweralky], aminoloweralkyl, substituted amino, loweralkoxycarbonyl, cyano, CONH2 and hydroxy; and additionally either R'and R'when adjacent or R'and Wwhen adjacent, togetherwith the 30 carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or hetero cyclic ring optionally carrying one or more substituents as defined above; R is an optionally substituted aryl or heteroaryl radical or a cycloalkyl radical containing 5to 7 carbon atoms; W, R 2, R 3 and R9 are each hydrogen or a lower alkyl group; n is 0 or 1; X is =0 or =S; Y is -0- or a direct bond and Z is -CO-or-CH2-with the provisosthat (i) when Ar is unsubstituted phenyl and R9 is hydrogen then Y is -0- and (ii) when Z is CH2 and Ar represents phenyl or pyridyl group either of which may be substituted then R' is hydrogen.

The term'lower'as used in connection with alkyl or alkoxy groups meansthatsuch groups contain 1 to 6 carbon atoms. 'Substituted amino'includes groups such as alkyl- ordialkyl- amino, acylamino e.g. lower alkylcarbonylamino, ureldo or sulphonylamino, e.g. lower alkylsulphonamido ordi-lower alkylsulphonylamino.

Pharmaceutical compositions comprising compounds of formula (11) are claimed in our UK Patent Publica tion No. 2108489B.

The compounds of formula 11 were tested for psychotropic activity bytheir abilityto inhibit p-chloro amphetamine (pCA) induced hyperactivity andlor by their ability to inhibit 5-hydroxytryptamine (5-HT) re uptake in brain slices.

We have now surprisingly found that a small class of compounds, not specifically disclosed in either of the above mentioned specifications, having formula 11 above wherein Ar is naphthyl or quinolyl and R is quinolyl are extremely potent inhibitors of pCA induced syndrome.

Accordinglythis invention provides compounds of formula so R R 2 R 1 <X CH2 N YNHCONHCO-Ce N (I) wherein =X- is =CH- or= W, Rand R' independently represent hydrogen, halogen or lower alkoxy and R % 60 hydrogen or a substituent selected from halogen, lower alkyl, lower alkoxy or halolower alkyl. "Lower" means 1 to 6 carbon atoms.

Examples of the group R (and W) are hydrogen, fluorine, chlorine and methoxy. Examples of R 2 are hydrogen, fluorine, chlorine, trifluoromethyl, methyl and methoxy. Especially preferred compounds of formula 1 have a naphth-2-yImethyl or quinol-4 or 6-yImethyl group bonded to the piperidine moiety, each 65 2 GB 2 182 935 A 2 optionally substituted as described above. Most preferably the compounds have a 6-fluoronaphth-2-yimethyl or unsubstituted quinol-6-yl methyl g rou p.

Also preferred are compounds wherein the urea function is substituted by a quinol-4 or 6-oyl group optionally substituted as herein before described. Most preferably the urea function is substituted by an unsubstituted quinol-6-oyl group.

Preferred compounds of the invention are N-[[[1 -(2-naphthalenyimethyi)-4piperidinyllaminol-carbonyll6-quinolinecarboxamide, (A) N-[[[1-(quinol-6-yimethyi)-4-piperidinyllaminol-carbonyll-6quinolinecarboxa mide, (B) and N-[[[1-(6-fluoro-2-naphthalenylmethyi)-4-piperidinyll-aminolcarbonyll-6-qui nolinecarboxamide. (C) Representative compounds of this invention were tested for their abil ityto inhibit pCA induced syndrome in rats bythe standard procedure described below:

Inhibition ofp-chloroamphetamine (pCA)-inducedstereotypy Vehicle ordrug (5 dose levels) were administered p.o.to sixgroups of 6-8 male Sprague-Dawley rats (300-4009) followed, 90 minutes later, by pCA (1 Omg/kg i.p.). The animals were then placed in individual is observation chambers and, 30 minutes after pCA administration, the intensity of the pCA-induced 5-HTsyndrome was assessed according to the following scoring system:

hind-limb abduction) head-weaving 0,1,2or3accorclingto 20 severity fore-paw treading tremor 0 (absent) or 1 (present) Therefore, the maximum score for each animal was 10. The inhibition of pCA induced stereotypy is calculated for each dose level asfollows:

C-T 100% C where C= control group total score at 30 minutes post pCA.

T =group total score of treated group at30 minutes post pCA.

For each dose a% effect is calculated.

The results obtained from the tests using 5 different dose levels of the drug allowthe ED50 value (i.e. the 35 dose required to produce 50% inhibition of pCA induced stereotypy) to be calculated.

In the aforementioned test the representative compounds A, Band C antagonised pCA-induced stereotypy in a dose-dependent manner and gave thefollowing EDro values:

Compounds ofFormulal ED50 (mglkg) 40 A 2.7 B 6.5 C 2.1 The testwas carried out using the free bases except for compound C which was tested in the form of its 45 maleate salt and the result corrected for amount of active material.

These values are markedly more potentthan values found for compounds disclosed in the specification of

UK Patent Publication No. 2073176B.

At 50 mg/kg the compounds A, B and C showed a 99% inhibition of syndrome.

In the same test one of the most preferred compounds from UK Patent Publication No. 2073176B namely, 50 1 -benzoyi-3-[1 -(na phth-2-yl methyl) pi perid-4-yll urea (panuramine) had an ED50 of 16.2 mglkg (mono hydrochloride corrected for amount of active ingredient). At 50 mg/kg this compound showed a ca. 78% inhibition of syndrome.

In addition compounds of the present invention have also been found to possess a long duration of action in reducing the intensity of the pCAsyndrome. In a test involving administering compound C at a dose level 55 of 6 mglkg p.o. to a group of 8 male Sprague-Dawley ratsthe percentage inhibition of pCA-induced stereo typy (assessed according to the method above) atvarioustimes after administration of 5-HT inhibitorwas as shown below:

Time from 5-HT dosing % Inhibition ofpCA 60 induced stereotyp y 2 ca. 79% 6 82.8 12 56.9 16 57.6 65 W 3 GB 2 182 935 A 3 In a related test (with modified scoring) panuramine at a dose level of 15 mg/kg produced a 65.1%inhibition aftertwo hours and 12.2% inhibition after 16 hours indicating a much shorterduration of action. Along duration of action hasthe advantage that dosing is lessfrequent and accordingly patient compliance with the dosing regimen is generally improved, especially if reduced to once a day.

The compounds B and Cwere also tested fortheirabilityto potentiate 5hydroxy-L-tryptophan induced 5 behavioural syndrome in rats. Thetest procedure is described below (updated from that described in UK 2073179B).

Potentiation of 5-hydroxytryptophan (5-HTP)-inducedbehaviour Groups of 10maleSprague-Dawley rats (310-360g) were dosed p.o. with vehicle or drugs. Ninety minutes 10 later 5-HTP(50 mg/kg s.c.) was administered and the an ima Is placed in individual observation chambers (peripheral decarboxylation was prevented by 25mgAg i. p. carbidopa administered 60 m in utes before 5 HTP). Head shakes were counted overthe period 30-45 minutes after 5-HTP and the intensity of the 5-HT syndrome was scored i m mediately afterwards using the system described for the pCA procedure above.

Percentage potentiation of syndrome was calculated as follows:

is hind-limb abduction 0, 1, 2 or 3 according to severity head-weaving tremor 0 (absent or 1 (present) fore-paw treading 20 Percentage potentiation was calculated from the following:

test sco re - co ntro 1 sco re X 100 maximum possible score -control score 25 In this test compounds Band Chad an ED50 value of 7.3 mg/kg and 2.4 mg/kg respectively (the latter corrected for amount of active ingredient).

These values are also markedly lowerthan the value found forthe compound panuramine HCI saltwhich in the same test had an ED50 value of 27.4 mg/kg (corrected for amount of base).

In vitro tests have shown that compounds of formula] also have a marked degree of selectivity in inhibiting uptake of 5-HT into rat brain synaptosomes relative to uptake of 'H noradrenaline. The test procedure in volved obtaining synaptosomal preparations from male Sprague Dawley rats according to the method of Grey and Whittaker as modified by Wood& Wyl lie. A[ iquots of the synaptosomal preparation were then incubated with tritrated noradrenaline (NA) or 5-HT at a temperature of 37'for 4 minutes. The active syn- 35 aptosomal accumulation of labelled substrate was measured by filtration and scintillation counting. The effect at a range of concentrations of test compound enabled 1C50 values and selectivity ratios to be calculat ed.

Grey and Whittaker, -J.Anat.9679 (1962) Wood and Wyl lie, J.Neurochemistry,37,795 (1981) The values found for compounds Band C and panuramine are shown below:

Compound ICEO(KM) 5-HTuptake NA Selectivity 45 Ratio B 0.043 8.9 207 C 0.082 37.0 450 panuramine 0.063 8,5 135 so 50 The compounds of the present invention can be prepared by any of the appropriate general procedures described in our UK Patent Publication 2073176B.

In particularthe compounds of the present invention can be prepared by reacting a compound of formula R 55 R 1 1 CH 2 W X 60 wherein X, R and R' are as defined above and W represents a leaving group such as halogen (e.g. chlorine, bromine or iodine), an organic sulphonyloxy radical (e.g. tosyloxy, mesyloxy) or a radical of formula - OSO2OR 3 where R 3 is 4 GB 2 182 935 A 1 R -CH 2W) -R X (i.e. sulphate) with a compound of formula IV 4 HNC- NHCONHCO R 2 10 eCN (IV) 15 wherein R' is as hereinbefore defined.

This reaction is preferably carried out in the presence of base e.g. an alkali metal carbonate such as K2C03 or an amine such as triethylamine or diisopropylethyla mine, otherwise the reaction maybe carried out by heating in the presence of an inert solvent, e.g. toluene.

A second method for preparing the compound of this invention comprises reacting a compound of 20 formula R R 1 1 CH 2NC-NH 2 -c:c X (V) wherein X, Rand R' areas defined above with a compound of formula R 2 55;, OWC0 (VI) 35 -t J.

wherein R'isas hereinbefore defined. This reaction is conveniently carried out at room temperature and in -an inert solvent. The starting material (V) may be prepared by processes described in U K Patent Specification

No. 1,345,872.

Afurther process for preparing the compounds of this invention comprises reacting the starting materia1V with a compound of formula R 45 H 2 NCONHCO nu wherein R 2 is as defined above.

Conveniently this reaction is carried out in the presence of a suitable inert solvent, for exampletoluene, pyridine, xylene, chlorobenzene, dimethylformamide or dioxan; pyridine being preferred. Preferablythe reaction is carried out by heating at reflux until complete.

A still further process for preparing the compound of this invention comprises acylating a compound of formula R 1 R WX, ".- CH 2 N 0 r 11 1 N-WH 2 VIII wherein R, R' and X areas defined above, with an acylating agent containing the group GB 2 182 935 A 5 _OC N R 2 Exampiesare reactive derivatives of quinoline carboxylic acid such astheacid anhydride, mixedanhydride,acid halide or activated estersuch as used in peptide chemistry. Othermethodsof acylation arewell known in the art such as those employing coupling reagents such as carbodiimides, e.g. dicyclohexylcarbodiimide. The compound of this invention may also be prepared by reducing a compound of formula 0 0 R 11 11 1 R CH 2 NC/- MC MC N or R N 0 0 1 H 2 -N A NJ R _CX B X o" R 2 2 N (IX) (X) wherein B represents an anion, e.g. a halide ion. Forexample catalytic hydrogenation e.g. in the presenceof 30 Raney nickel or platinum catalyst givesthe compounds of the invention. The reduction may also be effected by a process described and claimed in our UK Patent Specification No. 1542137. Such a reduction process employs an alkali metal borohydride in a secondary alkanol having 3-5 carbon atoms, e.g. isopropanol.

Alternatively reduction of the compound of formula (X) using an alkali metal borohydride in methanol gives the dehydropiperidine compound of formula (]X).

Yet a further process for preparing the compound of this invention comprises reacting a compound of formula 11 wherein W is hydroxywith a compound of formula W in the presence of a catalyst, e.g. a nickel catalyst such as Raney nickel.

In any of the aforementioned processes the compounds of the invention may be isolated in free baseform or as salts, e.g. an acid addition salt. Quaternisation of the tertiary nitrogen of the piperidine ring may be included as an optional after step, e.g. using alkyl or aryl lower alkyl halides, e.g. methyl iodide, benzyl chloride.

Acid addition salts include salts with pharmaceutically acceptable acids such as the hydrochloric, sulphu ric, nitric, hydrobromic, hydroiodic, acetic, citric, tartaric, phosphoric, fumaric, malonic, formic and maleic acid addition salts.

This invention further provides a pharmaceutical composition comprising a compound of formula.] or a pharmaceutically acceptable saitthereof in association with a pharmaceutical ly acceptable carrier. Anysuit able carrier known in the artcan be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid ora mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), 50 suppositories and pessaries. Asolid carriercan be, for example, one or more substanceswhich may also act asfiavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet-disinteg rating agents; it can also be an encapsulating material. In powders the carrier is afinely divided solid which is in admixture with the finely divided active ingredient. In tabletsthe active ingredientis mixed with a carrier having the necessary compression properties in suitable proportions and compacted in 55 the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers includejor example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium car boxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to includethe formulation of an active ingredientwith encapsulating 60 material as carrierto give a capsule in which the active ingredient (with orwithout 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 ingredientjor example, can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutical ly 65 6 - GB 2 182 935 A 6 acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, perservatives, 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 containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols 5 and polyhydric alcohols e.g. glycerol and glycols) and their derivatives, and oi Is (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also bean oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral adminis tration.

1() Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised 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.

Preferably the pharmaceutica I composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient, the 15 unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be for exam pie, 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 a dose of composition maybe 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 carrierwhere the compounds are in unit dosage form.

The following Examples illustrate the invention:

Example 1

N-[[[1-(2-Naphthalenylmethyl)-4-piperidinyllaminolcarbonyll-6quinolinecarbo xamide A suspension of 4-amino-1 -(2-naphthalenyl methyl)-piperidine (1.4g, 5. 83m mol) and N-aminocarbony]-6quinoline carboxamide (1.08g, 5.02mmol) in pyridine (7cM3) was refluxed for 7 hours. The mixture was leftat room temperature overnightthen more 4-amino-1 -(2-na phtha 1 e nyi-m ethyl) pi perid ine (0.3g, 1Ammol) was added and refluxing was continued for 5 hours. Unclissolved solid was filtered off f rom the hot mixture and the filtrate was diluted with water (8cm') and filtered again. The filtrate was further diluted with water and cooled in ice. The deposited solid was collected and dried (0.46gJ then recrystallised from ethanol (50cmIJito give 0.30g of the title compound, m.p. 211-13'C.

Analysis Found: C, 73.79; H, 6.07; N, 12.64 C27H26N402 requires C,73.95; H, 5.98; N, 12.78.

Example 2

N-[[[1-(quinol-6-ylmethyl)-4-piperidinyllaminol-carbonyll-6quinolinecarboxa mide Asuspension of 4-amino-1 -(6-quinolinyimethyi)piperdine (1.0g, 4.15mmol) and N-aminocarbony]-6quinolinecarboxamide (0.7g, 3.26mmol) in pyridine (6mi) was refluxed rapidlyfor 6 hours. More 4-amino-l (6-quinolinyimethyi)piperidine 0.2g, 0.83mmol) was added and refluxing continued for a further 6 hours. The mixture was cooled slightly and diluted with ethyl acetate (1 Orni) then cooled in ice. The precipitated solid was collected, washed well with ethyl acetate and dried (0.97g,).

The productwas triturated in boiling ethyl acetate for 1/2 hour and collected from the hot mixture to givethe 45 title compound 0.85g, mp 202-4'C.

Analysis Found: C, 70.05 H, 5.93, N, 15.59 C26H25N502.1/41-120 requires C,70.33; 1-1,539; N, 15.77 The maleate 1/41- 120 salt of the title compound has an m.p. 190-1 OC.

Eka mp le 3 N-[[[1-(6-Fluoro-2-naphthalenylmethyl)-4-piperidinyll-aminolcarbonyll-6quin olinecarboxamide N-[[(4-Piperidinyl)aminolcarbonyll-6-quinolinecarboxamide (1.49g, 5mmol) was ground in a mortar and 55 pestle and suspended in dry DIM F (1 5m 1) then diisopropylethyla mine (0. 65g, 5.04mmol) was added. To this stirred mixture was added a solution of 2-bromomethyi-6-fluoronaphthalene (1.32g, 5.02mmol) in dry DIVIF (5mi)overl hour. After stirring the mixture fora further 1 hour, more 2- bromo-methyi-6-fluoronaphthalene (0.1 g, 0.38mmol) in dry DMF (2mi) was added. The mixture was stirred at room temperature overnightthen diluted with water (40mi) to precipitate a solid which was collected, washed well with water and sucked dry 60 on the sinter. This was washed well with diethyl ether, dissolved in chloroform and the solution dried over M9S04 and evaporated to give a solid (2.38g).

The productwas suspended in boiling ethanol (35mi) and maleic acid (0.64g, 5.52mmol) was added. The mixture was stirred while cooling to room temperature for 3 hours, and the title compound as the maleate salt was collected and dried (1.81 g) m p 200-VC (softens).

Z 7 W 10 Analysis Found: C, 65.02; H, 5.26; N, 9.86; C27H25FN402.C4H404requires C, 65.03; H, 5.10; N,938.

GB 2 182 935 A 7 Example4 N-[[[1-(6-Fluoro-2-naphthalenylmethyl)-4-piperidinyllaminolcarbony11-6-quin oline carboxamide A solution of 6-isoquinolinoylisocyanate (4.16g, 5% excess) in CH2C12 (20 mi) is added dropwise to a stirred solution of 4-amino-1 -[(6-fluoro-2naphthalenyl)-rpethyllpiperidine (5.29, 20 mmol) in CH2C12 (100 M0 protected f rom atmospheric moisture. After addition is completed the reaction is stirred for a further 1 hour, then evaporated. The residue is crystallised from ethanol to give the title compound. m.p. 200-1 OC (softens maleatesalt).

Example 5 N-fffl-(6-Fluoro-2-naphthalenylmethyl)-4-piperidinyllaminolcarbonyl1-6-quin oline carboxamide A mixture of 6-quinolinoyl chloride (4.77g, 22 mmol), N-ffi6-FI uo ro-2-n a phth a lenyl) methyl] -4piperidinyllurea (6.02g, 20 mmol), dry pyridine (2.5mi) and 1,2dichloroethane (30 mi) is stirred at refluxfor 18 hours. The solution isthen cooled, washed with aqueous sodium carbonate solution, dried and evaporated. The residue is crystallised from ethanol to givethetitle compound, mp 200-20VC (softens, maleatesalt).

Example 6 N-[[[1-(6-Fluoro-2-naphthalenylmethyl)-4piperidinyllaminolcarbonyl1-6-quin oline carboxamide 2-Bromomethy]-6-fluoronaphthalene (1 2g, 50 mmol) is added in one portion to a solution of N-[[[4pyridyllaminolcarbonyll-6-quinolinecarboxamide (14. 9g, 50 mmol) in dimethylformamide (50 mi). The mixture is stirred for2 hours and then diluted with water (100 ml) to precipitate N[[[1-[(64luoro2naphthalenyi)methyll-4-pyridinium]amino]carbonyll-6-quinoli necarboxamide bromide.

The above product is suspended in isopropanol (100 mi), sodium borohydride (6g, 180 mmol) is added and the mixture stirred at refluxfor 16 hours. The solvent is evaporated and the residue triturated with water. The precipitated product is collected and crystallised from ethanol to give thetitle compound, m.p. 200-201 OC (softens, maleate salt).

Claims

1. A compound of formula R R X CH 2 No-NHCONHCO-ce 1 R 2 (I) or a saitthereof, wherein =X- is =CH- or =N-, Rand R' independently represent hydrogen, halogen or lower alkoxy and R 2 is hydrogen ora substituent selected from halogen, lower alkyl, lower alkoxy orhaloloweralkyl.

2. A compound as claimed in Claim 1 wherein Rand Ware selected from hydrogen, fluorine, chlorine and 45 methoxy.

3. A compound as claimed in Claim 1 or Claim 2 wherein the group bonded to the piperidine nitrogen is naphth-2-yImethyl, qui nol-4-yl methyl or quinol-6-yl methyl.

4. A compound as claimed in anyone of Claims 1 to 3 wherein the group bonded to the urea function is quinol-4-oyl or quinol-6-oVI.

5. N-[[[1-(2-naphthalenyimethyi)-4-piperidinyllamino]-carbonyll-6quinolinecarb oxamideorapharma- ceutically acceptable salt thereof.

6. N-[[[1-(quinol-6-ylmethyl)-4-piperidinyllamino]carbonyll-6quinolinecarboxam ideora pharmaceutic ally acceptable salt thereof.

7. N-[[[1-(6-fluoro-2-naphthalenyimethyll-4-piperidinyllaminolcarbonyl-6quinol inecarboxamideora 55 pharmaceutical ly acceptable saitthereof.

8. A process for preparing a compound of formula R R X H 2 C-NHCONHCO j W:' 2 R (I) 8 GB 2 182 935 A 8 or a saitthereof, wherein =X- is =CH- or= W, Rand R' independently represent hydrogen, halogen or lower alkoxy and R 2 is hydrogen or a substituent selected from halogen, lower alkyl, lower alkoxy or halolower alkyl, which comprises (a) reacting a compound of formula 5 R CH 2 W <X) (III) whereX, R and R' are as defined baove and W represents a leaving group or a radical formula 0S02OR 3 where R % R -CH 2 1 R 1 <: GX with a compound of formula HN Y NHCONHCO 1 N where R 2 is as defined above; (b) reacting a compound of formula R 30 R R > 1 CH 2 No-NH 2 t X ( IV) wherein X, Rand R' areas defined above, with a compound of formula 2 OWC0 N ora compound of formula H NCONHCO 2 (VI) 2 (VII) wherein R 2 is as defined above, or (c) acylating a compound of formula R CH 2 NoNHCONH 2 (VIII) wherein R is as defined above, with an acylating agent containing the group 2 -CO N j 1 so j t 9 GB 2 182 935 A 9 or (d) reducing a compound of formula R 0 0 R 2 1 0 11 R 1 CH 2 NO/--NHCNHC (IX) or # 10 N R R 2 0 0 R NHC NHC 1 CH2qC <X D IN" Z11.1 N 11-1 EQ wherein B represents an anion and X, R, R' and R 2 are as defined above, or (e) reacting a compound of formula R 1: nIx 1 > CH 2 OH (VIII) wherein X, Rand R' areas defined above with a compound of formula W as defined above in the presence of 25 a nickel catalyst; or (f) converting a basic compound of formula 1 to an acid addition or quaternary ammonium salt; or (9) converting an acid addition salt of a compound of formula 1 to the free baseform.

9. A process (a) as claimed in Claim 8 wherein W is bromine or chlorine.

10. A process (c) as claimed in Claim 8 wherein the acylating agent is an acid halide, anhydride, mixed anhydride or active ester.

11. A process (d) as claimed in Claim 8 wherein the reduction is carried out using an alkali metal borohydride in a secondary alkanol of 3 to 5 carbon atoms.

12. A process (g) as claimed in Claim 8 in which the free base is acidified with maleic acid to give the maleate salt.

13. A process as claimed in anyone of Claims 8to 12 wherein Rand R' are each selected from hydrogen, fluorine, chlorine and methoxy.

14. A process as claimed in anyone of Claims 8to 13 wherein the group bonded to the piperidine nitrogen is naphth-2-yl methyl, qu inol-4-yl methyl or q uinol-6-yl methyl.

15. A process as claimed in anyone of Claims 8 to 14 wherein the group bonded to the urea function is quinol-4-oylorquinol-6-oyi.

16. A process as claimed in anyone of Claims 8to 15 in which the compound prepared is N-[[[1 -(2 naphthalenyi-methyl)-4-piperidinyllaminolcarbonyll-6-quinolinecarboxamide or a pharmaceutically accept able salt thereof.

17. A process as claimed in anyone of Claims 8to 15 in which the compound prepared is W[[[1 -(quinol-6yimethyf)-4-piperidinyllaminol-carbonyll-6-quinolinecarboxamide or a pharmaceuticaliy acceptable salt thereof.

18. A process as claimed in anyone of Claims 8 to 15 in which the compound prepared is W[[[1 -[(6-fluoro 2-naphthalenyi)methyll-4-piperidinyllam inolca rbonyl-6-q uinol ineca rboxam ide or a pharmaceutical ly acceptable saitthereof.

19. A process as claimed in Claim 8 substantially as herein before described with reference to anyone of Examples 1 to 6.

20. A compound of formula 1 as defined in Claim 1 whenever prepared by a process as claimed in anyone of Claims 8 to 19.

21. A pharmaceutical composition comprising a compound of formula] as defined in anyone of Claims 1 55 to 7 or a pharmaceutical ly acceptable acid addition or quaternary am moniu m salt thereof and a pha rma ceutically acceptable carrier.

22. A composition as claimed in Claim 21 which is in the form of a tablet or capsule.

GB 2 182 935 A Amendments to the claims have been filed, and have the following effect:(b) New ortextually amended claims have been filed as followsNewclaim8 8. A process for preparing a compound of formula R%.ir 1 -- R -H 2 tN - NHCONHCO X \_i (1) or a salt thereof, wherein =X- is =CHor= W, Rand R' independently represent hydrogen, halogen or lower alkoxy and R 2 is hydrogen or a substituent selected from halogen, lower alkyl, lower alkoxy or halolower alkyl,which comprises (a) reacting a compound of formula is R.. CH1)W (111) 20 where X, R and R' are as defined baove and W represents a leaving group or a radical formula 0S02OR1 whereR'is R 25-CH 21rxR 1 with a compound of formula 2 30 H, NE1COYMC0 (IV) N 35 where R' is as defined above; (b) reacting a compound of formula R R CH Nt H 40 2 2 1", X (V) wherein X, R and R' are as defined above, with a compound of formula 2 45 so OWC0 -e IN" (V1 so or a corn pound of formu la 2 H 2 NCONHCO 55 N (VII) wherein R 2 is as defined above, or (c) acylating a compound of formula R R X CH 2 No- NFICONH 2 (VIII) 65 j 11 GB 2 182 935 A 11 wherein R is as defined above, with an acylating agent containing the group 2 1 l,' N -CO or (d) reducing a compound of formula 0 10 1 J R 1 - 0 0 R R CH 2 N01 --NHCNHC N or 2 R R CH2qC\- 0 0 NHIC NHC <X J0 wherein B represents an anion and X, R, R' and R 2 are as defined above, 25 or (e) reacting a compound of formula R R 1 n CH 2 OH X 1::)- ( IX) D2 (IX) wherein X, R and R' are as defined above with a compound of formula IV as defined above in the presenceof a nickel catalyst; or (f) converting a basic compound of formula 1 to an acid addition or quaternary ammonium salt; 35 or (g) converting an acid addition salt of a compound of formula 1 to thefree baseform.

Printed for Her Majesty's Stationery Office by Croydon Printing Company (U K) Ltd,4187, D8991685. Published by The Patent Office, 25 Southampton Buildings, London WC2A l AY, from which copies maybe obtained.

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