IE47510B1 - 4-amino-6,7-dialkoxy-2-substituted quinazolines - Google Patents

Abstract

A process for the preparation of new 4-amino-2-piperidine-quinazoline derivatives of formula: *** see image 01 where R is lower alkyl and, X is a group of formula: -O-alq-OR1 where Does it represent an ethylene group optionally substituted with one or two lower alkyl groups and R1 is hydrogen, lower alkyl, C3-C6 cycloalkyl or a group of the formula: *** see image 02 where R2 and R3 each independently represent hydrogen, lower alkyl, halogen, CF3, -CONR4R5 or SO2NR4R5.

Description

The invention relates to therapeutic agents which are novel derivatives of 4-amino-2-piperidino-quinazoline, and is particularly concerned with derivatives liaving a substituted alkoxy group in the 4-position of the piperidino group. Such compounds are useful as regulators of the cardiovascular system and, in particular, in the treatment of hypertension.

The novel compounds according to the invention are those having the general formula:- o---(I) wherein R is lower alkyl; and X is a group of the formula:-O-alk-OR1 wherein alk represents an ethylene group optionally substituted and by 1 or 2 lower alkyl groups; R1 is hydrogen; lower alkyl; C^-Cg eycloalkyl; or a group of the formula: - 3 2 3 wherein R and R each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, CF^, -CONKERor -SOjMR^R^ wherein and each independently represent hydrogen or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof.

In this specification, halogen means fluorine, chlorine, bromine or iodine. The term lower applied to an alkyl or alkoxy group indicates that such group contains from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and, where such group contains from 3 to 6 carbon atoms, it may be straight or branched chain.

Pharmaceutically acceptable acid addition salts are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or p-toluenesulphonate salts.

The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs or individual isomers may be separable by physic»l methods, e.g. by fractional crystallisation of suitable salts. 47S10 - 4 The invention includes the separated pairs as well as mixtures thereof, as racemic mixtures or as separated d- and 1- optically active isomeric forms.

R is preferably methyl. ι ι 3 i X is preferably -OC^CHgOR , -OCH2-CH-OR , or CH, I 3 1 -O-CH.-C-OR . 2 I CH, R is preferably hydrogen, C^-C^ alkyl, cyclopentyl, or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl or carbamoyl.

In one preferred group of compounds R is other than 3 C-C, cvcloalkyl and R and R are other than trifluoromethyl.

J o The two preferred individual compounds are those in which (a) R is CH^, alk is -CHjCHj- and is CgH^ and (b) R is CH3, alk is -CH2CH2- and R* is phenyl.

The compounds of the invention may be prepared by a number of routes, including the following:47510 (1) The compounds may be prepared by reacting a quinazoline of the formula: wherein Q represents a facile leaving group such as chloro, 5 bromo, iodo, lower alkoxy, (lower alkyl)thio or (lower alkyl) sulphonyl, with a piperidine of the formula: X (III).

Q is preferably chloro or bromo.

Typically the reaction is carried out in the presence 10 of a base such as triethylamine or excess reagent of the formula (III).

In a typical procedure the reactants are heated together, e.g. at a temperature of 70 to 130 °c, preferably under reflux, in an inert organic solvent, e.g. rr-butanol, for periods of up to about 48 hours. The product may be isolated and purified by conventional procedures. - 6 For example, the product is typically obtained in crude form by evaporation of the reaction mixture in vacuo, and the crude product may be purified either by reerystallisation from a suitable solvent, or by conversion to e.g. the hydrochloride salt by reaction with hydrogen chloride in e.g. ethanol followed by reerystallisation of the salt. In some cases of course the product of the reaction will be theiydrochloride salt. In some cases also the crude product may be purified chromatographically, e.g. by basifying it and extracting with chloroform, evaporating the chloroform extracts, and chromatographing the residue on e.g. neutral alumina, the product being eluted with chloroform or with a mixture of chloroform and methanol. The eluted product may be purified by conversion to the hydrochloride salt followed by reerystallisation, as above.

The intermediates of the formula (II) are in general known compounds or may be prepared by methods analogous to those of the prior art.

The intermediates of the formula (III) are either known compounds or may be prepared by conventional methods, e.g. as follows: (a) (1) NaH/DMF (2) Rlo-alk-Br, RjO-alk-Cl or R O-alk-mesyl (R^ not hydrogen) hydrolysis (acidic or \ N s' basic) I c=o 1' CH, /DMF = dimethylformamide/ (b) The piperidines in which alk is an ethylene group substituted by 1 or 2 lower alkyl groups are also preparable via the corresponding l-acetyl-4-alkenoxypiperidines, e.g. as follows (R^ may be hydrogen in this route):OH c=o CHCH CH, I hydrolysis ^(acidic or basic) (c) 4-(2-Hydroxyethoxy) piperidine may be prepared by the previously described route:- CHgPh (d) 4-(2-Hydroxyalkoxy) piperidines may also be prepared by the following conventional routes:47510 θ·9- OH HaH/HrCHCH R OBt / R OCII.CH (i) DMF OBt ·> OEt '''OBt Prot.

Prot.

Prot. h+/h2o /in which Prot. is a suitable N-protecting group, for example 5 acetyl or benzyl, and can be removed by conventional methods at (Prot. and R“ are as defined above) Prot.

(Prot. and R are as defined above) (e) 4-(2-Alkcy.y alkoxy) piperidines may be prepared by reaction of an N-protected 4-(2-bydroxyalkoxy) piperidine obtained by one of the above routes with an alkyl halide or mesylate in the presence of a strong base, e.g.: R R” Prot. (i) NaH/DMF (ii) R1!, RlBr or p/oso CH .

OH R R’ I I OCH-CH Prot.

(Prot. and R are as defined above; R“‘ = H or lower alkyl) and (f) 4-(2-AryJ.oxyalkoxy) piperidines may be prepared by: 4*7510 -10 (i) reaction of an N-acetyl-4-(2-hydroxyalkoxy) piperidine obtained as above with an appropriately substituted phenol in the presence of triphenylphosphine and diethyl azodicarboxylate (R and R‘ are as defined above) (ii) 4-(2-Aryloxyalkoxy) piperidines may alternatively be prepared from an N-protected-4-(2-hydroxyalkoxy) piperidine, obtained as above, and fluorobenzene or a substituted fluorobenzene in the presence of NaH and •11 (R and R' are as defined above) - 12(2) The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) may be prepared by conventional procedures, e.g. by mixing the free base with the· appropriate acid in a suitable solvent, e.g. iso-propanol, filtering, and if 5 necessary recrystallising the thus-produced salt to purity.

Often of course the product of route (1) will be in the form of an acid addition salt. - 13 47510 The antihypertensive activity of the compounds of tlie invention is shown by their ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hypertensive dogs, when administered orally at doses of up to 5 mg/kg.

The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

Thus the invention also provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for the treatment of hypertension by either the oral or parenteral routes, and may be administered orally at dosage levels approximately within the range I to X0 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses. - 14 Intravenous dosage levels would be expected to be about |th to th of the daily oral dose. Thus for an average adult patient, individual oral doses in tablet or capsule form will be approximately in the range from 5 to 100 mg of the active compound. Variations 5 will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.

The following Examples illustrate the invention:47510 - 15 EXAMPLE 1 Preparation of 4-Amino-6, 7-dimethoxy-2-/4-(2-ethoxyethoxy) piper id ino/quinasol in e hydrochl or ide CH3? och2ch2oc2h5CIV 0^2°¾ 4-(2-ethoxyethoxy)piperidine (3.2 g) and triethylamine (10 ml) in n-butanol (400 ml) were heated at reflux overnight under an atmosphere of nitrogen. The mixture was then cooled, evaporated in vacuo, and the residue basified (aqueous Na2CC>3) and extracted 3 times with chloroform. The combined chloroform extracts were evaporated and the residue chromatographed on neutral alumina (150 g, Grade I, deactivated with 5 ml water). Elution with chloroform gave the crude product (3.6 g) which was converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol.

The hydrochloride was then recrystallised from ethanol/isopropanol to give 4-amino-6,7-dimethoxy-2-/4-(2-ethoxyethoxy)piperidino/quinazoline hydrochloride (3.4 g), m.p. 219-220°c.

Analysis Found: C, 55,4; H, 7.2; H, 13.5 Calculated for C, N.0,.HCl: l9fl28W4U4 C, 55.3; H, 7.1; N, 13.6 - 16 4 7 510 EXAMPLES 2-7 The following guinazolines were prepared similarly to Example 1, starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriately substituted piperidine, and were isolated in the form indicated.

O'BO Analysis % (Theoretical in brackets) C Η N 60.9 7.7 13.8 (61.5 7.7 14.4) 60.1 6.4 12.0 (60.7 6.6 11.8) 57.9 7.2 12.4 (58.3 7.4 12.4) Ό <-* ω U rH 0 W CM H · e 5 k Ό ο ϋ in « Free base, 130-134° i d SB 1 Hydrochloride 210—211° ' * CM tn tc u § CM ffi 8s s o I in a Φ u o 9 o CM 8s tc □ o 1 in Γ- . - 19 47510 The following minor differences in procedure from Example 1 should be mentioned. In Example 3, the product from the chromatographic purification was recrystallised directly without prior conversion to a hydrochloride salt. In Examples 5 and 7, silica was used for the chromatographic purification. In Example 6, the residue remaining after the evaporation of the original reaction mixture (which was a hydrochloride salt) was recrystallised from dimethylformamide and then directly chromatographed on silica.

EXAMPLE & 4-Amino-6,7-dimethoxy-2-/4-(2-methoxy-n-propoxy) piperidino/ quinazoline hydrochloride 4-Amino-2~chloro-6,7-dimethoxyquinazoline (3.6 g), 4-(2methoxy-n-propoxy) piperidine (3.0 g) and triethylamine (1.5 g) in n-butanol were heated under reflux for 30 hours. The solvent was evaporated in vacuo, the residue stirred with diethyl ether, the solid collected and recrystallised twice from isopropanol to give 4-amino-6,7-dimethoxy-2-/4- (2-methoxy-ii-propoxy) piperidino/ quinazoline hydrochloride (2.8 g), m.p. 239-241°C.

Analysis Found: C, 55.1; H, 7.2; N, 13.6 Calculated for C|gH28N4°4'HC1! C, 55.2; H, 7.1; N, 13.6. - 20 EXAMPLES 9-22 The following quinazolines were prepared similarly to Example 8, starting from 4-amino~2-chloro-6,7-dimethoxyguinazoline and the appropriately substituted piperidine, and were isolated ir. the form indicated. - 21 47510 O HO ·· 22 47510 a CH,O. \\ - 23 4*7510 HO ΟΉΟ Analysis % (Theoretical in brackets) C Η N 53.8 7.0 14.1 (54.2 6.8 14.0) Form Isolated and m.p.. ( c) ΦΟ fl Ν •rl Ν k ro 5 . •So o ro m ro fl EC X . sc υ o C4 EC s o I 0 «—I i' κ ω co - 26 47 510 The following Examples illustrate the preparation of certain of the starting materials used in the previous Examples: EX&MPU5 A Preparation of 4-(2-aethoxyethoxy)piperidine 5 A solution of N-acetyl-4-hydroxypiperidine (30.5 g) in dimethylformamide (200 ml) was added dropwise to a stirred suspension of sodium hydride (11.25 g, 50% dispersion in mineral oil) in dimethylformamide (300 ml) under an atmosphere of nitrogen. The reaction temperature was kept below 30°C by external cooling and, after the addition was complete, stirring was continued for a further 1- hours. A solution of l-bromo-2-methoxyethane (32.6 g) in dimethylformamide (100'ml) was then added dropwise with external cooling, and the resulting clear solution was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (Ka^SO^) and evaporated to leave a crude residue (16.1 g). The above aqueous phase was saturated with sodium chloride, further extracted with chloroform, and the organic phase was dried (Na^SO^), and evaporated to leave a further residue (9.2 g). This residue was combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 ml, 2N). The reaction mixture was extracted with chloroform to remove residual mineral oil, the aqueous phase concentrated, basified with sodium hydroxide (pH 12), then re-extracted with chloroform. - 27 47510 The organic extracts were washed with brine, dried and evaporated to leave 4-(2-methoxyethoxy) piperidine (8.3 g). A sample of this product in ethyl acetate was converted to the oxalate salt by the addition of ethereal oxalic acid followed by recrystallisation from ethanol, the oxalate having an m.p. of 86-88°C.

Analysis 4:Found: C, 48.1; H, 7.6; N, 5.6 Calculated fox CeH17NO2.(CO2H)2: C, 48.2; H, 7.7; N, 5.6.

The following piperidine derivatives were prepared by procedures similar to that of Example A, starting from ti-acetyl-4— hydroxypiperidine and the appropriate bromide. Hydrolysis of the N-acetylated intermediates in Examples B and D was carried out using dilute sodium hydroxide in place of dilute hydrochloric acid.

HN Example Y Form Isolated and m.p. (°C) Analysis % (Theoretical in brackets) C H N B -och2ch2oc6h5 Oxalate 144 - 145° 58.5 (57.9 6.8 6.8 4.3 4.5) C -OCH2CH2O-n-C4H9 Oxalate hemihydrate 86 - 88° 52.4 (52.0 8.4 8.7 4.8 4.7) D -0CHnCHo0C-H_ 2 2 2 5 Oxalate 93 - 95° 50.5 (50.2 8.2 8.0 5.2 5.3) - 28 EXAMPLE Ε Preparation of N-Acetyl-^-allyloxypiperidine A solution of N-acetyl-4-hydroxypiperidine (100 g) in dimethylformamide (250 ml) was added dropwise to sodium hydride (38 g, 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours then allyl bromide (93 g) was added slowly whilst maintaining the reaction temperature at 25°C by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml) and ether (500 ml), filtered, and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypippridine (Γ08.8 g), b.p. 128°C/2 mm., identified spectroscopically.

EXAMPLE F Preparation of 4-(2-Ethoxy-n-propoxy)piperidine A solution of N-acetyl-4-allyloxypiperidine (6.4 g) in absolute ethanol (10 ml) was added dropwise to a stirred suspension of mercuric acetate (11.5 g) in ethanol (50 ml) at room temperature.

After 20 minutes the mercuric acetate had dissolved and the mixture was stirred for a further 40 minutes, cooled in ice-water, and sodium hydroxide (20 ml, 5N) was then added. A yellow precipitate formed during the addition. A solution of sodium borohydride (1.3 g) in sodium hydroxide (20 ml, 5N) was then added, the mixture stirred for 10. minutes, and’ acetic acid added to bring the pH to 6. The mixture was filtered from precipitated mercury, the ethanol evaporated in vacuo, and the resulting aqueous phase extracted with chloroform. - 29 47510 The organic extracts were dried (NajSO^), evaporated in vacuo, and the resulting crude residue (7.5 g) taken up in ethanol (50 ml) and heated under reflux overnight with sodium hydroxide (20 ml, 5n) and water (20 ml). Most of the ethanol was then removed in vacuo, the aqueous layer extracted with ether, the extracts dried (Ka2SO4) and evaporated to leave a residue (5 g). Thin layer chromatography indicated incomplete hydrolysis of the acetyl function had occurred so the residue was treated with hydrochloric acid (20 ml, 2N) and heated on a steam bath for 10 hours. The mixture was then washed with ether, the aqueous phase basified (NajCOj), extracted with ether and the organic extract dried (Na2SC>4) and evaporated to leave a residue (4.3 g). Distillation of the residue gave 4-(2-ethoxy-n-propoxy)piperidine (3.0 g), b.p. 112 - 116°C/10 mm, from which sesquioxalate salt was prepared by reacting an ethereal solution of the piperidine with ethereal oxalic acid, followed by recrystallisation from ethyl acetate, the oxalate having an m.p. of 68 - 70°C.

Analysis Found: C, 48.3; II, 7.5; N, 4.7 Calculated for C10H21NO2.l. 5 (COgH) 2: C, 48.4; H, 7.5; N, 4.4. - 30 EXAMPLE G Preparation of 4-(2-Hydroxy-n-propoxy)piperidine N-Acetyl-4-allyloxypiperidine (18 g) in tetrahydrofuran (30 ml) was added dropwise to a stirred yellow suspension of mercuric acetate (34 g) in a mixture of water (120 ml) and tetrahydrofuran (120 ml). The suspension dissolved during the addition and the resulting clear solution was stirred at room temperature for 20 minutes, then sodium hydroxide (70 ml, 5N) was added, accompanied by ice/water cooling. The intermediate thus obtained was then reduced by the addition of sodium borohydride (2 g) in sodium hydroxide (40 ml, 5N), the excess hydride being destroyed after 10 minutes with glacial acetic acid. The liguid phase was then decanted off, saturated with sodium chloride, the organic phase separated, and the remaining aqueous layer extracted four times with chloroform. The combined organic phases were dried (NajSO^,, and evaporated in vacuo to leave a colourless oil (23 g) This oil was stirred with 5N sodium hydroxide at room temperature for 16 hours, then at 100°C for 2 hours. The solution was then extracted with chloroform (four times), the combined extracts dried (NajSO^), and evaporated in vacuo to leave a crude crystalline product (16.1 g). This was taken up in methylene chloride, filtered, evaporated, and the residue triturated with petroleum ether (b.p. 40°/60°C) to yield 4-(2-hydroxy-ii-propoxy) piperidine (11.0 g), m.p. 55 - 57°C. The oxalate salt thereof was prepared as in Example F and recrystallised from isopropanoi, m.p. 104 - 105°C. - 31 47510 Analysis ¢:Found: C, 48.2; Ii, 7.7; N, 5.6 Calculated for ΟθΗ^ΝΟ,,. (COjH)2: C, 48.2; H, 7.7; N, 5.6 EXAMPLE H Preparation of N-acetyl-4-(2-roethylallyloxy)piperidine This compound was prepared similarly to Example E, starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride, and was distilled and used directly in the next stage.

It had a b.p. of 128°C@ 1 mm.

EXAMPLE I Preparation of 4-(2-methoxyr-2-methyl-n-propoxy)piperidine This compound was prepared similarly to Example F, starting from N-acetyl-4-(2-methylallyloxy)piperidine and mercuric acetate/methanol. The compound was characterised as the hemioxalate m.p. 208 - 210°C.

Analysis Found: C, 56.7; H, 9.5; N, 5.9 Calculated for c1qh2ino2-)3(COjH)C, 56.9; H, 9.6; N, 6.0. - 32 47S10 EXAMPLE J Preparation of 4-(2-hydroxy-2-methyl-ιι-propoxy)piperidine This compound, m.p. CO - 82°, was prepared similarly to Example G, starting from N-acetyl-4-(2-methylallyloxy)pipe»3ine and mercuric acetate in a mixture of water and tetrahydrofuran.· Analysis %:Found: C, 62.2; H, 11.1; N, 8.3 Calculated for C^H^NOj: C, 62.4; H, 11.1; N, 8.1.

EXAMPLE K Preparation of 4-(2-Ethoxy-2-methyl-nppropoxy)piperidine This compound was prepared similarly to Example F, starting from N-acetyl-4-(2-methy lallyloxy) piperidine and mercuric acetate/ethanol followed by basic hydrolysis to remove the Macetyl group. A sample was converted to the hemi-oxalate salt which was recrystallised from ethyl acetate/methanol, m.p. 184 - 185°C.

Analysis Found: C, 58.6; H, 9.7; 9, 5.8 Calculatedfor C^HjjNOjACjBjC^.· c, 58.5; H, 9.8; N, 5.7 EXAMPLE L Preparation of 4-(2-isopropoxyethoxy)piperidine This compound was prepared similarly to Example A from N-acetyl-4-hydroxypiperidine and l-bromo-2-isopropoxyethane.

The compound was characterised by spectroscopic techniques. - 33 EXAMPLE Μ Preparation of 4- (2-methoxy-n-propoxy)piperidine This compound was prepared similarly to Example F, starting from N-acetyl-4-allyloxypiperidine and mercuric acetate in methanol. To improve the conversion of starting material to product the mercuric acetate/methanol treatment was repeated twice to give N-acetyl-4-(2-metboxy-n-propoxy)piperidine, which was hydrolysed in sodium hydroxide and methanol solution to give 4-(2-methoxy-n-propoxy)piperidine. A sample was characterised as the oxalate salt, m.p. 09 - 91°C.

Analysis Found: C, 49.6; H, 7.9; N, 5.3 Calculated for CgHjgN02.C2H2O4: C, 50.2; H, 8.1; N, 5.3.

EXAMPLE H Preparation of 4-(2-Phenoxy-n-propoxy)piperidine N-Acetyl-4-(2~hydroxy-n-propoxy)piperidine (12 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (5.0 g, 50% dispersion in mineral oil) in D.M.F. (50 ml) at 60 - 70°C under an atmosphere of nitrogen. The suspension was stirred for 3 hours, then fluorobenzene (6.4 g) in D.M.F. (50 ml) added dropwise and the suspension stirred at 100°C for 50 hours. The cooled solution was treated with isopropanol (20 ml) then water·(200 ml), extracted with petroleum ether (3 x 200 ml) and chloroform (3 x 200 ml). The combined chloroform extracts were dried (Na^O^) and the solvent evaporated in vacuo. - 34 47510 The residue (9.0 g) in sodium hydroxide solution (20 ml, 5n) and methanol (20 ml) to bring about solution was heated under reflux for 5 hours. The methanol was evaporated, the residue diluted with water then extracted with chloroform (3 x 50 ml). The combined chloroform extracts were washed with 2lf KC1 (3 x 30 ml), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3 x 50 ml). The combined chloroform layers were dried (NajSO^), solvent evaporated in vacuo, then the residue triturated with ether and filtered. The filtrate was concentrated then distilled to give 4- (2-phenoxy-n-propoxy)piperidine (0.5 g), b.p. 118-122°C/ 0.3 mm., characterised spectroscopically. • 35 EXA11PLE Ο 4-(2-/2,6-Dimratnoxyphenoxy/othoxy)piperidine /AC = ch3co-7 Methanesulphonyl chloride (23 g) was added dropwise 5 to a stirred solution of 2-/2,6-dimethoxyphenoxy/ethanol (20 g) (J. Med. Chem. 1969, 12, 326) in pyridine (50 ml). The solution was left at room temperature for 60 hours, then the solvent evaporated under reduced pressure. The residue v/as taken up in chloroform, washed with water (3 x 100 ml) and sodium bicarbonate solution (5%, 3 x 100 ml), dried and the solvent evaporated. - 36 The residue was triturated with n-hexane and the solid collected to give 2-/2,6-dimethoxyphenoxy/-ethyl mesylate (11.3 g) characterised spectroscopically.

N-Acetyl-4-hydroxypiperidine (4.3 g) in D.M.F. (50 ml) was added 5 dropwise to a stirred suspension of sodium hydride (3.0 g, 50% dispersion in mineral oil) in D.M.F. (50ml) under an atmosphere of nitrogen. After stirring for 3 hours at room temperature 2-/2,6-dimethoxyphenoxy/ethyl mesylate (9.0 g) in D.M.F. (50 ml) was added dropwise and stirring continued for 20 hours at room temperature. The solvent was evaporated in vacuo, the residue taken up in water, extracted with chloroform (3 x 100 ml), the organic layer dried (Na2SO4) and the solvent evaporated. Distillation gave Nacetyl-4-(2-/2,6-dimethoxyphenoxj,7ethoxy)piperidine (6.0 g) , b.p. 200°C @ 1 mm.

This product (6.0g) in methanol (40 ml) and sodium hydroxide solution (20 ml, 5N) was heated under reflux for 20 hours. Methanol was evaporated under reduced pressure, the aqueous residue extracted with petroleum ether (3 x 30 ml) and ether (3 x 30 ml). The ether extract was dried (Na^SO^) and the solvent evaporated. The residue in ether was treated with ethereal hydrogen chloride and the precipitated solid reerystallised from isopropanoi to give 4-(2-/2,6-dimethoxyphenoxy/ethoxy)piperidine hydrochloride (1.4 g) m.p. 143 - 145°C.

Analysis Found: C, 56.4; H, 7.6,- N, 4.3 Calculated for CJ gH^NO^. HCl: C, 56.7; H, 7.6; N, 4.4 - 37 EXAMPLE Ρ (A) Preparation of H-Acetyl-4-(2,2-diethoxy7ethoxy)piperidine N-Acetyl-4-hydroxypiperidine (57.2 g) in dry D.M.F. (250 ml) was added dropwise to a stirred suspension of sodium hydride (23.2 g, 50% dispersion in mineral oil) in dry D.M.F. (200 ml) under an atmosphere of nitrogen and with external cooling in an ice/water bath. The suspension was allowed to warm to room temperature then stirred for 5 hours. Bromoacetaldehyde diethylacetal (94.7 g) was added slowly to the stirred reaction mixture with cooling then the mixture was stirred at room temperature for 18 hours. A further quantity of sodium hydride (23.2 g) was added portionwise and stirring continued until effervescence had ceased. A further 100 ml dry D.M.F. was added and the mixture cooled in an ice/water bath while a second batch of bromoacet15 aldehyde diethylacetal (9 4.7 g) was slowly added. The mixture was stirred at room temperature for 3 hours then isopropanol (150 ml) added to destroy excess sodium hydride. The suspension was -filtered, the filtrate concentrated under reduced pressure then the residue taken up in water and extracted with chloroform. The chloroform extract was dried (Na2SO4), the solvent evaporated in vacuo and the residue distilled to give N-acetyl-4-(2,2-diethoxyethoxy)piperidine (61.5 g), b.p. 142 - 145°C/3 mm., characterised by n.m.r. - 38 (B) Preparation of N-acetyl-4-(2-hydroxyethoxy)piperidine N-Acetyl-4-(2,2-diethoxycthoxy)piperidine (12 g) in 0.5N hydrochloric acid (50 ml) was stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted several times with chloroform (total 500 mis). The chloroform extract was dried (Na^SO^) and the solvent evaporated in vacuo and with a bath temperature below 30°C. The resultant intermediate aldehyde (9.8 g) was reduced immediately with sodium borohydride (0.75 g) in ethanol (75 ml), at pH 6, After stirring for 3 hours at room temperature reduction was complete. Water was then added to the stirred solution and the organic solvent evaporated in vacuo. The residue was taken up in water (30 ml), extracted with chloroform ( 10 x30 ml), the combined chloroform extracts dried (NajSO^) and the solvent evaporated in vacuo. The residue was taken up in water (70 ml) and washed with petroleum ether (2 x 10 ml). The aqueous phase was concentrated to give N-acetyl4-(2-hydroxyethoxy)piperidine (6.9 g) characterised spectroscopically.

A sample was distilled and had a b.p. of 139 - 140°C/0.3 mm.

Analysis Found: C, 57.5; H, 9.1; N, 7.6 Calculated for CgHj^NOj: C, 57.8; H, 9.1; t N, 7.5. - 39 47510 (C) 4-(2-Cyclopentyloxyethoxy)piperidine N-Acetyl-4-(2-bydroxyetboxy)p.iperidine (5.0 g) in D.M.F. (25 ml) was added dropwise to a stirred suspension of sodium .in dry D.M.F. (50 ml) hydride (1.28 g, 50¾ dispersion in mineral oil)'under an atmosphere 5 of nitrogen. When effervescence had ceased, cyclopentyl mesylate (4.4 g)(Tetrahedron 1972, 28, 2469) in D.M.F. (10 ml) was added slowly and the mixture stirred at room temperature for 40 hours. Additional quantities of sodium hydride (0,64 g) and then cyclopentyl mesylate (2.2 g) were added and the mixture stirred at 60°C for 7 hours, then at room temperature for 64 hours. Isopropanol was added, the mixture filtered, and the filtrate concentrated in vacuo.

The residue in ethanol (30 ml) and 5N sodium hydroxide solution (30 ml) was heated under reflux for 3 hours. The ethanol was removed in vacuo, the residue diluted with water and extracted 15 with chloroform. The chloroform extract was dried (NajSO^), solvent evaporated in vacuo, then the residue in chloroform treated with ethereal hydrogen chloride. The solvent was decanted and the residue triturated with ether to give 4-(2-cyclopentyloxyethoxy) piperidine hydrochloride as a gum. The product contained some 4-(2-hydroxyethoxy)piperidine impurity but was used directly. - 40 EXAMPLE Q Preparation of 4-(2-p-fluorophenoxyethoxy)piperidine A solution of N-acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g), triphenylphosphine (8.4 g), diethyl azodicarboxylate 5 (5.6 g) and p-fluorophenol (3.36 g) in freshly distilled tetrahydrofuran (75 ml) was stirred in an ice bath for 2 hours and then left at room temperature for 48 hours. Solvent was evaporated in vacuo, the residue taken up in chloroform and washed twice with IN sodium hydroxide solution and twice with water, dried (NajSO^J and the solvent evaporated in vacuo. The residue was taken up in the minimum volgme of refluxing ether, then set aside to cool in a refridgerator. The precipitated solid was collected, the filtrate evaporated and the residue taken up in ether and set aside to cool. The precipitated solid was03ain removed, the filtrate evaporated and the residue extracted with refluxing petroleum ether (60 - 80°, 5 x 100 ml). The solvent was evaporated in vacuo and the residue in ethanol (50 ml) and sodium hydroxide solution (50 ml) was heated under reflux for 5 hours, then neutralised with 2N hydrochloric acid and the organic solvent evaporated. The aqueous residue was acidified to pH 2 with 2N hydrochloric acid and extracted twice with ether. The aqueous phase was basified to pH 12 with 2N sodium hydroxide solution then extracted with chloroform (3 x 100 ml). - 41 47510 The combined chloroform extracts were dried (Na^SO^) and the solvent evaporated in vacuo to give 4-(2-p-fluorophenoxyethoxy) piperidine (1.3 g).

A sample of this product in chloroform was converted 5 to the hydrochloride salt by treatment with ethereal hydrogen chloride and had an m.p. 144 - 145°C.

Analysis 4:Found: C, 56.1; H, 6.8; N, 5.5 Calculated for ci3HigFNO2,Hcl·' C, 56.6; H, 6.9; N, 5.1.

EXAMPLES R TO ϋ The following piperidine derivatives v/ere prepared by a similar procedure to that of Example Q, starting from N-aoetyl4-(2-hydroxyethoxy)piperidine and the appropriate phenol. 47810 OCHoCHn—OR - 44 EXAMPLE V Preparation of 4-/2-(4-piperidyloxy)ethoxy/benzamide N-Acetyl-4-(2-hydroxyethoxy)piperidine (1.0 g), 4hydroxybenzamide (0.82 g), diethyl azodicarboxylate (1.12 g) and triphenylphosphine (1.68 g) in tetrahydrofuran (30 ml) were stirred at room temperature for 66 hours. The precipitated solid was collected and dried to give 4-/2-(N-acetyl-4-piperidyloxy) ethoxy/benzamide (0.72 g), m.p. 154 - 155°C.

Analysis %:10 Found: C, 62.7? H, 7.1? N. 9.1 Calculated for C16H22N2°4: ' C' 62‘7f H' 7,2f N' 9,2 4-/2-(N-acetyl-4-piperidyloxy)ethoxy/benzamide (4.3 g) in ethanol (60 ml), water (30 ml) and 2N hydrochloric acid (10 ml) was heated under reflux for 24 hours then the solvent evaporated in vacuo. The residue was taken up in water and extracted three times with chloroform, the aqueous phase was adjusted to pH 12 with sodium carbonate solution and extracted three times with chloroform. The combined chloroform extracts were discarded, the aqueous phase was saturated with sodium chloride and’ extracted 20 with chloroform, the chloroform layer dried (Na2SO4), and the solvent evaporated in vacuo to give 4-/2-(4-piperidyloxy)ethoxy/ benzamide (0.36 g). The aqueous phase was concentrated in vacuo and the residual solid extracted with refluxing ethyl acetate (200 ml). - 45 47510 The solid was removed by filtration and the filtrate evaporated in vacuo to give further 4-/2-(4-piperidyloxy)ethoxy/benzamide (0,30 g) identical with that obtained above. A sample of this product in chloroform/methanol was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride, then recrystal·, lisation from ethyl acetate/isopropanol, m.p. 244 - 246°C, characterised spectroscopically.

EXAMPLE W Preparation of 3-/2-(4-Piperidyloxy)ethoxy/benzamide N-Acctyl-4-(2-hydroxyethoxy)piperidine (5.0 g), 3hydroxybenzamide (4.4 g), diethyl azodicarboxylate (5.6 g) and triphenylphosphine (8.4 g) in dry tetrahydrofuran (100 ml) were o stirred at 0 C for 2 hours then at room temperature for 64 hours.

The solvent was evaporated in vacuo, then the residue treated with 15 refluxing ether (3 x 100 ml) and the mother liquors decanted.

Tlie residual oil was taken up in chloroform and washed with dilute sodium hydroxide solution (40 ml) and water (40 ml). The chloroform layer was dried (MgSO^) then the solvent evaporated in vacuo The residual oil was treated with ether (50 ml) and set aside in the fridge. The resulting solid was collected, slurried with ether (30 ml), filtered and the solid washed with ether (30 ml) to give 4-/2-(N-acetyl-4-piperidyloxy)ethoxy/benzamide (3.7 g) containing some triphenylphosphine oxide (approximately 25% by n.m.r.). - 45 The product in ethanol (48 ml), uater (24 ml) and 2N hydrochloric acid (8 ml) was heated under reflux for 24 hours then the ethanol evaporated in vaeuo The aqueous residue was extracted with ether (2 x 100 ml), then chloroform (100 ml), then the aqueous phase was adjusted to pH 12 with sodium hydroxide solution and extracted with chloroform (2 x 100 ml). The organic layer was dried (MgSO^) and the solvent evaporated in vacuo to give 3-/2-(4-piperidyloxy) ethoxy/benzamide (0.55 g). The aqueous phase was saturated with sodium chloride and extracted with chloroform (3 x 100 ml).

The combined chloroform extracts were dried (MgSO4) and the solvent evaporated in vacuo to give a second crop of 3-/2-(4-piperidyloxy) ethoxy/benzamide (0.26 g) identical with that obtained above.

This sample was characterised as the hydrochloride salt by treatment of an ethanol solution with ethereal hydrogen chloride, m.p. 144 15 146°C.

Analysis Found: C, 56.0; H, 7.2; N, 9.2 Calculated for C^H^qIIjO^-HCI: C, 55.9; H, 7.1-, N, 9.3.

Claims (5)

1. WHAT WE CLAIM IS:1. Compounds of the formula:- -- (I) and X is a group of the formula: -O-alk-OR 1 wherein alk represents an ethylene group optionally substituted by 1 or 2 lower alkyl groups; and R 1 is hydrogen; lower alkyl; C^-Cg cycloaikyl; or a group of the formula: -oi. 2. 3 wherein R and R each independently represent hydrogen, lower 4 5 4 5 alkyl, lower alkoxy, halogen, CF^, -CONF? R or -SC^NR R wherein 4 5 R and R each independently represent hydrogen or lower alkyly - 48 and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 wherein R is CH,, X CH- cn- -s CH, 1 I 1 1 1 1 is -OCH 2 CH 2 OR , -OCH 2 -CHOR or -OCH 2 -C-OR , and R is H, C j -C 4 ch 3 alkyl, cyclopentyl, or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl or carbamoyl.

3. A compound as claimed in claim 1 wherein R is CH g , “alk 1 . is -CH 2 CH 2 -, and R is or CgH g .

4. A compound as claimed in claim 1 wherein R is other than 2 3 Cj-Cg eycloalkyl and R and R are other than CP g .

5. A process for preparing a compound of the formula (I) as claimed in claim 1, which comprises reacting a compound of the formula:' ---(II) RO H NH, 15 wherein R is as defined in claim 1 and Q is a facile leaving group, with a piperidine of the formula: — (Ill) wherein X is as defined in claim 1. 4 7 510 6. A process as claimed ill claim 5 wherein Q is chloro or bromo. 7. A process as claimed in claim 5 substantially as hereinbefore described in any one of Examples 1 to 22. 58. A compound of the formula (I) as claimed in claim 1 or pharmaceutically acceptable acid addition salt thereof, which has been prepared by a process as claimed in any one of claims 5 to 7. ». A pharmaceutical composition comprising a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.