CA1088068A - Piperidino-quinazolines - Google Patents

Abstract

A B S T R A C T
The invention relates to new compounds of the formula (I) wherein R is lower alkyl; and X is a group of the formula:--0-alk-OR1 wherein "alk" represents an ethylene group optionally substituted by 1 or lower alkyl groups and R1 is hydrogen; lower alkyl; C3-C6 cycloalkyl; or a group of the formula:

Description

``` ~0~806B

The invcntion relates to therapeutic agents which are novel derivatives of 4-amino-2-piperidino-quinazoline, and is particularly concerned with derivatives having 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:-B l ~
RO ~ N ~ r N ~ X --- (I) RO ~ N3 wherein R is lower alkyl;
and X is a group of the formula:--O-alk-OR
.
wherein "alk" represents an ethylene group optionally substituted by 1 or 2 lower alkyl groups;

and R1 is hydrogen; lower alkyl; C3-C6 cycloalkyl;
or a group of the formula:

~R2 ~PLC. 273) '. , ~

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wherein R2 and R3 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, CF3, -CoNR4R5 or -So2NR4R wherein R4 and R5 each independently represent hydrogen or lower alkyl;
and the pharmaceutically acceptable acid addition salts thereofO
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 atomsO
Preferably such groups contain from 1 to 4 carbon atoms. Where such group contains at least 3 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 hydro-chloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or p-toluenesulphonate saltsO
The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs of individual isomers may be separable by physical methods, eOgO by fractional crystallisation of suitable saltsO

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~088068 The invention includes the separated pairs as well as mixtures thereof, as racemic mixtures or as separated d- and l- optically active isomeric forms.

R is preferably methyl. CH
X is preferably -OCH2CH20R , -OCH2-CH-OR , or ,...
R is pFeferably hydrogen, C1-C4 alkyl, cyclopentyl, . or phenyl optionally substituted by lower alkyl, lower alk.oxy,; halogen, trifluoromethyl or carbamoyl.
In one preferred group of compounds R is other than C3-C6 cycloalkyl and R and R are other than trifluoromethyl.
The two preferred individual compounds are those in which (a) R is CH3, "alk" is -CH2CH2- and R is C2H5 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:- -(PLC. 273) :, :

108t3068 (1) The compounds may be prepared by reacting a quinazolineof the formula:

.

RO ~ N ~ ~ Q

RO ~ N
wherein Q represents a facile leaving group such as chloro, 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 r~eaction is carried out in the presence 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 ~, preferably under reflux, in an inert organic solvent, e.g. n-butanol, for periods of up to about 48 hours. The product may be isolated and purified by conventional procedures.

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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 recrystallisation from a suitable solvent, or by conversion to e.g. the hydrochloride salt by reaction with hydrogen chloride in e.g. ethanol followed by recrystallisation of the salt. In some cases of course the product of the reaction will be the~drochloride 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 recrystallisation, as above.
The intermediates of the formula (II) æ e 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) OH X X

~1) NaH/DMF ~ hydrolysis ~ J (2) R1O-alk-Br, ¦ ¦(acidic or ¦
- NRlO-alk-Cl ~ N ~ basic) ~ N
Ior R O-alk-mesyl I H
C=O(R1 not hydrogen) C=O

/DMF = dimethylformamide7 (PLC. 273) .

lOB8068 (b) The piperidines in which "alk" is an ethylene grOUp substituted by 1 or 2 lower alkyl groups are also preparable via the corresponding 1-acetyl-4-alkenoxypiperidines, e.g. as follows (R may be hydrogen in this route):-OH OCH2.CH=CH2 O.CH2CHOR
~ (1) NaH/DMF ~ (l)HgoAc/R OH ~ c~3 N J (2) CH2=cH.cH2Br ~ J (2)NaBH4 ~ N J
C=O C=O C=O

hydrolysis ~(acidic or basic) N
- H

(c) 4-(2-Hydroxyethoxy) piperidine may be prepared by the previously described route:-. OcH2cH2oH I 2 20H

LiAl ~ ~ Hz on Pd>

N CH2Ph CH2Ph (d) 4-(2-Hydroxyalkoxy) piperidines may also be prepared by the following conventional routes:-(PLC. 273) ' ,.'.

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R" OEt R" OEt e.g. OH NaH/BrCHCH ~ OCH.CH
(i) ~ OEt N N
I I
Prot. Prot.
,,;~, R" R"
OCH.CH20H OCH.CHO

Prot. Prot.

/in which Prot. is a suitable N-protecting group, for example acetyl or benzyl, and can be removed by conventional methods at the final stage, and R" is H or lower alkyl7 IR
, OH fCH.CO2C2H5 (i) NaH/DMF
R" >
N ~ (ii) BrCHCO2H ~ N
¦ (iii) EtOH/H+
Prot. Prot.
LiBH4/THF

(Prot. and R" are as defined above) Prot.
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l l~ OH
or (iii (i) NaH, ~MF, THF ~ ~

Prot. Prot.

(Prot. and R" are as defined above) (e) 4-(2-Alkoxyalkoxy) piperidines may be prepared by reaction of an N-protected 4-(2-hydroxyalkoxy) 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"' R" R"' l I I I
O~H-~ OCH-CH\
OH ~ OR
(i) NaH/DMF
(ii) R1I, R1Br - N
or R1OSO2CH3.
Prot. Prot.

¦ de-protection ~/ :
R R
CH-CH\
~ OR

(Prot. and R" are as defined above; R"'= H or lower alkyl) f) 4-(2-Aryloxyalkoxy) piperidines may be prepared by:

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(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 ("D.E.A.D."): OH 3 R" R"' ~ IR" Rl''~ ~

[~ :R ~R ~ [~
NPh3P/D.E A D., N

C=o C=O

hydrolysis (acid or base) R" R"' ~ -CH \ ~ R3 (R" and R'~ are as define~d above) (ii) 4-(2-Aryloxy~lkoxy) 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 D.M.F.:

(PLC. 273) ' . . : . ' ' ' - :. .

1~88068 R" R"' . R" R"' ~CN-OH CC~lN _~

>
N ~NaH/D.M.F. ~ N

C=O F
3 ~ , 100 C
- ¦ hydrolysis \~
R" R"' OCN-CH --e3 IN
H

(R" and R"' are as defined above) tPLC! 273) ,: ' : : :

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(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 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.
The invention also includes the pharmaceutically-acceptable bioprecursors of the compounds of the formula (I) and said salts thereof.

(PLC. 273) .

The term "pharmaceutically acceptable bioprecursor"
requires some explanation. It is of course, common practice in pharmaceutical chemistry to overcome some undesirable physical or ~ chemical property of a drug by converting the drug into a chemical 1 5 derivative which does not suffer from that undesirable property, ,` but which, upon administration to an animal or human being, is converted back to the parent drug. For example, if the drug is ¦ not well absorbed when given to the animal or patient, by the oral route, it may be possible to convert the drug into a chemical ¦ 10 derivative which is well absorbed and which in the serum or ¦ tissues is reconverted to the parent drug. Again, if a drug is unstable in solution, it may be possible to prepare a chemical ¦ derivative of the drug which is stable and may be administered in solution, but which is reconverted in the body to give the parent drug. The pharmaceutical chemist is well awæ e of the possibility of overcoming intrinsic deficiencies in a drug by ¦ chemical modifications which are only temporary and are reversible upon administration to the animal or patient.
For the purpose of this specification the term "pharma-! 20 ceutically acceptable bioprecursor" of a compound of the formula (I) means a compound hav ng a structural formula different from the compounds of the formula (I) but which nonetheless, upon administration to an animal or human being, is converted in the patients body to a compound of the formula (I).

(PLC. 273) I

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1~88068 The antihypertensive activity of the compounds of the 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 sub-cutaneously. For parent~ral 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 ¦ 20 comprising a compound of the formula (I) or a pharmaceutically acceptable acid addition saltthereof 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 ' 25 approximately within the range ¦ to ~0 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses.
(PLC. 273) I

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~088068 Intravenous dosage levels would be expected to be about 5th to 10th 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 S 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 invention yet further provides a method of treating an animal, including a human being, having hypertension, which comprises administering to the animal an antihypertensive amount of a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof or pharmaceutical composition as defined above.
The following Examples illustrate the inventi~n:-.
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108~068 Preparation of 4-Amino-6,7-dimethoxy-2-/4-(2-ethoxyethoxy) piperidino/quinazoline hydrochloride '

3\~N ~l/cQ~c3 ~ ~ ~ 32 N2 Z S

CHl}; H CH31~ N

4-Amino-2-chloro-6,7-dimethoxyquina701ine (4.3 g), 4-(2-ethoxyethoxy)piperidine (3.2 g) and triethylamine (10 ml) in -1 n-butanol (400 ml) were heated at reflux overnight under an atmos-phere of nitrogen. The mixture was then cooled, evaporated in vacuo, and the residue basified (aqueous Na2C03) and extracted 3 times with chloroform.` l~he combined chloroform extracts were evaporated and the residue chromatographed on neutral alumina (150 g, Grade I, deactivated with 5 ml water). Elution with chloro-form 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)piperidino7quinazoline .
hydrochloride (3.4 g), m.p. 219-220C.
Analysis %:-~, Found: ~ C, 55.4; H, 7.2; t~ 13.5 Calculated for C1gH28N44 HCl C, 55.3; H, 7.1; N, 13.6 (PLC. 273) .
.. . .
-: . . - :
. . : -:. - , . .

" ~088V68 The following quinazolines were prepared similarly to Example 1, starting from 4-amino-2-chloro-6,7-dimethoxyquina~oline and the appropriately substituted piperidine, and were isolated in the form indicated.

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1~

r ~

J~ ,~Q ~o ~,o,,, ~J ~1 i;

(PLC . 273 ) ~ ~ ~, o C~, ~
~~ ~rN ~ N N

>1 0t~ r-- ~D ~D N ~
Fl-o _~ U)~ r~ ~ ~
. 0~ 00 ~_ ' ~i~~ ô~ ~ro ~ h O
H R ~~! ~ :~ N
J ea) Oh ~ o o Z
0~ 0~ ~6 , ^~
. ~,1 ~ o (PI~ . 273 ) ~088068 The following minor differences in procedure from Example 1 should be mentioned. In Example 3, the product from the chromatographic purification was recrystallised directly with-out prior conversion to a hydrochloride salt. In Examples 5 and

5 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 chromato-graphed on silica.

EXAMPLE a 4-Amino-6,7-dimethoxy-2-/4-(2-methoxy-n-propoxy) piperidino7 quinazoline hydrochloride 4-Amino-2-chloro-6,7-dimethoxyquinazoline (3.6 g), 4-'2-methoxy-n-propoxy) piperidine (3.0 g) and triethylamine (1.5 g) in 15 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-n-propDxy)piperidino7 quinazoline hydrochloride (2.8 g), m.p. 239-241C.
-20 Analysis 96:-Found: ~ C, 55.1; H, 7.2; N, 13.6 - Calculated for C1gH28N4O4.HCl: C, 55.2; H, 7.1; N, 13.6.

(PLC.. 273) : :

108~3068 EXAMæLES 9-22 The following quinazolines were prepared similarly to B ample 8, starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriately substituted piperidine, and were isolated in the form indicated.
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E~ O ~ O 0~ I~ r-U~ Ul ~ U~ U~ U~

~o 'S~ ~ ~ ~Ot~
. ' U~ ~ O ~ ~ ~ O
~ 8 ~ In o ~ ~ o ~

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~0 ~ `O raO ~ ~0 H . S h I h ~ h ~
~ U ~ Ll~ U ~ U S 1`

~: r ~ ~

~ ~ g ~Z ~ ~ ~r . .

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~088068 ~VDZ oo o~ _ . ~S ~ _ _._ D o~ ~ ~0 :~ ~ e s ,~ s '` D ~

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~ C~ u7 ~ C~ O ~ _~ O r~
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~ ~ 1_~ ~ I .~ .C ~ I o0`1 r ~ ~

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:

The following Examples illustrate the preparation of certain of the starting materials used in the previous Examples:
EXAMPLE A
Preparation of 4-(2-Methoxyethoxy)piperidine A solution of N-acetyl-4-hydroxypiperidine (30.5 g) in dimethylformamide (200 ml) was added dropwise to a stirred sus-pension of sodium hydride (11.26 g, 50% dispersion ir mineral oil) in dimethylformamide (300 ml) under an atmosphere of nitrogen. The reaction te~perature was kept below 30 C by external cooling and, after the addition was complete, stirring was continued for a further 14- hours. A solution of 1-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 pa~tltioned between water and chloroform, the or~anic extracts dried (Na2SO4) 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 (Na2SO4), 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 (p~ 12), then re-extracted with chloroform.

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~ 088068 - 2a-The organic extracts were washed with brine, dried (Na2SO4) 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 86-88C.
Analysis %:-Found:C, 48.1; H, 7.6; N, 5.6 Calculated for C8H17N2'(C2H)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 N-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.

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Example Form Isolated Analysis ~
and m.p. (C) ~Theoretical in _ C H N

B -OCH CH OC H Oxalate 58.5 6.8 4.3 2 2 6 5 144 - 145 (57 96.8 4-5) ..
C-OCH2CH2O-n C4 9 Oxalate 52.4 8.4 4.8 _ hemihydrate ~52.08.7 4.7) , ' . 86 - 88 D-OCH2CH2OC2H5 Oxalate 50.5 8.2 5.2 93 - 95 (50.28.0 5.3) .::, ~- :: : . : . ., . ::- . :: .. ~ ., . :
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EXAMPLE E
Preparation of N-Acetyl-4-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 25C
by external cooling. The mixture was then stirred at room tempera-ture overnight, diluted with isopropanol (20 ml) and ether (500 ml), filtered, and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypiperidine (1`08.8 g), b.p. 128C/2 mm., identified spectroscopically.
EXAMPLE F
Preparation of 4-(2-Ethoxy-n-propoxy)piperidine A sclution of N~acetyl-4-allyloxypiperidine (6.4 g) in absolute ethanol tl0 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 io 6. The mixture W2S filtered from precipitated mercury, the ethanol evaporated in vacuo, and the resulting aqueous phase extracted with chloroform.

(PLC. 273) .

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, l~B8068 The organic extracts were dried (Na2SO4), evaporated in vacuo, and the resulting crude residue (7.5 g) taken up in ethanol (50 ml) and heated under reflux overnight with sodium hydro;ide (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 (Na2SO4) 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 (Na2CO3), extracted with ether and the organic extract dried (Na2SO4) 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 prépared by lS reacting an ethereal sol~tion 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; H, 7.5; N, 4.7 Calculated for CloH21NO2.1.5(CO2H)2:C, 48.4; ~, 7.5; N, 4.4.

~PLC. 273) :: . :.-: . : - -. : . : : -, -31 ~
EXAMPLE G
Preparation of 4-(2-Hydroxy-n-propoxy)piper~ine I N-Acetyl-4-allyloxypiperidine (18 g) in tetrahydrofuran ¦ (30 ml) was added dropwise to a stirred yellow suspension of t 5 mercuric acetate (34 g) in a mixture of water (120 ml) and tetra-' hydrofuran (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 liquid phase was then decanted off, saturated with sodium chloride, the organic phase separated, and the remaining aqueous layer extrac~ed four times with chloroform.~ ~he combined organic phases were dried (Na2SO4), 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 (Na2SO4), and evaporated in vacuo to leave a crude I 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-n-propoxy) i piperidine (11.0 g), m.p. 55 - 57 C. The oxalate salt thereof was prepared as in Example F and recrystallised from isopropanol, m.p. 104 - 105C.
(PLC. 273) ; ~

~l 1088068 ~ 32-I Analysis ~:-!
Found: C, 48.2; H, 7.7; N, 5.6 ~ Calculated for C8H17N2 (C2H)2 C, 48.2; H, 7.7; N, 5.6 ¦ EXAMPLE H
Preparation of N-acetyl-4-(2-methylallyloxy)piperidine ~ This compound was prepared similarly to Example E, ; starting from N~acetyl-4-hydroxypiperidine and 2-methylallyl I chloride, and was distilled and used directly in the next stage.
It had a b.p. of 128& @ 1 mm.
¦ 10 EXAMPLE I
Preparation of 4-(2-methoxy-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 compoupd was characterised as the hemioxalate : 15 m.p. 208 - 210C.
Analysis %:-Found: C, 56.7; H, 9.5; N, 5.9 Calculated for C~0~21~2 ~(C2~)2 C, 56.9; H, 9.6; 9, 6Ø

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1~88068 EXAMPLE J
Preparation of 4-(2-hydroxy-2-methyl-n-propoxy)piperidine This compound, m.p. 80 - 82 , was prepared similarly to Example G, starting from N-acetyl-4-(2-methylallyloxy)pipe~dine and mercuric acetate in a mixture of water and tetrahydrofuran.
Analysis %:-Found: - C, 62.2; H, 11.1; N, 8.3 Calculated for CgHlgNO2: C, 62.4; H, 11.1; N, 8.1.
EXAMPLE K

Preparation of 4-(2-Ethoxy-2-methyl-n-propoxy)piperidine _ . .
This compound was prepared similarly to Example F, starting from N-acetyl-4-(2-methylallyloxy)piper~ine and mercuric acetate/ethanol followed by basic hydrolysis to remove the N-acetyl group. A sample was converted to the hemi-oxalate salt which was 15 recrystallised from ethyr ac.eta-te/methanol, m.p. 184 - 185 C.
Analysis %:-Found: C, 58.~; H, 9.7; N, 5.8 Calculatedfor CllH23NO2-~C2 24 C, 58.5; H, 9.8; N, 5.7 EXAMPLE L
Preparation of 4-(2-isopropoxyethoxy)piperidlne ,~
This compound was prepared similarly to Example A
from N-acetyl-4-hydroxypiperidine and 1-bromo-2-isopropoxyethane.
The compound was characterised by spectroscopic techniques.

- (PLC. 273) .

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~ . ' , EXAMPLE M

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-methoxy-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. 89 - 91C.
Analysis %:-Found: C, 49.6; H, 7.9; N, 5.3 I 9 19 2 2 24 C, 50.2; H, 8.~; N, 5.3.
¦ EXAMPLE N
Preparation of 4-(2-Phenoxy-p-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 sus-pension 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 (Na2SO4) and the solvent evaporated in vacuo.
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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 2N HCl (3 x 30 ml), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3 x 50 mlj. The combined chloroform layers were dried (Na2SO4), 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. 118-122C/
0.3 mm., characterised spectroscopically.

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' 108~068 EX~MPLE O
4-(2-/2,6-Dimethoxyphenoxy7ethoxy)piperidine 3 2 > ~ 2 2 2 H3 l Ac- ~ OH

CH30~

2C~

~ J 3 h~ v~ CH3 /Ac = CH3 co 7 Ac Methanesulphonyl chloride (23 g) was added dropwise to a stirred solution of 2-/2,6-dimethoxyphenoxy7ethanol (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 was 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.

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~ 37-The residue was triturated with n-hexane and the solid collected to give 2-/2,6-dimethoxyphenoxy7-ethyl mesylate (11.3 g) characterised spectroscopically.
N-Acetyl-4-hydroxypiperidine (4.3 g) in D.M.F. (50 ml) was added 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 tèmperature 2-/2,6-dimethoxyphenoxy7ethyl mesylate ~9.0 g) in D.M.F. (50 ml) was added dropwise and stirring continued for 20 hours at room te~perature. 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 N- .-^
acetyl-4-(2-/2,6-dimethoxyphenox~7ethoxy)piperidine (6.0 g), b.p.
200C @ 1 mm. r Thisproduct (6.0g) in methanol (40 ml) and sodlum 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 (Na2SO4) and the solvent evaporated. The residue in ether was treated with ethereal hydrogen chloride and the precipitated solid recrystallised from isopropanol to give 4-(2-/2,6-dimethoxyphenoxy7ethoxy)piperidine hydrochloride (1.4 g) .
m.p. 143 - 145C.
Analysis %:-Found: ~ C, 56.4; H, 7.6; N, 4.3 Calculated for C15H23NO4.HCl: C, 56.7; H, 7.6; N, 4.4 (PLC..273) -108806~

_ 38_ EXAMPLE P
(A) Preparation of N-Acetyl-4-t2,2-diethoxy~ethoxy)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 diethyl-acetal (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 bromoacet-aldehyde diethylacetal (9~4~.7 g) was slowly added. The mixturewas 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-diethoxy-ethoxy)piperidine (61.5 g), b.p. 142 - 145C/3 mm., characterised by n.m.r.

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~088068 (B) Preparation of N-acetyl-4-(2-hydroxyethoxy)piperidine . .
N-Acetyl-4-(2,2-diethoxyethoxy)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 mls). The chloroform extract was dried (Na2SO4) and the solvent evaporated in vacuo and with a bath temperature below 30C. The resultant intermediate aldehyde (9.8 g) was reduced ~mediately 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 (Na2SO4) 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-acetyl-4-(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 96:-Found: C, 57.5; H, 9.1; N, 7.6 Calculatedfor CgH17NO3: C, 57.8; H, 9.1; N, 7.5.

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~88068 (C) 4-(2-Cyclopentyloxyethoxy)piperidine N-Acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g) in D.M.F.

I (25 ml) was added dropwise to a stirred suspension of sodium in dry D.M.F. (50 ml) hydride (1.28 9, 50~ dispersion in mineral oil) under an atmosphere of nitrogen. When effervescence had ceasedlcyclopentyl 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 60C for ¦ 10 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 (Na2SO4), 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.

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~ 41-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 (5.6 g) and _-fluorophenol (3.36 g) in freshly distilled tetra-hydrofuran (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 lN sodium hydroxide solution and twice with water, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was taken up in the minimum volume 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 was ~ain 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).

.

(PLC. 273) , ' :, ' ' 108~068 _ 42_ The combined chloroform extracts were dried (Na2S04) and the solvent evaporated in vacuo to give 4-t2-p-fluorophenoxyethoxy) piperidine (1.3 g).
A sample of this product in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and had an m.p. 144 - 145 C.
Analysis %:-Found: C, 56.1; H, 6.8; N, 5.5 13 18 N02.HCl C, 56.6; H, 6.9; N, 5.1.
EXAMPLES R TO U

The following piperidine derivatives were prepared by a similar procedure to that of Example Q, starting from N-acetyl-4-(2-hydroxyethoxy)piperidine and the appropriate phenol.

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~08~3068 EXAMPLE V

Preparation of 4-/2-(4-piperidyloxy)ethoxy7benzamide _ N-Acetyl-4-(2-hydroxyethoxy)piperidine (1.0 g), 4-hydroxybenzamide (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) ethoxy7benzamide (0.72 g), m.p. 1 54 - 155C.
Analysis %:-Found: C, 62.7; H, 7.1; N. 9.1 Calculated for C16H22N2O4 C, 62.7; H, 7.2; 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 f~Qr 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 ad~usted 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 io with chloroform, the chloroform layer dried (Na2SO4), and the solvent evaporated in vacuo to. give 4-/2-(4-piperidyloxy) ethoxy7 benzamide (0.36 g). The aqueous phase was concentrated in vacuo and the residual solid extracted with refluxing ethyl acetate (200 ml).

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'~ - '' ' :, 1~88V68 i ~ 46 The solid was removed by filtration and the filtrate evaporated in vacuo to give further 4-/2-(4-piperidyloxy) ethoxy7benzamide tO.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 - 246C, characterised spectroscopically.
EXAMPLE W
Preparation of 3-/2-(4-Piperidyloxy)ethoxy7benzamide . .
N-Acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g), 3-hydroxybenzamide (4.4 g), diethyl azodicarboxylate (5.6 g) and triphenylphosphine (8.4 g) in dry tetrahydrofuran (100 ml) were 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.
The 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 (MgSO4) then the solvent evaporated ln vacuo.
The residual oil was treated with ether (50 ml) and set aside in 20 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)ethoxy7benzamide (3.7 g) containing some triphenylphosphine oxide (approximately 25% by n.m.r.).
~ .

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~088068 The product in ethanol (48 ml), water (24 ml) and 2N hydrochloric acid (8 ml) was heated under reflux for 24 hours then the ethanol evaporated in vacuo. The aqueous residue was extracted with ether ~2 x 100 ml), then chloroform (100 ml), ther the aqueous phase was adjusted to pH 12 with sodium hvdroxide solution and extracted with chloroform (2 x 100 ml). The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to give 3-/2-(4-piperidyloxy) ethoxy7benzamide (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) ethoxy7benzamide (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 -146C.
Analysis %:- ~
Found: C, 56.0; H, 7.2; N, 9.2 Calculited for C14U2~N2O3.~CI: C, 55.9; 3, 7.l; N, 9.3.

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Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula --(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 by 1 or 2 lower alkyl groups; and R1 is hydrogen; lower alkyl; or C3-C6 cycloalkyl; or R1 is a group of the formula:

wherein R2 and R3 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, CF3, -CONR4R5 or -SO2NR4R5 wherein R4 and R5 each independently represent hydrogen or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof;
which comprises reacting a compound of the formula:

-- (II) wherein R is as defined above and Q is a facile leaving group, with a piperidine of the formula:

--- (III) wherein X is as defined above; and where required converting any base of formula (I) so produced into a pharmaceutically acceptable acid addition salt thereof, or any acid addition salt into the free base of formula (I).

2. A process as claimed in claim 1 wherein in the starting materials R is CH3; and X is -OCH2CH20R1, -OCH2-?HOR1 or -OCH2-?-OR1, in which R1 is H, C1-C4 alkyl, cyclopentyl, or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl or carbamoyl.

3. A process as claimed in claim 1 wherein in the starting materials R is CH3, "alk" is -CH2CH2- and R is C2H5.

4. A process as claimed in claim 1 wherein in the starting materials R is CH3, "alk" is -CH2CH2- and R1 is C6H5.

5. A process as claimed in claim 1 wherein in the starting materials R1 is other than C3-C6 cycloalkyl and R2 and R3 are other than CF3.

6. A process as claimed in claim 1, 2 or 5 wherein Q is chloro or bromo.

7. A process as claimed in claim 3 or 4 wherein Q is chloro or bromo.

8. Compounds of the formula (I) defined in claim 1 and their pharma-ceutically acceptable acid addition salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

9. A process for the preparation of 4-amino-6,7-dimethoxy-2-[4-(2-ethoxyethoxy)piperidino]quinazoline and its hydrochloride which comprises re-acting 4-amino-2-chloro-6,7-dimethoxyquinazoline with 4-(2-ethoxyethoxy)piper-idine, and where required converting the product into its hydrochloride salt.

10. A process for the preparation of 4-amino-6,7-dimethoxy-2-[4-(2-phenoxyethoxy)piperidino]quinazoline and its hydrochloride which comprises re-acting 4-amino-2-chloro-6,7-dimethoxyquinazoline with 4-(2-phenoxyethoxy)piper-idine, and where required converting the product into its hydrochloride salt.