Compounds of formula ##STR1## in which X represents oxygen or sulphur; PA0 Y represents --CHOH-- or ##STR2## Z represents ##STR3## or a direct bond; R represents cycloalkyl group having 5 to 7 carbon atoms or an optionally substituted aryl or heteroaryl radical, or when --Z-- is a direct bond R also represents hydrogen; PA0 R.sup.1 represents hydrogen or lower alkyl. and PA0 R.sup.2 represents hydrogen, halogen, lower alkyl or lower alkoxy; or PA0 a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof, are disclosed which reduce heart rate or have hyperglycaemic activity.

This invention relates to piperidine derivatives having pharmaceutical 
activity, to processes for their preparation, to pharmaceutical 
compositions containing them, and to intermediates useful in their 
preparation. 
U.S. Pat. No. 3,910,930 issued Oct. 7th, 1975 describes 
1-{1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl}-2-benzamidazol 
inones useful as antihypertensive agents. One of the compounds disclosed 
therein, namely 
erythro-1-{1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl}-2-benz 
imidazolinone, has been further evaluated and its mode of action discussed 
in Arch, int Pharmacodyn. 215, 91-132 (1975). Heart rate is reduced 
although only significantly at high doses. No .alpha.- or .beta.- 
adrenoceptor blocking activity has been reported for this compound. 
1-(Benzodioxan-2-yl alkyl)-4-benzamido-piperidine derivatives are disclosed 
in U.S. Pat. No. 3,919,242 issued Nov. 11th, 1975 which are useful in the 
treatment of disorders and diseases of the cardiovascular system. No 
.alpha.- or .beta.- blocking activity has been reported for these 
compounds. 
This invention provides compounds having the formula 
##STR4## 
wherein X represents oxygen or sulphur; Y represents --CHOH-- or 
##STR5## 
Z represents 
##STR6## 
or a direct bond; R represents cycloalkyl having 5 to 7 carbon atoms or an 
optionally substituted aryl, or heteroaryl radical, or when Z is a direct 
bond R can also represent hydrogen; R.sup.1 represents hydrogen or lower 
alkyl; R.sup.2 represents hydrogen, halogen, lower alkyl or lower alkoxy, 
and acid addition and quaternary ammonium salts thereof. 
The term "lower" as used herein in connection with a group or molecule 
means that the group or molecule contains 1 to 6 carbon atoms. 
Examples of R.sup.2 are hydrogen, methyl, ethyl, propyl, chlorine, bromine, 
methoxy, ethoxy and propoxy. 
Examples of R when other than hydrogen are: aryl radicals such as phenyl 
and phenyl substituted by one or more groups such as lower alkyl (e.g. 
methyl, ethyl, propyl or isopropyl), lower alkoxy (e.g. methoxy, ethoxy, 
propoxy or isopropoxy, methylenedioxy, halogen (e.g. fluorine, chlorine or 
bromine) perhalolower alkyl such as trifluoromethyl, nitro, amino and 
hydroxy; cycloalkyl radicals such as cyclohexyl and heteroaryl radicals, 
wherein the heteroatom is selected from oxygen, nitrogen or sulphur such 
as thienyl (e.g. 2-thienyl) furyl (e.g. 2-furyl) and pyridyl (e.g. 
3-pyridyl). 
Examples of R.sup.1 are hydrogen methyl, ethyl, n-propyl. 
Examples of acid addition salts are those formed with pharmaceutically 
acceptable acids such as the hydrochloride, sulphate, phosphate, acetate, 
maleate, fumarate, tartrate, formate, methanesulphonate, 
p-toluensulphonate, benzoate, succinate, lactate and salicylate. 
Examples of quaternary ammonium compounds are those formed with alkyl and 
aralkyl halides, particularly methyl and ethyl halides such as ethyl 
bromide and methyl iodide, and benzyl halides such as benzyl chloride. 
It will be apparent to those skilled in the art that the compounds of 
formula I possess at least one, and sometimes two asymmetric centres and 
hence optical isomers and sometimes diastereoisomers are possible. All 
such optically active forms and mixtures thereof, are intended to be 
included within the scope of this invention. More particularly when Y 
represents the group --CHOH-- in formula I above then two asymmetric 
centres are present and therefore such a compound can exist in one of four 
optically active forms, i.e. two pairs of enantiomers--one pair of 
enantiomers being the diastereoisomers of the other pair. Such 
diastereoisomeric forms are termed threo and erythro and have the relative 
configurations shown below; 
##STR7## 
Separation of diastereoisomers and enantiomers may be effected by standard 
techniques known in the art. 
Compounds of formula I, wherein Y is CHOH, having the erythro configuration 
are particularly preferred. 
The compounds of this invention possess pharmaceutical activity and some 
are intermediates for other compounds of this invention. 
More particularly when Y is --CHOH-- the compounds of formula I possess the 
ability to reduce heart rate when administered in a standard test to renal 
hypertensive rats. The erythro series of diastereoisomers are particularly 
active in reducing heart rate. Representative of the compounds of formula 
I wherein Y is --CHOH-- is erythro 
1-benzoyl-3-[1-(2--[1,4-benzodioxan-2-yl]-2-hydroxyethyl)-piperid-4-yl] 
urea, hydrochloride, which possesses marked ability to reduce heart rate 
in the above mentioned test, producing a 48.5% and 51.5% decrease in heart 
rate at a time period of 2 hours and 6 hours respectively after dosing. 
The compounds of formula I wherein Y is --CHOH-- also possess hypotensive 
activity when administered in a standard test to normotensive rats. 
Representative of such compounds are threo-and 
erythro-1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4- 
yl]urea hydrochloride, which compounds produced a lowering in diastolic 
blood pressure of .gtoreq.30 mm Hg sustained for 15 minutes. For the threo 
isomer the dose level was 12.8 mpk (2 rats) and for the erythro the dose 
level was 12.8 mpk (1 rat) and 6.4 mpk (1 rat). 
The erythro series of diastereoisomers also possess .alpha. and .beta. 
adrenergic blocking activity as evidenced by standard tests on isolated 
animal tissue. Thus the representative compound 
erythro-1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4- 
yl]urea hydrochloride was found to possess an .alpha.-adrenoceptor blockade 
PA.sub.2 value of 7.0 when tested on rat perfused mesentery. This compound 
showed a PA.sub.2 value of 8.0 when tested for .beta..sub.1 -adrenoceptor 
blocking activity in guinea-pig spontaneously beating atria using 
concentrations showing minimal cardioinhibition. It also showed a PA.sub.2 
value of 6.8 when tested for .beta..sub.2 -adrenoceptor activity on 
guinea-pig isolated tracheal spiral. 
Compounds possessing the ability to lower heart rate and/or possessing 
.alpha. and .beta. adrenergic blocking activity may be useful in the 
treatment or prophylaxis of coronary artery disorders. 
Compounds of formula I wherein Y represents --CO-- possess hyperglycaemic 
activity, as shown by a standard test on warm blooded animals. The 
compounds can be tested for hyperglycaemic activity by the following 
procedure. 
Male rats weighing 170-200 grams are fasted overnight. A control blood 
sample taken from the tail and the sample of test compound is then 
administered by stomach tube. Subsequent blood samples are taken at hourly 
intervals for three hours and the change in the blood sugar concentration 
is determined. 
In this procedure it was found that a representative compound of formula 
(I) namely 
1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]urea, 
hydrochloride produced an increase in blood sugar of more than 20% for 
more than one of the hourly test samples when administered at 50 mpk. 
Hyperglycaemic agents can be of use for administration to patients having 
too low a blood sugar concentration following, for example, administration 
of too large a dose of hypoglycaemic agent such as insulin. Hyperglycaemic 
agents can also be used to produce hyperglycaemic animals which can be 
used in screening for hypoglycaemic compounds in pharmacological 
procedures. 
It is possible to interconvert the compounds of formula I and hence all the 
compounds are useful as intermediates for other compounds of formula I. 
Thus compounds of formula I wherein Y represents --CO-- are useful for 
preparing compounds of formula I wherein Y represents --CHOH--. Compounds 
of formula I wherein RZ--represents an acyl group, especially those as 
herein defined, are useful in the preparation of compounds of formula I 
wherein R is H and Z is a direct bond; which compounds can be acylated to 
give other compounds of this invention wherein RZ-- is an acyl group. 
This invention also provides processes for preparing the compounds of 
formula I. 
One such process for preparing a compound of formula I wherein Y represents 
--CO-- or --CHOH-- comprises reacting a compound of formula 
##STR8## 
wherein R.sup.2 and Y are as defined above and W represents a halogen 
(e.e. chlorine or bromine) or equivalent replaceable radical such as an 
organic sulphonyl radical, e.g. tosylate (--Otosyl), with a compound of 
formula 
##STR9## 
wherein Z, R and R.sup.1 are as defined above; R being other than 
hydrogen. Such a reaction is conveniently carried out in the presence of 
base, e.g. an alkali metal carbonate such as potassium carbonate or a 
lower alkyl amine, e.g. triethylamine, in a suitable inert solvent, e.g. 
dimethylformamide, dichloromethane, isopropanol and the like. 
A further process for preparing compounds of formula I comprises reacting a 
compound of formula 
##STR10## 
wherein R.sup.1, R.sup.2 and Y are as hereinbefore defined with a compound 
of formula (V) 
EQU RZN.dbd.C.dbd.X (V) 
wherein X, Z and R are as defined in connection with formula I, R being 
other than hydrogen. This reaction should be conducted under mild 
conditions to avoid the possibility of reaction between the amine IV (when 
Y is --CO--) and the oxoethylene radical of another molecule of amine IV 
giving a Schiffs base. Usually the reaction to form the compound of 
formula I takes place at room temperature. 
The starting materials of formula IV wherein R.sup.1 is hydrogen may be 
prepared by methods described in our British Specification No. 1,345,872. 
The starting materials of formula (IV) wherein R.sup.1 is lower alkyl may 
be prepared by alkylating corresponding compounds of formula IV wherein 
R.sup.1 is hydrogen, or by methods analogous to those described in 
Specification No. 1,345,872. 
The starting materials of formula III may be prepared by reacting 
1-benzyl-4-aminopiperidine with a compound of formula V wherein X is 
oxygen and removing the 1-benzyl group by hydrogenolysis. 
Compounds of formula I wherein R is hydrogen may be prepared by hydrolysis, 
e.g. using aqueous sodium hydroxide, of the corresponding compounds of 
formula 
##STR11## 
wherein X, R.sup.1, R.sup.2 and Y are as defined above the Acyl represents 
an acyl radical, e.g. aroyl or heteroaroyl. Once a compound of formula I 
wherein R is hydrogen has been prepared then that compound may be acylated 
to give other compounds of this invention wherein RZ-- represents an acyl 
radical, for example, using an active derivative of an acid of formula 
EQU R COOH (VII) 
wherein R is cycloalkyl of 5 to 7 carbon atoms, aryl or heteroaryl. 
Examples of reactive derivatives of the acid of formula VII are the 
halide, e.g. the chloride, and the anhydride. 
If necessary, in any of the reactions herein described, reactive 
substituent groups may be blocked during a reaction and released at a 
later stage. 
A further method of preparing compounds of formula I wherein R.sup.1 is a 
hydrogen and Z is a direct bond comprises reacting a compound of formula 
IX: 
##STR12## 
with an amine of formula 
EQU R NH.sub.2 (X) 
wherein X, Y as defined above and R is as defined in connection with 
formula I except hydrogen. This reaction should be conducted under mild 
conditions to avoid any possibility of the amine reacting with the 
oxoethylene group to form a Schiffs base. 
Compounds of formula (IX) may be prepared by treatment of a compound of 
formula IV, wherein R.sup.1 is hydrogen with phosgene followed by 
treatment of the product with calcium oxide according to the following 
reaction scheme: 
##STR13## 
Other standard methods may be used to prepare compound (IX). 
A method for preparing compounds of formula I wherein R is hydrogen and X 
is oxygen comprises reacting a compound of formula IV with nitrourea 
(H.sub.2 NCONH.NO.sub.2). 
The compounds of formula (I) wherein Y is --CHOH-- are also obtained by 
reacting a compound of formula (III) 
##STR14## 
with a 2-epoxyethyl-1, 4-benzodioxan of formula X 
##STR15## 
In a suitable organic solvent such as an aromatic hydrocarbon for example, 
benzene, toluene, xylene and the like; a halogenated hydrocarbon such as 
chloroform and methylene chloride; or a lower alkanol, such as, for 
example, methanol, ethanol, 2-propanol and the like and preferably in a 
mixture of an aromatic hydrocarbon and a lower alkanol. The reaction may 
be promoted by the addition of alkali. 
Once a compound of formula I wherein Y is --CO-- has been prepared then 
such a compound may be reduced to give other compounds of formula I 
wherein Y is --CHOH--. For example reduction may be effected with a 
hydride transfer agent such as an alkali metal borohydride, e.g. sodium 
borohydride, and sodium tri-t-butoxyborohydride. Other methods applicable 
to the reduction of a ketone to a secondary alcohol are known in the 
literature--see for example "Compendium of Organic Synthetic Methods" Ian 
T. Harrison, Shuyen Harrison, Published by Wiley Interscience, Volume I, 
1971. 
Once a compound of formula I wherein Y is --CHOH-- has been prepared then 
such a compound may be oxidised to give other compounds of formula I 
wherein Y is --CO--. For example, chromic acid oxidation may be used to 
effect the above mentioned conversion. Other methods for oxidising 
secondary alcohols to ketones are known in the literature see, for 
example, the above mentioned textbook of Harrison and Harrison. 
Separation of diastereoisomers and resolution of enantiomers may be 
effected by standard techniques known in the art after any of the above 
mentioned processes where racemic starting materials are employed. For 
example diastereoisomers can generally be separated by techniques such as 
fractional crystallisation or chromatography. 
Alternatively it will be apparent to those skilled in the art that if it is 
desired to prepare a final product having a specific stereochemistry then 
it is possible in some instances to employ a starting material already 
having the desired stereochemistry. Such routes to erythro compounds of 
formula I are preferred. For example erythro compounds of formula (IV) as 
defined above may be reacted with compounds of formula V to give 
corresponding erythro compounds of formula I. 
Erythro compounds of formula IV may be prepared by reacting an appropriate 
erythro 2-bromo-1-[1,4-benzodioxan-2-yl]ethanol with 
4-benzamidopiperidine, hydrolysing the product to remove the benzoyl group 
to give the erythro 4-aminopiperidine derivatives of formula IV; which 
compound may be alkylated to give 4-loweralkylamino derivatives. 
The invention also includes pharmaceutical compositions containing as 
active ingredient an active compound of formula I as above defined. The 
active compound may be micronised if desired. In addition to the active 
ingredient, the compositions also contain a non-toxic carrier. Any 
suitable carrier known in the art can be used to prepare the 
pharmaceutical compositions. In such a composition, the carrier may be a 
solid, liquid or mixture of a solid and a liquid. Solid form compositions 
include powders, tablets and capsules. A solid carrier can be one or more 
substance which may also act as flavouring agents, lubricants, 
solubilisers, suspending agents, binders, or tablet-disintegrating agents; 
it can also be an encapsulating material. In powders the carrier is a 
finely divided solid which is in admixture with the finely divided active 
ingredient. In tablets the active ingredient is mixed with a carrier 
having the necessary binding properties in suitable proportions and 
compacted in the shape and size desired. The powders and tablets 
preferably contain from 5 to 99, preferably 10-80% of the active 
ingredient. Suitable solid carriers are magnesium carbonate, magnesium 
stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, 
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low 
melting wax and cocoa butter. The term "composition" is intended to 
include the formation of an active ingredient with encapsulating material 
as carrier to give a capsule in which the active ingredient (with or 
without other carriers) is surrounded by carrier, which is thus in 
association with it. Similarly cachets are included. 
Sterile liquid form compositons include sterile solutions, suspensions, 
emulsions, syrups and elixirs. The active ingredient can be dissolved or 
suspended in a pharmaceutically acceptable sterile liquid carrier, such as 
sterile water, sterile organic solvent or a mixture or both. Preferably a 
liquid carrier is one suitable for parenteral injection. Where the active 
ingredient is sufficiently soluble it can be dissolved in normal saline as 
a carrier; if it is too insoluble for this it can often be dissolved in a 
suitable organic solvent, for instance aqueous propylene glycol or 
polyethylene glycol solutions. Aqueous propylene glycol containing from 10 
to 75% of the glycol by weight is generally suitable. In other instances 
compositions can be made by dispersing the finely-divided active 
ingredient in aqueous starch or sodium carboxymethyl cellulose solution, 
or in a suitable oil, for instance arachis oil. Liquid pharmaceutical 
compositions which are sterile solutions or suspensions can be utilised by 
intramuscular, intraperitoneal or subcutaneous injection. In many orally 
either in liquid or solid composition form. 
Preferably the pharmaceutical composition is in unit dosage form. In such 
form, the composition is sub-divided in unit doses containing appropriate 
quantities of the active ingredients; the unit dosage form can be a 
packaged composition, the package containing specific quantities of 
compositions, for example packeted powders or vials or ampoules. The unit 
dosage form can be a capsule, cachet or tablet itself, or it can be the 
appropriate number of any of these in package form. The quantity of active 
ingredient in a unit dose of composition may be varied or adjusted from 5 
mg. or less to 500 or more, according to the particular need and the 
activity of the active ingredient. The invention also includes the 
compounds in the absence of carrier where the compounds are in unit dosage 
form.

The following examples illustrates the invention; and the preparation of 
intermediates. 
EXAMPLE 1 
1-Benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl)-2-oxoethyl]piperid-4-yl]urea 
1-Benzoyl-3-(piperid-4-yl)urea (2.46 g, 0.01 mol) and 
2-bromoacetyl-1,4-benzodioxan (2.57 g, 0.01 mol) in dry dimethylformamide 
(40 mls) were stirred at room temperature. Triethylamine (1,1 g, 1.5 
cm.sup.3) was added and the suspension stirred for 1 hour. Water was added 
and the solid filtered off (4.20 g, 100%). The solid was suspended in 
methanol (40 mls) and ethanolic hydrogen chloride added until the solution 
was acidic. The title compound was filtered off as the hydrochloride salt 
and dried (yield 3.51 gm 76% yield). Melting pt. 160.degree.-161.degree. 
C. 
Analysis C.sub.23 H.sub.25 N.sub.3 C.sub.2 .cndot.HCl requires C, 60.06; H, 
5.70; N, 9.14%. Found; C, 60.12; H, 5.71; N, 9.02% 
EXAMPLE 2a 
Threo 
1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]-urea 
1-Benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]-urea 
(7.21 g, 0.017 mol) was suspended in methanol (80 cm.sup.3) and was 
stirred at room temperature. Sodium borohydride (1.0 g, 0.026 mol) in 2N 
sodium hydroxide (10 cm.sup.3) was added dropwise to the stirring solution 
and then left to stir for a further hour. Water was added and the solid 
filtered off and dried (5.41 g, 75%). A. T.L.C. of a small portion of the 
solid was run in freshly prepared toluene: ethanol: 0.880 ammonia (90:10:1 
by volume) on a silica plate and was found to contain two components 
having R.sub.F values of about 0.30 and 0.34. The solid was recrystallised 
from n-butyl acetate (9 times) to give the component (1.19 g) with the 
lower R.sub.F value. This was suspended in a small amount of methanol and 
ethanolic HCl added until the solution was just acidic. The hydrochloride 
of the title compound (0.96 g, 74%) was collected. 
Melting pt. 212.degree.-214.degree. C. 
Microanalysis C.sub.23 H.sub.27 N.sub.3 O.sub.5 .cndot.HCl1/4H.sub.2 O 
requires C, 59.22 H, 6.15, N, 9.01%. Found: C, 59.22, H, 6.44, N, 8.50%. 
EXAMPLE 2b 
Erythro 
1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl ]-ure 
a, 
The method liquors from the first five recrystallisations obtained in 
Example 2b above were combined, evaporated and recrystallised from n-butyl 
acetate (4 times) to give the component with the higher R.sub.F value 
(0.34 approx) (0.9 g). This was suspended in a small amount of methanol 
and ethanolic hydrogen chloride added until the solution was just slightly 
acidic. The hydrochloride of the title compound (0.63 g, 64%) was 
collected. 
Melting pt. 213.degree.-216.degree. C. 
Microanalysis C.sub.23 H.sub.27 N.sub.2 O.sub.5 .cndot.HCl requires C, 
59.80; H, 6.11; N, 9.1%. Found: C, 59.46; H, 6.30; N, 8.9%. 
EXAMPLE 3 
(a) Erythro 1-(1,4-Benzodioxan-2-yl)-2-bromoethanol 
2-Bromoacetyl-1,4-benzodioxan(53.8 g) in methanol (500 mls) was cooled to 
-70.degree. C. Sodium borohydride (10.3 g) was added and the solution 
stirred at -70.degree. C. for 12 hours. The solution was treated with 
hydrobromic acid until acidic and the solvent evaporated. The residue was 
dissolved in ether and the ether extracts were washed with sodium 
bicarbonate solution; then water and dried (MgSO.sub.4) and evaporated to 
give a white solid. This was recrystallised eight times from petroleum 
spirit 60-80 to give 14 grams of the title compound. 
(b) 
Erythro-4-benzamido-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine 
Erythro 
1-(1,4-benzodioxan-2-yl)-2-bromoethanol (7.03 g 0.03 m). 
4-benzamidopiperidine (5.59 g 0.027 m) and triethylamine (4 g 0.04 m) were 
refluxed in ethanol (250 mls) for 24 hours. The solvent was evaporated and 
the residue dissolved in chloroform and the chloroform extract washed with 
water, dried (MgSO.sub.4) and evaporated to give a white solid (7.95 g 
69%). This solid (1.5 g) was dissolved in the least amount of methanol and 
acidified with ethanolic HCl. The title compound crystallized, was 
filtered off and dried (1.04 g) 
Melting pt. 246.degree.-249.degree. C. 
Microanalysis; C.sub.22 H.sub.26 N.sub.2 O.sub.4 .multidot.HCl requires C, 
63.08%; H, 6.50%; N, 6.69%; Found: C, 62.99%; H, 6.55%; N, 6.39% 
(c) Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine 
Erythro-4-benzamido-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine 
(14.23 g) prepared according to Example 3(b) was suspended in 6 N 
hydrochloric acid (250 mls) and boiled under reflux for 8 hours. The solid 
was filtered off and washed with water. The aqueous filtrate and washings 
were treated with anhydrous potassium carbonate powder until basic and 
these extracted with chloroform. The combined chloroform extracts were 
washed with water, dried (MgSO.sub.4), and evaporated to give title 
compound (10.4 g 100%) 
EXAMPLE 4 
Erythro 
1-Cyclohexyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]ur 
ea, 
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine (2.0 
g, 0.0072 m) prepared according to Example 3(c) in sodium dried benzene 
was treated with cyclohexyl isocyanate (0.99 g 0.008m) in sodium dried 
benzene (25 mls). The mixture was stirred at room temperature for 18 
hours. The solid was filtered off and washed with benzene. The white solid 
was suspended in ethyl acetate and acidified with ethanolic hydrogen 
chloride until the solution was acidic. The title compound was filtered 
off, washed with ether and dried (1.47 g 46.5%) 
Melting pt. 214.degree.-216.degree. C. 
Microanalysis C.sub.22 H.sub.33 N.sub.3 O.sub.4 .multidot.HCl requires C, 
60.06%,; H, 7.79%; N, 9.55%. Found: C, 60.04%; H, 7.81% N, 9.58. 
EXAMPLE 5 
Erythro 1-phenyl-3-[-b 
1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]urea 
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine (2.0 
g 0.007 m) prepared according to Example 3(c) was dissolved in sodium 
dried benzene (100 mls). To the stirring solution was added phenyl 
isocyanate (0.76. 0.0072 m) in sodium dried benzene (25 mls). The solution 
was stirred at room temperature for 18 hours. The solid was filtered off, 
then dissolved in ethanol and acidified with ethanolic hydrogen chloride 
to give the hydrochloride salt of the title compound, (0.87 g 28%). 
Melting pt: 214.degree.-215.degree. C. 
Microanalysis: C.sub.22 H.sub.27 N.sub.3 O.sub.4 .multidot.HCl requires 
C,60.89%; H, 6.50%; N, 9.68%. Found: C, 60.88; H, 6.45%; N, 9.82%. 
EXAMPLE 6 
Erythro 
1-p-methoxybenzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4 
-yl]urea 
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethyl]piperidine (2.0 
g 0.0072 m)) was dissolved in sodium dried benzene (100 mls). To the 
stirring solution was added p-methoxy benzoyl isocyanate (1.27 g 0.0072m) 
in benzene (20 mls) and the solution stirred at room temperature for 18 
hours. The solvent was evaporated and the residue heated with isopropyl 
alcohol. The insoluble solid was filtered off and triturated with hot 
ethanol, filtered and dried to give the title compound (0.5 g 15%). 
Melting pt: 198.degree.-199.degree. C. 
Microanalysis: C.sub.24 H.sub.29 N.sub.3 O.sub.6 .multidot.1/2H.sub.2 O 
requires C, 62.06% H, 6.51%; N,9.05%. Found C, 62.08%; H, 6.39%; N, 9.01%. 
EXAMPLE 7 
Erythro 
1-p-chlorobenzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4- 
yl]thiourea 
Ammonium thiocyanate (0.6 g 0.0076 m) was stirred in dry acetone (7 mls) 
and p-chlorobenzoyl chloride (1.26 g 0.0072 m) was added and the solution 
refluxed for 5 minutes. Erythro 4-amino-1-[-b 
2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine (2.0 g 0.0072 m) in dry 
acetone (15 ml) was added to the hot solution and the mixture refluxed for 
15 minutes. The solution was poured into water and the resulting 
precipitate was extracted with chloroform, dried (MgSO.sub.4), and 
evaporated to give a solid which was recrystallised from ethanol. The 
recrystallised material was dissolved in ethanol and acidified with 
ethanolic hydrogen chloride to give the hydrochloride salt of the title 
compound (0.65 g 20%). 
Melting Pt: 187.degree.-189.degree. C. 
Microanalysis: C.sub.23 H.sub.26 N.sub.3 C10.sub.4 SHCl.multidot.1/2H.sub.2 
O requires C, 52.77%; H, 5.39%; N, 8.03%. found: C, 52.77%; H, 5.39%; 
N,8.03%. 
EXAMPLE 8 
Repeating the procedure of Example 4(when X is oxygen) or Example 7(when X 
is sulphur) the following compounds of formula I may be prepared according 
to the reaction: 
______________________________________ 
##STR16## 
##STR17## 
R Z X R.sup.1 
______________________________________ 
(a) p-Fluorophenyl 
direct bond 
oxygen H 
(b) p-Chlorophenyl 
direct bond 
oxygen H 
(c) p-Chlorophenyl 
CO oxygen H 
(d) 3,4-Dichlorophenyl 
CO oxygen H 
(e) 2,5-Dimethylphenyl 
CO oxygen H 
(f) Phenyl CO oxygen methyl 
(g) Phenyl CO sulphur H 
(h) o-Methylphenyl 
CO oxygen H 
(i) p-Trifluoromethylphenyl 
CO oxygen H 
(j) 2-Thienyl CO oxygen H 
______________________________________ 
EXAMPLE 9 
1-Cyclohexylcarbonyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid- 
4-yl]urea 
1-Cyclohexylcarbonyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl 
]urea, prepared by reacting 1-cyclohexylcarbonyl-3-(piperid-4-yl)urea with 
2 -bromoacetyl-1,4-benzodioxan in DMF/Et.sub.3 N, may be reduced using 
sodium borohydride in 2 N sodium hydroxide to give the title compound. 
EXAMPLE 10 
1-[2-Thienyl]-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]ur 
ea 
1-[2-Thienyl]-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]urea, 
prepared by reacting 1-(piperid-4-yl)-3-(2-thienyl)urea with 
2-bromoacetyl-1,4-benzodioxan in DMF/Et.sub.3 N, may be reduced using 
sodium borohydride in 2 N sodium hydroxide to give the title compound. 
EXAMPLE 11 
1-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]urea 
The title compound may be prepared by hydrolysis of 
1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)-piperid-4-yl]urea 
using aqueous sodium hydroxide. 
EXAMPLE 12 
1-[2-Furoyl]-3-[1-(2-[1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid-4-yl]ure 
1-[2-Furoyl]-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]urea, 
prepared by reacting 1-(piperid-4-yl)-3-(2-Furoyl)urea with 
2-bromoacetyl-1,4-benzodioxan in DMF/Et.sub.3 N, may be reduced using 
sodium borohydride in 2 N sodium hydroxide to give the title compound. 
EXAMPLE 13 
Erythro 
1-benzoyl-3-[1-(2-[6-methoxy-1,4-benzodioxan-2-yl]-2-hydroxyethyl)piperid- 
4-yl]urea 
Using the procedure of Example 4 erythro 
4-amino-1-[2-(6-methoxy-1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine 
may be reacted with benzoyl isocyanate to give the title compound. 
EXAMPLE 14 
Erythro 
1-benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]2-hydroxyethyl)piperid-4-yl]urea 
Erythro 1-(1,4-benzodioxan-2-yl)-2-bromoethanol (7.04 g), 
3-benzamido-1-(piperid-4-yl)urea (6.65 g) and triethylamine (4 g) were 
refluxed in ethanol (250. cm.sup.3) for 24 hours. The solvent was 
evaporated and the residue dissolved in chloroform. The chloroform extract 
was washed with water, dried (MgSO.sub.4) and evaporated to give a white 
solid. This was suspended in ethanol (200 cm.sup.3) and acidified with 
ethanolic hydrogen chloride. The title compound (hydrochloride salt) 
crystallised out and was filtered off and dried. (8.85 g (71%). 
Melting point. 206.degree.-207.degree. C. 
C.sub.23 H.sub.27 N.sub.3 O.sub.5. HCl requires C, 59.80%; H, 6.11%; N, 
9.10%. Found: C, 59.58%; H, 5.95; N, 9.04%.