Note: Descriptions are shown in the official language in which they were submitted.
``` ~0~806B
-- 2 --
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
R3
~PLC. 273)
'. , ~
: ~. : ,
' . ' ~
1088068
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
, '. :,, . ' ' :
- :. : ,- ~ . :
~088068
-- 4 --
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
-O-CH2-C-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.
(PLC. 273)
. ~ .
' ''' : :
, ' ' ............ ' ~
1088068
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 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
3 CH3
/DMF = dimethylformamide7
(PLC. 273)
.
lOB8068
-- 7 --
(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
CH3 CH3 CH3
hydrolysis
~(acidic or basic)
O-CH2CHOR
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)
'
,.'.
: . : ... : --: :.: -:-
.. : . ~
- i : - . ~ ::
- :::: . : :. . . :
::~: ,.. :.... ...
:- , ~ ~. . :
.
: .
::: :
1088068
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
OCHCH20H
(Prot. and R" are as defined above)
Prot.
~PLC. 273)
.
.. . . .
.. - : .
, :~
. .
1088~)68
_ 9 _ R"
OH OCH2CH
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:
(PLC. 273)
.: , . ~. -
.. . :.:
. ": ' ;, ~ . . , :
. : : :..... ,
- .::
::
1088068
-- 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
("D.E.A.D."): OH 3
R" R"' ~ IR" Rl''~ ~
[~ :R ~R ~ [~
NPh3P/D.E A D., N
C=o C=O
CH3 3
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
-- 11 --
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)
,: ' : : :
., . , ... . : .: :-
~88068
~ 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
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)
.
1088068
- 13-
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
: ' , , , , ' :,
'- : ': ~ : :
.. : ., .. :- .,:,, : :
- ~ ' ' :; ' -: ': ~ -" '.' ' . .. , :
1~88068
- 14-
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
.
: :
~088068
-- 15 --
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:-
.
,
(PLC. 273)
:;.:.:: ::.: ,
,: :: :: :. :,:: : ~: :, ,.:
-: , :: ~
. . :~ ::::,. :
108~068
-- 16--
EXAMPLE 1
Preparation of 4-Amino-6,7-dimethoxy-2-/4-(2-ethoxyethoxy)
piperidino/quinazoline hydrochloride
'
OCH2CH20C2H5
3\~N ~l/cQ~c3 ~ ~ ~ 32 N2 Z S
CHl}; H CH31~ N
NH2 NH2
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
-17-
EXAMPLES 2-7
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.
(PLC. 273)
~' '' - ; " ~ -' '- : ,', ',' ''`:' ,:'
1088~)68
- 18 -
_ ~r~, o~ _~
1~
r ~
J~ ,~Q ~o ~,o,,,
~J ~1 i;
(PLC . 273 )
1088068
~ ~ ~, o C~, ~
~~ ~rN ~ N N
0
>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
- 20-
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
- -21 -
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.
-
-(PLC. 273)
: , -:: ; : : - : . , :
:.:: : :
: :.. ::
:, :.:. :. .::
8068
-- 22--
JJZ _~ __ oî~
~ a -~ ~ -~ ~
~ $ ~ 1
~ ~D~O 0~ ~
E~ O ~ O 0~ I~ r-
U~ Ul ~ U~ U~ U~
~o 'S~ ~ ~ ~Ot~
. ' U~ ~ O ~ ~ ~ O
~ 8 ~ In o ~ ~ o ~
(PLC. 273)
.-: ::. : , :. :: . , ` . .:. , .: :
: , - :
-: - : ~ ... .
.
1088068
- 23
V Z -_ oo _-~
,~ ~ u~ r~ ~ ~ ~r
~ ~ ~ ~ ~o
h
E~ O ~ ~ ~ ~
_ ISl Ul In In Ln Ul
~a _ .
~0 ~ `O raO ~ ~0
H . S h I h ~ h ~
~ U ~ Ll~ U ~ U S 1`
~: r ~ ~
~ ~ g
~Z ~ ~ ~r
. .
(PLC. 273 )
'. ` ' ' ' "" ' ' ' : ~.
. ` . :' . ' : '
: ' ' ' ' ` ' `' ' ~ ` ,
.
~088068
- 24-
~VDZ oo o~ _
. ~S ~ _ _._
D o~ ~ ~0
:~ ~ e s ,~ s '` D ~
- (PLC. 273 )
:: . :
: : : :
- ~ ' . : ': ' ~ :
: ~
1088068
-- 25--
_ . _
Z ~r
~ .
U o
_ . ..
., ~ C~ . ''
- (PLC . 27 3 )
.. :
~088068
-- 26--
~ æ ~
I~wloO 1'`'` 1~ IU`~
~ C~ u7 ~ C~ O ~ _~ O r~
~OU ~0 u~r~ ~-~0 ~0
~ r-l N O ~ ~ ~ ~ N
~ ~ 1_~ ~ I .~ .C ~ I o0`1
r ~ ~
~ ~t 3
(PLC. 273)
- : , ,:,:,: , : :,
- , : , :: . :
:
1088068
- 27-
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.
(PLC. 273)
.. , : . - : -
- ,: ~ : . ~ , ,
.. . ...... .
~ 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.
` ' ~
~ ~Y
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)
.::,
~- :: : . : . ., . ::- . :: .. ~ ., . :
.. : . . - . : ::: :: :
~: . :: ::: : . .. : . .
,, ... ..~
1088068
- 29 -
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)
.
.
:: ,. '.` . ' ;- :.: ..... .
,
l~B8068
- 30-
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)
:: . :.-: . : - -. : . : : -,
1088068
-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
.
l ~PLC, 273)
.`1 ' ' ' .
'
~) ~.,- . :
:: : . . : :: . . ::
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)
.
, , .
. , ~. .. .. , -- - - - ,, ~-; .. ~ . - . '
- , ~ . - . " , . .- ~ . ,
.
~ . ' ,
1098068
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.
:
(PLC. 273)
~; . - - - , . ~ :
: . -.: . ;: : : , ,
~ ; ,, . . , : ~ ::
::
~.: : ,. . , : .
. . .
1088068
- 35-
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.
, .
.
tPLC. 273)
- ;.- -~ :
~ , , .
'
108~068
36-
EX~MPLE O
4-(2-/2,6-Dimethoxyphenoxy7ethoxy)piperidine
OCH3 OCH3
3 2 > ~ 2 2 2 H3
H3 - OCH3
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.
(PLC. 273)
;
... .... , .:, .
' :';: :.,. . :
. . . .
68
~ 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.
~PLC. 273)
~ .
. . ~. . . . : ... : `' ::'' ' :: `
.. : ,
` ' :: :: :~ ;:: :.:: : :: : ..
- ~ ':: ::. :.: :: : :: ;
: . , : :.. :~ .. , : . ,: :
~088068
-- 39--
(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.
(PLC. 273)
' ~ ~ . : - ' '
;
~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.
- (PLC. 273)
.
-~ , : ,. . :. .. , :
-. -
:. . . ..
., , : . : :; .: :
1088068
~ 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.
(PLC. 273)
. ..- ', '
,
~' : ,. . ` ,
~0~3068
- --43 ~- -
~ . ~, I~r, .
~r r~
rJ
dP R
~n ~ ~ r.~l r ~ rr) r~
rJ ,~ r r 1~ ~ n In
~0
E~ ~ ~ r~ ~ ~r 1~
. ~ r r O o
~s) u~u~ ~
_~ . .
g rJ -- ~10~ ,1 r al r~
:q O ~ ~r ~ ~ r~
r~l r ~ S I S I r~ I
~ O Lr) o ~-- o r.~l
~1 1~ rJ ~, r~ r~l .
~ J . ~,~. ,. .
rJ Z ~r; r~ E~
. ~ _ . ......
.
(PLC.- 273)
: ~, ;: ' `' -::
:.... . ~ :
: `
1088068
--44 --
U~
~1 ~
h
~ ~ .'
g ~ O ~ . .
:~ O Q~ ~
[~ 1~
tPLC. 273)
.
~08~3068
-- 45
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).
~PLC. 273)
,, . - , . , ., . , ,.~ :
'~ - '' ' :,
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.).
~ .
(PLC. 273)
.
:. , : ., : :;. .~:
, . : ~: , ~ . . : :
~088068
- 47 -
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.
1. .
i
(PLC. 273)
:
. .
- : :, . .
. .
