Note: Descriptions are shown in the official language in which they were submitted.
11~4545
CARBOXYLIC ACID DERIVATIVES
Ihis inventicn relates to novel carboxy~c acid deriv-
atives and, more particularly, it relates to novel l-
benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid
derivatives which inhibit the aggregation of blood
platelets in vivo and, therefore, may be of application
in the treatment or prophylaxis of thrombosis or
occlusive vascular disease.
It is known that various N-benzyl 4,5,6,7-
tetrahydrothieno~3,2-c]pyridine and N-benzyl-4,5,6,7-
tetrahydrofuro[3,2-c]pyridine derivatives possess anti-
inflammatory and blood platelet aggregation inhibitory
properties (M Podesta et alia, European J.Med.Chem.,
Chim.Therapeutica, 1974, 2, 487-490). It is also
known that various l-benzyl-1,2,5,6-tetrahydropyridine-
4-carboxylic acid esters are chemical intermediates
(West German Offenlegungsschrift No.2221770 and Annalen,
1972, 764, 21-27). We have now discovered that certain
novel l-benzyl-1,2,5,6~tetrahydropyridine-3-carboxylic
acid derivatives unexpectedly also possess the property
of inhibiting the aggregation of blood platelets in vivo,
and this is the basis for our invention. Two related
compounds, l-benzyl-1,2,5,6-tetrahydropyridine-3-
carboxylic acid methyl and ethyl esters, are known
[Zhur.Obschei.Khim.1957, 27, 3162-3170 (Chemical Abstracts,
1958, 52, 9162c-i) and J.Chem.Soc.Chemical Communications,
1975, 682, respectively] but no useful pharmacological
properties have been ascribed to them.
According to the invention there is provided
a l-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid
derivative of the formula:-
11~4S45
-- 2 --
wherein Rl is a hydroxy, amino, (1-4C)alkylamino, or
di-[(1-4C)alkyl]amino radical, a benzyloxy radical
optionally bearing a halogeno substituent, or a (1-6C)-
alkoxy radical optionally bearing a (1-4C)alkoxy,
morpholino or di-[(1-4C)alkyl]amino substituent; and
benzene ring A bears one or two substituents selected
B from halogeno, (1-4C)al~yl, cyano, ca~ ox~mi~o, tri-
fluoromethyl and hydroxy radicals; or a pharmaceutically
acceptable salt thereof.
Particular values for Rl are, by way of example
only ~
wh.en it is a (l-4C~alkylamino radical, a
m~hylamino or ethylamino radical;
when it is a di-[(1-4C)alkyl]amino radical, a
dimethylamino or diethylamîno radical;
when it is a (l-6C)alkoxy radical, a methoxy,
ethoxy, propoxy, butoxy or am~loxy radical; and
when it is a substituted (1-6C)alkoxy radical,
an ethoxy, propoxy, butoxy or amyloxy radical bearing a
methoxy, ethoxy, morpholino, dimethylamino or diethyl-
amino substituent,
Particular values for a substituent on
benzene ring A are, by way oP example only:-
when it is a halogeno radical, a fluoro, chloro
or bromo radical; and
when it i8 a (1-4C~alkyl radical~a methyl,
ethyl, n-propyl or isopropyl radical.
Partîcular values for benzene ring A are, for
example, wh~en it is a 2-chlorophenyl, 2-cyanophenyl, 2-
aar~ox.~ ~ ~oph ~ yl, 4-chlorophenyl, 4-bromophenyl, 4-
methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 4-
cyanophenyl, 4-hydroxyph.enyl, 3,4-dichlorophenyl or 3,5-
dichloroph.enyl radical70f which values, 2-cyanophenyl
and 2-chlorophenyl are preferred.
The compounds of formula I are sufficiently
basic to form addition salts with acids. Particular
pharmaceutically acceptable acid-addition salts of
compounds of formula I are, for example, salts wi.th
inorganic acids, for example with hydrogen chloride,
114~545
hydrogen bromide, sulphuric acid or phosphoric acid,
or salts with organic acids, for example oxalic or
citric acîd.
In addition, compounds of formula I wherein
Rl is a hydroxy radical can form addition salts with
bases. Particular base-addition salts of such compounds
of formula I are, for example, alkali or alkaline
earth metal salts, for example sodium, potassium,
calcium or magnesium salts, aluminium or ammonium salts,
or salts with organic bases affording a pharmaceutically
acceptable cation, for example with triethanolamine.
Specific groups of compounds of formula I
which are of particular interest comprise those compounds
of formula I defined abo~e wherein in addition:-
(i) Rl is a hydroxy radical;
(ii) R1 is an amino radical;
(iii~ Rl is a (1-6C~aIkoxy radical, and in
particular a methoxy, ethoxy or butoxy radical;
(iv) benzene ring A bears one or two
halogeno substituents; and
~ (v~ benzene ring A bears a cyano or
JL~ Car~ox ~ do radical;
together in each case with the pharmaceutieally
acceptable salts thereof as appropriate.
A preferred group of compounds of the invention
comprises those compounds of formula I wherein R1 is a
hydroxy, amino or (1-4C~alkoxy radical, and benzene
ring A bears a 2-chloro or 2-cyano substituent; or a
pharmaceutîcally acceptable salt thereof.
Specific compounds of formula I are described
in the accompanying Examples and, of these, 1-(2-chloro-
benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-(2-cyanobenzyl~-1,2,5,6-tetrahydropyridine-,-carboxylic
acid and the respective methyl esters thereof, or
pharmaceutically acceptable salts thercof, are of
. special interest.
The compounds of formula I may be manufactured
by any general process of organic che~istry known to
be applicable to the synthesis of analogous
11~454~
pyridine derivatives. Such processes are provided
as a further feature of the invention and are
illustrated by t~e following procedures, in which
and benzene ring A have any of the meanings defined
hereinbefore:-
a) Reacting a compound of the formula:-
~1.C ~ ~ NR II
~J .
with a benzyl halide of the formula:-
Hal.CH2 ~ III
~ A J
lO wherein Hal. is a halogeno radical, for examplea chloro, bromo or `odo radical.
The process may be conveniently carried
out in the presence of a base, for example an
alkali metal carbonate or acetate, such as potassium
15 carbonate or sodium acetate, preferably in a suitable
sol~ent or diluent, for example methanol or ethanol,
and at a temperature of, for example 20-120C.
The compound of formula II wherein Rl
is a hydroxy radical is known and the remaining
20 starting materials of formula II may be obtained
therefrom in conventional manner.
b) Reacting a compound of formula II with an
aldehyde of the formula:-
H C0
¦¦ A ¦ I~
.. ' \~
1144545
5 -
in the presence of a reducing agent.
A particularly suitable reducing agent is,
for example, an inorganic hydride, for example
sodium or potassium borohydride, or lithium or
sodium cyanoborohydride.
~ he process is preferably carried out in a
solvent or diluent, for example a Cl_4-alkanol, for
example ethanol and,conveniently,at or near room
temperat~re, for example at 15-30C.
Process (b) i5 of the reaction type known
as reductive amination and as 6uch may proceed
wholly or in part via an intermediate of the formula:-
0~
Rl. CO ~ V
formed in situ and which is subsequently reduced. It
15 is to be understood that this invention also embraces
the separate reduction of an intermediate of formula
V produced, ~r example, by reacting a compound of
formula II ~ith an aldehyde of formula IV in the
absence of a reducing agent.
The aldehydes of formula IV may be obtained
by standard procedures of organic chemistry.
c) For a compound of formula I wherein Rl i8
a hydroxy r,adical
shydr~lysing a ca~ound of the fo~a:-
R2.CC ~ ~ ~2 ~ ~ VI
11~4~4
-- 6 --
wherein R has the same value as Rl other than a
hydroxy radical.
A particularly suitable value for R2 is for
example, a methoxy, ethoxy, benzyloxy or chloro-
benzyloxy radical.
The hydrolysis may be carried out in thepresence of aqeuous acid or base, for example an
aqueous mineral acid, such as hydrochloric or
sulphuric acid, or an aqueous strong base, such as
sodium or potassium hydroxide, may be used. A solvent
or diluent, for example ethanol or acetic acid, may be
conveniently used, and the process ma~ ~e performed
at a temperature of, for example, 20-120C.
d) For a compound of formula I wherein Rl is a
hydroxy or amino radical and benzene ring A bears a
~ c; a r6~ Y/
e~o~ D s~stitue~ hydrolysing a compound of the formula:-
~ N ~C~2 ~ VII
wherein R3 is ahy~y, (1-6C)a~o~ or-~ino radical andbenzene
ring C has one of the values defined for ring A which
is a cyanophenyl radîcal.
The hydrolysis may be carried out using
conventional conditions for the production of amides
from nitriles for example using similar reagent3 and
solvents to those described in process (c) hereinabove.
However in general shorter reaction times are preferred
to minimise further hydrolysis of the amide lin~age
when formed. It willbe ~derstood that when R3 is a (l-~C)-
a~oxy ra~cal in the compound of fo~a VII, the ~nal product
from the prc~oess is nevertheless a conpound of formulaI wherein
3o Rlis a;~c~oxy radical.
1144S45
7 --
Wherea~ter, for a compound of formula I
wherein Rl is other than a hydroxy radical, the
corresponding compound of fo~l~ula I wherein Rl is
a hydroxy radical, or a reactive derivative thereof,
; 5 ~or example the corresponding acid chlor de, bromide
or anhydride, is reacted using well known esteri~ic-
ation or amidi~ication procedures and conditions
with the appropriate compound of the fo~mula R2.H
wherein R2 has the same valuesas Rl other than a
10 hydroXY radical.
The pharmaceutically acceptable salts as
defined hereinbefore may be made by conventional
procedures, b~ reaction with the appropriate acid
or base affording a pharmaceutically acceptable
15 anion or cation respecti~ely.
As stated above the compounds of formula
I possess the property of inhibiting the aggregation
of blood platelets. This property may be demonstrated
in vivo, using standard tests in laboratory animals,
20 for example, in the following test in rabbits
In this test blood samples are taken by
a standard open flow technique from the central ear
artery of rabbits. The samples are taken into a
3.8% I~/v solution of trisodium citrate as anti-
25 coagulant and then centrifuged at first 150 g , andthen at 1000 g , to prepare platelet rich and platelet
poor plasma fractions, which a~e used to calibrate
an instrument for measurin~ light t~ransmittance and
thus the amount o~ platelet aggregation. The extent
30 of platelet aggregation following addition of
adenosine 5'-diphos~hate ~ADP) (final concentration
0~5, 1.0, 2.0, 4.0 or 8.o ~M) to the platelet rich
11~4545
-- 8 --
plasma fraction is then determined, and the value
of maximum aggregation in res~onse to each
concentration of ADP is recorded. The rabbits are
then dosed orally with test compound, and arterial
blood samples are withdrawn at intervals after
dosing. The platelet rich plasma fraction is pre-
pared and ADP is added as above, and the extent of
aggregation assessed by measuring the light
transmittance of the sample. This value is compared
with that obtained from the same rabbit before dosing,
~o that a measure of the extent of inhlbition of ADP
induced blood platelet aggregation is obtained. By
way of example only, the compound l-(2-chlorobenzyl)-
1,2,~,6-tetrahydropyridine-3-carboxylic acid showed
significant inhibition of the aggregation of blood
platelets two hours after an oral dose (as its
hydrochloride) of 25 mg./kg. However, in general,
compounds of formula I produce significant inhibition
in the above test following oral doses of 100 mg./kg.,
or much less,without any signs of overt toxicity at
the active dose.
Compounds which inhibit the aggregation of
blood platelets, ~or example acetylsalicylic acid,
have been used in the treatment or prophylaxis of
~5 thr~mbosis or occlusive vascular disease, and it is
envisaged that the compounds of the present invention
will be used in a generally similar manner, and for
the same clinical indications.
When used to inhibit the aggregation o~
3 blood platelets ;n ~Jarm-blooded animals including
man, a compound of formula I may be administered at
a daily oral dose in the range 1-30 mg.~kg. and
preferably in the range 1-10 mg./kg., or an equivalent
amount of a pharmaceuticall~ acceptable salt thereof.
3~ In man these doses are equivalent to daily oral doses
of approx~mately 0.07-2.1 g. and 0.07-0.7 g. respect-
ively, or an equivalent amount of a pharmaceutically
1~4S45
.
g
acceptable salt, ~ ~n in divided doses if neoessa~.
The compounds of formula I are preferably
administered in the form of pharmaceutical compos-
itions, and according to a further feature of the
invention there is provided a pharmaceutical
composit~on which comprises a compound of formula I,
or a pharmaceuticall~ acceptable salt thereof as
defined hereinbefore, together with a pharmaceutically
acceptable diluent or carrier. Such a composition
is conveniently in a form suitable for oral
administration, for example as a tablet, capsule,
aqueous or oily suspension, syrup or elixir.
Alternatively it may be in a form suitable for
parenteral administration by infusion or injection,
for example as a sterile injectable solution or
suspension, or in a form suitable for rectal
administra~ion, for example as a suppository.
Such compositions may be obtained by
conventional procedures and using conventional
excipients. A composition for oral administration
should preferably contain from ~-500 mg. of active
ingredient per unit dose, a composition for parenteral
administration, 0.5-20 mg./ml. of active ingredient,
and ~ composition for rectal administration, 50-
500 mg. of active ingredient.
A composition of the invention may alsoconveniently contain one or more agents wh~ch can
have a beneficial effect on t~rombosis or occlusive
vascular disease, or on associated conditions,
selected from, ~or example, clofibrate, sulfinpyrazone,
and dipyridamole.
The invention is illustrated by the
ollow ng Examples in which (i), yields are by way
of example only and are not to be construed as the
maximum attainable; (ii), eva~orations were carried
out in vacuo to dryness ~here possible, using a
S45
- -- 10 --
rotary evaporator; and (iii), melting points were
determined in sealed glass capillary tubes:-
Example 1
Triethylamine (2.2 g.) and 2-chloro-
benzyl chloride (1.63 g.) were added to a solutionof methyl 1,2,5,6-tetrahydropyridine-3-carboxylate
hydrochloride (1.63 g.) in methanol (10 ml.). The
solution obtained was kept for 24 hours at 20-25C.
and then evaporated. Water (20 ml.) and 10% w/v
sodium carbonate solution were then added to the
re~idue to gi~e a mixture of pH 10. rhis mixture
was extracted with ether (2 x 20 ml.). The combined
extracts were washed with water, dried (MgS04) and
evaporated. The residual oil was dissolved in
acetone to give a solution which was treated with a
9 light exces~ of ethereal hydrogen chloride. The
solid which precipitated was collected by filtration
and washed ~ith acetone to give methyl l-(2-chloro-
benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
hydrochloride (1.5 g.) m.p~ 171-175C.
Example 2
A solution o~ methyl 1-(2-chlorobenzyl)-
1,2,5,6-tetrahydropyridine-3-carboxvlate h~drochlor-
ide (0.45 g.) in concentrated hydrochloric acid
(10 ml.) was heated at 95-100C. for 2 hours, cooled
and evaporatedt The residue was evaporated several
times with acetone and toluene to remove remaining
traces of ~ate~. The solid obtained was stirred
with acetone and then collected by ~iltration to
give 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-
3-carboxylic acid hydrochloride (0.4 g.), m.p. 208-
210C (dec,).
Example 3
4-Hydroxybenzaldehyde (1.34 g.) and sodium
cyanoborohydride (0.7 g.) were added to a solution
o~ methyl 1,2,5,5-tetrah~dro~yridine-3-carboxylate
hydrochloride (3.1 g.) in methanol (30 ml.). The
11~4S45
mixture was stirred for 3 days at 25C., evaporated '
and water (30 ml.) added to the residue followed
by ~oncentrated hydrochloric acid to pH 1. This
mixture was extracted with etAer (2 x 20 ml.) and
the extracts discarded. The aqueous phase was
basified to pH 9 with 10% w~v sodium carbonate
solution and then extracted with ether (2 x 30 ml.).
The combined extracts were dried (MgS04) and
evaporated. The oil obtained ~as dissolYed in
acetone and treated with a slight excess of ethereal
hydrogen chloride. The solid which was precipitated
was collected by filtration to give methyl ~-(4-
hydroxybenzyl)-1,2,5,6-tetrahydropyridine-3-carboxy-
late hydrochloride (2.05 g.). A portion ~as re-
crystallised from methanol and acetone to give purematerial o~ m.p. 212-214C. (dec~).
E'x'am'pl'e 4 (Note : all parts are by weight)
A mixture of micro-crystalline cellulose
(1~6 parts) and finely divided 1-(2-chlorobenzyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic acid hydro-
chloride (200 parts) was sieved through a 30 me~h
screen. Magnesium stearate (60 mesh particle size)
(4 parts) was then added and, after thorough mixing,
the mixture was compressed into tablets weighing
400 mg. and containing 200 mg. of active ingredient,
which may be administered to man for therapeutic '
purposes,
Using a similar procedure, tablets contain-
ing 20, 50, 100 a~d 400 mg, o~ active ingredient may
~0 be obtained.
Similarly the active ingredient ma~ be
replaced by another compound of formula I, for
example a compound described in an~ one of Examples
1, 3, or 5-20.'
1144545
-- 12 --
Exan~ les 5-8
Using a similar procedure to that described
in Example 1 but starting from the appropriate benzyl
halide of formula III and the appropriate ester of
formula II there were obtained:- rr.ethyl 1-(2-cyano-
benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
hydrochloride (Example 5) m.p. 183-4C., in 54% yield
after recrystallisation from methanol/acetone;
ethyl 1-(3,4-dichlorobenzyl)-1,2 ,5,6-tetrahydro-
I0 pyridine-3-carboxylate hydrochloride (Example 6)
m.p. 192-9 C., in 76g yield;
methyl 1(4-methylbenzyl)-1,2,5 ,6-tetr~hydropyridine-
3-carboxylate hydrochloride (Example 7 ) m.p. 183-4C.,
in 81% yield after recrystallisation from methanol~
ethyl acetate; and
methyl l-(3,4-dichlorobenzyl)-1,2,5 ,6-tetrahydro-
pyridine-3-carbo~late hydrochloride (Example 8 )
m.p. 185-188C., in 71% yield.
Examp le 9
Using a 3imilar procedure to that described
in Example 2, hydrolysis of methyl 1-(3,4-dichloro-
benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
hydrochloride gave l-(3,4-dichlorobenzyl)-1,2,5,6-
tetrahydropyridine-3-carboxylic acid, m.p. 240-245C.
Example 10
A mixture of 1-(3,4-dichlorobenzyl)-1,2,5,6-
tetrahydropyridine-3-carboxylic acid hydrochloride
(2.0 g.) and thionyl chloride (15 ml.) was heated under
re flux for 30 minutes. Excess thionyl chloride was
removed by evaporation and the residue was mixed
with toluer~ and then evaporated. n-Butyl alcohol
(30 ml.) was added to the cooled residual solid and
the mixture was stirred at 25C. ~or 1 hour, during
which time all the solid dissolved. The soluti on
obtained was heated under reflux for 10 minutes and
then excess n-butyl alcohol was removed by evaporation.
The residue was recrystallised from acetone~et;her to
give n-butyl 1-(3~4-dichlorobenzyl)-1,2,5,6-tetra-
hydropyridine~3-carboxylate hydrochloride (102 g.),
~1~45~5
m.p. 160-162C.
Examples 11-15
Using a similar procedure to that described
in Example 10 but using the appropriate alcohol or
B 5 amine, the following esters or aarboxamldcs of
formula I (ring A = 3,4-dichlorophenyl) were obtained
as their hydrochloride salts (unless otherwise stated).
Exan~le ~ Yield (%) m.p. (C.) RecIystallisation
solYent
.. .. _ . . ..
11 PhCH2086 166-169 Me2a)~EtOAc
12 Et2NC~I2CH20 21 20~2~1*
13 H2N-ap 18 145-150 iPrOH
14 Et~- 61 224-228
Et2N 72 200 202 EtO~ e200
* Dihydrochloride, 13/4 H20
10 ~ Free b ase, ~ H20
Examples 16-18
Using a similar procedure to that described
in Example 2 but starting from the appropriate methyl
ester, there were obtained: 1-(4-methylbenzyl)-1,2,5,6-
15 tetrahydropyridine-3-carboxylic acid hydrochloride
(Example 16) in 71% yield, m.p. 230-6 C (after
recrystallisation from ethanol~acetone); and
1-(4-b romobenzyl)-1,2,5,6-tetrahydropy ridine-3-
carb oxy li c acid hydroch loride (Example 17) in 94%
20 yield, m.p. 248-253C.
The starting material for Example 17 was
ob taine d usin g a p rocedure similar tv that described
- in Example 1 but starting from 4-bromoben2yl chloride
to give, methyl 1-(4-bromobenzyl)-1,2,5,6-tetrahydro-
25 py~idine-3-carboxylate hydrochloride,m.p. 200-2û5C.
(Example 18)
~4~5~5
- 14
Example 19
A mixture of 1,2,5,6~tetrahydropyridine-3-
carboxylic acid bydrochloride C4.0 g.~, triethylamine
(8.2 g.) and 2-cy-anobenzylbromide (4.0 g.~ in methanol
(20 ml.) was heated at ~5-100C. for 3 hours. me
mixture ~as evaporated to dryness and an excess of
aqueous sodium carbonate solution added. The mixture
was again evaporated to dryness and acidified with 2N
hydrochlori-c acid to pH 2-3. The subsequent mixture was
evaporated to dr~ness. m e residue was suspended in
toluene (30 ml.~ and evaporated to dryness. The
resultant solid was dissolved in dry ethanol (10 ml.)
ar.dthe residue (largely sodium chloride) was discarded.
The solution was evaporated and the residue recrystallised
from ethanol/ether to give 1-(2-cyanobenzyl)-1,2,5,6-
tetrahydropyridine-3-carboxylic acid hydrochloride as
a solid, m.p. 206-212C.
Example 20
A mixture of methyl 1-(2-cyanobenzyl)-1,2,5,6-
tetrahydropyridine-3-carboxylate ( 0.5 g.) and concen-
trated hydrochloric acid ( 5.0 ml.~ was heated at
95-lOO~C. for 1-2 hours. The mixture was evaporated
to dryness and the residue was triturated with acetone
to give 1-(2- ~ ~o~c~ 1)-1,2,5,6-tetrahydro-
pyridine-3-carboxylic acid hydrochloride, m.p.219-222 C.
(dec.) after recrystallisation from ethanol/acetone.
