HETEROCYCLIC COMPOUNDS

PRODUITS HETEROCYCLIQUES

English Abstract

ABSTRACT OF THE DISCLOSURE
A class of isothiazolopyridines having an
optionally substituted alkyl group
attached to the nitrogen of the isothiazolo
moiety, are effective in inhibiting platelet
aggregation.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of an isothiazolopyridine
of formula (I):
(I) <IMG>
or a pharmaceutically acceptable non-toxic acid addition salt
thereof, wherein R is a C1-4 alkyl group or C1-4 alkyl group sub-
stituted with
phenyl or chlorine substituted phenyl,
a group of formula (II):
<IMG> (II)
wherein R1 and R2 are the same and are C1-4 alkyl,
or a group <IMG> wherein <IMG> is an aromatic or non-
aromatic mono- or polycyclic heterocyclic containing 5
to 9 atoms in the rings and one of these atoms may be
another heteroatom selected from oxygen, sulfur and
nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a
fused pyridine ring substituted with up to three groups selected
from C1-6 alkyl, heterocyclyl and phenyl,
which process comprises:
(a) cyclising a compound of formula (VII):
24

<IMG> (VII)
wherein R and Z are as defined above; or
(b) treating a compound of formula (VIII):
<IMG> (VIII)
wherein R and Z are as defined above; and R is an alkyl group
with a base; or
(c) reacting a compound of formula (IX):
<IMG> (IX)
wherein Z is as defined above and X and Y are the same or different
and each represents chlorine or bromine; with amine of formula
R.NH2; or
(d) treating a dimer of formula (X):

<IMG> (X)
wherein R and Z are as defined above; with either chlorine or a
base; or
(e) when R represents an alkyl group substituted either
with a nitrogen-containing ring attached via the ring nitrogen; or
with a group of formula (II) <IMG> as defined, reacting a
compound of formula (XI)
<IMG> (XI)
wherein Z is as defined for formula (I), Alk represents a straight
or branched alkylene chain and U represents a readily displaceable
group; with a compound of formula
<IMG> (XIIA) or <IMG> (XIIB)
wherein R1 and R2 are as defined for formula (I) and Q is the resi-
due of the heterocyclic ring defined as <IMG> for formula (I);
and recovering the compound of formula (I) and where required
converting it to a pharmaceutically acceptable salt thereof.
26

2. A process as claimed in claim 1 (a) wherein the
compound of formula VII is prepared by reacting a compound of
formula
<IMG>
with a compound of formula R.NH2 wherein Z and R are as already
defined and cyclizing the compound of formula VII in situ by
treating the reaction mixture with iodine, chlorine, bromine,
phosphorus pentachloride or thionyl chloride.
3. A compound of the formula (I)
<IMG> (I)
wherein R is a C1-4 alkyl group or C1- 4 alkyl group substituted
with
phenyl or chlorine substituted phenyl, or
a group of formula (II) <IMG> wherein R1 and R2
are the same and are C1-4 alkyl, or
a group <IMG> wherein <IMG> is an aromatic or non-
aromatic mono- or polycyclic heterocyclic containing 5
to 9 atoms in the rings and one of these atoms may be
another heteroatom selected from oxygen, sulfur and
nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a
fused pyridine ring substituted with up to three groups selected
27

from C1-6 alkyl, heterocyclyl and phenyl; and pharmaceutically
acceptable salts thereof when prepared by the process of claim 1
or 2 or an obvious chemical equivalent.
4. A process for the preparation of the compound 2-(2-
pyrrolidin-1-yl ethyl)-isothiazolo[5,4-b]pyridin-3-one which
comprises reacting N-(2-pyrrolidin-1-yl-ethyl)-2-mercaptonicotin-
amide with iodine in the presence of a base and a solvent and
recovering the required compound.
5. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-b]pyridin-3-
one when prepared by the process of claim 4 or an obvious chemical
equivalent.
6. A process for the preparation of the salt 2-(3-morpholin-
1-yl propyl)-isothiazolo[5,4-b]pyridin-3-one hydrochloride which
comprises reacting N-(3-morphol-1-yl propyl)-2-mercaptonicotinamide
with iodine in the presence of a base and a solvent and recovering
2-(3-morpholin-1-yl propyl)-isothiazolo[5,4-b]pyridin-3-one and con-
verting it to the hydrochloride salt and recovering said salt.
7. 2-(3-morpholin-1-yl propyl)-isothiazolo[5,4-b]pyridin-3-
one hydrochloride when prepared by the process of claim 6 or an
obvious chemical equivalent.
8. A process for the preparation of the compound 2-(p-
chlorobenzyl)-isothiazolo[5,4-b]pyridin-3-one which comprises
28

reacting N-p-chlorobenzyl-2-mercaptonicotinamide with I2 in the
presence of a base and a solvent and recovering the required
compound.
9. 2-(p-chlorobenzyl)-isothiazolo[5,4-b]pyridin-3-one when
prepared by the process of claim 8 or an obvious chemical equiva-
lent.
10. A process for the preparation of the compound 2-n-butyl-
isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-n-butyl-
2-mercaptonicotinamide with I2 in the presence of a base and a
solvent and recovering the required compound.
11. 2-n-butylisothiazolo[5,4-b]pyridin-3-one when prepared
by the process of claim 10 or an obvious chemical equivalent.
12. A process for the preparation of the compound 2-(2-
pyrid-2-ylethyl)-isothiazolo[5,4-b]pyridin-3-one which comprises
reacting N-(2-pyrid-2-ylethyl)-2-mercaptonicotinamide with iodine
in the presence of a base and a solvent and recovering the required
compound.
13. 2-(2-pyrid-2-ylethyl)-isothiazolo[5,4-b]pyridin-3-one
when prepared by the process of claim 12 or an obvious chemical
equivalent.
14. A process for the preparation of the compound 2-[2-(3-
azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo[5,4-b]pyridin-3-one
29

which comprises reacting N-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]-
2-mercaptonicotinamide with iodine in the presence of a base and
a solvent and recovering the required compound.
15. 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo[5,4-
b]pyridin-3-one when prepared by the process of claim 14 or an
obvious chemical equivalent.
16. A process for the preparation of the compound 2-(2-
piperidin-1-yl-ethyl)-isothiazolo[5,4-c]pyridin-3-one which com-
prises reacting 1,2-dithiolo[5,4-c]-pyridin-3-one with N-(2-
piperidin-1-yl)ethylamine in a solvent and after addition of a
base treating the reaction mixture with iodine and recovering the
required compound.
17. 2-(2-piperidin-1-yl-ethyl)-isothiazolo[5,4-c]pyridin-3-
one when prepared by the process of claim 16 or an obvious chemi-
cal equivalent.
18. A process for the preparation of the compound 2-(2-
pyrrolidin-1-yl ethyl)-isothiazolo[5,4-c]pyridin-3-one which com-
prises reacting 1,2-dithiolo[5,4-c]pyridin-3-one and N-(2-pyrroli-
din-1-yl)ethyl amine in a solvent and after addition of a base
treating the reaction mixture with iodine and recovering the
required compound.
19. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-c]pyridin-
3-one when prepared by the process of claim 18 or an obvious

chemical equivalent.
20. A process for the preparation of the compound 2-[2-(3-
azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo[5,4-c]pyridin-3-one
which comprises reacting 1,2-dithiolo[5,4-c]pyridin-3-one with
N-[2-(3-azabicyclo(3.2.2)non-3-yl)]ethyl amine in a solvent and
after addition of a base treating the reaction mixture with iodine
and recovering the required compound.
21. 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo
[5,4-c]pyridin-3-one when prepared by the process of claim 20 or
an obvious chemical equivalent.
22. A process for the preparation of the compound 2-(2-
pyrrolidin-1-yl ethyl)-isothiazolo[4,5-b]pyridin-3-one which com-
prises reacting 1,2-dithiolo[4,5-b]pyridin-3-one with N-(2-pyrroli-
din-1-yl)ethyl amine in a solvent and after addition of a base
treating the reaction mixture with iodine and recovering the
required compound.
23. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[4,5-b]pyridin-3-
one when prepared by the process of claim 22 or an obvious chemical
equivalent.
24. A process for the preparation of the compound 2-(3-
dimethylaminopropyl)-isothiazolo[4,5-b]pyridin-3-one which com-
prises reacting 1,2-dithiolo-[4,5-b]pyridin-3-one with 3-dimethyl-
aminopropylamine in a solvent and after addition of a base treating
31

the reaction mixture with iodine and recovering the required com-
pound.
25. 2-(3-dimethylaminopropyl)-isothiazolo[4,5-b]pyridin-3-
one when prepared by the process of claim 24 or an obvious chemi-
cal equivalent.
26. A process for the preparation of the compound 2-(2-
piperidin-1-yl ethyl)-isothiazolo[4,5-c]pyridin-3-one which
comprises reacting 1,2-dithiolo[4,5-c]pyridin-3-one with
N-(2-piperidin-1-yl)ethylamine in a solvent and after addition
of a base, treating the reaction mixture with iodine and recover-
ing the required compound.
27. 2-(2-piperidin-1-yl ethyl)-isothiazolo[4,5-c]pyridin-
3-one when prepared by the process of claim 26 or an obvious
chemical equivalent.
28. A process for the preparation of the compound 2-(2-
diethylaminoethyl)-5-phenylisothiazolo[5,4-b]pyridin-3-one which
comprises reacting 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one with
2-diethylaminoethylamine in a solvent and after addition of a base,
treating the reaction mixture with iodine and recovering the
required compound.
29. 2-(2-diethylaminoethyl)-5-phenylisothiazolo[5,4-b]pyridin-
3-one when prepared by the process of claim 28 or an obvious
chemical equivalent.
32

30. A process for the preparation of the compound 2-[2-(4-
methylthiazol-2-yl)ethyl]-5-phenylisothiazolo[5,4-b]pyridin-3-one
which comprises reacting 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one
with 2-(4-methylthiazol-2-yl)ethylamine in a solvent and after
addition of a base, treating the reaction mixture with iodine and
recovering the required compound.
31. 2-[2-(4-methylthiazol-2-yl)ethyl]-5-phenylisothiazolo
[5,4-b]pyridin-3-one when prepared by the process of claim 30 or
an obvious chemical equivalent.
32. A process for the preparation of the salt 2-(2-pyrrolidin-
1-yl ethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one dihydro-
chloride monohydrate which comprises reacting N-(2-pyrrolidin-1-yl
ethyl)-2-mercapto-4,5,6-trimethyl nicotinamide with iodine in the
presence of a base and a solvent and recovering 2-(2-pyrrolidin-1-
yl ethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one and
converting it to the dihydrochloride monohydrate and recovering
said salt.
33. 2-(2-pyrrolidin-1-yl ethyl)-4,5,6-trimethyl-isothiazolo
[5,4-b]pyridin-3-one dihydrochloride monohydrate when prepared by
the process of claim 32 or an obvious chemical equivalent.
34. A process for the preparation of the salt 2-(2-pyrrolidin-
1-yl ethyl)-4,6-dimethylisothiazolo[5,4-b]pyridin-3-one dihydro-
chloride which comprises reacting N-(2-pyrrolidin-1-ylethyl)-4,6-
33

dimethyl-2-mercaptonicotinamide with iodine in the presence of a
base and a solvent, recovering 2-(2-pyrrolidin-1-yl ethyl)-4,6-
dimethylisothiazolo[5,4-b]pyridin-3-one and converting it to the
hydrochloride salt.
35. 2-(2-pyrrolidin-1-yl ethyl)-4,6-dimethylisothiazolo
[5,4-b]pyridin-3-one dihydrochloride when prepared by the process
of claim 34 or an obvious chemical equivalent.
34

Description

10~34~1
This invention relates to a class of isothiazolopyridine~
which are of value in the prophylactic and therapeutic
treatment of thrombotic diseases. The invention also relates
to a method for the preparation of such compounds and to
pharmaceutical compositions comprising them.
Arterial thrombosis develops initially from the
aggregation of blood platelets within the artery. This
aggregate may eventually lead to the formation of fibrin
and the formation of a consolidated occlusive thrombus.
The most widely used therapy for thrombosis is the use
of anti-coagulant agents, which influence blood clotting.
However, although effective in venous thrombosis, where the
thrombus is formed mainly of fibrin, anti-coagulant therapy
has no effect on platelet aggregation and has therefore
limited effectiveness in arterial thrombosis. It is now
accepted that anti-coagulant drugs have little to offer
in the treatment of arterial thrombosis.
With the increasing recognition of the primary role of
platelets in thrombosis, attention had turned to drugs which
are capable of inhibiting the aggregation of platelets.
It has now been found that a class of isothiazolopyridines
are effective in inhibiting platelet aggregation.
Accordingly, the present invention provides a compound
of formula (I) or a pharmaceutically acceptable non-toxic
acid addition salt thereof:,
~ S/ (I)
, , ,~ . :' ,

iO~3461
wherein R is an alkyl group optionally substituted with an
aryl group, with a heterocyclic group, or with a group of
formula (II):
~ Rl
- N (II)
\R2
wherein Rl and R2 are the same or different and each is
hydrogen, a Cl 6alkyl or phenyl group,
and Z is the residue of a fused pyridine ring which is
optionally substituted with up to three groups selected from
Cl 6alkyl, heterocyclyl, phenyl and substituted phenyl.
Suitable acid addition salts of the compounds of formula
(I) include inorganic salts such as the sulphate, nitrate,
phosphate and borate, hydrohalides such as hydrochloride,
hydrobromide and hydroiodide, and or~anic acid addition
salts such as acetate, oxalate, tartrate, maleate, citrate,
succinate, benzoate,ascorbate, methanesulphonate and
p-toluenesulphonate.
The alkyl group R may be straight or branched and may
suitably have from 1 to 10 carbon atoms, especially from 1 to
6 carbon atoms. When the group R is an aryl substituted
alkyl group, the aryl moiety may be for example, optionally
substituted phenyl. Suitable substituents for the phenyl
group include halogen, especially chlorine.
When the group R is an alkylgroup substituted with a
heterocyclic ring, such a ring may be aromatic or non-aromatic
mono- or polycyclic and may contain up to four heteroatmSselecteQ
from oxygen~ sulphur and nitrogen. The attachment to the
alkyl group may be via a carbon or nitrogen atom which is
present in the ring. Examples of such rings include pyrimidyl,
-- 3 --
-. - . .,- .,.
-: :- :
. ;:.

l~q3461
2-, 3-, or 4-pyridyl, thiazolyl, thiazolinyl, diazolyl,
triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl,
purinyl, benzimidazolyl, benzoxazolyl, benzisothiazolonyl,
piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azabicyclo-
[3.2.2.]non-yl, azabicyclo[3.3.1]non-yl, homopiperidinyl,
azabicyclo[2.2.2]oct-yl.
Suitable groups for the substituents R and R2 in formula
(II) include methyl, ethyl, n- and iso-propyl, n-, sec, iso-
and tert-butyl. Suitably, Rl and R2 are methyl or ethyl.
The nitrogen atom in the pyridine moiety Z-may be at any
one of the four possible positions. Suitably the nitrogen
is present at position 7 of the nucleus. For Example, the moiety
Z is unsubstituted or substituted with Cl 6 alkyl. Thus,
one sub-class of compounds falling within the scope of this
invention comprises compounds of formula (III) and
pharmaceutically acceptable non-toxic acid addition salts
thereof:
R5 ~ ~
~ ~7 ~ 12~ R (III)
,
.
wherein R4, R5 and R are hydrogen, Cl 6alkyl or phenyl and R is
as defined above with respect to formula (I). Preferably R ,
R and R are all hydrogen.
A specific compound of formula (III), wherein R is a.
; Cl_6alkyl group, is:
-- 4
:. : , :.:. - . ., .. : .:,: :: :~ ::: :: . . ..
- . - . . . .. . ..
: ~. : , ::: ., : :
: I . . . ~ . : . .. .. . .
:: : - -.

1073461
2-n-butylisothiazolo~5,4-b]pyridin-3-one.
A specific compound of formula (III) wherein R i3 an
aryl substituted al~l group i~
2-(~-chlorobenzyl)isothiazolo[5,4-b]pyridin-3-one.
Specific compounds of formula (III) wherein R is a
heterocyclyl substituted alkyl group and wherein the alkyl
chain has from 2 to 6 carbon atoms include the following:
2-(2-pyrrolidin-l-ylethyl)-isothiazolo~5,4-b]pyridin-3-one,
2-(2-pyrrolidin-1-yl-ethyl)-isothiazolo[5,4-b]pyrid-in-3-one-
dihydrochloride;
2-(3-morph~lin-l-ylpropyl)-isothiazolo[5,4-b]pyridin-3-one:
2-(2-pyrid -2-ylethyl)isothiazolo[5,4-b]pyridin-3-one,
2-r2-(3.-aza}~icyclo(3.2.2)non-3-yl)-ethyl]isothiazolo[5,4-b~-
pyridin-3-one~
2-[2-(4-methylthiazol-Z-yl)ethyl~-5-phenylisothiazolo[5,
4-b~-pyridin~3-one,
- 2-(2-pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo[5,4-b]-
pyridin-3-one,
2-(2-py~rolidin-l~ylethyl)-4,5,6-trimethylisothiazolo-
[5,4 b]-pyridin-3-one.
Another sub-group of compounds within the present
invention is represented by formula (IVA), (IVB), and (IVC)
and pharmaceutically acceptable non-toxic acid addition salts
thereof:
RlO , R13 o
25R )~ ~ Rli~ ~5
(IVA) (IVB) (IVC)
- 5 -
. ............: ..... : :- : , . ;
- . : , ; - :; :

~ ~073461
in which formulae R is as defined with respect to formula (I)
above, and the groups R7 to R15 each represent hydrogen, Cl 6alkyl
heterocyclyl, phenyl or substituted phenyl.
Specific compounds within formulae (IVA), (IVB), and
(IVC) include:
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[4,5-b]pyridin-3-one.
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[5,4-c]pyridin-3-one.
2-(2-piperidin-1-ylethyl)-isothiazolo[5,4-c]pyr~in-3-one.
2-[2-(3-azabicyclo~3.2.2]non-3-yl3ethyl]isothLazolo[5,4-c]-
pyridin-3-one.
2-(2-piperidin-1-ylethyl)isothiazolo~4,5-c]pyridin-3-one.
A further sub-class of compounds is represented by formula
(V) and pharmaceutically acceptable non-toxic acid addition salts
thereof: O
(V) Z ~ - A - B - R16
wherein Z is as defined with respect to formula (I) above,
A and B each represent a straight or branched chain alkylene
group each having from 1 to 6 carbon atoms and R16 represents
a heterocyclyl group or a group of formula (II) above.
Specific compounds of formula (V) include:
2-[2-(diethylamino)ethyl]-5-phenyl-isothiazolo[5,4-b3-
pyridin-3-one.
2-[3-(dimethylamino)propyl]-isothiazolo[4,5-b]pyridin-3-one
2-[6-(dimethylamino)hexyl]-isothiazolo[5,4-b]pyridin-3-one.
A still further sub-class of compounds within the scope of
this invention is represented by formula (VI) and pharmaceutically
acceptable non-toxic acid addition salts thereof:

`"` 10~73461
.
X' R17
(VI) S
wherein Z is as defined with respect to formula (I) above, R17 is
hydrogen or a Cl 3 alkyl group, and R18 is a heterocyclic ring
attached via a carbon atom in the ring.
One example of a compound of formula (VI) is :
2-(1-methylpyrrolidin-2-ylmethyl)-isothiazolo[5,4-b]-
pyrid-3-one.
A particularly preferred group of compounds according
to the invention and to which the claims are directed are those of
formula (I) O
(I) z ~ N - R
wherein R is a Cl 4 alkyl group or Cl 4 alkyl group substituted
with
phenyl or chlorine substituted phenyl, or a group of
formula (II) R
N ~R2
wherein Rl and R2 are the same and are Cl 4 alkyl, or
a group -N ~ wherein -N ~ is an aromatic or non-
aromatic mono-or polycyclic heterocyclic containing
A
.. ,.. - .. -. -. ~. - ... .. ` .. ... -... ;. ... . .. .

`` 1073461
5 to 9 atoms in the rin~s and one of these atoms may be
another heteroatom selected from oxygen, sul~ur and
nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a
fused pyridine ring substituted with up to three groups selected
from Cl 6 alkyl, heterocyclyl and phenyl.
The compounds of this invention may be prepared by
cyclising a compound of formula (VII):
o
(VII) z ll NH - R
~ E - ~H
wherein R and Z are as defined above with respect to formula ~I).
The reagents for such a cyclisation are generally com-
pounds which halogenate the sulphur atom in structure (VII) and
allow subsequent dehydrohalogenation. A preferred reagent is
iodine in the presence of a base such as sodium bicarbonate or an-
hydrous potassium carbonate but other possibilities include chlorine,
bromine, phosphorus pentachloride and thionyl chloride. The reac-
tion may be performed in a solvent which does not react with the
intermediate or reagents employed. For example in the case of the
reagent iodine/sodium bicarbonate, a lower alkanol, especially
- 20 ethanol may be used as a solvent but for more reactive halogenating
-agents such as phosphorus pentachloride a more inert solvent is
employed, such as halogenated hydrocarbon, a higher ether or di-
methylformamide. The reaction is conveniently carried out at
ambient temperature.
~ -7a-
. , :: :

`' lOq346`1
The intermediate compounds of formula (VII) may be
conveniently prepared by the route shown in Scheme 1:
-7b-
A
- . . , .. .. ,~ .. ; . . . .. . . . .. .. .. ... . . .
. .. . ,., .. .`. . ; .. . .- . ` ~.. , . ~ . . . ~
. . . , . ..... ~ . . . . . .

1073461
SCHEME I
~~ C02H ~ c_C~
SH C~S/
mercuric
acetate
~VII) ~ R.~H2 ~ 11 S
C_s/
wherein R and Z are as defined above with respect to formula (I).
The intermediate (VII) may conveniently be prepared and cyclised
n situ to produce the corresponding compound of formula (I)
Furthermore, some of the above trithiones and dithiones in
Scheme I are novel intermediat~s and also form part of this invention.
A second method for the pre~aration of compounds of this
invent~.on comprises treating ~ comnoun~ of formula (VIII) ~.~ith
base: -
C _Co2R3
(VIII) Z C _S/ NH R
. - , . . ~ . . : . -::: :: ::: . . - . ; .
. . ......... ,, ::, , , .;: . .:
.. :. . ::-

` 1073461
wherein R and Z are as defined above with respect to formula (I)
and R is an alkyl group, preferably lower alkyl group.
Suitable bases for the reaction include alkali metal alXoxides,
alkali metal hydroxides, and tetramethylammonioum hydroxide in
lower alcohols.
The compounds of formula (I) may also be prepared by reacting
a compound of formula (IX):
f C~.X'
Z If (IX)
~~ ~S.Y
- wherein X and Y are the same or different and each represents
chlorine, or bromine, and wherein-R and Z are-a~ defined above
with respect to formula (I), with an amine of formula R.~H2.
Suitable solvents include carbon tetrachloride and other
halogenated hydrocarbons.
A fourth method for the preparation of compounds of
formula (I) comprises treating a dimer of formula (X):
- (X~
0~N~.R~ R~NH.CO~
C S ~~ - S ~'J
_ 9 _
. . . - ., . ~ - . ~ .,~ ,. . .
.~ ' :'' . . .' . .:.' ' '' ::
~ . ~. :-. ~, :.

10'73461
wherein R and Z are as defined above with re4pect to formula
(I), with either chlorine or a base.
Suitable bases include lOYo sodium hydroxide or other
aqueous alkali and the reaction may be carried out at room
temDerature or elevated temperature. If chlorine is employed
in this reaction it may be bubbled into a solution of compounl
(X) in an inert solvent such as carbon tetrachloride.
Compounds of this invention wherein R represents an
alkyl group substituted with either a n.itrogen - containing a
heterocyclic ring attached via the ring nitrogen, or with a group
of formula tII), may be prepared by reacting a compound of
formula (XI):
.
Z ~ AlX - U
(XI) ~ S
wherein Z is as defined with respect to formula ~I) above,
Alk represents a straight or branched alkylene chain and U
represents a readily displaceable group, with a compound of
formula (XIIA) or (XIIB):
~ R
NH Q ~H
~ --R2
(XIIA) (XIIB)
-- 10 --

107 ~ 6~
wherein Rl and R2 are as defined with re~erence to formula ~I)
and Q is the residue of a heterocyclic ring.
Suitably the group U is a halogen atom, for example chlorine
or bromine, a substituted sulphonyloxy group, for example
p-toluenesulphonyloxy or methanesulphonyloxy.
The reaction may suitably be carried out in a hydrocarbon
solvent such as toluene at an elevated temperature for example
100 - 120.
The invention also provide~ a pharmaceutical composition
which comprises a compound of formula (I) a~ defined above
together with at least one pharmaceutically acceptable carrier.
As is common practice, such compositions will usually be
accompanied by or associated with written or printed
directions for use in the medical treatment concerned, in this
case as an agent for the inhibition of platelet aggregation
or thrombus formation.
The compositions may be formulated for administration
by any route, although an oral administration is preferred. The
compositions may be in the form of tablets, capsules, powders,
granules, lozenges or liquid preparations, such as oral or sterile
parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit
dose presentation form, and may contain conventiona1
excipients such as binding agents, for example, syrup, acacia
gelatin sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers
for example, lactose, sugar, maize-starch, calcium phosphate,
sorbitol or glycine; tabletting lubricants, for example,
magnesium stearate, talc, polyethylene glycol or silica;
disintegrants, for example potato starch or acceptable wetting
agents such as sodium lauryl sulphate. The tablets may be
: :~: : : : :. .
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: : .. . :- , .-:: - . ,, . ~ :
- , , ~. . : .,
.: : ' ' ' .- .' , ' ~ -

`` 1073461
coated according to methods well known in normal pharmaceutical
practice. Oral liquid preparations may be in the form of,
for example, aqueous or oily suspensions, solutions, emulsions,
syrups, or elixirs, or may be presented as a dry product for
reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives
such as suspending agents, for example sorbitol, syrup, methyl
cellulose, glucose syrup, gelatin, hydroxyethylcellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated
edible fats, emulsifying agents, for example lecithin, sorbitan,
monooleate, or acacia; non-aqueous vehicles (which may include
edible oils), for example, almond oil, propylene glycol, or
ethyl alcohol, preservatives, for example methyl or propyl
~-hydroxybenzoate or sorbic acid, and if desired conventional
- 15 flavouring or colouring agents. The compound may also if
desired be incorporated in a foodstuff, for example in the form
of a biscuit.
For parenteral administration, fluid unit dosage forms are
prepared utilising the compound and a sterile vehicle, water
being preferred. The compound, depe~ding on the vehicle and
concentration used, can be either suspended or dissolved in the
vehicle. In preparing solutions the compound can be dissolved
in water for injection and filter sterilised before filling into
a suitable vial or ampoule and sealing. Advantageously, adjuvants
such as a local anesthetic, preservative and buffering agents
can be dissolved in the vehicle. To enhance the stability, the
composition can be frozen after filling into the vial and the
water removed under vacuum. The dry lyophilised powder is
then sealed in the vial and an accompanying vial of water for
injection is supplied to reconstitute the liquid before use.
' ~ , ~' - ,'',- ' , .' '.': -' ''' ' ` '
.
:~ .-: :,:. .
: '' ~ - .. ': ''' :

10~ ~ 61
Parenteral suspensions are prepared in substantially the
same manner except that the compound is suspended in the
vehicle instead of being dissolved and sterilisation cannot be
accomplished by filtration. The compound can be sterilised
by exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is
included in the composition to facilitate uniform distribution
of the compound.
The compositions may contain from 0.1% to 99~ by weight,
preferably from 10-60% by weight, of the active material,
depending on the method of admin~tration. Where the compositions
comprise dosage units, each unit will preferably contain from
l-SOOmg. of the active ingredient. The dosage employed for
adult treatment will of course depend on the dose-response
characteristics of the particular active ingredient, and
also on the blood volume and condition of the patient, but
will normally be in the range of O.01 to 30 mg/kg/day depending
on the route and frequency of administration. The preferred
- dose is lO to 500 mg. orally, l to 3 times a day for an adult
human.
The compositions of the invention are useful for
administration to humans and animals to prevent clot formation for
example after surgery to prevent postoperative thrombosis in
geriatric patients to prevent transient cerebral ischemic attacks;
and long term prophylaxis following myocardial lnfarcts and
strokes.
The compounds of formula (I) may also have application in
the storage of whole blood in blood banks, and whole blood to be
used in heart-lung machines, or to be circulated through organs
- 13 -
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. ... . , ~ - .. ...~: , . . .
- ' ~ . ` .:., .: '' ' ;: .,. ' . , :

107346~
e.g. the heart, and kidneys, which have been removed from a
cadaver and prior to transplant.
Accordingly, t~s invention also provides a proces~
for inhibiting platelet aggregation in vitro comprising the
S addition of a compound of the formula (I) or a pharmacologically
acceptable acid addition salt of such a compound to whole blood
or platelet-rich concentrate.
The dQsage for such an addition is preferably from 0.01
to 50 micrograms/ml of whole blood.
The invention also provides a composition comprising whole
blood and a compound of formula (I) above or a pharmacologically
acceptable acid addition salt of such a compound having a
basic nitrogen atom in the molecule.
The following Examples illustrate the preparation of some
of the compounds of this invention.
~ . .
, : -
_ 14 _
!, , '' ,'.' . . ': . ~ ' .

1073461
Example 1
2-(2-Pvrrolidin-l-vl-ethyl)isothiazolo~5,4-bl~yridin-3-one
(a) 1,2-Dithiolor5,4-blpyridin-3-thione
2-Mercaptonicotinic acid (17.65g., O.llmole) and phosphorus
pentasulphide (lSg., 0.06 mole) in pyridine (150ml) were heated
under reflux for 2 hours. The reaction mixture was then
cooled, diluted with water and the product filtered off.
Recrystallisation from ethanol yielded 1,2-dithiolo[5,4-b]-
pyridi~-3 ~hione (7.89g; 37%), red ned~les m.p. 185-6.
(b) 1,2-Dithiolor5,4-bl~Yridin-3-one
To a stirred suspension of mercuric acetate (17.0g., 0.053 mole)
in glacial acetic acid (200 ml), a solution of 1,2-dithiolo[5,4-bj-
pyridin-3-thione (5g, 0.025mole) in chloroform (lOOml) was a~ded
and the mixture stirred at room temRerature, for 3 days. Celite
(ca,25g.) was added to the mixture, filtered and the filtrate
evaporated. The residue was treated with dichloromethane (ca.
lOOml) the solid filtered off and the filtrate evaporated. This
latter process was repeated several times. The product was then
taken up in dichloromethane (20ml) and filtered through a short
column of silica-gel made up in dichloromethane. The column was
washed with sufficient dichloromethane to reco~7er all the product
and the combined filtrates evaporated. Recrystallisation of the
residue from ethanol yielded 1,2-dithiolo~5,4-b]pyridin-3-one
(3.21g., 70%), pale yellow needles, m.p. 96-97 .
(c) N-(2-Pyrrolidin-l-yl-eth~It2-merca~tonicotinamide.
1~2-Dithiolo~5~4-b]pyridin-3-one(~l~sg; ~OO9~Qle~ 2-amino-
ethyl)-pyrrolidine ~l.lg., 0.01 mole) and ethanol (30ml) were
- :,- . ,. .:: .

iO7 ~ 6~
heated under reflux for 1.5 hours. The mixture was filtered
hot and the filtrate evaporated to dryness. The oily residue
was triturated with dichloromethane and the resulting tan ~olid
recrystallised from ethanol to yield the product (0.75g., 34%)
tan prisms, m.p. 202-205.
(d) 2-(2-PYrrolidin-l-Yl-ethvl)isothiazolor5,4-blpyridin-3-one
A stirred suspension of N-(2-pyrrolidin-1-yl-ethyl)-2-
mercapton~cotinamide (13g. 0.05 mole) and sodium bicarbonate
(8.7g., 0.105 mole) in ethanol (130ml) was treated portionwise
with iodine (12.35g., 0.049 mole) over 2.5 hours, and then
stirred at room temperature for a further 8 hour~. The mixture
was then filtered and the filtrate evaporated to dryness.
The solids from the filter and the residue from the filtrate were
suspended in water (200ml) and extracted thoroughly~with
chloroform (3 x 60 ml) and dried (anhyd. MgS04). Evaporation
of the dried solution yielded 8.8g of crude product which was
crystallised from diisopropyl ether (including charcoal treatment)
yielding pure 2~2-pyrrolidin-1-yl-ethyl)isothiazolo[5,4-b]pyridin-
-3-one (4~7g, 37%) as tan needles, m.p. 67-69.
-
- .
16
, _ _
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. , . -. . ~, . . - . -
-, .
:. . :: ,. ..

1073461
Exam~les 2-6
From 1,2-dithiolo[5,4-b]pyridin-3-one, the intermediate '
prepared in Example l(b), the following compound~ were
prepared by the method of Example l(c) and l(d) respectively:
Example No.
2. (a) N-(3-Morphol-l-ylpropyl)-2-mercaptonicotinamide,
m.p. 139-140.
(b) 2-(3-Morpholin-l-ylpropyl)-isothiazolo[5,4-b]-
pyridin-3-one hydrochloride, m.p. 258-259C.
3. (a) N-P-chlorobenzyl-2-mercaptonicotinamide
m.p. 216-219C.
(b) 2-(~-Chlorobenzyl)isothiazolo[5,4-b]-pyridin-
3-one, m.p. 160-162&.
4. (a) N-n-Butyl-2-mercaptonicotinamide, m.p. 129-131& .
(b) 2-n-Butylisothiazolo~5,4-b]-pyridin-3-one,
m.p. 62-64C.
- 5. (a) N-(2-Pyrid-2-ylethyl)-2-mercaptonicotinamide,
m.p. 188-190C.
(b) 2-(2-Pyrid-2-ylethyl)isothiazolo[5,4-b]-
pyridin-3-one, m.p. 85-86C.
6. (a) N-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]-
2-mercaptonicotinamide hydrochloride, m.p.
237-240C.
(b) 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]-
isothiazolo~5.4-b]pyridin-3-one, m.p. 133-135C.
- 17 -

1073461
Exam~le 7
(a) 1,2-Dithiolor5,4-cl~Yridin-3-thione, m.p. 155-156&
was prepared by the method of Example l(aj.
(b) 1,2-Dithiolor5.4-cl~vridin-3-one, m.p. 142-142.5 C
was prepared from the above thione by the method of Example
l(b).
(c) 2-(2-piperidin-1-Ylethvl)isothiazolor5,4-cl~yridin-
3-one
A solution of N-(2-piperidin-1-yl)ethylamine (1.4g, O.Ollmole)
in ethanol (SOml) was treated with 1,2-dithiolo[5,4-c~-pyridin-
3-one (1.69g; O.Olmole) and heated under re'lux until
solution was complete (ca. 15 minutes). The reaction mixture
was cooled to 25 and anhydrous potassium carbonate (2g, 0.014mole3
was added. The resulting suspension was stirred and treated
dropwise with a solution of iodine (2.54g, O.Olmole) in
methanDl (lSml) over 1 hour and then allowed to stand at room
temperature over night. The reaction mixture was evaporated
to dryness under reduced pressure and the residue suspended
in water and ex~racted with dichloromethane (3x50ml). The
organic extract was washed with a solution of sodium
thiosulphate (50ml - 10%), saturated brine (50ml) and dried
over ~nhydrous MgS04. Removal of the drying agent and solvent
yielded a gummy solid which after chromatography on silica-
gel, eluting with l~/o MeOH/CH2C12 and recrystallisation from
~H2C12/di-isopropylether yielded pure 2-(2-piperidin-1-ylethyl)-
isothiazolo[5,4-c]pyridin-3-one, 0.78g, m.p. 101-103C,
yield 29%.
- 18 -
-
::- : -: , .

107346~ .
Examples 8-9
From 1,2-dithiolo[5,4-c]pyridin-3-one (Example 7(b),
the following compounds were prepared by the method of
Example 7(c):
Example ~o.
8. 2-(2-Pyrrolidin-l-ylethyl)isothiazolo~5;4-c]- -
pyridin-3-one, m.p~ 75-77C.
9. 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]isothia~olo-
; ~5,4-c]pyridin-3-one, m.p. 117-119C.
Example 10.
(a) 1,2-Dithiolor4,5-blpYridin-3-thione, m.p. 174-176 C
was prepared by the method of Example l(a).
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p. 133-135C
was prepared from the above thione by the method of Example
l(b).
(c) 2-(2-Pvrrolidin-l-vlethvl)isothiazolor4,5-blpyridin-
3-one, m.p. 93-95C was prepared from 1,2-dithiolot4,5-b]-
pyridin-3-one and 2-pyrrolidin-1-ylethylamine by the method
of Example 7(c).
~- Example 11.
2-(3-DimethYlaminoproPYl)isothiazolor4~5-blpyridin-3-one~
m.p. 59-60 C was prepared from 1,2-dithiolo-[4,5-b]pyridin-
3-one, (Example lO(b))and 3-dimethylaminopropylamine by the
method of Example 7(c).
Example 12. ~)S-C
A ( a) 1,2-Dithiolor1,5 bl~Yridin-3-thione. m.p.206-208
was prepared by the method of Example l(a)
- 19 -

1073461
C
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p.157-160
was prepared from the above thione by the method of
Example l(b).
(c) 2-~2-Pi~eridin-l-vlethYl)iSothiaZolOr4~5
pyridin-3-one, m.p. 96-98 C. was prepared from
1,2-dithiolo[4,5-c]pyridin-3-one and 2-piperidin-1-ylethyl-
7(c~
amine by the method of Example ~.
Example 13.
(a) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-thione, m.p.l35
was prepared by the method of Example l(a)
(b) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-one, m.p.l49-150.5,
was prepared from the above thione by the method of Example
l(b).
(c) 2-(2-DiethYlaminoethvl)-5-Phenylisothiazolor5~4-bl-
pYridin-3-one, m.p. 85-87 was prepared from 5-phenyl-1,2-
dithiolo[5,4-b]pyridin-3-one and 2-diethylaminoethylamine by
the method of Example 7(c).
Example 14. phcnylIso~zolo
2-r2-(4-MethYlthiazol-2-yl)ethY11-5 ohonylioothia~olo
ridin-3-one, m.p. 115-116 was prepared from
5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one (Example 13(b)) -i`
and 2-(4-methylthiazol-2-yl)ethylamine by the method of
Example 7(c).
.
- 20 _
. . .

10~3~46
Exam~les 15-16
Following the procedure of Examples l(a) - l(d)
respectively, the following compounds were prepared:
Exam~le ~o~
15. (a) 4,5,6-Trimethyl-1,2-dithiolo~5,4-b]pyridin-
3-thione, m.p. 155-157C.
(b) 4,5,6-Trimethyl-1,2-dithiolo[5,4-b]pyridin-
3-one, m.p. 182-184C.
(c) ~-(2-Pyrrolidin-l-ylethyl)-2-mercapto-4,5,6-
trimethyl nicotinamide, m.p. 158-160C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,5,6-trimethyl-
isothiazolo[5,4-b]pyridin-3-one,di~ydrochloride
monohydrate, m.p. 198-203 C (dec).
16. (a) 4,6-9imethyl-1,2-dithiolo~5,4-b]pyridin-3-thione,
m.p. 140-141C.
(b) 4,6-Dimethyl-1,2-dithiolo~5,4-b]pyridin-3-one,
m.p. 168-169C.
(c) N-(2-Pyrrolidin-l-ylethyl)-4,6-dimethyl-2-mercapto-
nicotinamide, m.p. 181-183 C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo-
[5,4-b~-pyridin-3-one dihydrochloride, m.p. 193-
- 196C.
:: . - .: . . :

1073461
BIOLOGICAL DATA
~he compounds of Examples 1-16 above were treated for
their ability to inhibit platelet aggregation in vitro as
follows:-
Human blood (20ml) is drawn into a plastic syringe and
immediately anti-coagulated by mixing with 0.1 volumes of
3.8% (w/v) trisodium citrate dihydrate. Platelet-rich-plasma
(PRP) is prepared by centrifuging the anti-coagulated blood
at 180g., for 12 min., at room temperature. Collagen (ex
bovine achilles tendon) is suspended in 0.9% (w/v) saline,
using a commercially available mixer emulsifier. PRP was mixed
with O.l volumes saline ( control) or compound dissolved in
saline and incubated at 37 for 3 min., before the addition
of collagen. Water-insoluble compounds were added to PRP
dissolved in 0.005 volumes dimethylformamide, the solvent being
- included in controls when appropriate. The final concentration
of each compound was 100~M.
; Platelet aggregation in response to collagen was measured
photometrically (Born, G.V.R., 1962, ~ature, 94, 927) in a
- 20 Bryston aggregOmQter coupled to a Vitatron linear pen recorder.
The activity of each compound was expressed as percentage
inhibition of the aggregation response to a dose of collagen
producing a just-maximal change in light transmission in
control PRP.
- 22 -
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.
- -
. . -
' ,

10~3461
Results
Table I lists % inhibition of platelet aggregation in
response to collagen by~lOO~M solutions of several compounds
of this invention.
TABLE I
Compound of % Inhibition
Exam~le ~o.
100
2 100
3 100
. 4 100
- 5 100
6 100
: 7 100
~ 8 . 85
9 100
.
' .
13 69
. 14 100
100
16 100
- 23 -
.. . ....
,,