PREPARATION DE PYRIMIDO-(2,1-B)-BENZOTHIAZOLES ET DE LEURS SELS

PROCESS FOR PREPARING PYRIMIDO (2,1-B) BENZOTHIAZOLES AND SALTS THEREOF

Abrégé anglais

A B S T R A C T
The invention relates to a process for preparing compounds
of formula (I) :
<IMG> (I)
wherein
R and R3 represent hydrogen, alkyl C1-6 or together cycloalkyl
C3-6 ;
R1 represents hydroxy, alkoxy C1-6 or <IMG> ;
R5 and R6 represent hydrogen, alkyl C1-6 or together
piperidino or morpholino ;
R2 represents hydrogen, alkyl C1-6, alkoxy carbonyl C2-7,
cycloalkyl C3-6, aralkyl, aryl, aryl substituted by halogen,
by alkyl C1-6 or by alkoxy C1-6 or heteroaryl and salts thereof.
The new compounds have valuable pharmacological properties,
especially antiallergic properties.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A process for preparing a compound of
formula (I):
(I)
<IMG>
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a hydroxy
group, a straight or branched C1-6 alkoxy group or a group
of formula
<IMG> (A)
(wherein R5 and R6, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening nitrogen atom
represent a piperidino or morpholino group); and R2 repre-
sents a hydrogen atom, a straight or branched C1-6 alkyl
group, a straight or branched C2-7 alkoxycarbonyl group, a
C3-6 cycloalkyl group, a benzyl group, a phenyl or naphthyl group
(unsubstituted or substituted by one or more halogen atoms
or a straight or branched C1-6 alkyl, a straight or branched
C1-6 alkoxy or nitro groups), or a thienyl group] and
pharmaceutically acceptable salts thereof, characterized in
that
32

(a) when R1 represents an hydroxy group or a
straight or branched C1-6 alkoxy group a
compound of formula (II):
(II)
<IMG>
wherein R and R3 are as hereinbefore defined
R'1 represents a hydroxy group or a straight
or branched C1-6 alkoxy group is reacted with
a compound of formula (III):
R2-C?C-CO2R4 (III)
wherein R2 is as hereinbefore defined and R4 represents
a straight or branched alkyl group, to obtain a com-
pound of formula (I) as defined above wherein
R1 represents an hydroxyl group or a straight
or branched C1-6 alkoxy group and, if desired,
the obtained compound of formula (I) as
defined above is converted to a pharmaceuti-
cally acceptable salt thereof,
(b) when R1 represents an hydroxyl group a com-
pound of formula (IA):
<IMG> (IA)
wherein R, R3 and R2 are as hereinbefore
defined and R'1 represents a straight or
branched alkoxy radical is subjected to a
33

saponification treatment to obtain a compound
of formula (I) as defined above wherein R1 is
an hydroxyl group and, if desired, the
obtained compound of formula (I) is converted
to a pharmaceutically acceptable salt thereof,
(c) when R1 represents a straight or branched
C1-6 alkoxy group a compound of formula (IB):
<IMG> (IB)
wherein R, R3 and R2 are as hereinbefore
defined is esterified by an alcohol of
formula (IV):
HO-R"1 (IV)
wherein R"1 represents a straight or branched
C1-6 alkyl radical to obtain a compound of
formula (I) as defined above wherein R1 repre-
sents a straight or branched C1-6 alkoxy
group and, if desired, the obtained compound
of formula (I) is converted to a pharmaceuti-
cally acceptable salt thereof,
(d) when R1 represents a straight or branched
C1-6 alkoxy group a compound of formula (IA):
<IMG> (IA)
wherein R, R3 and R2 are as hereinbefore
defined and R'1 represents a straight or
34

branched alkoxy radical is subjected to
a transesterification reaction with an
alcohol of formula (IV)
HO-R"1 (IV)
wherein R"1 represents a straight or branched
C1-6 alkyl radical to obtain a compound of
formula (I) as defined above where R1 repre-
sents a straight or branched C1-6 alkoxy group
and, if desired, the obtained compound of
formula (I) is converted to a pharmaceutically
acceptable salt thereof,
or (e) when R1 represents a group of the formula:
<IMG>
wherein R5 and R6 are as defined above a
compound of formula (IB):
<IMG> (IB)
wherein R, R3 and R2 are as hereinbefore
defined is reacted with a compound of formula
<IMG>
wherein R5 and R6 are as hereinbefore defined
to obtain a compound of formula (I) as
defined above wherein R1 represents a group
of the formula:

<IMG>
wherein R5 and R6 are as defined above and,
if desired, the obtained compound of formula
(I) is converted to a pharmaceutically
acceptable salt thereof.
2. A compound of formula (I):
(I)
<IMG>
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a hydroxy
group, a straight or branched C1-6 alkoxy group or a group
of formula
<IMG> (A)
(wherein R5 and R6, which may be the same or different,
each represents a hydrogen atom or a straight or branched
C1-6 alkyl group or together with the intervening nitrogen
atom represent a piperidino or morpholino group); and R2
represents a hydrogen atom, a straight or branched C1-6
alkyl group, a straight or branched C2-7 alkoxycarbonyl
group, a C3-6 cycloalkyl group, a benzyl group, a phenyl or naphthyl
group (unsubstituted or substituted by one or more halogen
atoms or a straight or branched C1-6 alkyl, a straight or
36

branched C1-6 alkoxy or nitro groups), or a thienyl
group] and pharmaceutically acceptable salts thereof.
3. A process for preparing a compound of formula
(I):
<IMG> (I)
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a hydroxy
group, or a straight or branched C1-6 alkoxy group and R2
represents a hydrogen atom, a straight or branched C1-6
alkyl group, a straight or branched C2-7 alkoxycarbonyl
group, a C3-6 cycloalkyl group, a benzyl group, a phenyl or naphthyl
group (unsubstituted or substituted by one or more halogen
atoms or a straight or branched C1-6 alkyl, a straight or
branched C1-6 alkoxy or nitro groups), or a thienyl
group] and pharmaceutically acceptable salts thereof,
characterized in that a compound of formula (II):
(II)
<IMG>
37

wherein R and R3 are as hereinbefore defined R'1 represents
a hydroxy group or a straight or branched C1-6 alkoxy group
is reacted with a compound of formula (III):
R2-C?C-CO2R4 (III)
wherein R2 is as hereinbefore defined and R4 represents a straight or
branched C1-3 alkyl group, to obtain a compound of formula (I) as defined
above wherein R1 represents an hydroxyl group or a straight
or branched C1-6 alkoxy group and, if desired, the obtained
compound of formula (I) as defined above is converted to a
pharmaceutically acceptable salt thereof.
4. A compound of formula (I):
<IMG> (I)
wherein R and R3, which may be the same or different,
each represents a hydrogen atom or a straight or branched
C1-6 alkyl group or together with the intervening carbon
atom represent a C3-6 cycloalkyl group; R1 represents a
hydroxy group, or a straight or branched C1-6 alkoxy group
and R2 represents a hydrogen atom, a straight or branched
C1-6 alkyl group, a straight or branched C2-7 alkoxycarbonyl
group, a C3-6 cycloalkyl group, a benzyl group, a phenyl or naphthyl
group (unsubstituted or substituted by one or more halogen
atoms or a straight or branched C1-6 alkyl, a straight or
branched C1-6 alkoxy or nitro groups), or a thienyl
group] and pharmaceutically acceptable salts thereof.
38

5. A process according to claim 3, characterized
in that:
- the reaction of the compound of formula (II)
with the compound of formula (III) is carried out, when R2
represents a hydrogen atom, under reflux in a solvent in the
presence of a catalyst; and in that
- the reaction of the compound of formula (II)
with the compound of formula (III) is carried out, when R2
is other than a hydrogen atom, by heating together the
compounds of formula (II) and (III) in the absence of a
solvent.
6. A process according to claim 3, characterized
in that in the starting compound of formula (II), R and R3
which may be the sme or different represent a hydrogen atom
or a methyl or ethyl radical.
7. A process according to claim 5, characterized
in that in the starting compound of formula (II), R and R3
which may be the same or different represent a hydrogen atom
or a methyl or ethyl radical.
8. A process according to claim 3, characterized
in that in the starting compound of formula (II), R and R3
which may be the same or different represent a hydrogen atom
or a methyl or ethyl radical, and in the starting compound
of formula (III), R2 represents a hydrogen atom, a straight-
chain or branched C1-6 alkyl group, a methoxy carbonyl group
or a phenyl group optionally substituded by one or more
halogen atoms or methyl, methoxy or nitro groups.
39

9. A process according to claim 5, characterized
in that in the starting compound of formula (II), R and R3
which may be the same or different represent a hydrogen atom
or a methyl or ethyl radical, and in the starting compound
of formula (III), R2 represents a hydrogen atom, a straight-
chain or branched C1-6 alkyl group, a methoxycarbonyl group
or a phenyl group optionally substituted by one or more
halogen atoms or methyl, thoxy or nitro groups.
10. A compound having the formula (I) as defined
in claim 4, wherein R and R3 which may be the same or
different represent a hydrogen atom or a methyl or ethyl
radical, and pharmaceutically acceptable salts thereof.
11. A compound having the formula (I) as defined
in claim 4, wherein R and R3 which may be the same or
different represent a hydrogen atom or a methyl or ethyl
radical, and R2 represents a hydrogen atom, a straight-chain
or branched C1-6 alkyl group, a methoxycarbonyl group or a
phenyl group optionally substituted by one or more halogen
atoms or methyl, methoxy or nitro groups, and pharmaceu-
tically acceptable salts thereof.
12. A process for preparing ethyl 2-oxo-4-phenyl
2H-pyrimido [2,1-b] benzothiazole-8-acetate and pharmaceu-
tically acceptable salts thereof characterized in that ethyl
2-aminobenzothiazole-6-acetate is reacted with

<IMG> to obtain ethyl 2-oxo 4-phenyl 2H-pyrimido
[2,1-b] benzothiazole-8-acetate and, if desired, the obtained
ethyl 2-oxo 4-phenyl 2H-pyrimido [2,1-b] benzothiazole-8-
acetate is converted to a pharmaceutically acceptable salt
thereof.
13. Ethyl 2-oxo 4-phenyl 2H-pyrimido [2,1-b]
benzothiazole-8-acetate and pharmaceutically acceptable
salts thereof.
14. A process for preparing ethyl 2-oxo 4-(p-
methoxyphenyl) 2H-pyrimido [2,1-b] benzothiazole 8-acetate
and pharmaceutically acceptable salts thereof characterized
in that ethyl 2 -aminobenzothiazole 6-acetate is reacted
with <IMG> to obtain ethyl 2-oxo 4-(p-
methoxyphenyl) 2H-pyrimido [2,1-b] benzothiazole 8-acetate
and, if desired, the obtained ethyl 2-oxo 4-(p-methoxyphenyl)
2H-pyrimido [2,1-b] benzothiazole 8-acetate is converted to
a pharmaceutically acceptable salt thereof.
15. Ethyl 2-oxo 4-(p-methoxyphenyl) 2H-pyrimido
[2,1-b] benzothiazole 8-acetate and pharmaceutically
acceptable salts.
16. A process for preparing ethyl 2-oxo 4-(o-
chlorophenyl) 2H-pyrimido [2,1-b] benzothiazole 8-acetate
and pharmaceutically acceptable salts thereof characterized
in that ethyl 2-aminobenzothiazole 6-acetate is reacted with
<IMG> to obtain ethyl 2-oxo 4-(o-chlorophenyl)
2H-pyrimido [2,1-b] benzothiazole 8-acetate and, if desired,
41

the obtained ethyl 2-oxo 4-(o-chlorophenyl) 2H-pyrimido-
[2,1-b] benzothiazole 8-acetate is converted to a pharmaceu-
tically acceptable salt thereof.
17. Ethyl 2-oxo 4-(o-chlorophenyl) 2H-pyrimido
[2,1-b] benzothiazole 8-acetate and pharmaceutically
acceptable salts thereof.
18. A process for preparing ethyl .alpha.-methyl 2-oxo
4-phenyl 2H-pyrimido [2,1-b] benzothiazole 8-acetate and
pharmaceutically acceptable salts thereof characterized in
that ethyl 2-amino-.alpha.-methylbenzothiazole-6-acetate is
reacted with <IMG> to obtain ethyl .alpha.-methyl
2-oxo 4-phenyl 2H-pyrimido [2,1-b] benzothiazole 8-acetate
and, if desired, the obtained ethyl .alpha.-methyl 2-oxo 4-phenyl
2H-pyrimido [2,1-b] benzothiazole 8-acetate is converted to
a pharmaceutically acceptable salt thereof.
19. Ethyl .alpha.-methyl 2-oxo 4-phenyl 2H-pyrimido
[2,1-b] benzothiazole 8-acetate and pharmaceutically
acceptable salts thereof.
20. A process for preparing ethyl .alpha.-methyl 2-oxo
4-(p-chlorophenyl) 2H-pyrimido [2,1-b] benzothiazole 8-
acetate and pharmaceutically acceptable salts thereof
characterized in that ethyl 2-amino .alpha.-methylbenzothiazole
6-acetate is reacted with <IMG> to obtain
ethyl .alpha.-methyl 2-oxo 4-(p-chlorophenyl) 2H-pyrimido [2,1-b]
benzothiazole 8-acetate and, if desired, the obtained ethyl
.alpha.-methyl 2-oxo 4-(p-chlorophenyl) 2H-pyrimido [2,1-b] benzo-
thiazole 8-acetate is converted to a pharmaceutically
42

acceptable salt thereof.
21. Ethyl .alpha.-methyl 2-oxo 4-(p-chlorophenyl) 2H-
pyrimido [2,1-b] benzothiazole 8-acetate and pharmaceutically
acceptable salts thereof.
22. A process for preparing ethyl .alpha.-ethyl 2-oxo
4-phenyl 2H-pyrimido [2,1-b] benzothiazole 8-acetate and
pharmaceutically acceptable salts thereof characterized in
that ethyl 2-amino .alpha.-ethylbenzothiazole 6-acetate is reacted
with <IMG> to obtain ethyl .alpha.-ethyl 2-oxo 4-phenyl
2H-pyrimido [2,1-b] benzothiazole 8-acetate and, if desired,
the obtained ethyl .alpha.-ethyl 2-oxo 4-phenyl 2H-pyrimido [2,1-b]
benzothiazole 8-acetate is converted to a pharmaceutically
acceptable salt thereof.
23. Ethyl .alpha.-ethyl 2-oxo 4-phenyl 2H-pyrimido
[2,1-b] benzothiazole 8-acetate and pharmaceutically
acceptable salts thereof.
24. A process for preparing a compound of
formula (I):
<IMG> (I)
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
43

alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; and R2 represents a
hydrogen atom, a straight or branched C1-6 alkyl group, a
straight or branched C2-7 alkoxycarbonyl group, a straight
or branched C3-6 cycloalkyl group, a benzyl group, a phenyl
or naphthyl group (unsubstituted or substituted by one or more
halogen atoms or a straight or branched C1-6 alkyl, a
straight or branched C1-6 alkoxy or nitro groups), or a
thienyl group] and pharmaceutically acceptable salts
thereof, characterized in that a compound of formula (IA):
<IMG> (IA)
wherein R, R3 and R2 are as hereinbefore defined and R'1 represents a
straight or branched C1-6 alkoxy radical is subjected to a saponifica-
tion treatment to obtain a compound of formula (I) as
defined above wherein R1 is an hydroxyl group and, if
desired, the obtained compound of formula (I) is converted
to a pharmaceutically acceptable salt thereof.
25. A compound of formula (I):
<IMG> (I)
[wherein R and R3, which may be the same or different, each
44

represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; and R2 represents a
hydrogen atom, a straight or branched C1-6 alkyl group, a
straight or branched C2-7 alkoxycarbonyl group, a C3-6
cycloalkyl group, a benzyl group, a phenyl or naphthyl group (unsub-
stituted or substituted by one or more halogen atoms or a
straight or branched C1-6 alkyl, a straight or branched
C1-6 alkoxy or nitro groups), or a thieny group] and
pharmaceutically acceptable salts thereof.
26. A process for preparing a compound of
formula (I):
<IMG> (I)
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a straight
or branched C1-6 alkoxy group; and R2 represents a hydrogen
atom, a straight or branched C1-6 alkyl group, a straight
or branched C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl
group, a benzyl group, a phenyl or naphthyl group (unsubstituted or
substituted by one or more halogen atom or a straight or
branched C1-6 alkyl, a straight or branched C1-6 alkoxy or
nitro groups), or a thienyl group] and pharmaceutically

acceptable salts thereof, characterized in that a compound
of formula (IB):
<IMG> (IB)
wherein R, R3 and R2 are as hereinbefore defined is
esterified by an alcohol of formula (IV):
HO-R"1 (IV)
wherein R"1 represents a straight or branched C1-6 alkyl
radical to obtain a compound of formula (I) as defined
above wherein R1 represents a straight or branched C1-6
alkoxy group and, if desired, the obtained compound of
formula (I) is converted to a pharmaceutically acceptable
salt thereof.
27. A compound of formula (I):
<IMG> (I)
[wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight or branched C1-6
alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a straight
or branched C1-6 alkoxy group; and R2 represents a hydrogen
46

atom, a straight or branched C1-6 alkyl group, a straight
or branched C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl
group, a benzyl group, a phenyl or naphthyl group (unsubstituted or
substituted by one or more halogen atoms or a straight or
branched C1-6 alkyl, a straight or branched C1-6 alkoxy
or nitro groups), or a thienyl group] and pharmaceuti-
cally acceptable salts thereof.
28. A process for preparing a compound of
formula (I):
(I)
<IMG>
[wherein R and R3, which may be the same or different,
each represents a hydrogen atom or- a straight or branched
C1-6 alkyl group or together with the intervening carbon
atom represent a C3-6 cycloalkyl group; R1 represents, a
straight or branched C1-6 alkoxy group and R2 represents a
hydrogen atom, a straight or branched C1-6 alkyl group, a
straight or branched C2-7 alkoxycarbonyl group, a C3-6
cycloalkyl group, a benzyl group, a phenyl or naphtyl group (unsub-
stituted or substituted by one or more halogen atoms or
a straight or branched C1-6 alkyl, a straight or branched
C1-6 alkoxy or nitro groups), or a thienyl group] and
pharmaceutically acceptable salts thereof, characterized
in that a compound of formula (IA):
47

<IMG> (IA)
wherein R, R3 and R2 are as hereinbefore defined and R'1
represents a straight or branched C1-6 alkoxy radical is subjected
to a transesterification reaction with an alcohol of formula
(IV):
HO-R"1 (IV)
wherein R"1 represents a straight or branched C1-6 alkyl
radical to obtain a compound of formula (I) as defined
above where R1 represents a straight or branched C1-6
alkoxy group and, if desired, the obtained compound of
formula (I) is converted to a pharmaceutically acceptable
salt thereof.
29. A compound of formula (I}:
(I)
<IMG>
[wherein R and R3, which may be the same or different,
each represents a hydrogen atom or a straight or branched
C1-6 alkyl group or together with the intervening carbon
atom represent a C3-6 cycloalkyl group; R1 represents a
straight or branched C1-6 alkoxy group; and R2 represents
48

a hydrogen atom, a straight or branched C1-6 alkyl group,
a straight or branched C2-7 alkoxycarbonyl group, a C3-6
cycloalkyl group, a benzyl group, a phenyl or naphthyl group (unsub-
stituted or substituted by one or more halogen atoms or
a straight or branched C1-6 alkyl, a straight or branched
C1-6 alkoxy or nitro groups), or a thienyl group] and
pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition containing, as
active ingredient, at least one compound of formula (I) as
defined in claim 4, 10 or 11, or a physiologically acceptable
salt thereof in admixture with at least one pharmaceutical
carrier.
31. A pharmaceutical composition containing, as
active ingredient, at least one of the compounds rected in
claim 15, 17 or 19 or a physiologically acceptable salt
thereof in admixture with at least one pharmaceutical
carrier.
32. A pharmaceutical composition containing, as
active ingredient, at least one of the compounds rected in
claim 21 or 23 or a physiologically acceptable salt thereof
in admixture with at least one pharmaceutical carrier.
49

Description

~;~5~72~3
.
15D143-344
Chemical Compounds
The pre~ent invention relates to a process for preparing
novel pyrimi~o /2,1-b/ benzothiazoles ~nd s~lts thereof.
We have found certain novel pyrimido t2~l b]henzo-
thiazoles to possess interesting pharmacological
properties, in particular antiallergic activities.
Accordingly, in one aspect the invention
provides a novel pyrimido /2,1-b/
benzothiazole of formula I :
R2
h
OR1
[wherein R and ~3, which may be the same or different,
each represents a hydrogen atom or a straight or
branched Cl 6 alkyl group or together with the
intervening carbon atom represent a C3_6 cycloalkyl
group; Rl represents a hydroxy group, a straight
or branched Cl 6 alkoxy group or a group of formula
~ R5
-N \ ~A)
R6
~wherein R5 and R6, which may be the same or different,
each represents a hydrogen atom or a Cl 6 alkyl
group or together with the interYening nitrogen
atom represent a piperidino or morpholino group);
and R2 represents a hydrogen atom, a straight or

1;~5~72~!3
- 2 -
branched Cl_6 alkyl r~ up, a C2_7 alkoxycarbonyl group, a C3 6 cycloalkyl
group, an aralkyl group (benzyl), an aryl group ~phenyl or
naphthyl unsubstituted or substituted by one or more halogen
atoms or Cl 6 alkyl, C1 6 alkoxy or nitro groups), or a hete-
roaryl group (thienyl)~ and salts thereof.
In accordance with another aspect the present
invention provides a process for preparing a compound of
formula (I):
R~
>=~
R~ ~5~=
ORl
~wherein R and R3, which may be the same or different,
each represents a hydrogen atom or a straight or branched
Cl 6 alkyl group or together with the intervening carbon
atom represent a C3 6 cycloalkyl group; Rl represents a
hydroxy group, a straight or branched Cl 6 alkoxy group or
a group of formula
/R5
-N \ (A)
R6
(wherein R5 and R6, which may be the same or different,
each represents a hydrogen atom or a straight or branched
Cl 6 alkyl group or together with the intervening nitrogen
atom represent a piperidino or morpholino group); and R2
represents a hydrogen atom, a straight or branched Cl 6
alkyl group, a straight or branched C2 7 alkoxycarbonyl
group, a C3 6 cycloalkyl group, an aralkyl group, an aryl
group (unsubstituted or substituted by one or more halogen
d.

- 2a - 1 25~259
atoms or a straight or branched Cl_6 alkyl, a straight or
branched Cl 6 alkoxy or nitro groups), or a heteroalkyl
group~ and pharmaceutically acceptable salts thereof,
characterized in that
(a) when Rl represents an hydroxy group or a
straight or branched Cl 6 alkoxy group a
compound of formula (II):
OR'l
wherein R and R3 are as hereinbefore defined
R'l represents a hydroxy group or a straight
or branched Cl_6 alkoxy group i~ reacted with
a compound of formula (III):
R2-C-C-C02R4 (III)
wherein R2 ls as hereinbefore defined and R4 represents
a straight or branched alkyl group, to obtain a com-
pound of formula (I) as defined above wherein
Rl represents an hydroxyl group or a straight
or branched Cl 6 alkoxy group and if desired,
the obtained compound of formula (I) as
defined above is converted to a pharmaceuti-
cally acceptable salt thereof,
(b) when Rl represents an hydroxyl group a com-
pound of formula (IA):
R \ (IA)
COR ' l

~L~57~:5~3
- 2b -
wherein R, R3 and R2 are as hereinbefore
defined and Rl' represents a straight or
branched alkoxy radical is subjected to
a saponification treatment to obtain a com-
pound of formula (I) as defined above wherein
Rl is an hydroxyl group and, if desired, the
obtained compound of formula (I) is converted
to a pharmaceutically acceptable salt thereof,
(c) when Rl represents a straight or branched
Cl 6 alkoxy group a compound of formula (IB):
~ ~ (IB)
COOH
wherein R, R3 and R2 are as hereinbefore
defined is esterified by an alcohol of formula
(IV):
HO-R" (IV)
wherein R"l represents a straight or branched
Cl 6 alkyl radical to obtain a compound of
formula (I) as defined above wherein Rl
represents a straight or branched Cl 6 alkoxy
group and, if desired, the obtained compound
of formula (I) is converted to a pharmaceuti-
cally acceptable salt thereof,
~d) when Rl represents a straight or branched
Cl 6 alkoxy group a compound of formula (IA):
R2~
R ~ ~ (IA)
COR'l

- 2c - ~25725.9
wherein R, R3 and R2 are as hereinbefore
defined and R' represents a straight or
branched alkoxy radical is sub~ected to
a transesterification reactio-n with an
alcohol of formula (IV):
HO-R"l
wherein R"l represents a straight or branched
Cl 6 alkyl radical to obtain a compound of
formula (I) as defined above where Rl repre~
sents a straight or branched Cl_6 alkoxy
group and, if desired, the obtained compound
of formula ~I) is converted to a pharmaceuti-
cally acceptable salt thereof,
or (e) when Rl represents a group of the formula
/ R5
-N \
R6
wherein R5 and R6 are as defined above a
compound o formula (IB):
R~
>~
R ~ (IB)
COOH
wherein R, R3 and R2 are as hereinbefore
defined is reacted with a compound of formula
/R5
HN \
wherein R5 and R6 are as hereinbefore defined,
to obtain a compound of formula ~I) as defined
above wherein Rl represents a group of the
formula

- 2d - 1~57259
/ R5
-N
R6
wherein R5 and R6 are as defined above and,
if desired, the obtained compound of formula
(I) is converted to a pharmaceutically
acceptable salt thereof.
The invention pro~ides in particular, among the
compounds of formula I, the compounds wherein R and R3,
which may be the same or di~ferent, each represents a
hydrogen atom or a straight or branched Cl 6 alkyl group
or together with the intervening carbon atom represent a
C3 6 cycloalkyl group; Rl represents a hydroxy group or a
straight or branched Cl_6 alkoxy group and R2 represents a
hydrogen atom, a straight or branched Cl 6 alkyl group, a
C2 7 alkoxycarbonyl group, a C3 6 cycloalkyl group, an aryl
group (unsubstituted or substituted by one or m~re halogen
atoms or Cl 6 alkyl, Cl 6 alkoxy or nitro groups?, or a
heteroaryl group and salts thereof.
In respect of formula I above, where straight or
branched Cl 6 alkyl groups are referred to, these may for
example be methyl, ethyl, propyl, isopropyl, butyl, iso-
butyl, pentyl or hexyl groups J Straight or branched Cl 6
alkoxy groups may for example be methoxy, ethoxy, propoxy,
isopropoxy, butoxy, pentoxy or hexyloxy groups. C3 6
cycloalkyl groups may for example be cyclohexyl groups.
Aralkyl groups may for example be benzyl groups. Aryl
groups may for example be C6 12 groups such as phenyl or
naphthyl groups. C2 7 alkoxycarbonyl groups may for example
be methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl groups.
Where halogen atoms are referred to~ these may for example
be chlorine, fluorine or bromine atoms. Heteroaryl groups
may contain one or more hetero, e.g. sulphur, atoms in the
aryl ring and may be ~or example 2-thienyl groups.

_ 3 _ 1~57X59
The compounds of formula I wherein Rl represents a
hydroxy group are acidic in character and can form salts
with metals or nitrogen bases. Salts with metals may for
example be salts with alkali metals, for example sodium,
potassium and lithium, with alkaline earth metals, for
example calcium or salts with metals such as aluminium and
magnesium. Salts with nitrogen bases include, for example,
ammonium salts and salts with amines, e.g. tromethamine and
triethanolamine, and with lysine and arginine.
The compounds of formula I in which Rl represents
an alkoxy gxoup or a group of formula (A) are basic in
character and may form acid addition salts.
The acid addition salts may be formed with
inorganic or organic acids; they may, for example, be salts
formed with hydrochloric, hydrobromic, hydroiodic, nitric,
sulphuric, phosphoric, propionic, acetic, formic, benzoic,
maleic, fumaric, succinic, tartaric, citric, oxalic,
glyoxylic and aspartic acids, alkane-sulphonic acids (eg
methanesulphonic acid) and arylsulphonic acids ~eg
benzenesulphonic acid). Such salts may however be
susceptible to hydrolysis to form the free base in water.
As examples of the preferred compounds obtained
according to the invention, particular reference may be made
to those compounds of formula I and salts thereof in which
one or both of R and R3 represent hydrogen atoms or methyl
or ethyl groups.
Also as examples of preferred compounds obtained
according to the invention mention may be made of those
compounds of formula I and salts thereof wherein one or both
of R and R3 represent hydrogen atoms or methyl or ethyl
groups and R2 represents a hydrogen atom, a straight-chain
or branched Cl_6 alkyl group, a methoxycarbonyl group or a
phenyl group optionally substituted by one or more halogen
atoms or methyl, methoxy or nitro groups.
~'

~L~572~.9
- 3a -
Especially preferred compounds obtained according
to the invention are for example:
/
~7

~ 5 9
ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzo-
thia~ole-8 acetate:
ethyl 2-oxo-4-(p-methoxyphenyl)-2H-pyrimido[2,1-b]-
benzothiazole-8-acetate;
ethyl 2-oxo-4-~o-chlorophenyl)-2H-pyrimido~2,1-b]-
benzothiazole-8-acetate;
ethyl ~-methyl-2-oxc-4-phenyl-2H-pyrimido[2,1-b]
benzothiazole-8-acetate;
ethyl a-methyl-2-oxo-4-(p-chlorophenyl)-2H-
pyrimidot2,1-b~benzothiazole-8-acetate:
ethyl ~-ethyl-2-oxo-4-phen~1-2H-pyrimido[2,1-b]
benzothiazole-8-acetate;
and salts of these compounds.
The process for the preparation of the novel
pyrimido /2,1-b/ benzothiazoles of ~ormula I, subject
of the invention. may, in particular, comprise reacting
a compound of formula II:
R ~ ~ (II)
: OR1'
~wherein R and R3 are as hereinbefore defined
and Rl' represents a hydroxy group or a C1_~ alkoxy
group, preferably a Cl 6 alkoxy group) with a compound
of formula III
R2-C~C-CO2R4 (III)
(wherein R2 is as hereinbefore defined and R4 represents
an alkyl group, preferably a Cl 3 alkyl group)

725~3
to give a compound of formula (IA) :
R2 ~ (IA)
R
COR~1
(wherein R, R3, R'1 and R2 are as herein before defined) and
- either isolating and, if desired, salifying the compound
of formula (I) thus obtained,
- _ saponifying a compound of formula (IA) wherein R'1 re-
presents an alkoxy radical, to give a compound of formula
(IB) :
2 ~
~ ~ ~ O (IB)
3 COOH
(wherein R, R3 and R2 are as herein before defined) which is
isolated and, if desired, salified, or which is esterified
by an alcohol of formula (IV) :
HO-R"1 (IV)
(wherein R"1 represents C1 6 alkyl radical, to give a
corresponding compound of formula (I), wherein R1 has the
meaning of R"1,which is isolated, and, if desired, salified ;
- or transesterifying a compound of formula (IA) wherein
R'l represents an alkoxy radical, by the actio.. of an
alcohol of formula (IV), to give a corresponding compound
of formula (I), which is isolated, and, if desired, salified;
- _ reacting a compound of formula (IA) wherein R'1 represents
a hydroxy radical, with a compound of formula :
~ R5
-HN R6
(wherein R5 and R~ are as herein before defined)~ to give
a corresponding compound of formula (I) which is isolated
and, if desired, salified.
The above process of the invention is preferably carried
out in the following manner.

2~9
The reaction of the 2-amino benzothiazole of
formula II with the propiolate of formula III
may be, and where R2 is hydrogen preferably is,
effected under re1ux and in the presence of an
alcohol such as ethanol and a catalyst such as
palladium. ~owever, where in the propiolate of
formula III R2 is other than hydrogen, the reaction
is preferably effected under heating, e.g to 100-
180C, and in the absence of a solvent- The saponi~
cation of a compound of formula I wherein Rl represents
alkoxy group is suitably effected with the use
of a weak base such as potassium carbonate.
The reaction of a compound of formula (IA) with a
compound of formula HNR5R6 may be carried out in the
presence of l,l-diimidazole, e.g. l,l'-carbonyl diimidazole.
Salts with metal ions or nitrogen bases of compounds
of formula I wherein R1 is a hydroxy group may be
prepared by reacting the said compounds of formula I
with an appropriate base, such as an alkali metal, alkali
earth metal or nitrogen base.
- Salts with acids of compounds of formula I wherein
h1 is an alkoxy group or a group o~ formula -NR5R6 may be
prepared by reacting the said compounds of formula I with
an appropriate ~cid.
The compounds of the present invention have
interesting pharmacological properties. In particular,
compounds which have been tested exhibit remarkable
antiallergic properties. These properties are
illustrated by experimental test results given
hereinafter. It will be appreciated therefore
that the compounds of the invention may be useful
in medicine. For pharmaceutical use, it will of
course be the case that the salts of the compounds
of formula I will be physiologically acceptable.
Other salts may however find use, for example,
in the preparation of compounds of formula I and
their physiologically acceptable salts.

7 1~5725.~
The compounds of formula I and physiologically
acceptable salts thereof may thus find use in the
treatment of allergy in the human or animal body.
Preferred in this connection are compounds of
formula I wherein one or both of R and R3 represent
hydrogen atoms or methyl or ethyl groups and pharmacolo-
gically acceptable salts of such compounds. Especially
preferred are compounds of formula I wherein one
or both of R and R3 repre~ent hydrogen atoms or
methyl or ethyl groups and R2 represents a hydrogen
atom, a Cl_6 alkyl group, a methoxycarbonyl group -
or a phenyl group optionally substituted by one
or more halogen atoms or methyl, nitr~ or methoxy
groups and the physiologically acceptable salts
of such compounds.
Particularly suitable ~or use as medicaments
are the following compounds:
ethyl 2-oxo 4-phenyl-2H-pyrimido[2,l-b]benzo-
thiazole-8-acetate;
ethyl 2-oxo-4-(p-methoxyphenyl)-2H-pyrimidot2~l-b]
benzothiazole-8-acetate:
ethyl 2~oxo-4-(o-chlorophenyl)-2~-pyrimido[2,l-b]-
benzothiazole-8-acetate;
ethyl ~-methyl-2-oxo-4-phenyl-2H-pyrimido~2,l-b]
benzothiazole-8-acetate;
ethyl ~-methyl-2-oxo-4-(p-chlorophenyl)-2~-
pyrimido12,l-b~benzothiazole-8-acetate;
ethyl ~-ethyl-2-oxo-4-phenyl-2H-pyrimido-
t2,l-blben20thiazole-8-acetate;
and their physiologically acceptable salts.
Such compounds may have utility for example
in the treatment of allergic asthma and asthmatiform
bronchitis of allergic origin.
The compounds of formula I and their physiologically
acceptable salts may be used to prepare pharmaceutical
compositions containing as active ingredient at least one
compound of formula I or a physiologically acceptable salt
thereof in admixture with at least one pharmaceutical carrier
and/or excipient.
For pharmaceutical administration, the compounds

~ 7~ 5
-- 8 --
of formula I and their physiologically acceptable
salts may for example be incorporated in compositions
~or oral, rectal and parenteral ~including topical)
administration, optionally in administration with
other active ingredients. The pharmaceutical compositions
may be for example solids or liquids, presented
in conventional form for use in human or animal
medicine, for example tablets, (including plain
or coated tablets), yelatine capsules, granules,
suppositories, syrups, aerosols, creams, ointments
; and injectable preparations, prepared in conventional
manner.
The active ingredient(s) may be used in conjunction
with excipients customarily employed in pharmaceutical
compositions for example; talc, gum arabic, lactose,
starch, magnesium stearate, cocoa butter, aqueous
or non-aqueous vehicles, animal or vegetable fats,
paraffin derivatives, glycols, and various wetting,
dispersing or emulsifying agents and/or preservatives.
Advantageously, the compositions may be formulated
as dosage units, each unit being adapted to supply
a fixed dose of active ingredient. Suitable dosage
units for adult human treatment may contain from
0.1 to 1,000 mg, preferably from 1 to 200 mg of
active ingredient. The daily dosage will vary
depending on the product employed but will generally
be in the range 1 to 1,0`00 mg per day fcr oral
administration for adult human treatment.
Certain compounds of formula II used as starting
materials for the preparation of the compounds

~;~57259
_ g _
of formula I are known compounds being described
by for example S.N. Sawhney ~t al in Ind. J. Chem.
16B, 605 (1978), and in German Offenlegungsschrift
2~1S158, US Patent No. 3656958 and European Patent
~pplication Publication No. 17543A. However certain
compounds of formula II
~" `I ' ~ I
OR1 ~
~wherein R, Rl' and R3 are as defined above with
the provisos that where Rl' represents a hydroxy
group the moiety R3~ represents other than a
group of formula CH3CH' or~CH2 and that where
Rl' represents an ethoxygroup the moiety R3RC~
represents other than a methylene group) which
are useful as intermediates in the preparation
of compounds of formula I ? are novel.
The compounds of formula II wherein R and
R3 represent hydrogen atoms which are not known
from the literature may be prepared from p-nitrophenyl-
acetic acid according to the following reaction
scheme:

1~5~5.~3
- lQ -
~' ~,so4 ; H2 ~l2
COOH EtOH C~R1 '
AcOH ~ N~
Br2 ~'~NH2
COR1 '
(wherein Rl' is a Cl 6 alkoxy group).
Compounds of formula II which are not known
from the literature may also be prepared from a-
phenyl aldehydes by the following reaction scheme:

2 S ~ X 5~
~? NH20 S03H ~ ~ N02
R1'H ~ N02 . ~ Z KSCN
R3~ 3 1
NH2
3 OR1~
(wherein Rl' is a Cl ~ alkoxy group)
Where compounds in which R and R3 are Cl_
6 alkyl groups are to be prepared, it is preferable
to prepare the intermediate of formula V in theabove reaction scheme by the alkylation of an ~ntermediate
of formula VI
H ~ No2 (VI)
COR1' (wherein R is a Cl ~
alkyl group and Rll is
a Cl 6 alkoxy group)
; using for example an alkyl iodide R3I and a base such

~5~25
-- 12 --
as lithium dissopropylamide or lithium N~i~opropylcyclo--
hexylamide in a suitable solvant such as tetrahydrofuran.
The preparation of the intermediates of formula
VI themselves is described further below.
The compounds of formula II wherein the moiety
R3R~ represents a group of formula CH3CH~ may
in an alternative process be prepared from a-phenyl-
propionic acid by the following reaction scheme:
R1'H/HC1 ~ HNO ~2
C~ C~
NH2
CH ~ KSCN/Br2 ~ __--N
~ AcOH C ~ 11 ~ NH
OR1 ~R1 ~
(wherein R; is a Cl 6 alkoxy group)
The compounds of formula II wherein R3 (or
R) represents a hydrogen atom may also be prepared
from l-chloro-4-nitrobenzene by the following reaction
scheme ~the early stages of which are developed
from the reaction scheme discussed by R. Hino et
al. in J. Med. Chem. 26, 222-226 (1983)):

125~5~
R
~ 1) Na~/DMSO or DMF
Cl ~ 2 ~ 2~- ~ 2
2) RC~(~OzC2~5)2
C02C2~5
(not isolated)
/ ) NaOH/H20/C2H50H
/ 2) HCl
R ~
H ~ H2504~ H ~ N02
C02H COR1' ~VI~
~ ~ Pd-C
C2H50H
~ C~3COOH R ~ N
Br2~S~ NH2
COR1 '
(wherein R is a hydrogen atom or a Cl_6 alkyl group,
preferably a methyl or ethyl group, and Rl is a
S Cl ~ alkoxy group).
The follo~ing non-limiting Examples illustrate
the present invention. In these Examples, temperatures
are given in C and percentages are by we;ght unless
otherwlse indicated.

- 14 ~ 57~59
Example 1 : EthYl 2-oxo-2H-pyrimido 12,1-b~ benzothiazole-
8-acetate
A stirred mixture of ethyl 2-aminobenzothiazole-
6-acetate (5 9), methyl propiolate ~1.95 g), and
ethanol ~30 ml) was heated under reflux for ~ hr.
The mixture was allowed to cool and the crude product
was collected and then recrystallised from n-butyl
alcohol giving the ethyl 2-oxo-2~-pyrimido t2,1-b]benz-
othiazole-8-acetate as yellow needles (2.88 g, 48
yield).
The ethyl 2-aminoben~othiazole-6-acetate
used as starting material can be prepared according
to S. N. Sawhney et al., Ind J. Chem. 16B, 605
~1978).
Example 2 : EthYl 2-oxo-2H-~yrimido !2,1-b] benzothiazole-
8-~-methyl3cetate
Using a method similar to that used in Example
1, but starting from the corresponding compound
of formula ~I in which R represents a methyl group
(ethyl 2-amino-~-methylbenzothiazole-6-acetate)
and from methyl propiolate under reflux for 17
~ hours, the ethyl 2-oxo-2H-pyrimido [2,1-b]benzothiazole-
! 8-a-methylacetate was prepared (yield 42~).
The ethyl 2-amino ~-methylbenzothiazole-6-
acetate used as starting material was preparedas indicated below:
Step A : 2-amino-~-methyl benzothiazole-6-acetonitrile.
Bromine (27.4 g) in 95~ v/v acetic acid (87.5 ml)
was added dropwise to a stirred mixture of ~
aminophenyl) propionitrile (2S g3 (see for example
British Patent No. 1198212), potassium thiocyanate
~66.8 9), and 95~ v/v acetic acid ~300 ml) at ambient
temperature. The mixture wa~ then kept stirring
at 50~C for a further 2 hr. before being poured
into water (1.5 litres). The solution obtained
was filtered through celite and sodium hydrogen
carbonate was then added to the filtrate until

25.'3
-- 15 --
no further precipitation occurred. The precipitate
was collected and recrystallised from methanol/water
to give the title product as yellow prism~ (19.4 g, 56%).
M.pt. 165.1C.
I~maX 3400, 3280 (NH2~, 2220 (CN), 1640, 1540,
1460 and 815 cm
Analysis
Calculated %C 59.09; %~ 4.46; ~N 20.67; %S 15.77
Found %C 58.76; %H 4.42; ~N 20.74; %S 15.74
for ClOH9~3S-
Ste~ B : Ethyl 2-amino-~-methylbenzothiazole-6-
acetate.
;A s~irred solution of 95~ ethanol (10 ml),
conc. H2SO4 ~10 g), and the compound of step A
.'15 above ~0.5 g) was heated under reflux for 20 hr.
The mixture was then cooled, diluted with water
and the e~hanol was evaporated off. Tbe resulting
solution was neutralised with sodium hydrogen carbonate
to give a solid which was collected and recrystallised
from methanol/water to give the title product as
off-white needles ~0.38 9, 61~).
M.pt. 146C
IRmaX 3370, 3120, 2980, 1710 (ester CO), 1640,
1540, 1470, 1375f 1330, 1295, and 1225 cm 1
Analysis -
Calculated %C 57.60; %H 5.65: ~N 11.20; ~S 12.80
Found ~C 57.65; ~H 5.65; ~N 11.20; %S 12.95.
for Cl2~l4N2o2s-
The ethyl 2-amino -methylbenzothiazole-6-
acetate used as starting material can also be prepared
as indicated below.
Ethyl 2-(~-aminophenyl) propionate (154.6 g)
~see Arzneim. Fors~h, 23, 1090 (1973)) was dissolved
in 95QO acetic acid and potassium isothiocyanate
(261 g) was added with stirring. A solution of
8r2 1149.4 g) in 95~ acetic acid (750 ml) was then
added dropwise at 18-25C over 2hrs. The mixture

1~5~25.9
-- 16 --
was stirred for an extra half hour, then poured
into water (8 litres), filtered through cellte
and then neutralised to pH 5-6 using 2~% ~a2CO~
solution ~6+ litres). The product was then extracted
into CH2Cl~ and the organic layer was separated,
washed with water, dried over MgSO4 and finally
filtered and evaporated down. The crude product
was then dissolved in hot ethyl acetate (300 ml)
and an equal volume of petroleum ether t40-60)
was added. On cooling, cream coloured crystals
were formed which were filtered off, washed with
ethyl acetate/petroleum ether and dried giving
the product 97 9 (48.5% yield), m.pt. lA6C A
second crop of 29 g was obtained from the mother
liquors. Total yield 63~.
~xamPle 3 : Ethyl 2-oxo-4-Phenvl-2H-pYrimido ~rl-b]
benzothiazole-8-acetate
A stirred mixture of ethyl 2-aminobenæothiazole-
6-acetate (5 g) and ethyl phenylpropiolate (6 g)
~0 ~as heat~d at 20~C in an oil bath for 1 hour.
The crude mixture was then purified on a column
(2~0 g Silica) using CHC13 as eluant. The product
obtained was highly coloured and was crystallised
from CHC13 and recrystallised from ethanol giving
ethyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-
8-acetate as orange plates (1.99 g, 26% yield).
Exam~le 4 : MethYl 2-oxo-4-phenyl-2H-pyrimido t2,1-b~
benzothiazole-8-acetate
~sing a method similar to that used in Example
1~ but startin~ from the corresponding compound
of formula II in which Rl' represents a methoxy
group and from ethyl phenylpropiolate (compound
of formula III) the desired compound was obtained.
Example 5 : n-Propyl 2-oxo-4-phenYl-2H-Pyrimido
12,1-b] benzothiazole-8-acetate
Using a method similar to that used in Example
3, but starting from the corresponding compound

~ 5
17 -
of formula II in which Rll represents a n-propoxy
group and from ethyl phenylpropiolate ~compound
of formula III), the desired compound was obtained.
Example 6 : IsoproPyl 2-oxo-4 phenyl-2H-Pyrimido
[2,1-b~ benzothiazole-8-acetate
Using a method similar to that used in Example
3, but starting from the corresponding compound
o~ formula II in which Rl' represents an isopropoxy
group and from ethyl phenylpropiolate ~compound
of formula III)~ the desired compound was obtained.
Example 7 : n-ButYl 2-oxo-4-phenyl-2H-pyrlmido
~2,l-bl benzothia~ole-8-acetate
Using a method similar to that used in Example
3, but starting from the corresponding compound
of formula II in which Rl' represents a n butoxy
group and from ethyl phenylpropiolate (compound
of formula III), the desired compound was obtained.
Example 8 : 2-Oxo-4-PhenYl-2~-pYrimido 12,l-b]
benzothiazole-8-acetic acid
A stirred mixture of th~ ethyl-2-oxo-4-phenyl-
2H-pyrimido [2,l-b3benzothia20le-8-acetate tof
Example 3, 2.47 g), methanol (lO0 ml), and aqueous
potassium carbonate solution (2.47 g in 20 ml)
was kept at ambient temperature overnight. The
methanol was evaporated, the remainder diluted
with water, then acidified with concentrated HCl.
The precipitate was collected, dried, then recrystallised
twice from methanol to give the 2-oxo-4-phenyl-
2H-pyrimido 12,1-~] benzothiazole-8-acetic acid
as yellow plates ~l.72 g, 75% yield).
Examples 9 to l9
J- Using methods similar to that used in Example
~3, but starting from ethyl 2-aminobenzothiazole-
6-acetate of formula II and from the compounds
of formula III in which R2 has the meanings indicated
in Table I below and R~ represents an ethyl group,
the following compounds were prepared:

~5725~3
-- 18 --
~xamp~e 9 : Ethyl 4-~4-methoxyphenyl)-2-oxo-2H-
pyrimido [2,1-b] benzothiazole-8-acetate.
Example 10 : Ethyl 4-(4-nitrophenyl)-2-oxo-2H-pyrimido
12,1-b] benzothiazole-8-acetate.
Example 11 : Eth~l 4-(4-chlorophenyl)-2-oxo-2H-
pyrimido [2,1-b] bPnzothiazole-8-acetate.
Example 12 : Ethyl 4-(2-chlorophenyl)-2-oxo-2H-
pyrimido 12,1-bl benzothiazole-8-acetate.
Example 13 : Ethyl 4-(4-methylphenyl)-2-oxo-2H-
pyrimido [2,1-b] benzothiazole-8-acetate.
Example 14 : Ethyl 4-~3-chlorophenyl)-2-oxo-2~-
pyrimido [2,1-b] benzothiazole-8-acetate.
Example 15 : ~thyl 4-methyl-2-oxo-2H-pyrimido 12,1-b]
benzothiazole-8-acetate.
Example 16 : Ethyl 4-ethyl-2-oxo-2~-pyrimido [2,1-b]
benzothiazole-8-acetate.
Example 17 ~ Ethyl 2-oxo-4n-propyl-2H-pyrimido
t2,1-b~ benzothiazole-8-acetate.
Example 18 : Ethyl 4-n-butyl-2-oxo-2H-pyrimido
12,1-b] benzothiazole-8-acetate.
Example 19 : Ethyl 4-methoxycarbonyl-2-oxo-2H-pyrimido
t2,1-b]benzothiazole-8-acetate.
ExamPle 20 : EthYl a-methYl-2-oxo-4-phenyl-2H-Pyrimido
[2,1-b]_benzothiazole-8-acetate
A mixture of ethyl 2-amino-a-methylbenzothiazole-
6-acetate (50 g) and ethyl phenylpropiolate (34.9 g)
was heated with stirring in an oil bath at 100C
for 20 hours, after which time a further 7 9 of
ethyl phenylpropiolate was added. Heating was
continued for a further 96 hours and HPLC then
showed the reaction to be 93% completed. Ether
(SOOml) was then added cautiously and the mixture
was stirred under reflux for 2 hours. Seeds of
ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b]
benzothiazole-8-acetate were added and the solution
was cooled. The crystalline product so obtained
was filtered off and washed with ether, then dried,

~57~5-9
- 19 --
giving ethyl ~-methyl-2-oxo-4-phenyl-2H-pyrimido
t2,1-b] benzothiazole-6-acetate ~39 g, 51% yield),
99.9% pure HPLC, m.p~ 127-31C.
The ethyl 2-amino-~-methylbenzothiazole-6-
acetate was prepared as indicated in the preparationo~ Example 2.
Example 21 : -Methyl-2-oxo-4-phenyl-2H-pyrimido
2rl-bl_benzothiazole-8-acetic acid
Using a method similar to that used in Example
8, but starting ~rom the ethyl -methyl-2-oxo-4-
phenyl-2H-pyrimido [2,1-b] benzothia201e-8-acetate
of Example 20, the desired compound was obtained.
Examples 22 to 24
Using methods similar to that used in Example
20, but startiny from ethyl 2-amino-~-methylbenzothiazole-
6-acetate and from the compounds of formula III
in which R2 has the meanings indicated in Table
I below and R4 represents an ethyl radical, the
following compounds were prepared.
Example 22 : Ethyl -methyl 4-(4-chlorophenyl)
; 2-oxo-2H-pyrimido 12,1-b] benzothiazole-8-acetate
Example 23 : ~thyl -methyl ~-(3-chlorophenyl)
2-oxo-2H-pyrimido [2,1-bl benzothiazole-8- acetate
Example 24 : Ethyl a-methyl-2-oxo-4n-propyl-2H-
pyrimido [2,1-b] benzothiazole-8-acetate
Example 25_to 43
Using methods similar to thos~ described
above and starting from approprate compo~nds of
formulae II and III, the following compounds were
prepared:
Example 25: Ethyl 4-isopropyl-2-oxo-2H-pyrimido[2,1-b]-
benzothiazole-8-acetate.
Example 26: Ethyl 4-benzyl-2-oxo-2H-pyrimidol2,1-bl-
benzothiazole-8-acetate.
Example 27: Ethyl ~-methyl-4-benzyl-2-oxo-2~-pyrimido-
[2,1-b]benzothiazole~8-acetate.

~57~5.'3
-- 20 --
Example 28: Ethyl ~-methyl-4-isopropyl-2-oxo-2H-
pyrimido[2,1-b]be~zothiaæole-8-acetate.
Exa~ple 29: Ethyl ~-ethyl-4-phenyl-2-oxo-2H-pyrimido-
[2,1-b]benzothia~ole-8-acetate.
Example 30: Ethyl 4-cyclohexyl-2-oxo-2H-pyrimido[2,1-b~-
benzothiazole-8-acetate.
Exam~ 31: ~thyl ~-methyl-4-cyclohexyl-2-oxo-
2H-pyrimido~2,1-blbenzothiazole-8-acetate.
Example 3~: Ethyl a-propyl-4-phenyl-2-oxo-2H-pyrimido-
t2,1-b]benzothiazole-8-acetate.
Example 33: Ethyl ~-isopropyl-4-phenyl-2-oxo-2~-
pyrimidot2,1-b]benzothiazole-8-acetate.
Example 34: Ethyl a-butyl-4-phenyl-2-oxo-2H-pyrimido-
12,1-blbenzothiazole-8-acetate.
Example 35: Isopropyl ~-methyl-4-phenyl-2-oxo-
; 2~-pyrimido[2,1-b~benzo~hiazole-8-acetate.
Example 36- Eth~l a,~-dim~thyl-4-phenyl-2-oxo-
2~-pyrimido~2,1-blbenzothiazole-8-acetate.
ExamPle 37: Ethyl ~-ethyl-~-methyl-4-phenyl-2-
oxo-2R-pyrimidol2,1-b~benzothiazole-8-acetate.
Example 38: Ethyl ~-methyl-~-propyl-4-phenyl-2-
oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate.
Example 39: t-Butyl ~-methyl-4-phenyl-2-oxo-2H-
pyrimidol2,1-blbenzothiazole~8-acetate.
Example 40: Ethyl ~,~-diethyl-4-phenyl-2-oxo-2H-
pyrimido[2,1-blbenzothiazole-8-acetate.
Example 41: Ethyl ~-ethyl-~-propyl~4-phenyl-2-
oxo-2H-pyrimido[2,1-b~benzothiazole-8-acetate.
Ex~ple 42: Ethyl ~-butyl--methyl-4-phenyl-2-
oxo-2H~pyrimido[2,1-b]benzothiazole-8-acetate.
Example 43: 2,2-Dimethylpropyl a-methyl-4-phenyl-
2-oxo-2H-pyrimido~,l b]benzothiazole-8-acetate~
Example 44: N,N-~imethyl-2-oxo-4-Phen~-2H-pyrimido-
~2,1-b]benzothiazole-8-acetamide
3 g of 2-Oxo-4-phenyl-2H-pyrimido [2,1-b]
benzothiazole-8-acetic acid was dissolved in tetrahydrofuran
(40 ml) and l,l'-~arbonyldiimidazole ~2 g) was added.
The mixture was stirred at room ~emperature for 1

~5~5.~3
hour until dissolution took pla~e. Excess dimethylamine
(30% in EtOH) was added and the mixture was stirred
for a further 40 minutes. The THF was then removed
under vacuo and the residue was taken up in dichloromethane
and washed with water, bicarbonate solution, water
then dried (MgSO4), filtered and evaporated down.
A pale buff solid was obtained which was purified
by flash ch,romatography on silica. Yield 1.1 g,
melt;ng point 238-4~C.
Examples 45 to 48
Using methods similar to those described
above but using the appropriate amine starting
material, the following compounds were prepared:
; Example 45: N-Ethyl-2-oxo-4-phenyl-2H-pyrimidot2,1-bl-
benzothiazole-8-acetamide.
Examele 46~ N-Morpholino)-2-(2-oxo-4-phenyl-2H-
pyrimido[2,1-b]benzothiazol-8-yl)ethanone.
Example 47: N,N-Diethyl-2-oxo-4-phenyl-2H-pyrimido-
[2,1-b3benzothiazole-8-acetamide.
2xample 48~ -Piperidino)-2-(2-oxo-4-phenyl-2H-
pyrimido[2,1-b~benzothiazol-8-yl)ethanone.

- 22 - ~ ~ S ~Z 5.9
TABLE 1
.
Example R Rl R2 R3 M.pt.C
,
1 H EtO H H 276
2 Me EtO R H 129
3 H EtO Ph H 206
4 H MeO Ph H 225-6
H nPrO Ph H 133.5-
H 134.5
6 H i PrO Ph H 171.5-172.5
7 H nBuO Ph H 136-7
8 ~ HO Ph H slight
decompos.
136C
m.256~C
9 H EtO ~-MeOPh H 152
H EtO ~-N2Ph H 246
11 H EtO ~-ClPh H 220
12 H EtO o-ClPh H 196.5
13 H EtO ~-MePh H 183-4
14 H EtO m-ClPh H 176-9
H EtO Me H 251-3
16 H EtO Et H 166.7
17 H EtO nPr H 158-60
1~3 H EtO nBu H 149.6
19 H EtO CO2Me H 163
Me EtO Ph H 127-31
21 Me HO Ph H 239-46
22 Me EtO ~-ClPh H 190-1
23 Me EtO m-ClPh H 76-9
24 Me EtO nPr H 125-6
.

1~:57X5~
- 23 -
TABLE 1 tContinued~
.
Example R Rl R2 R3 Mopt~C
25 ~ EtO ls~Pr H 170-7
26 H EtO CH2Ph H 197-9
27 Me EtO CH2Ph H 99--101
28 Me EtO isoPr H 149-51
29 Et EtO Ph H 143-5
30 H EtO cyclohexyl H 169-71
31 Me EtO cyclohexyl ~ 148-50
32 nPr EtO Ph ~ 131-3
33 1 Pr EtO Ph ~ 1~6-8
34 Bu EtO Ph ~ 92-~4
Me isoPrO Ph H 153-S
36 Me EtO Ph Me 133-5
37 ~e EtO Ph Et 159-61
38 Me EtO Ph Pr 174-6
39 Me t-BuO Ph H L22-5
Et EtO Ph Et 13~-40
41 Et EtO Ph Pr 16~-4
42 Me EtO Ph Bu 143-4
43 Me t-BuC~O Ph ~ 12~-3
44 H ~e2~ Ph ~ 23~-~0
~ EtEN Ph ~ 21~-2
46 H O ~ Ph H 214-6
\J
47 H Et2N Ph H L~7-~
48 H ~ Ph H 1~0-1

~5~XS.9
, ~ _
TABLE 1 (Continued)
CALCULATED
.
ExampleFormula ~C %H N% S~
1C14H12N23S 58.3 4.2 9.7 11.1
C15~14N23S 59.6 4.65 9.25 10.6
C20H16N23S 65.9 4.4 7.7 8.8
4 - ~
21H18N23S 66.65 4.8 7.4 B.45
6C21H18N23S 66.65 4.8 7.4 8.45
22H19N23S 67.35 5.15 7.15 8.15
818H12N23S 64.25 3.6 8.35 9.55
C21H18N24S 63.95 4.6 7.1 8.15
10C20~15N35S 58.65 3~7 10.25 7.85
11C20H15N2O3ClS 60.2 3.8 7.0 8.05
12C2oHl5N2o3cls 60.2 3.8 7.0 3.Q5
1321H18N2O3S 66.65 4.8 7.4 8.45
14C20H15N2O3ClS 60.2 3.8 7.0 8.05
15C15~14N23S 59.6 4.65 g.25 10.6
16C16H16N23S 60.75 5.1 8.85 10.15
17C17R18N23S 61.8 5.5 8.5 9.7
18C18H20N23S 62.75 5.85 8.15 9.3
1916H14N2sS 55-5 4 05 8.1 9.25
2021 18 2O3S 66.65 4.8 7.4 8.45
21C19~14N23S 66.15 4.05 8.0 9.15
22C21H17N2O3ClS 61.1 4.15 6.8 7.75
23C21H17N2O3ClS 61.1 4.15 6.8 7.75
24C18H20N23S 62.75 5.85 ~.lS 9.3

~5725~
- 25 -
TA8LE 1 (Continued)
CALCULATED
ExampleFormula %C %H N% S~
2517H18N2O3S 61.80 5.49 8.48 9.70
2621H18N2O3s 66.65 4.79 7.40 8.47
C22H2oN2o3s~l/2H2o 65.82 5.27 6.98 7.99
2818~20N2O3S 62.77 5.85 8.1~ 9.29
2922H20N2o3s 67.33 5.14 7.14 8.17
20H22N2O3S 64.84 5.99 7.56 8.65
3121~24N2O3S 65060 6.29 7O28 8.34
3223~22N2O3S 67.96 5.46 ~.89 7.89
C23~22N2o3s.l/2H2o 66.49 5.58 6.74 7.72
34C24H24N2O3S 68.55 5.75 ~.66 7.62
22H20N~o3s 67.33 5.14 7.14 8.17
3622~20N2O3S 67.33 5.14 7.14 8.17
37C23~22N2O3S 67.96 5.46 6.89 7.89
3824~24N23S 68.55 5.75 6.66 7.62
39C23~22N2O3S 67.96 5.46 6.89 7.89
C24~24N23S 68.55 5.75 6.66 7.62
4125H26~2O3S 69~10 6.03 S.45 7.38
4225~26N2O3S 69.10 6.03 6.45 7.38
43C24H24N23S 68.55 5.75 6.66 7.62
~4C20H17N3o ~ .1/2H2o 64.50 4.87 11.28 8.61
45C20~l7N3o2s~ 1/2~20 11 . 28 8 . 61
46C~ 4N3O~S. l/2H~o 63.75 4.86 10.14 7.73
47C22~2lN3o~s 67.50 5.41 10.73 8.19
4823~2lN3~2s 68.45 5.25 10.41 7.95

5~259
TABLE 1 ~Continued)
FOUND
.
~xample %C ~H %N %S
.
1 58.25 4.25 9.75 11.1
2 59.5 4.65 9.3 10.45
3 66.~ 4.5 7.65 8.85
4 - _ _ _
66.55 4.85 7.35 8.35
6 66.65 4.85 7.~ 8.45
7 67.35 5.15 7.2 8.2
8 64.25 3.65 8.3 9.55
9 6~.0~ 4.65 7.1 8~2
1~ 58.6 3.75 10.25 7.8
11 60.15 3.85 6.95 ~.05
12 60.25 3.9 7.0 8.1
13 66.45 4.85 7.A0 8.6
14 60.~5 3.9 7.05 8.1
59.6 ~.7 9.3 10.55
16 60.5 5.1 8.8 10.15
17 61.7 5.5 8.45 9.~5
18 62.5 5.9 8.15 9,~5
19 55.3 4.15 8.0 9.15
~0 66.5 4.85 7,45 8.4
21 64.9 4.0~ 8.0 9.1
22 61.1 4.25 ~.75 7.~5
23 60.~5 4.3 6.75 7,85
~4 62.65 5.85 B.15 9~3
.

S9
- 27 -
TABLE 1 ~Continued~
FOUND
Example %C ~H %N ~S
61.88 5.51 8.51 9.64
26 66.55 4.85 7.37 8.43
27 65.94 5.34 6.88 8.02
28 62.73 5.93 ~.11 9.17
29 67 7 43 5.16 7.14 8~12
64.85 5.95 7.~2 8.64
31 65.~2 6.34 7.21 8.35
32 67.84 5.54 6.85 7.75
33 66.56 5.5g 6.61 7.65
34 G8.35 5.83 6.62 7.72
~7.27 5.20 7.08 7.97
36 67.42 5.16 7.09 8.22
37 67.66 5.66 ~.67 7.59
38 68.30 5.8~ 6.54 7.53
39 68.10 5.50 6.84 7.8
4~ 68.47 5.85 ~.58 7.61
41 69.08 6.14 6.34 7.37
42 68.91 6.14 6.32 7.28
43 ~8.62 5.78 6.66 7.63
64.50 4.72 11.18 8.54
~5 64.4~ 4.71 11.28 8.62
46 63.86 4.76 10.00 7~75
47 67.20 5.40 10.58 8.17
48 68.19 5.31 1~.26 7.95
.. . . .

1~57~5
-- 28 --
Example 49
Tablets were prepared according to the formulation:
- compound of Example 3.~........... ~......... 15 mg ;
- excipient q. s. for one one tablet up to....100 mg.
~Details of the excipient : lactose, starch, talc,
magnesium s~earate~.
E~ample 50
A dosed aerosol was prepared delivering per
dose:
- compound of Example ~0....................... 2 mg ;
- emulsifier........................ .O.lS mg ;
- propellant........................ 50 mg.
Example 51
Tablets were prepared according to the formulation:
- compound of Example 20...................... 15 m~ ;
- excipient q. s. for one tablet up to ...... 100 mg.
(De~ails of the excipient : lactose, starch, talc,
magnesium stearate)
P~ARMACO~OGICAL ACTIVITY
Test : Antigen induced elevation of lung ~erfusion
Pressure
Animals
Male Dunkin ~artley guinea pigs (Porcellus,
450-7009) are used (four per drug concentration)
housed in cages. Animals are sensitised ~y two
weekly exposures to aerosol ovalbumen (1~ W/V).
Drugs
Animals are anaesthetised with 2 5 mg/kg
diazepam i. p. and 1 ml/kg ~ypnorm i.m.
Method
Following anaesthesia, the animals are exsanguinated
by severing both carotid arteries. The chest is
opened and the lungs remo~ed, split into two at
the carina and both cannulated via the main lobar
bronchus and connected to a perfusion system.

- ~5725~3
-- 29 --
Lungs were perfused with aerated krebs fluid (95
0~ : S% CO2) at 37~C. Ovalbumen (5pg in 0.1ml)
was injected through an in~ection port proximal
-to each lung. Elevation of perfusion pressure
by the antigen is recorded. Sixty minutes la~er,
15 ~g ovalbumen is administered. Research compounds
are added to the krebs fluid reservior, thirty
minutes prior to the second antigen dose. For
each weekly batch of animals used, control measurements
are made without drug treatment (n=10).
The second antigen response is expressed
as a percentage of the first. For drug treatments
at least our lungs ~from four different animals)
are used per concentration. Percentage inhibition
of antigen induced bronchoconstriction is calculated.
(IC50UM) .
Results are given in Table 2 below.

1~5~25~3
-- 30 --
TA:BLE 2
. . . ~
Product of Example IC50 uM
2 3~100
` 3
4 10
C10
6 1-10
7 ~10
~0-100
11 10
12 0 . 1-1
13 ~1
14 _1
10-100
16 100
17 1-10
18 10
0.1
2~ 0. 1-1
23 ~1
~4 ~ 10
.

~;~5~5!3
-- 31 --
TABLE 2 (Conti nued )
Product of Example IC50 uM
.~
lO-100
27 lO-lOû
28 10-~00
29 0.1
l-10
31 ~ 10
32
33 10-lOO
34 l-10
0 . 1-l
36 l-10
3~ l
38
39 0.1
10-lOO
41 lO-100
42 lO-100
43 û.l
44 lO~
10-lOO
46 ~ 100
47 10
48 10-100
. . _ _ . _ _