ANTI-ALLERGIC PYRIMIDO[2,1-L-B]BENZOTHIAZOLES

PYRIMIDO-2,LB-BENZOTHIAZOLES

English Abstract

ABSTRACT OF THE DISCLOSURE:
This invention is concerned with novel pyrimido-/
2,1-b/ benzothiazoles of formula I
<IMG> (I)
wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight-chained or branched
C1-6 alkyl group or together with the intervening carbon atom
represent a C3 6 cycloalkyl group; R1 represents a C7-12
straight-chained, branched or cyclic alkoxy group; and R2
represents a hydrogen atom, a straight-chained or branched
C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cyclo-
alkyl group, an aralkyl group, an aryl group (unsubstituted
or substituted by one or more halogen atoms or C1-6 alkyl,
C1-6 alkoxy or nitro groups) or a heteroaryl group, and
its pharmaceutically acceptable salts. These novel com-
pounds of formula I and their salts exhibit remarkable
pharmacological properties especially anti-allergic pro-
perties.

Claims

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
<IMG> (I)
wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight-chained or branched
C1-6 alkyl group or together with the intervening carbon atom
represent a C3-6 cycloalkyl group; R1 represents a C7-12
straight-chained, branched or cyclic alkoxy group; and R2
represents a hydrogen atom, a straight-chained or branched
C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloal-
kyl group, a benzyl group, a C6-12 aryl group (unsubstituted or
substituted by one or more halogen atoms or C1-6 alkyl, C1-6
alkoxy or nitro groups) or a heteroaryl group containing one or
more sulphur atoms in the aryl ring-and its pharmaceutically acceptable
acid addition salts, which comprises
either reacting a compound of formula II
(II)
<IMG>
-19-

(wherein R, R1 and R3 are as hereinbefore defined) with a
compound of formula III
R2-C?C-CO2R4
(wherein R2 is as hereinbefore defined and R4 represents an
alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is
transesterified by an alcohol of formula IV
H-R'1 (IV)
(wherein R'1 represents a C7-12 straight chained, branched
or cyclic alkoxy group) to give a corresponding compound
of formula I wherein R1 has the meaning of R'1, which is
isolated and, if desired, sulfide,
or reacting a compound of formula V
(V)
<IMG>
(wherein R"1 represents a hydroxy group or a C1-6 alkoxy
group) with an alcohol of formula VI
H-R1 (VI)
(wherein R1 represents a C7-12 straight-chained, branched or
cyclic alkoxy group), to give a corresponding compound of
formula I which is isolated and, if desired, salified.
2. A process for the preparation of a compound of
-20-

formula I as claimed in claim 1, which comprises reacting a
compound of formula II
<IMG> (II)
(wherein R, R1 and R3 are as defined in claim 1) with a
compound of formula III
R2-C?C-CO2R4 (III)
(wherein R2 is as defined in claim 1 and R4 represents an
alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is
transesterified by an alcohol of formula
H-R'1 (IV)
(wherein R'1 represents a C7-12 straight chained, branched
or cyclic alkoxy group) to give a corresponding compound
of formula I wherein R1 has the meaning of R'1 which is
isolated and, if desired, salified.
3. A process according to claim 2 wherein the
reaction is effected under reflux in the presence of an
alcohol and a catalyst.
-21-

4. A process according to claim 3 wherein the
alcohol used is ethanol and the catalyst used is palladium.
5. A process according to claim 2 wherein the
reaction is effected by heating to 100-180°C in the absence
of a solvent.
6. A process according to claim 2 wherein in the
starting compound of formula III, R4 represents a C1-3 alkyl
group.
7. A process according to claim 2, wherein in the
starting compound, one or both of R and R3 represent hydrogen
atoms or methyl or ethyl groups.
8. A process according to claim 2 wherein in the
starting compound, one or both of R and R3 represent hydro-
gen atoms or methyl or ethyl groups and R2 represents a hy-
drogen atom, a straight-chained or branched C1-6 alkyl group,
a methoxycarbonyl group or a phenyl group optionally substi-
tuted by one or more halogen atoms or methyl, methoxy or
nitro groups.
9. A process according to claim 2, wherein in the
starting compound, one or both of R and R3 represent hydrogen
atoms or methyl or ethyl groups, R2 represents a phenyl group
and R1 represents a 1-methylcyclohexyloxy or 1-adamantyloxy
group.
10. A process for the preparation of a compound
of formula I as claimed in claim 1, which comprises reacting
a compound of formula V
-22-

<IMG> (V)
(wherein R, R2 and R3 are as defined in claim 1 and R"1
represents a hydroxy group or a C1 6 alkoxy group) with an
alcohol of formula VI
H-R1 (VI)
(wherein R1 represents a C7-12 straight-chained, branched
or cyclic alkoxy group), to give a corresponding compound
of formula I which is isolated and, if desired, salified.
11. A process according to claim 10 wherein in the
starting compound, one or both of R and R3 represent hydrogen
atoms or methyl or ethyl groups.
12. A process according to claim 10 wherein in the
starting compound, one or both of R and R3 represent hydrogen
atoms or methyl or ethyl groups and R2 represents a hydrogen
atom, a straight-chained or branched C1-6 alkyl group, a
methoxycarbonyl group or a phenyl group optionally substitu-
ted by one or more halogen atoms or methyl, methoxy or nitro
groups.
-23-

13. A process according to claim 10, wherein in
the starting compound, one or both of R and R3 represent
hydrogen atoms or methyl or ethyl groups, R2 represents a
phenyl group and R1 represents a 1-methylcyclohexyloxy or 1-
adamantyloxy group.
14. A process for preparing 1-methylcyclohexyl-.alpha.
methyl-2-oxy-4-phenyl-2H-pyrimido/2, 1-b/benzothiazole-8-
acetate and its pharmaceutically acceptable acid addition
salts, which comprises reacting 1-methylcyclohexyl 2-amino-
.alpha.-methylbenzothiazole-8-acetate with ethyl phenylpropiolate
and, if desired, salifying the so obtained product.
15. A process for preparing 1-adamantyl-.alpha.-methyl-
2-oxy-4-phenyl-2H-pyrimido/2,1-b/benzothiazole-8-acetate and
its pharmaceutically acceptable acid addition salts, which
comprises reacting 1-adamantyl 2-amino-.alpha.-methylbenzothiazo-
le-8,-acetate with ethyl phenylpropiolate and, if desired,
salifying the so obtained product.
16. A compound of formula I:
<IMG> (I)
-24-

wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight-chained or branched
C-6 alkyl group or together with the intervening carbon
atom represent a C3-6 cycloalkyl group; R1 represents a
C7-12 straight-chained, branched or cyclic alkoxy group; and
R2 represents a hydrogen atom, a straight-chained or
branched C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a
C3-6 cycloalkyl group, a benzyl group, a C6 12 aryl group
(unsubstituted or substituted by one or more halogen atoms
or C1-6 alkyl, C1-6 alkoxy or nitro groups) or a heteroaryl
group containing one or more sulphur atoms in the aryl ring,
and its pharmaceutically acceptable acid addition salts.
17. A compound of formula I as defined in claim
16, wherein one or both of R and R3 represent hydrogen atoms
or methyl or ethyl groups.
18. A compound of formula I as defined in claim
16, wherein one or both of R and R3 represent hydrogen atoms
or methyl or ethyl groups and R2 represents a hydrogen atom,
a straight-chained or branched C1-6 alkyl group, a methoxy-
carbonyl group or a phenyl group optionally substituted by
one or more halogen atoms or methyl, methoxy or nitro
groups.
19. A compound of formula I as defined in claim
16, wherein one or both of R and R3 represent hydrogen atoms
or methyl or ethyl groups, R2 represents a phenyl group and
R1 represents a 1-methylcyclohexyloxy or 1-adamantyloxy
group.
20. 1-Methylcyclohexyl-.alpha.-methyl-2-oxo-4-phenyl-
2H-pyrimido/2,1-b/benzothiazole-8-acetate.
-25-

21. 1-Adamantyl-.alpha.-methyl-2-oxo-4-phenyl-2H-pyri-
mido/2,1-b/benzothiazole-8- acetate.
22. A pharmaceutical composition comprising an
effective amount of a compound of formula (I) as defined in
claim 16 in admixture with a pharmaceutically acceptable
carrier.
23. A pharmaceutical composition comprising an
effective amount of a compound of formula (I) as defined in
claim 17, 18 or 19 in admixture with a pharmaceutically
acceptable carrier.
24. A pharmaceutical composition comprising an
effective amount of a compound as claimed in claim 20 or 21
in admixture with a pharmaceutically acceptable carrier.
-26-

Description

\
lZ~3~iZ~
The present invention relates to a process for
preparing novel pyrimido-/2,1-b/ benzothiazoles and their
pharmaceutically acceptable salts.
The invention also relates to these novel pyrimi-
do~2,1-b~ benzothiazoles and to their pharmaceutically accep-
table salts, which have been found to possess interesting
pharmacological properties, in particular antiallergic
activities.
The novel pyrimido/2,1-b/benzothiazoles according
to the invention are of formula I
R2
lS U R ~ ~ (I)
wherein R and R3, which may be the same or different, each
represents a hydrogen atom or a straight-chained or branched
Cl 6 alkyl group or together with the intervening carbon atom
represent a C3 6 cycloalkyl group; Rl represents a C7 12
straight-chained, branched or cyclic alkoxy group; and R2
represents a hydrogen atom, a straight-chained or branched
Cl 6 alkyl group, a C2 7 alkoxycarbonyl group, a C3 6 cyclo-
alkyl group, an aralkyl group, an aryl group (unsubstituted
or substituted by one or more halogen atoms or Cl 6 alkyl,
Cl 6 alkoxy or nitro groups) or a heteroaryl group.
In respect of formula I above, where straight-
chained or branchled Cl 6 alkyl groups are referred

~L28~
to, these may, for example, be methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, pentyl or hexyl groups.
C3 6 cycloalkyl groups may, for example, be cyclohexyl groups.
C7 12 straight-chained, branched or cyclic alkoxy groups may,
for example, be heptyloxy, octyloxy, nonyloxy,decyloxy, l-me-
thylcyclohexyloxy or l-adamantyloxy 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 methoxycar-
bonyl, ethoxycarbonyl or propoxycarbonyl groups. Where
halogen atoms are referred to these may, for example, be
chlorine, fluorine or bromine atoms. Where Cl 6 alkoxy
groups are referred to, these may, for example, be methoxy,
ethoxy, propoxy, butoxy, pentoxy or hexyloxy groups. Hete-
roaryl groups may contain one or more hetero, e.g. sulphur,
atoms is the aryl ring and may, for example, be 2-thienyl
groups.
The compounds of formula I as hereinbefore defined
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, hydriodic, nitric, sulphuric,
phosphoric, propionic, acetic, formic, benzoic, maleic,
fumaric, succinic, tartaric, citric, oxalic, glyoxylic and
aspartic acids, alkanesulphonic acids (e.g. methanesulphonic
acid) and arylsulphonic acids (e.g. benzenesulphonic acid).
As examples of the preferred compounds according
to the invention, particular reference may be made to those
compounds of formula I, and acid addition salts thereof,
wherein one or both of R and R3 represent hydrogen atoms or
methyl or ethyl groups.

12~
Also as examples of preferred compounds according
the invention, ~ention may be made of those compounds of
formula I, and acid addition salts thereof, wherein one or
both of R and R3 represent hydrogen atoms or methyl or ethyl
groups and R2 reprensents a hydroglen atom, a straight-chained
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.
As examples of especially preferred compounds accor-
ding to the invention,mention may be made of those com-^
pounds of formula I, and acid addition salts thereof, wherein
one of both of R and R3 represent hydrogen atoms or methyl
or ethyl groups, R2 represents a phenyl group and Rl repre-
sents a l-methylcyclohexyloxy or l-adamantyloxy group.
More particularly preferred compounds according to
the invention include:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2H-
pyrimid~ ,1-b~benzothiazole-8-acetate;
l-adamantyl a-methyl-2-oxo-4-phenyl-2H-pyrimido-
L2,1-b] benzothiazole-8-acetate;
and aci~ addition salts of these compounds.
The process for the preparation of the novel pyrimi-
do/2,1-b/benzothiazoles of formula I and their pharmaceuti-
cally acceptable acid addition salts according the invention,
comprises reacting a compound of formula II
R ~ ~ H2
R3 ~ (II)
OR
(wherein R, Rl and R3 are as hereinbefore defined) with a
compound of formula III
R2_c_c_.co2R4 (III)
. : . . ..

~ Z86~9~
-- 4 --
(wherein R2 is as hereinbefore defined and R4 represents
an alkyl group, preferably a Cl_3 alkyl group) to give a
corresponding compound of formula I which is isolated, and,
if desired, salified/or which is transesterified by an
alcohol of formula IV
H-R' (IV)
(~-herein R'l represents a C7 12 straight chained, branched
or cyclic alkoxy group) to aive a correspording compound of
formula I wherein R1 has the mearing of R'l, which is
isolated and,if desire~,salified.
The above process of the invention is preferably
carriea out in the following manner.
The reaction of the 2-aminobenzothiazole of
formula II with the propiolate of formula III may
be effected under reflux and in the presence of an
alcohol such as ethanol and a catalyst such as palladium.
~owever, the reaction is preferably effected under
heating, e.g. to 100-180C, and in the absence of a
solvent.
Alternatively, the process for the preparation of
the compounds of formula I, according of the invention,
comprises reacting a compound of formula V
R3R "~'~=
0~ 1

-
~L2~36Z90
Iwherein R "l represents a hydroxy group or a Cl 6 alkoxy
group) with an alcohol of formula VI
H-Rl (VI)
(wherein Rl represents a C7 12 straight-chained, branched or
cyclic alkoxy group), to give a corresponding compound of
formula I which is isolated and, if desired, salified.
The compounds of formula I obtained from either of
the processes described above may subsequently be converted
into the acid addition salts thereof, particularly the phy-
siologically acceptable acid addition salts thereof with
inorganic or organic acids, by any conventional method such
as for example by reacting the compounds as bases with a
solution of the corresponding acid in a suitable solvent.
Conversely, the acid addition salts of the compounds of for-
mula I may, if desired subsequently be converted into com-
pounds of formula I.
The compound according to the present invention haveinteresting pharmacological properties. In particular, com-
pounds which have been tested exhibit remarkable antiallergic
properties. These properties are illustrated by experimental
test results given hereinafter. It will be appreciatedtherefore that the compounds according to the invention may
be useful in medecine. For pharmaceutical use, it will of
course be the case that the acid addition salts of the com-
pounds of formula I will be physiologically acceptable. Other
acid addition salts may, however,

`" ~L2
-- 6 --
find use, for example in the preparation of compounds
of formula I and their physiologically acceptable
acid addition salts.
The compounds of formula I and physiologically
acceptable acid addition salts thereof may thus find
use in the treatment of allergy in the human or ar.imal
body.
Preferred in this connection are compounds
of formula I wherein one or both o~ R and R3 represent
hydrogen atoms or methyl or ethyl groups and physiolog-
ically acceptable acid addition salts of such compounds.
Also preferred are compounds of formula I wherein
one or both of R and R3 represent hydrogen atoms
or methyl or ethyl groups and R2 represents a hydrogen
atom, a straisht-chained or branched Cl ~ alkyl g~oup,
a methoxycarbonyl group
or a phenyl group optionally substituted by one
or more halogen atoms or methyl, nitro or methoxy
groups and physiologically acceptable acid addition
salts of such compounds. Especially preferred
are compounds of formula I wherein one or both
of R and R3 represent hydrogen atoms or methyl
or ethyl groups, R2 represents a phenyl group and
Rl represents a l-methylcyclohexyloxy or l-adamant-
yloxy group and physiologically acceptable acid
addition salts of such compounds.
Particularly suitable for use as medicaments
are the following compounds:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-
2~-pyrimido[2,1-b]benzothiazole-8-acetate;
l-adamantyl ~-methyl-2-oxo-4-phenyl-2H-pyrimido-
~2,1-b]benzothiazole-8-acetate;
and their physiologically acceptable acid
addition salts.
Such compounds may have utility for example
in the treatment of allergic asthma and asthmatiform
bronchitis o~ allergic origin.
,

86~90
The compounds of formula I and their physiologically
acceptable acid addition salts may be used to prepare
pharmaceutical compositions containing as active
ingredient at least one compound of formula I or
a physiologically acceptable acid addition salt
thereof in admixture with at least one pharmaceutical
carrier and/or excipient.
For pharmaceutical administration, the compounds
of formula I and their physiologically acceptable
acid addition salts may for example be incorporated
in compositions for oral, re~:tal and parenteral
(including topical) administration, optionally
in conjunction 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), gelatine
~0 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
ac~ive inqredient. The daily dosage will vary
depending on the product employed but will generally
be in the range 1 to 1,000 mg per day for oral

862~)
administration for adult human treatment.
Certain compounds of formula II used as starting
materials for the preparation of the compounds
of formula I are known compounds being described
by, for example, S.N. Sawhney et al. in Ind. J.
Chem., 16~, 605 (1978), and in German Offenlegungsschrift
2,015,158; US Patent No. 3,656,958 and European laid-
open Patent Application No. 01,017,543. However certaincompounds of formula II are novel.
- The compounds of formula II wherein R and
R3 represent hydroqen atoms which are not known
~5 from the literature may be prepared from p-nitrophenyl-
acetic acid according to the following reaction scheme:
~t~ 0~ Pd-C
~ H~S04 ~ H2
COO~ COR1 EtOH CORt
AcOH ~ N~
Br2 ~ ~/>--NH2
CORl
(wherein Rl is as hereinbefore defined).
Compounds oE formula II which are not known
Erom the literature may also he prepared from ~-
phenyl aldehydes by the following reaction scheme:

1~8~i290
_
R3~ 3~3 R3~/
_~ ~ 10% Pd-~ ~ NH2 KSCN
H ~ R ~ ~VII) R ~ AeOH~r2_ r
3 OR1 3 OR
R ~ \ ~ NH2
3 OR1
(wherein R, Rl and R3 are as hereinbefore defined).
~ here compounds in which R and R3 are Cl 6
alkyl groups are to be prepared, it is preferable
S to prepare the intermediate of formula VII in`the
above reaction scheme by the alkylation of an intermediate
of formula VIII
H ~ No2 (VIII)
CORl
(wherein R is a Cl_6 alkyl group and Rl is as hereinbefore
defined) using for example an alkyl iodide R3I
and a base such as lithium diisopropylamide or
lithium N-isopropylcyclohexylamide in a suitable
, .
.. . . , ~ .

- lZ~6290
-- 10 --
solvent such as tetrahydrofuran. The preparation
of the intermediates of formula V~} themaeLyes ls
described ~urther below.
The compounds of formula II wherein the moiety
R3RC~ represents a group of formula CH3CH may
in an alternative process be prepared from 2-phenyl-
propionic acid by the following reaction scheme:
R1-H/HCl ~ HN03 ~ 2
c~ C~
OOH CO~l COR1
~ C~ ;~, ~ r
ORl ~R1
twherein Rl is as hereinbefore defined).
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 K. Hino et
al. in J. Med. Chem., 26, 222-226 (1983)]:

128~29l0
~ 1) Na~/DM~O or DMF ~
Cl ~ 2 ~C~2c- ~ 2
2) RCH~C02C2H~)2
C02C2H5
(not lsolated)
~; NaOH/H20/C2~50H
/ 2) HCl
R R
Rl-- ~N02
C2H COR1 (VIII)
/ ~ Pd-C
/ 2 5
fr--~ CH3COOH R ~ N
H ~ NH XSCN ~ ~ ~ NH2
CORl COR1
(wherein R is a hydrogen atom or a Cl 6 alkyl group,
preferably a methyl or ethyl group, and Rl is as
hereinbefore defined).
Alternatively, the compounds of formula
~ 2
CH ¦ ll
,~,
CoRl

~2~6290
- 12 -
~wherein Rl is as hereinbefore defin~ed) may be
prepared from 2-~p-nitrophenyl)propionic acid by
the following reaction scheme~
CH3 ~ ~ 2 1) SOC12 C
H / COOH 2) Ri H ~ / CO-Rl
~ he compounds of formula V ~7herein R, R2 and R3 are
as defined hereinbefore and R"l represents a`hydroxy
radical or a Cl 6 alkoxy group may be prepared according
to the process described in European ~aid-open Patent
Application n 0 153 230.
The following non-limiting Examples are intended
to illustrate the present invention. In these
Examples, temperatures are given in C and percentages
are by weight unless otherwise indicated.

Example 1: 1-MethYlcyclohexyl -methyl-2-oxo-4-
phenyl-2H-Pyrimido[2,1-b]benzothiazole-8-acetate
Step A: l-Methylcyclohexyl 2-(p-nitrophenyl)propionate.
A stirred mixture of 2-~p-nitrophenyl)propionic
acid (97.5 9) [see J. Med. Chem., 26, 222-226 (1983)],
thionyl chloride (40 ml) and ~ry toluene (500 ml)
was heated at 80C for 5 hours. The mixture was
then allowed to cool and the solvent removed under
reduced pressure. The residual oil was dissolved
in dry toluene (400 ml), and l-methylcyclohexanol
(100 9) was then added to the solution. The stirred
mixture was heated at 80C for 1 hour and then
at ambient temperature overnight. The solution
was washed with 5% NaHCO3 solution, then water,
dried over MgSO4 and finally evaporated to dryness.
The crude mixture was purified on a column ~600 9
silica) using C'~C13 as the eluant, giving l-methyl-
cyclohexyl 2-(p-nitrophenYl)propionate as a golden
yellow liquid (34.95 g, 24% yield).
}R vmax (thin film): 2940, 1725 (ester), 1520, 1345
and 1150 cm 1
Step B: l-Methylcyclohexyl~2-(p-aminophenyl)propionate.
A stirred solution of l-methylcyclohexyl
2-(p-nitrophenyl)propionate (34.9 g) in absolute
ethanol (250 ml) was hydrogenated at atmospheric
pressure in the presence of 10% palladium on carbon
catalyst. After the uptake of hydrogen gas was
complete, the catalyst was ~iltered off through
CELITE~ and the filtrate evaporated to dryness.
Trituration of the residue with petroleum ether
gave l-met~ylcYclohexyl 2-(p-aminophenYl)propionate

lX8629~
_ 14 _
as creamy white crystals (21.02 9, 6796 yield)O
M.p.: 85-87C.
IR vmax (KBr~: 3640 (-NH2), 3370 (-N~I2), 2940, 1710
and 1215 cm 1,
Step C: l-Methylcyclohexyl 2-amino-~-methylbenzothiazole-
6-acetate.
A stirred mixture of l-methylcyclohexyl 2-
(p-aminophenyl)propionate ~20.9 g) and potassium
10 thiocyanate (31.0 g) in glacial ac~tic acid (150 ml)
was heated in an oil bath at 50C and a solution
of Br2 (25.6 g) in glacial ac~etic acid (15 ml) was
added dropwise over 30 mins. The mixture was stirred
at 50C for an extra 30 mins, then cooled and poured
15 into a 3:2 water/ethyl acetate mixture (1,000 ml).
The resulting mixture was neutralised to pH 5-6
using solid NaCO3 and filtered through CELITE
and the orgarlic layer was then separated, washed
with water, dried over MgSO,t and finally evaporated
20 to dryness. Trituration of the residual oil with
petroleum ether gave l-methYlcYclohexyl 2-amino-
c~-methYlbenzothiazole-6-acetate as creamy white
crystals (18.62 g, 73Y6 yield).
M.p.: 165-167C.
25 IR vmax (KBr): 3410, 2930, 1710 (ester), 1550 and
1215 cm
Step D: l-Methylcyclohexyl a-methyl-2-oxo-4-phenyl-
2H-pyrimido[2,1-b]benzothiazole-8-acetate.
A stirred mixture of l-methylcyclohexyl 2-
amino-~-methylbenzothiazole-6-acetate (3.2 91 and
ethyl phenylpropiolate (3.5 9) was heated in an
oil bath (160C) for 30 mins during which time
a further 3.5 g of ethyl phenylpropiolate was added
35 dropwise. The mixture was then cooled to 60C
and ether (30 ml) was added cautiously. Further
cooling gave 1-methYlcyclohexyl c~-methyl-2-oxo-
* trade mark
~ r~

~X86X9~3
4-phenYl-2~-Pyrimid-ol2~l-b]benzothiazole-8-acetate
as pale yellow crystals ~1.82 g, 41% yield).
M.p.: 168-170C.
IR ~max (~Br): 2930, 1720 (e5ter), 1650, 1510 and
S 1145 cm
Analysis:
Calculated %C 69 . 93, ~H 5.87, %N 6.27, %S 7.18.
Found %C 69.87, %~ 5.90, ~N 6.23, %s 7.23.
Example 2: l-Adamantyl ~-methYl-2-oxo-4-phenyl-
2~-pyrimido[2 r 1-b]benzothiazole-8-acetate
Step A: l-Adamantyl 2-(p-nitrophenyl)propionate.
~ sing a method similar to that used in the preparation
of l-methylcyclohexyl 2-(p-nitrophenyl)propionate
starting from 2-(p-nitrophenyl)propionic acid (14.6 9)~
but using l-adamantanol instead of l-methylcyclohexanol,
the desired product was obtained as a light yellow
viscous liquid t22.74 9, 92% yield).
IR ~max (thin film): 2920, 1725 (ester), 1520, 1345
and 1055 cm 1.
Step B: l-Adamantyl~ 2-(p-aminophenyl)propionate.
Using a method similar to that used in the
preparation of l-methylcyclohexyl 2-(p-aminophenyl)-
propionate, but starting from l-adamantyl 2-(p-
nitrophenyl)propionate (21.4 9), the title comPound
was obtained as a light yellow viscous liquid (19.42 9,
100% yield).
IR ~max (thin film): 3450 (-NH2), 3370 (-NH2), 2910,
172Q (ester) and 1055 cm 1
Step C: l-Adamantyl 2-amino-~-methylbenzothiazole-
6-acetate.
Using a method similar to that used in the
preparation of l-methylcyclohexyl 2-amino-~-methyl-
benzothiazole-6-acetate, but starting from l-adamant-
yl 2-(p-aminophenyl)propionate (19.1 g), the

~28~2~3
_ 16 _
title comPound was obtained as a creamy white solid
(lB.97 g, 83% yield~.
M.p.: 151-153C.
IR ~max (RBr): 3400, 2910, 1710 (ester), 1540 and
1210 cm~l.
Step D: l-~damantyl ~-methyl-2-oxo-4-phenyl-2R-
pyrimido[2,1-b~benzothiazole--8-acetate.
Using a method similar to that used in the
preparation of l-methylcyclohexyl ~-methyl-2-oxo-
4-phenyl-2~-pyrimidot2,1-b]benzothiazole-8-acetate,
but starting from l-adamantyl 2-amino-~-methyl-
benzothiazole-6-acetate (8.9 9) and heating at
160C for 1 hour, the title compound was obtained
lS as a light yellow solid after recrystallisation
from ethyl acetate/petroleum ether (4.73 9, 39%
yiela) .
M.p.: 188-190C.
IR ~max (RBr): 2910, 1720 (ester), 1640, 1510 and 1390 cm 1
Analysis:
Calculated %C 71.88, %H 5.82, %N 5.78, ~S 6.62.
Found %C 71.71, %H 5.87, %N 5.75, %S 6.57.
Example 3
Tablets were prepared according to the formulation:
- compound of Example 1...................... ..15 mg
- excipient g.s. for one tablet up to........ .100 mg.
(Details of the excipient : lactose, starch, talc,
maynesium stearate).
Example 4
A dosed aerosol was prepared delivering per
dose:
- compound of Example 2...................... .2 mg
- emulsifier................................ 0.15 mg
35 - propellant................................. 50 mg.

ExamPle 5
Tablets were prepared according to the formulation:
- compound of Example 2..................... ..15 mg
- excipient q.s. for one tablet up to ...... 10~ mg.
(Details of the excipient : lactose, starch, talc,
magnesium stearate)
PHARMACOLOGICAL ACTIVITY
Test : Antiqen induced elevation of lung perfusion
10 Pressure
Animals
Male Dunkin ~artley guinea pigs (Porcellus,
450-700 g) are used (four per drug concentration)
housed in cages. Animals are sensitised by two
~ee~ly exposures to aerosol ovalbumen (1% W/V).
Druqs
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 removed, split into two at
the carina and both cannulated via the main lobar
bronchus and connected to a perfusion system.
Lungs are perfused with aerated krebs fluid (95
2 : 5% CO2) at 37C. Ovalbumen (5~9 in 0.lml)
is injected through an injection port proximal
to each lung. Elevation of perfusion pressure
by the antigen is recorded. Sixty minutes later,
15 pg ovalbumen is administered. Research compounds
are added to the krebs fluid reservoir, 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 four lungs tfrom four different animals)

~.2~6290
- 18 -
are used per concentration. Percentage inhibition
of antigen induced bronchoconstriction is calculated
50 1~)
Results are given in Table I below.
Table I
. _ ._ _
Product of Example IC50 ~M
_ __ _ ,
1 1- 10
. .. _

Representative Drawing