GB2154583A

GB2154583A - pyrimidobenzthiazoles

Info

Publication number: GB2154583A
Application number: GB08503541A
Authority: GB
Inventors: David Alun Rowlands; Julian Marian Charles Golec
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1984-02-13
Filing date: 1985-02-12
Publication date: 1985-09-11
Also published as: ES553574A0; DK63385D0; HU192318B; FI79323B; EP0153230A3; KR850005847A; ES8800243A1; DK63385A; ZA85696B; NZ211104A; FI850582A0; CA1257259A; ES540332A0; EP0153230A2; GB8503541D0; PT79955B; HUT38649A; ATE44745T1; GB8403739D0; AU3867285A

Abstract

Compounds of formula I <IMAGE> [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 <IMAGE> (wherein R5 and R6, which may be the same or different, each represents a hydrogen atom or a 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 C1-16 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl 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 salts thereof are antiallergic agents.

Description

SPECIFICATION Chemical compounds The present invention relates to novel pyrimido [2,1 -b]benzothiazoies and salts thereof, processes for their preparation, and their application as drugs.

We have found certain novel pyrimido [2,1-b]benzothiazolesto possess interesting pharmacological properties, in particular antiallergic activities.

Accordingly, in one aspect the invention provides novel pyrimido [2,1-b]benzothiazoles of formula I

[wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight or branched C 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 offormula

(wherein B5 and R6, which may be the same or different, each represents a hydrogen atom or a Ci.s 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 C2 7 alkoxycarbonyl group, a C3.6 cycloalkyl group, an aralkyl group, an aryl group (ubsubstituted or substituted by one or more halogen atoms or C1 6 alkyl, C1-6 alkoxy or nitro groups), or a heteroaryl group] and salts thereof.

In respect of formula I above, where straight or branched C1.6 alkyl groups are referred to, these may for example be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl groups. Straight or branched C,-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 for example 2-thienyl groups.

The compounds of formula I wherein R1 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 R1 represents an alkoxy group 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 of 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 of the invention mention may be made of those compounds of formula land salts thereof wherein one or both of Rand R3 represent hydrogen atoms or methyl or ethyl groups and B2 represents a hydrogen atom, a straight-chain or branched 01.6 alkyl group, a methoxycarbonyi group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups.

Especially preferred compounds of the invention are for example: ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1 -b]benzothiazole-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 a-methyl-2-oXo-4-phenyl-2H-pyrimido]2,1-b]benzothiazole-8-acetate; ethyl α-methyl-2-oxo-4-(p-chlorophenyl)-2H-pyrimido[2,1-b]benzothiazole-8-acetate; ethyl α-ethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate; and salts of these compounds.

In a further aspect, the invention provides a process for the preparation of novel pyrimido[2,1 -b]- benzothiazoles of formula I wherein R1 is a hydroxy or alkoxy group and salts thereof, which process comprises reacting a compound of formula II

(wherein R and B3 are as hereinbefore defined and R1' represents a hydroxy group or a 01.6 alkoxy group, preferably a C1-6 alkoxy group) with a compound of formula III B2-0-=C-0O2B4 (III) (wherein B2 is as hereinbefore defined and R4 represents an alkyl group, preferably a 01.3 alkyl group) followed if desired by the isolation of, and/or formation of a salt of, the compound of formula I thus obtained.

Compounds of formula I in which B1 represents a group of formula (A) may, for example, be prepared by reaction of a compound of formula I in which R1 represents a hydroxy group with a compound of formula

(wherein B5 and B6 are as hereinbefore defined) in the presence of 1,1 '-carbonyldiimidazole. Such a process constitutes a further feature of the present invention.

Compounds of formula I wherein R1 represents a hydroxy group, whilst being compounds of the invention in their own right, may also be used as intermediates for the preparation of further compounds of the invention, for example by esterification by reaction with an alcohol of formula IV HO - B"1 (IV) (wherein R"1 represents a C,-6 alkyl group).

Similarly, compounds of formula I wherein R represents an alkoxy group may also be used as intermediates in the preparation of further compounds of the invention, for example by the following processes which also constitute further features of the invention: i) transesterifying a compound of formula i wherein R1 represents a C, 6 alkoxy group with an alcohol of formula IV HO - 1 (IV) wherein RUt represents a different C-6 alkyl group; and ii) deesterifying a compound of formula I wherein R represents a Cur 6 alkoxy group to obtain a compound of formula I wherein R1 represents a hydroxy group.

The above processes of the invention are preferably carried out in the following manner: The reaction of the 2-aminobenzothiazole of formula II with the propiolate of formula III may be, and where B2 is hydrogen preferably is, effected under reflux and in the presence of an alcohol such as ethanol and a catalyst such as palladium. However, where in the propiolate of formula III R2 is other than hydrogen, the reaction is preferably effected under heating, e.g. to 100-180 C,and in the absence of a solvent. The deesterification of a compound of formula I wherein R1 represents alkoxy group is suitably effected with the use of a weak base such as potassium carbonate.

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 B1 is an alkoxy group or a group of formula -NR5R6 may be prepared by reacting the said compounds of formula I with an appropriate acid.

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 land their physiologically acceptable salts.

The invention accordingly further provides compounds of formu la I and physiologically acceptable salts thereof for 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 B3 represent hydrogen atoms or methyl or ethyl groups and pharmacologically acceptable salts of such compounds.

Especially preferred are compounds of formula I wherein one or both of R and B3 represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a C,-6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, nitro or methoxy groups and the physiologically acceptable salts of such compounds.

Particularly suitable for use as medicaments are the following compounds: ethyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b]benzothiazo le-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 a-methyl-2-oxo-4-p henyl-2H-pyrimido [2,1 -b]benzothiazole-8-acetate; ethyl methyl-2-oxoA-(p-chlornphenyl-2H-pyrimido]2,1 -b] benzothiazol e-8-acetate; ethyl ol-ethyl-2-oxo-4-phenyl-2H-pyrimido[2,1 -b]benzothiazole-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.

In a yet further aspect, the invention provides the use of compounds of formula I or physiologically acceptable salts thereof for the treatment of allergy in the human or animal body.

In another aspect, the invention provides 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 of formula I and their physiologically acceptable salts may for example be incorporated in compositions for 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), gelatine 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 1,000 mg per day for oral administration for adult human treatment.

According to a yet still further aspect of the present invention there is provided a method of treatment of the human or animal body to combat allergy therein, which method comprises administering to the said body an effective amount of a compound offormula I our a physiologically acceptable salt thereof.

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. 16B, 605 (1978), and in German Offenlegungsschrift 2015158, US Patent No.3656958 and European Patent Application Publication No. 17543A. However certain compounds of formula II are novel.

In a further aspect, the invention provides novel compounds of formula II

(wherein R, B1, and B3 are as defined above with the provisos that where R1' represents a hydroxy group the moiety R3RC# represents other than a group of formula CH3CH or #CH2 and that where # CH2 and that where B1, represents an ethoxy group the moiety R3RC# represents other than a methylene group) which are useful as intermediates in the preparation of compounds of formula The compounds of formula II wherein R and R represent hydrogen atoms which are not known from the literature may be prepared from p-nitrophenylacetic acid according to the following reaction scheme:

(wherein R1' is a C-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:

(wherein R1' is a C. 1-6 alkoxy group) Where compounds in which R and B3 are Cur 6 alkyl groups are to be prepared, it is preferable to prepare the intermediate of formula V in the above reaction scheme by the alkylation of an intermediate of formula VI

(wherein R is a C1-6 is alkyl group and R1' is a C1-6 alkoxy group) using for example an alkyl iodide R31 and a base such as lithium diisopropylamide or lithium N-isopropylcyclohexylamide in a suitable solvent such as tetrahydrofuran.The preparation of the intermediates of formula Vi themselves is described further below.

The compounds of formula II wherein the moiety R3RCC represents a group of formula CH3CH may in an alternative process be prepared from a-phenylpropionic acid by the following reaction scheme:

(wherein R1' is a C-6 alkoxy group) The compounds of formula II wherein B2 (or R) represents a hydrogen atom may also be prepared from 1-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):

(wherein R is a hydrogen atom or a C -6 alkyl group, preferably a methyl or ethyl group, and R1 is a 01.6 alkoxy group).

The following non-limiting Examples illustrate the present invention. In these Examples, temperatures are given in C and percentages are by weight unless otherwise indicated.

EXAMPLE 1 Ethyl 2-oxo-2H-p yrimido 2, 1-bi benzo thiazole-8-acetate A stirred mixture of ethyl 2-aminobenzothiazole-6-acetate (5 g), methyl propiolate (1.95 g), and ethanol (30 ml) was heated under reflux for 2 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-2H-pyrimido [2,1-bjbenzothiazole-8- acetate as yellow needles (2.88 g, 48% yield).

The ethyl 2-aminobenzothiazole-6-acetate used as starting material can be prepared according to S.N.

Sawhneyetal.,IndJ. Chem. 16B, 605 (1978).

EXAMPLE 2 Ethyl 2-oxo-2H-pyrimido [Z 1-bi benzothiazole-8-a-methylacetate Using a method similar to that used in Example 1, but starting from the corresponding compound of formula II in which R represents a methyl group (ethyl 2-amino-α-methylbenzothiazole-6-acetate) and from methyl propiolate under reflux for 17 hours, the ethyl 2-oxo-2H-pyrimido [2,1 -bibenzothiazole-8-a- methyl acetate was prepared (yield 42%).

The ethyl2-amino a-methylbenzothiazole-6-acetate used as starting material was prepared as indicated below: Step A : 2-amino-a-methyl benzothiazole-6-acetonitrile.

Bromine (27.4 g) in 95% v/v acetic (87.5 ml) was added dropwise to a stirred mixture of 2-(p-aminophenyl) propionitrile (259) (see for example British Patent No. 1198212), potassium thiocyanate (66.8 g), and 95% v/v acetic acid (300 ml) at ambient temperature. The mixture was than 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 no further precipitation occurred. The precipitate was collected and recrystallised from methanol/waterto give the titleproduct as yellow prisms (19.4 g, 56%).

M.pt. 165.1 C.

IRmaX 3400,3280 (NH2), 2220 (ON), 1640, 1540, 1460 and 815 cm~ Analysis Calculated %C 59.09; %H 4.46; %N 20.67; %S 15.77 Found %C 58.76; %H 4.42; %N 20.74; %S 15.74 for CtoHgN3S.

Step B: Ethyl 2-amino-a-methylbenzothiazole-6-acetate.

A stirred solution of 95% ethanol (10ml), conc. H2SO4 (10 g), and the compound of step A above (0.5 g) was heated under reflux for 20 hr. The mixture was then cooled, diluted with water and the ethanol was evaporated off. The 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 g, 61 %) M.pt. 146"C IBrn0x3370,3120,2980, 1710 (ester CO), 1640,1540,1470,1375, 1330,1295, and 1225cm- 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 C12H14N202S.

The ethyl2-amino a-methylbenzothiazole-6-acetate used as starting material can also be prepared as indicated below.

Ethyl 2-(p-aminophenyl) propionate (154.6 g) (seeArzneim. Forsch,23, (1973)) was dissolved in 95% acetic acid and potassium isothiocyanate (261 g) was added with stirring. A solution of Br2 (149.4 g) in 95% acetic (750 ml) was then added dropwise at 18-25 C over 2 hrs. The mixture was stirred for an extra half hour, then poured into water (8 litres), filtered through celite and then neutralised to pH 5-6 using 20% Na2CO3 solution (6+ litres). The product was then extracted into CH2CL2 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 (40-60 ) 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 g (48.5% yield), m.pt. 146"C A second crop of 29 g was obtained from the mother liquors. Total yield 63%.

EXAMPLE 3 Ethyl 2-oxo-4-phenyl-2H-pyrimido [2, l-b]benzo thiazole-8-acetate A stirred mixture of ethyl 2-aminobenzothiazole-6-acetate (5 g) and ethyl phenylpropioiate (6 g) was heated at 200 C in an oil bath for 1 hour. The crude mixture was then purified on a column (200 g Silica) using CHCI3 as eluant. The product obtained was highly coloured and was crystallised from CHCl3 and recrystallised from ethanol giving ethyl 2-oxo-4-phenyi-2H-pyrimido ]2,1-b] benzothiazole-8-acetate as orange plates (1.99 g, 26% yield).

EXAMPLE 4 Methyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate Using a method similar to that used in Example 1, but starting from the corresponding compound of formula II in which R1' represents a methoxy group and from ethyl phenylpropiolate (compound of formula Ill) the desired compound was obtained.

EXAMPLE 5 n-Propyl 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 of formula II in which R' represents a n-propoxy group and from ethyl phenylpropiolate (compound of formula Ill), the desired compound was obtained.

EXAMPLE 6 Isoprop yl 2-oxo-4-phenyl-2H-p yrimido [2,1-b] benzothiazole-8-acetate Using a method similar to that used in Example 3, but starting from the corresponding compound of formula II in which R1' represents an isoproxy group and from ethyl phenylpropiolate (compound of formula Ill), the desired compound was obtained.

EXAMPLE 7 n-Butyl 2-oxo-4-phenyl-2H-p yrimido[2, 1-b] benzothiazole-8-acetate Using a method similar to that used in Example 3, but starting from the corresponding compound of formula II in which R1' represents a n-butoxy group and from ethyl phenylpropiolate (compound offormula Ill), the desired compound was obtained.

EXAMPLE 8 2-Oxo-4-phenyl-2H-pyrimido [2,1-b] b enzothlazole-8-acetic acid A stirred mixture of the ethyl-2-oxo-4-phenyl-2H-pyrimido [2,1 -b]benzothiazole-8-acetate (of Example 3, 2.47 g), methanol (100 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 HCI. The precipitate was collected, dried, then recrystallised twice from methanol to give the 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid as yellow plates (1.72 g, 75% yield).

EXAMPLES 9 to 19 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 Ill in which R2 has the meanings indicated in Table I below and B4 represents an ethyl group, the following compounds were prepared: Example 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 [2,1-b] benzothiazole-8-acetate.

Example 11: Ethyl 4-(4-chlorophenyl)-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 12: Ethyl 4-(2-chlorophenyl)-2-oxo-2H-pyrimido [2,1-b] benzoth iazole-8-acetate.

Example 13: Ethyl 4-(4-methyl phenyl)-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 14: Ethyl 4-(3-chlorophenyl)-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 15: Ethyl 4-methyl-2-oxo-2H-pyrimido [2,1 -b]benzothiazole-8-acetate.

Example 16: Ethyl 4-ethyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 17: Ethyl 2-oxo-4n-propyl-2H-pyrimido [[2,1-b] benzothiazole-8-acetate.

Example 18: Ethyl 4-n-butyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 19: Ethyl 4-methoxycarbonyl-2-oxo-2H-pyri mido [2,1 -b]benzothiazole-8-acetate.

EXAMPLE 20 Ethyl ol-meth yl-2-oxo-4-phenyl-2H-p yrimido [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 100 C for 20 hours, after which time a further 7 g of ethyl phenylpropiolate was added. Heating was continued for a further 96 hours and HPLC then showed the reaction to be 93% completed. Ether (500ml) 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, giving ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-6-acetate (39 g, 51% yield), 99.9% pure HPLC, m.pt 127-31"C.

The ethyl 2-amino--methylbenzothiazole-6-acetate was prepared as indicated in the preparation of Example 2.

EXAMPLE 21 a-Methyl-2-oxo-4-phen yl-2H-p yrimido [2,1-bl benzothiazole-8-acetic acid Using a method similar to that used in Example 8, but starting from the ethyl a-methyl-2-oxo-4-phenyl-2Hpyrimido [2,1-b] benzothiazole-8-acetate of Example 20, the desired compound was obtained.

EXAMPLES 22 to 24 Using methods similar to that used in Example 20, but starting from ethyl 2-amino-a-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 a-methyl 4-(4-chlorophenyl) 2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate Example 23: Ethyl methyl 4-(3-chlorophenyl) 2-oxo-2H-pyrimido [2,1-b] benzothiazole-8- acetate Example 24: Ethyl a-methyl-2-oxo.4n-propyl-2H-pyri mido [2,1-b] benzothiazole-8-acetate EXAMPLES 25 to 43 Using methods similar to those described above and starting from approprate compounds of formulae II and Ill, 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-pyrimido [2,1 -b]-benzothiazole-8-acetate.

Example 27: Ethyl a-methyl-4-benzyl-2-oxo-2H-pyrimido-[2,1 -b] benzothiazole-8-acetate.

Example 28: Ethyl a-methyl-4-isopropyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazole-8-acetate.

Example 29: Ethyl a-ethyl-4-phenyl-2-oxo-2H-pyrimido-[2,1 -b]benzothiazole-8-acetate.

Example 30: Ethyl 4-cyclohexyl-2-oxo-2H-pyrimido[2,1 -b]-benzothiazole-8-acetate.

Example 31: Ethyl a-methyl-4-cyclohexyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazole-8-acetate.

Example 32: Ethyl a-propyl-4-phenyl-2-oxo-2H-pyrimido-[2,1 -b]benzothiazole-8-acetate.

Example 33: Ethyl a-isopropyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazole-8-acetate.

Example 34: Ethyl a-butyl-4-phenyl-2-oxo-2H-pyrimido-[2,1 -b]benzothiazole-8-acetate.

Example 35: Isopropyl a-methyl-4-phenyl-2-oxo-2H-pyri mido[2,1 -b]benzothiazole-8-acetate.

Example 36: Ethyl a,a-dimethyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate.

Example 37: Ethyl a-ethyl-a-methyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazole-8-acetate.

Example 38: Ethyl a-methyl-a-propyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazo le-8-acetate.

Example 39: t-Butyl a-methyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -bjbenzothiazole-8-acetate.

Example 40: Ethyl a,a-diethyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -b] benzothiazole-8-acetate.

Example 41: Ethyl a-ethyl-a-propyl-4-phenyl-2-oxo-2H-pyrimido[2,1 -b]benzothiazole-8-acetate.

Example 42: Ethyl es-butyl-(x-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[2,1 -b] benzothiazole-8-acetate.

EXAMPLE 44 N, N-Dim eth yl-2-oxo-4ph en yl-2H-p yrimido-[2, 1-b]b enzothiazole-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 1,1 '-carbonyldiimidazole (2 g) was added. The mixture was stirred at room temperature for 1 hour until dissolution took place. 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 chromatography on silica.

Yield 1.1 g, melting point 238-40"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-pyrimido[2,1 -b]-benzothiazole-8-acetamide.

Example 46: 1 -(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-[ -b]benzothiazole-8-acetamide.

Example48: -(N-piperidino)-2-(2-oxo-4-phenyl-2H-pyrimido[2,1 -b]benzothiazol-8-yl)ethanone.

TABLE 1 Example R Rr R2 R3 M.pt C 1 H EtO H H 276 2 Me EtO H H 129 3 H EtO Ph H 206 4 H MeO Ph H 225-6 5 H nPrO Ph H 133.5 H 134.5 6 H isoPrO Ph H 171.5-172.5 7 H nBuO Ph H 136-7 8 H HO Ph H slight decompos.

136"C m.256"C 9 H EtO p-MeOPh H 152 10 H EtO p-NO2Ph H 246 11 H EtO p-CIPh H 220 12 H EtO o-CIPh H 196.5 13 H EtO p-MePh H 183-4 14 H EtO m-CIPh H 176-9 15 H EtO Me H 251-3 16 H EtO Et H 166.7 17 H EtO nPr H 158-60 18 H EtO nBu H 149.6 19 H EtO CO2Me H 163 20 Me EtO Ph H 127-31 21 Me HO Ph H 239-46 22 Me EtO p-Clph H 190-1 23 Me EtO m-CIPh H 76-9 24 Me EtO nPr H 125-6 25 H EtO isoPr H 170-2 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 H 148-50 32 nPr EtO Ph H 131-3 33 isoPr EtO Ph H 126-8 TABLE 1 (Continued) 34 Bu EtO Ph H 92-94 35 Me isoPrO Ph H 153-5 36 Me EtO Ph Me 133-5 37 Me EtO Ph Et 159-61 38 Me EtO Ph Pr 174-6 39 Me t-BuO Ph H 122-5 40 Et EtO Ph Et 138-40 41 Et EtO Ph Pr 163-4 42 Me EtO Ph Bu 143-4 43 Me t-BuCH2O Ph H 122-3 44 H Me2N Ph H 238-40 45 H EtHN Ph H 210-2 46 H T.I.H H 214-6 47 H Et2N Ph H 147-9 48 H T.l.H Ph H 190-1 CALCULATED * Example Formula %C %H N% S% 1 C14H12N2O3S 58.3 4.2 9.7 11.1 2 C15H14N203S 59.6 4.65 9.25 10.6 3 C20H16N203S 65.9 4.4 7.7 8.8 4 5 C21 Hf8N203S 66.65 4.8 7.4 8.45 6 C21H18N2O3S 66.65 4.8 7.4 8.45 7 C22H1gN203S 67.35 5.15 7.15 8.15 8 C18H12N2O3S 64.25 3.6 8.35 9.55 9 C21H18N204S 63.95 4.6 7.1 8.15 10 C20H5N3O6S 58.65 3.7 10.25 7.85 11 C20H15N203CIS 60.2 - 3.8 7.0 8.05 12 C20H16N2O3ClS 60.2 3.8 7.0 8.05 13 C21H18N203S 66.65 4.8 7.4 8.45 14 C20H16N2O3ClS 60.2 3.8 7.0 8.05 15 C15H14N2O3S 59.6 4.65 9.25 10.6 16 C16H16N203S 60.75 5.1 8.85 10.15 17 C17H18N203S 61.8 5.5 8.5 9.7 18 C18H20N203S 62.75 5.85 8.15 9.3 19 C16H,4N205S 55.5 4.05 8.1 9.25 20 C21H18N2O3S 66.65 4.8 7.4 8.45 21 C19H14N203S 66.15 4.05 8.0 9.15 22 C21H17N203CIS 61.1 41.5 6.8 7.75 23 C21 H17N2O3CIS 61.1 4.15 6.8 7.75 24 C18H20N203S 62.75 5.85 8.15 9.3 25 C17H18N203S 61.80 5.49 8.48 9.70 26 C21H18N203S 66.65 4.79 7.40 8.47 27 C22H20N2O3S.1/2H2O 65.82 5.27 6.98 7.99 28 C18H20N2O3S 62.77 5.85 8.13 9.29 29 C22H20N2O3S 67.33 5.14 7.14 8.17 30 C20H22N203S 64.84 5.99 7.56 8.65 31 C21H24N2O3S 65.60 6.29 7.28 8.34 32 C23H22N203S 67.96 5.46 6.89 7.89 33 C23H22N203S.1/2H2O 66.49 5.58 6.74 7.72 34 C24H24N203S 68.55 5.75 6.66 7.62 35 C22H20N203S 67.33 5.14 7.14 8.17 36 C22H20N203S 67.33 5.14 7.14 8.17 TABLE 1 {Continued) 37 C23H22N203S 67.96 5.46 6.89 7.89 38 C24H24N203S 68.55 5.75 6.66 7.62 39 C23H22N203S 67.96 5.46 6.89 7.89 40 C24H24N203S 68.55 5.75 6.66 7.62 41 C25H26N203S 69.10 6.03 6.45 7.38 42 C25H26N203S 69.10 6.03 6.45 7.38 43 C24H24N203S 68.55 5.75 6.66 7.62 44 C20H17N3O2S.1/2H20 64.50 4.87 11.28 8.61 45 C20H17N3O2S.1/2H2O 64.50 4.87 11.28 8.61 46 C22H19N3O3S.1/2H2O 63.75 4.86 10.14 7.73 47 C22H21N302S 67.50 5.41 10.73 8.19 48 C23H21N302S 68.45 5.25 10.41 7.95 FOUND * Example %C %H %N %S 1 58.25 4.25 9.75 11.1 2 59.5 4.65 9.3 10.45 3 66.2 4.5 7.65 8.85 4 5 66.55 4.85 7.35 8.35 6 66.65 4.85 7.4 8.45 7 67.35 5.15 7.2 8.2 8 64.25 3.65 8.3 9.55 9 64.05 4.65 7.1 8.2 10 58.6 3.75 10.25 7.8 11 60.15 3.85 6.95 8.05 12 60.25 3.9 7.0 8.1 13 66.45 4.85 7.40 8.6 14 60.25 3.9 7.05 8.1 15 59.6 4.7 9.3 10.55 16 60.5 5.1 8.8 10.15 17 61.7 5.5 8.45 9.75 18 62.5 5.9 8.15 9.45 19 55.3 4.15 8.0 9.15 20 66.5 4.85 7.45 8.4 21 64.9 4.05 8.0 9.1 22 61.1 4.25 6.75 7.75 23 60.85 4.3 6.75 7.85 24 62.65 5.85 8.15 9.3 25 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 8.11 9.17 29 67.43 5.16 7.14 8.12 30 64.85 5.95 7.62 8.64 31 65.62 6.34 7.21 8.35 32 67.84 5.54 6.85 7.75 33 66.56 5.59 6.61 7.65 34 68.35 5.83 6.62 7.72 35 67.27 5.20 7.08 7.97 36 67.42 5.16 7.09 8.22 37 67.66 5.66 6.67 7.59 38 68.30 5.86 6.54 7.53 39 68.10 5.50 6.84 7.87 40 68.47 5.85 6.58 7.61 41 69.08 6.14 6.34 7.37 42 68.91 6.14 6.32 7.28 43 68.62 5.78 6.66 7.63 44 64.50 4.72 11.18 8.54 45 64.46 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 10.26 7.95 EXAMPLE 49 Tables were prepared according to the formulation: - compound of Example 3....................................... 3 15 mg; - excipient q.s. for one one tablet up to...................................... to 100 mg.

(Details of the excipient: lactose, starch, talc, magnesium stearate).

EXAMPLE 50 A dosed aerosol was prepared delivering per dose; - compound of Example 20...................................... 20 2 mg; -emulsifier 0.15mg; - propellant 50 mg.

EXAMPLE 51 Tablets were prepared according to the formulation: - compound of Example 20 20...................................... 15 mg; - excipient q. s. for one tablet up to ........................................ 100 mg.

(Details of the excipient: lactose, starch, talc, magnesium stearate) PHARMACOLOGICAL ACTIVITY Test : Antigen induced elevation oflung perfusion pressure Animals Male Dunkin Hartley guinea pigs (Porcellus, 450-700g) are used (four per drug concentration) housed in cages. Animals are sensitised by two weekly exposures to aerosol ovalbumen (1 % WN).

Drugs Animals are anaesthetised with 2.5 mg/kg diazepam i. p. and 1 mi/kg Hypnorm 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 were perfused with aerated krebs fluid (95% 2 : 5% CO2) at 37 C. Ovalbumen (5 g in 0.1 ml) was injected through an injection port proximal to each lung. Elevation of perfusion pressure by the antigen is recorded. Sixty minutes later, 15 'ig ovalbumen is administered.

Research compounds are added to the krebs fluid reservior, thirty minutes prior to the second antigen dose.

For each weekly 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 (from four different animals) are used per concentration. Percentage inhibition of antigen induced bronchoconstriction is calculated. (IC60uM).

Results are given in Table 2 below.

TABLE 2 Product of Example IC60uM 2 > 100 3 1 4 10 5 < 10 6 1-10 7 > 10 9 1 10 10-100 11 10 12 0.1-1 13 < 1 14 15 10-100 16 100 17 1-10 18 10 20 0.1 22 0.1-1 23 24 > 10 25 10-100 27 10-100 28 10-100 29 0.1 30 1-10 31 < 10 32 1 33 10-100 34 1-10 35 0.1-1 36 1-10 37 1 38 1 39 0.1 40 10-100 41 10-100 42 10-100 43 0.1 44 10-100 45 10-100 46 > 100 47 10 48 10-100

Claims

1. Compounds of formula 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; R represents a hydroxy group, a straight or branched C1.6 alkoxy group or a group of formula R6 -N (A) B6 (wherein B5 and R6, which may be the same or different, each represents a hydrogen atom or a 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 C27 alkoxycarbonyl group, a C3.6 cycloalkyl group, an aralkyl group, an aryl group (unsubstituted or substituted by one or more halogen atoms or C1-6 alkyl, Cut 6 alkoxy or nitro groups), or a heteroaryl group] and salts thereof.

2. Compounds as claimed in claim 1 wherein R and R3, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group.

3. Oompounds as claimed in claim 2 wherein B2 represents a hydrogen atom, a straight-chain or branched C, 6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups.

4. Compounds as claimed in claim 1 selected from ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1 -b]benzothiazole-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 a-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1 -b]benzothiazole-8-acetate; ethyl a-methyl-2-oxo-4-(p-chlorophenyl)-2H-pyrimido[2,1 -b]benzothiazole-8-acetate; ethyl oc-ethyl-2-oxo-4-phenyl-2H-pyrimido]2,1 -b]benzothiazo le-8-acetate; and salts thereof.

5. Compounds as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

6. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a hydroxy or alkoxy group which comprises reacting a compound of formula II

(wherein Rand B3 are as defined in claim 1 and R1' represents a hydroxy group or a C1 6 alkoxy group) with a compound of formula Ill R2-C=-C-CO2R4 (Ill) (wherein R2 is as defined in claim 1 and R4 represents an alkyl group, followed, if desired, by the isolation of, and/or formation of a salt of, the compound of formula I thus obtained.

7. A process as claimed in claim 6 for the preparation of compounds as claimed in claim 1 wherein B2 represents a hydrogen atom wherein the reaction is effected under reflux in a solvent in the presence of a catalyst.

8. A process as claimed in claim 6 for the preparation of compounds in claim 1 wherein B2 is other than a hydrogen atom wherein the reaction is effected by heating together the compounds of formula II and Ill in the absence of a solvent.

9. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a C16 alkoxy group which comprises reacting a compound as claimed in claim 1 wherein R1 represents a hydroxy group with an alcohol of formula HO-B1,1 (IV) (wherein R1" represents a C16 alkyl group).

10. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a C16 alkoxy group which comprises transesterifying a compound of formula I wherein R1 represents a different C16 alkoxy group.

11. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a hydroxy group which comprises deesterifying a compound as claimed in claim 1 wherein R1 represents a C16 alkoxy group.

12. A process as claimed in claim 11 wherein deesterification is effected by means of potassium carbonate.

13. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a group of formula (A) as defined in claim 1 which comprises reacting a compound of formula I in which R1 represents a hydroxy group with a compound of formula

(wherein Rg and B6 are as defined in claim 1) in the presence of 1,1 '-carbonyldiimidazole).

14. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of the Examples.

15. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 6 to 14.

16. Pharmaceutical compositions comprising as active ingredient a compound of formula las defined in claim 1 or a physiologically acceptable salt thereof.

17. Composition as claimed in claim 16 in the form of dosage units, each dosage unit containing from 0.1 to 1000 mg of active ingredient.

18. Compositions as claimed in claim 17 wherein each dosage unit contains from 1 to 200 mg of active ingredient.

19. Pharmaceutical compositions substantially as herein described in any one of the Examples.

20. Compounds of formula I as defined in claim 1 and physiologically acceptable salts thereof for use in therapy.

21. A method of treatment of the human or animal body to combat allergy therein which method comprises administering to the said body an effective amount of a compound of formula las defined in claim 1 our a physiologically acceptable salt thereof.

22. Compounds of formula II

(wherein R, R1' and B3 are as defined in claim 1 with the provisos that where R1 represents a hydroxy group the moiety R3RC represents other than a group of formula CH3CH or CH2 and that where R1' represents an ethoxy group the moiety R3RC represents other than a methyiene group).