GB1585965A - 3,4-dihydropyrimido (1,2 - )benzimidazol - 2(1h) - ones - Google Patents

Description

(54) 3,4-DIHYDROPYRIMIDO [1,2-a] BENZIMIDAZOL-2(IH) ONES (71) We, IMPERIAL CHEMICAL INDUSTRIES LIMITED, Imperial Chemical House, Milibank, London-SWlP 3JF, a British Company, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to benzimidazole derivatives and more particularly it relates to pyrimido [1,2-a] benzimidazole derivatives which inhibit the aggregation of blood platelets.

According to the invention there is provided a pyrimido[1,2-a]benzimidazole derivative of the formula:

wherein R1 is hydrogen, or a C1-6-alkyl radical; R2 and R3, which may be the same or different, are hydrogen or C1-6-alkyl radicals; one, two or three of A6, A7, A8 and A9, which may be the same or different, are halogen atoms, C1-6-alkyl, C1-6-alkoxy, C2-6-alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radicals, or benzoyl radicals optionally substituted by a halogen atom, a C1-6-alkoxy or C1-6-alkyl radical, and the remainder of A5, A7, A8 and A9 are hydrogen; or an adjacent pair of A6, A7, A8 and A9 together constitute a C1-6-alkylenedioxy diradical, another of A6, A7, A8 and A9 is hydrogen, or is an atom or radical as defined above, and the remaining one of A6, A7, A8 and A9 is hydrogen; provided that when only one of A6, A7, A8 and A9 is a halogen atom, C1-6-alkyl or C1-6-alkoxy radical at least one of the remainder of A6, A7, A8 and A9 is other than hydrogen.

It will be observed that the compounds of formula I are derivatives of 3,4 dihydropyrimido[1,2-a]benzimidazol-2(1H)-one, which ring system will be numbered throughout this specification as shown, by way of example only, in the following formula:

It will be observed that compounds of formula I wherein Rl is hydrogen can exist in different tautomeric forms, one of which is depicted in formula II. It is to be understood that the structural designations and nomenclature used herein relate to the most probable and predominant tautomeric form, but that the invention embraces compounds of formula I wherein R' is hydrogen which are in any tautomeric form or a mixture of such forms.

It will further be observed that, depending on the nature of the substituents R2 and R3 and the substituents A6, A7, A8 and A9, a compound of formula I may contain one or more asymmetric carbon atoms, and may therefore be isolated in racemic forms or optically active forms. This specification is addressed to the racemic forms of a compound of formula I and to any optically active forms of such a compound which possess the above useful properties; it being a matter of common knowledge how to obtain an optically active form, for example by resolution of a racemic form, or by synthesis from an optically active starting material, and how to determine the biological properties of the optical isomers by the test described hereinbelow.

A particular value for any one of R1, R2 and R3, when it is a C1-6-alkyl radical, is, for example, a methyl or ethyl radical.

By way of example only, particular values for any one of A6, A7, A8 and A9 are: when it is a halogen atom, a fluorine, chlorine or bromine atom; when it is a C1-6-alkyl radical, a methyl, ethyl or propyl radical; when it is a C1-6-alkoxy radical, a methoxy, ethoxy or i-propoxy radical; when it is a C2-6-alkanoyl radical, an acetyl, propionyl or butyryl radical; when it is a 1-(hydroxy)-C1-6-alkyl radical, a hydroxymethyl or 1-(hydroxy) C2-6-alkyl radical, for example a 1-hydroxyethyl, 1-hydroxypropyl or 1-hydroxybutyl radical; when it is a C1-6-alkylthio radical, a methylthio or ethylthio radical; and when it is a C1-6-alkylsulphinyl radical, a methylsulphinyl or ethylsulphinyl radical.

Particular values for specific substituents which may be present on the benzene ring of a benzoyl radical when any one of A6, A7, A8 and A9 is such a radical, are by way of example only: for a halogen atom, a fluorine, chlorine or bromine atom; for a Cl~6-alkyl radical, a methyl radical; and for a C1-6-alkoxy radical, a methoxy radical.

A particular value for a C1-6-alkylenedioxy diradical when an adjacent pair of A6, A7, A8 and A9 constitute such a radical is, for example a methylenedioxy or isopropylidenedioxy diradical.

Particldarly suitable arrangements of substituents A6, A7, A8 and A9 are, for example, when two thereof are C1-6-alkyl or C1-6-alkoxy radicals, or a C1-6-alkyl radical and a halogen atom, or halogen atoms, or constitute a C1-6-alkylenedioxy diradical, and the remainder thereof, are hydrogen; or when one thereof is a C2-6alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radical, or a benzoyl radical optionally substituted as defined hereinabove, and the remainder thereof are hydrogen.

Specific suitable arrangements of radicals A6, A7, A8 and A9 are, for example, when two thereof constitute a 6,7-, 7,8-, 8,9- or 6,9-dimethyl radical, a 7,8-dichloro, 7-chloro-8-methyl, 7-methyl-8-chloro, 7,8-dimethoxy, 7,8diisopropoxy or a 7,8methylenedioxy diradical, and the remainder thereof are hydrogen; or when one thereof is a 7- or 3-acetyl, -butyryl, -benzoyl, -(p-chloro)benzoyl, -methylthio, -ethylthio, -ethylsulphinyl, -cyano or -[l-(hydroxy)ethyl] radical, and the remainder thereof are hydrogen.

It will be appreciated that various particular and individual compounds of the invention are comprised within the above general definition, namely those compounds of formula I, wherein one of the radicals R1, R2, R3, A6, A7, A8 and A9 has one of the above defined particular or specific values, and the remainder of the said radicals have any of the defined general, particular or specific values. However, specific groups of compounds of formula I which are of particular interest comprise those compounds of formula I wherein: (i) R1 is hydrogen; (ii) R1 is a C1-6-alkyl radical, and in particular a methyl or ethyl radical; (iii) R1, R2 and R3 are all hydrogen; (iv) one of A6, A7, A8 and A9 is a halogen atom, or a C1-6-alkyl or C1-6-alkoxy radical; another one or two of A6, A7, A8 and A9 is a halogen atom, or a C1-6-alkyl, C1-6-alkoxy, C2-6-alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkyl thio, C1-6-alkylsulphinyl or cyano radical, or a benzoyl radical optionally sub stituted as defined hereinbefore; or another adjacent pair of A6, A7, A8 and A9 together constitute a C1-6-alkylenedioxy diradical; and the remainder of A6, A7, A8 and A9 are hydrogen; (v) one, two or three of A6, A7, A8 and A9 are C2-6-alkanoyl, 1-(hydroxy)-C1-6 alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radicals, or benzoyl radicals optionally substituted as defined hereinabove; or an adjacent pair of A6, A7, A8 and A9 together, constitute a C1-6-alkylenedioxy diradical; and the re remainder of A6, A8 and A9 are hydrogen; and in each case the remainder of A6, A7, A8, A9, R1, R2 and R3 have any of the above general, particular or specific values.

Yet further specific groups of compounds of the invention which are particularly preferred comprise those compounds of formula I wherein: (a) R1 is hydrogen, R2 and R3, which may be the same or different, are hydrogen or methyl radicals, at least two of A6, A7, A8 and A9 are hydrogen, and the remainder of A6, A7, A8 and A9 have any of the above defined values other than hydrogen; (b) R1, R2 and R3 have the meanings defined in (a) immediately above, A7 and one of A6, A8 and A9 have any of the above defined values other than hydrogen, and the remainder of A6, A8 and A9 are hydrogen; (c) R1, R2 and R3 have the meanings defined in (a) immediately above, A8 and one of A6, A7 and A9 have any of the above defined values other than hydrogen, and the remainder of A6, A7 and A8 are hydrogen; (d) R1, R2 and R3 have the meanings defined in (a) immediately above, A7 and/or A8 have any of the above defined values other than hydrogen, and the remainder of A6, A7, A8 and A9 are hydrogen.

Still further groups of preferred compounds comprise those compounds defined in any of the above groups (a)-(d) wherein in addition: (i) A7 or A8 is cyano, acetyl, 1-(hydroxy)ethyl or benzoyl radical; or (ii) A7 and A8 together constitute a methylenedioxy diradical or are both methoxy, ethoxy or isopropyl radicals.

Particular compounds of the invention are described in the accompanying Examples, but specific compounds which are preferred are 7- and 8-acetyl-, 7- and 8-benzoyl-, 7- and 8-cyano, 7,8-disopropoxy- and 7,8-methylenedioxy - 3,4 - dihydropyrimido - [1,2-a]benzimidazol - 2 - (1H) - one, and 7- and 8-benzoyl - 4 - methyl3,4 - dihydropyrimido [1,2-a] benzimazol - 2(1H) - one.

The compounds of the invention may be obtained by any known general procedure for the synthesis of analogous compounds. Such procedures are illustrated by the following in which R1, R2, R3, A6, A7, A8 and A9 have any of the meanings defined above: (a) Reacting a 2-amino-benzimidazole of the formula:

with an ethylenic acid derivative of the formula: RS-CR= CR2--C03Z IV wherein Z is a halogen atom, for example a chlorine or bromine atom, or Z is a Cl~-alkoxy radical, for example a methoxy or ethoxy radical, The reaction may be carried out in an inert solvent or diluent, for example methanol, ethanol, acetone, tetrahydrofuran or acetonitrile, and may be accelerated by heating, for example, to the reflux temperature of the reaction mixture. The reaction is preferably carried out however, at a temperature of, for example 15 to 80"C.

When a compound of formula IV wherein Z is a halogen atom is used, a suitable base, for example a tertiary amine, for example trimethylamine, may also conveniently be present The starting materials of formula III may be obtained by standard methods used in benzimidazole chemistry. Thus when R1 is hydrogen, the starting materials may be made by analogy to 2-aminobenzimidazole, for example by reaction of a 1,2-diaminobenzene of the formula:

with cyanamide, or cyanogen bromide or chloride, optionally in the presence of base.

When R1 is an alkyl radical, the starting materials may be obtained by analogy with 2-methylaminobenzimidazole, for example, by reaction of an alkylamine with a 2bromo- or 2-chloro-benzimidazole, itself conveniently obtained, for example, by reaction of a compound of formula V with urea, followed by conventional halogenation with phosphorus oxybromide or oxychloride. Alternatively when R1 is an alkyl radical, the starting materials of formula III may be made by reaction of a compound of formula V with the appropriate N-alkyl cyanamide in the presence of base.

It will be appreciated that when benzene ring A is asymmetrically substituted the process (a) generally gives rise to a mixture of positional isomers. These isomers may be separated by conventional procedures of organic chemistry, for example by fractional crystallisation from a suitable solvent.

(b) Cyclising a compound of the formula:

wherein Q is a hydroxy or C14-alkoxy radical.

The cyclisation is preferably carried out thermally by heating a compound of formula VI at a temperature in the range, for example 30-2S0C. An inert solvent or diluent, for example, ethanol, dimethylformamide or diphenyl ether, may conveniently be present.

When Q is a C1-4-alkoxy radical the reaction may also conveniently be carried out in the presence of a base, for example sodium ethoxide or methoxide, preferably in a suitable solvent or diluent, for example ethanol or methanol, and at a temperature in the range, for example, 50-250 C.

When Q is a hydroxy radical the cyclisation may also be carried out in the presence of a dehydrating agent, for example a strong mineral acid, for example polyphosphoric acid, or a carbodiimide, for example dicyclohexylcarbodiimide, and conveniently in the presence of a suitable solvent or diluent,for example in the case of a carbodiimide, chloroform, and at a temperature in the range, for example, 15- 100 C.

Scheme 1

Reagents (a) - base, e.g. quaternary ammonium hydroxide.

(b) - hydrogen, palladium-on charcoal.

(c) - CN.Br (for R1=H or alkylcyanamide (for R1=alkyl); then strong base e.g. NaOH.

(d) - aqueous strong base e.g. NaOH.

The starting materials of formula VI may be obtained by conventional procedures, for example as described in the accompanying Examples, and as shown in Scheme 1, starting with an appropriately substituted o-nitroaniline. Alternatively and conveniently, an appropriately substituted o-nitro-chloro- or bromo-benzene may be reacted with a 3-aminopropionic acid of the formula:

wherein Q has the meaning defined above, conveniently at a temperature in the range 30-1500 C., and preferably in a solvent or diluent, for example, 2-methoxyethanol, and in the presence of an acid acceptor, for example sodium hydrogen carbonate. An intermediate of the formula:

is thereby obtained which can be employed in the above Scheme 1. The starting materials of formula VI may conveniently be prepared and used in situ in process (b) without their separate isolation and purification.

A particular advantage of process (b) is that, unalike process (a) hereinabove, it does not give rise to positional isomers when the benzene ring of the benzimidazole moiety of a compound of formula VI is asymmetrically substituted.

(c) For a compound of formula I wherein one of A6, A7, A8 and A9 is a 1-(hydroxy)-C1-6-alkyl radical, reducing a compound of formula I wherein one of A6, A7, A8 and A9 is a C1-6-alkanoyl radical.

The reduction may be carried out by any known procedure compatible with the other radicals present, for example by reduction with a metal hydride, or a similar active hydride reagent.

Thus, the reduction may be carried out, for example, using an alkali metal borohydride, for example sodium or potassium borohydride, preferably in a suitable solvent, for examole dimethyl formamide, and at a temperature in the range, for example, 10-1500C.

The necessary starting materials may be obtained by the processes described hereinbefore, or alternatively may be made by direct acylation or benzoylation of an appropriate compound of formula I using an acyl or benzoyl halide in the presence of a Friedel Craft catalyst.

(d) For a compound of formula I wherein one of A6, A7, A8 and A9 is a C1-6 alkylsulphinyl radical, oxidising a compound of formula I wherein one of A6, A7, A8 and A9 is a Cl~6-alkylthio radical.

The oxidation may be carried out by any known procedure for the production of sulphoxides, for example using hydrogen peroxide, a peracid, for example peracetic add or an alkali metal periodate, for example sodium or potassium periodate. The oxidising agent is preferably not present in large excess and the reaction temperature is generally best kept in the range, for example, 5-350C., in order to minimise sulphone formation. An inert solvent or diluent, for example, water, acetic acid or aqueous ethanol, is preferably also used.

As stated above, the pyrimido[1,2-a] benzimidazole derivatives of formula I possess the property of inhibiting the aggregation of blood platelets. This property may be demonstrated in vitro by adding a test compound to a stirred sample of citrate treated human, platelet-rich plasma, and measuring the effect of the test compound in delaying or reducing the aggregation of blood platelets caused by the addition of collagen or adenosine 5'-diphosphate. In this test, compounds of formula I markedly inhibit the aggregation of blood platelets at concentrations of 10-4 molar or less.

Thus, by way of illustration only, an equimolar mixture of 7- and 8 - acetyl3,4 - dihydropyrimido[1,2-a]benzimidazol - 2(1H) - one shows significant inhibition at a concentration of 10-6 molar.

Blood platelets when stored for several hours and then infused into an animal or man tend to lose most of their haemostatic activity. Compounds which inhibit the aggregation of blood platelets in vitro are therefore useful in helping to stabilise preparations of blood platelets and thus to preserve their haemostatic activity in vivo.

Such compounds may therefore usefully be added, for example, to whole blood for prolonged storage in blood-banks, to whole blood for circulation through isolated organs prior to their transplant or through heart-lung machines, and to suspensions of blood platelets prepared for use in the treatment of congenital or drug-induced thrombocytopenias.

The ability of compounds of formula I to inhibit the aggregation of blood platelets may also be demonstrated in vivo using standard tests in rats or mice in which thrombocytopenia has been produced. Thus for example a test compound is first dosed orally to rats and then, after several hours, adenosine 5'-diphosphate (ADP) (5 mg./kg.) is administered intravenously. After 15 seconds an arterial blood sample is taken and the blood platelet count is determined electronically using a Coulter counter. This count is then compared with the blood platelet count of an arterial blood sample taken immediately before the administration of the ADP. The administration of ADP produces a marked thromobocytopenia which is at its maximum after approximately 15 seconds. Compounds which inhibit this ADP-induced thiombo- cytopenia are considered to be active In a further standard test eight mice are dosed orally with a test compound.

After 4 hours four of the mice are injected intravenously with a solution of collagen (1 mg./kg.) in a diluent, and the remaining mice are injected with diluent only, so that they serve as a control group. After 1 minute, arterial blood samples are taken from each mouse in each group, and the blood platelet counts determined by standard means. Again, compounds which inhibit this collagen-induced thrombocytopenia are considered active.

The in vivo activity of any specific compound of formula I necessarily varies according to its precise chemical structure but, in general, compounds of formula I show activity in one or both of the above in vivo tests at a dose-of 100 mg./kg. - or less, and without any overt toxicity or adverse effects being observed at the active dose. Thus, by way of illustration only, an equimolar mixture of 7- and 8 - cyano 3,4 - dihydropyrimido[l,2-a] benzimidazol -- 2(1H) - one showed significant activity at an oral dose of 25 and 50 mg./kg. respectively in ADP-induced thermocytopenia, without any evidence of toxicity or adverse affects being observed.

Compounds which inhibit the aggregation of blood platelets in vivo have been used in the treatment of prophylaxis of thrombosis or occlusive vascular disease.

When used in vivo, a compound of formula I is conveniently administered in the form of a pharmaceutical composition comprising a compound of formula I - together with a pharmaceutically acceptable diluent or carrier. Such a composition is provided as a further feature of the invention and is, for example, conveniently in a form suitable for oral administration for example as a tablet, capsule, aqueous or oily suspension. Alternatively it may be in a form suitable for parenteral administration, for example, as a sterile injectable suspension.

Such compositions may be prepared by conventional methods using conventional excipients. A composition for oral administration should preferably contain from 50 mg. to 500 mg. per unit dose, and a composition for parenteral administration should preferably contain from 0.5 mg./ml. to 20 mg./ml. per unit dose; the more dilute compositions being useful for infusion rather than injection.

Compositions intended for use in the treatment or propylaxis of thrombosis or occlusive vascular disease may also contain one or more agents which can have a beneficial effect on the disease or on associated conditions, for example ticlopidine, clofibrate, sulfinpyrazone, dipyridamole, acetyl salicylic acid or methyl 4- Qamino- acetyl) phenoxyacetate.

When used to inhibit the aggregation of blood-platelets in warm blooded animals, a compound of formula I may be administered at a daily intravenous dose in the range of 0.2 mg./kg. to 5 mg./kg. Alternatively a compound of formula I may be administered at a daily oral dose in the range 5 mg./kg. to 20 mg./kg. The doses may be given more conveniently in divided form. In man these doses are equivalent to a total daily dose of from 25 mg. to 350 mg. by the intravenous route, or of from 0.35 g. to 1.4 g. by the oral route.

The invention is illustrated by the following non-limiting Examples in which: (i) All evaporations are carried out by rotary evaporation under reduced pressure unless otherwise stated; (ii) Unless otherwise stated, all operations were carried out at room temperature, that is at a temperature in the range 18-250C.; (iii) NMR spectra, unless stated otherwise, are for protons and were performed at 100MHz in hexadeuterodimethylsulphoxide (d6-DMSO) as solvent, using tetramethylsilane (TMS) as an internal standard; (i) TFA stands for trifluoroacetic acid; and (v) Yields, where given, are purely illustrative and are not to be construed as the maximum attainable.

Examples 1-3.

Methyl acrylate (15g.) was added to a solution of 2-amino-5,6-dimethylbenz imidazole (27.2g.) in ethanol (100ml.). After stirring for 2 days at room temperature, the crystalline precipitate which had formed in the reaction mixture was separated by filtration, washed with ethanol and then with ether, to give 7,8-dimethyl-3,4 dihydropyrimido [1,2-a]benzimidazol-2(1H)-one (37.2g.), m.p. 322-323 C.

In a similar manner, but using the appropriate 2-aminobenzimidazole of the formula:

and methyl acrylate (MA), there were obtained the following compounds of the formula:

Product IX Starting Materials Example Substituents Yield No. VIII (g.) MA (g.) on ring A I m.p. ( C.) | (g.) 0.9 0.5* 6,9-dimethyl 270-271 0.45 1.2 0.4' 7,8-di-isopropoxy 263-266 0.6 *reaction heated under reflux for 2 days in the absence of air, using a mixture of ethanol (10 ml.) and methanol (2 ml.) as solvent.

Those of the starting materials of formula VIII which are new were obtained as follows: (a) 2-amino-4,7-dimethylbenzimidazole (for Example 2).

A mixture (70.0g.) of p-xylene diamines (obtained by catalytic hydrogenation of the mixture of dinitro-p-zylenes formed on nitration of p-zylene) which contained approximately 60% of 3,6-dimethyl-1,2-diaminobenzene was converted to its mono- hydrochloride by addition of aqueous 2N hydrochloric acid (270ml.), followed by evaporation. A mixture of the monohydrochloride (86.2g.) in water (120ml.) was heated under reflux and a solution of cyanamide (23.1g.) in water (50ml.) was added to the boiling mixture during 20 minutes. After further heating under reflux for 1 hour, the reaction mixture was basified by addition of a solution of sodium hydroxide (20.8g.) in water (SOml.). The mixture obtained was then heated under reflux for 18 hours, and then cooled. The oil which formed, was separated by decantation and then triturated first with water (250ml.) and then with chloroform (3 x 1SOml.). The residual tar was partly dissolved in acetone (150ml.) and the solution obtained was purified by fractional chromatography on a column of silica gel (1.5kg.) using first methanol-chloroform (1:1 v/v), and then methanol as eluant.

Evaporation of the combined methanol fractions gave 2-amino-4,7-dimethyl-benzimidazole (13.9g.) which was further purified by recrystallisation from ethanol to give pure material (6.lg.), m.p. 164-1700C.

(b) 2-ammo5,6di-isopropoxybenzimidazole (for Example 3).

A solution of 1,2-diamino-4,5-di-isopropoxybenzene (2.24g.) in methanol (40ml.) was added to a mixture of cyanogen bromide (1.6g.) in water (40ml.). The mixture was stirred at 20-250C. for 70 hours and then basified by addition of an excess of aqueous ammonia solution (density 0.88). The mixture was then separated by filtration and the filtrate evaporated. The residue which was obtained was mixed with water (50ml.) and chloroform (50ml.). The chloroform phase was separated, dried (MgSO4) and evaporated. The residual gum obtained, wad purified by chromatography on a column of silica gel (40g.) using methanol-chloroform (1:3 v/v) as eluant, to give 2-amino-5,6-di-isopropoxybenzimidazole as a sticky solid (1.2g.), having characteristic absorption bands at v 3400, 3320, 3080, 1660 and 1565 cam~1, in the infrared (IR) spectrum).

Examples 4 and 5.

Using a similar procedure to that described in Example 1, there was obtained, from methyl acrylate (1.0g.) and 2-amino-5-chloro-6-methylbenzimidazole (1.7jg.), a 1:1 mixture (0.8g.) of 7-chloro-8-methyl-3,4-dihydropyrimido [1,2-a] benzimidazol- 2(1H)-one (Example 4) and 8-chloro-7-methyl-3,4-dihydropyrimido [1,2-a] benz- imidazol-2(1H)-one (Example 5). The mixture had m.p. > 3140C.

That the mixture was 1:1 was shown by the proton n.m.r. spectrum. The aromatic protons showed 4 signals 6 7.72(s), 7.59(s) and 7.60(s), 7.47(s) ppm in trifluoroacetic acid (TFA), relative to tetramethylsilane (TMS) as standard. The integration was the same for all the signals.

The 2-amino-5-chloro-6-methylbenzimidazole used as starting material was obtained in an analogous manner to that used for 2-amino-5,6-di-isopropoxybenzimidazole required for Example 3. Thus it was obtained as a solid (1.74g.) m.p.

240-2470C., from the reaction of cyanogen bromide (2.43g.) with 4-chloro-5-methyl- 1,2-diaminobenzene (2.4g.).

Examples 6 and 7.

Using a similar procedure to that described in Example 1, there was obtained from methyl acrylate 0.77g.) and 2-amino-5-methylthiobenzimidazole (1.45g.) a 1:1 mixture (0.9.g) of 7-methylthio-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)- one (Example 6) and 8-methylthio-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)- one (Example 7). The mixture had m.p. 234-2380C., and the Cia NMR spectrum (d4-acetic acid) showed 6 signals for the aromatic carbons at 8 108.9, 107.9, 116.0, 114.6 and 132.3, 130.9 ppm, relative to TMS as standard. The integration for each signal was the same.

The 2-amino-5-methylthiobenzimidazole used as starting material was obtained in analogous manner to that used for 2-amino-5,6-di-isopropoxybenzimidazole required for Example 3. Thus it was obtained as a solid (1.45g.), m.p. 195210 C., sufficientlye pure for further use, from the reaction of cyanogen bromide (2.06g.) with 4 methylthiol,2-diariinobenzere (2g.).

Examples 8-11.

Methyl acrylate (14.5g.) was added to 5-acetyl-2-aminobenzimidazole (26.6g.) in ethanol (200ml.). The solution was heated under reflux for 20 hours and the reaction mixture allowed to cool. The crystalline precipitate was separated by filtration and washed with ethanol and ether to give a solid (31.7g.) which was recrystallised from dimethylformamide (DMF) to give a 1:1 mixture of 7- and 8-acetyl-3,4 dihydropyrimido[ 1,2-a] benzimidaz diaminobenzonitrile (7.8g.) and cyanogen bromide (6.9g.), 2-amino-5-cyanobenzimidazole as a solid (8.lg.), m.p. 228-2330C., and of satisfactory purity.

(c) 2-Amino-5,6-methylenedioxybenzimidazole (for Example 12).

Cyanogen bromide (3.4g.) in water (60ml.) was added to 3,4-methylenedioxy-ophenylenediamine (3.8g.) in ethanol (60ml.) to give 2-amino-5,6-methylenedioxybenzimidazole (4.4g.) m.p. 23O-2430C.

Example 12.

5-Aceyl-2-amino-1-(2-cyanoethyl)-benzimidazole (1.2g.) was heated under reflux in ethanol (20ml.) containing potassium hydroxide (1.2g.) for 2 hours. The mixture was concentrated to low volume and water (20ml.) was added. The solution was acidified to pH 5 with acetic acid and kept at 40C. for 16 hours. The solid which formed was separated by filtration and dried by azeotropic distillation of a suspension in toluene to give 5-acetyl-2-amino- 1 - ( 2-carhoxyethyl ) benzimidazole (0.85g.) which was not characterised, but was heated at 250"C. for 5 minutes to give a tar, which was extracted with 3N-hydrochloric acid (3 x 10ml.). The acid extracts were basified by addition of an excess of saturated sodium carbonate solution to give a brown solid, which was washed with DMF, acetone and then ether to give 8-acetyl-3,4dihydropyrimido[1,2-a]benzimidazol-2(1H)-one (0.22g.), m.p. > 320 C; microanalysis: C12H11N3O2. 3/4 H2O requires C, 59.4; H, 5.1; N, 17.3%; found C, 59.3; H, 4.7; N, 17.0%; NMR: # 2.55 (S, 3 protons COCH3), 3.0 (t, 2-protons, C3-H2), 4.42 (t, 2 protons, C4-H2), 7.64 (d, 1 proton, C6-H), 7.95 (m, 1 proton, C7-H) and 8.05 (s, 1 proton CgH).

The 5-acetyl-2-amino-1-(2-cyanoethyl)benzimidazole used as starting material was obtained in the following manner: 4-Amino-3-nitroacetophenone (10.Og.), suspended in dioxan (25ml.) was treated, with stirring with choline hydrate (0.5ml of 45% solution in methanol) at 32"C.

Acrylonitrile (3.3g.) was added in portions at 320 C. and the temperature was raised to 50dC. and maintained at that temperature for 90 minutes. Ether (50ml.) was added to the thick reaction mixture. The solid was then separated by filtration to give 4- (2-cyanoethylamino ) -3 -nitroacetophenone, (11 .2g.), m.p. 138--142"C.

A solution of 4-(2-cyanoethylamino)-3-nitroacetophenone (10.2g.) in ethanol (200ml.) was hydrogenated over 10% w/w palladium-on-charcoal (1g.). 3N-Hydrochloric acid (50ml.) was added to the mixture after uptake of hydrogen was complete.

The mixture was then shaken, and separated by filtration. The filtrate was basified by addition of an excess of aqueous sodium carbonate solution. The precipitated solid obtained was separated by filtration, washed with water and then with acetone to give 4-(2-cyanoethylamino)-3-aminoacetophenone (6.2g.), m.p. 170-30 C., which was then dissolved in methanol (200ml.) and treated with cyanogen bromide (3.5g.). The mixture was stirred at room temperature overnight and then water (200ml.) and sodium carbonate solution was added to pH 7 to give 5-acetyl-2-amino-1-(2-cyanoethyl)benzimidazole (3.6g.) whose IR spectrum shows bands at v 3460, 3340, 2260, 1650, 1610 cm-1.

Example 13.

A 1:1 mixture of 7- and 8-acetyl-3,4-dihydropyrimido[1,2-a]benzimidazol- 2(111)-one, (1.5g.) was dissolved in boiling DMF (100ml.) and the solution seeded with a pure sample of 8-acetyl-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one (from Example 12). The solution was allowed to cool to room temperature whereupon two distinct crystal forms were deposited i.e. light crystals which were shown to be rich in the 8-acetyl isomer, and heavy crystals which were shown to be rich in the 7-acetyl isomer, in each case by NMR spectroscopic comparison with the authentic, 8-acetyl isomer. The two crystalline forms were separated by swirling the mixture and then removing the light crystals with the mother liquors by decantation. In this way a sample (A) (0.05g.) containing 80% 7-acetyl isomer was obtained. This sample (A) was then used to seed a crystallising solution of a fresh sample of the 1:1 mixture of 7- and 8-isomers (4.0g.) in boiling DMF (300ml.), which then gave crops of light crystals (B) and heavy crystals (C), which were separated by decantation. The light crystals (B) were then heated with their mother liquors, and the hot solution seeded with a sample of the pure 8-acetyl isomers, so that a further crop of light crystals (D) and heavy crystals (E) were obtained. The light crystals (D) were then again redissolved in their mother liquors and the solution again seeded with pure 8-isomer, so that a yet further crop of light crystals (F) and heavy crystals (G) was obtained.

The heavy crystal crops C, E and G were combined and recrystallized twice (without seeding) from boiling DMF to give 7-acetyl-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one (0.65g.), m.p. > 320 C.; microanalysis, found C, 62.4; H, 4.8; N, 17.9%; C12H11N3O2 requires C, 62.9; H, 4.8; N, 18.3%; NMR (in TFA solution): # 2.87 (s, 3 protons, COCH3), 3.42 (t, 2 protons, C3H2, 4.75 (t, 2 protons, C4-H2), 7.84 (d, 1 proton, C9-H), 8.32 (d, 1 proton, C8-H), 8.40 (s, 1 proton, C6-H).

Similarly recrystallisation of light crystal crop F from boiling DMF gave a sample of 8-acetyl-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one having identical physical properties to those described in Example 12.

Example 14.

Sodium borohydride (0.4g.) was added to a 1:1 mixture of 7- and 8-acetyl-3,4dihydropyrimido[1,2-a] benzimidazo-2(1H)-one (2.3g.) in DMF (10ml.). The mixture was heated at 100 C. for 30 minutes, and then evaporated. Water (100ml.) was then added and the solution was neutralised with acetic acid, and then heated to 100 C. for 30 minutes. The suspension obtained was then cooled to 5 C. and the solid separated by filtration, washed with cold water, acetoneand then ether to give a 1:1 mixture of 7- and 8-(1-hydroxyethyl)-3,4-dihydropyrimido [1,2-a] benzimidazol2(1H)-one (1.4g.). This material was purified by solution in boiling methanol (100ml.) followed by concentration to 30ml. to give 8-(1-hydroxyethyl)pyrimido[1,2-a]benzimidazol-2[1H]-one (0.4g.) m.p. 270-8 C,; microanalysis, C12H13N3O2 requires: C, 62.3; H, 5.6; N, 18.2%; found: C, 62.1; H, 5.6; N, 17.9%. The NMR spectrum shows a signal at 8 7.38 (s, 1 proton, C9-H).

The mother liquors from the above crystallisation slowly deposited a mixture of 8- and 7-(1-hydroxyethyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one (0.74g.), mp 247-252 C. This mixture was shown by NMR spectroscopy to contain 60 parts of the 8-isomer to 40 parts of the 7-isomer by comparing the integration of their respective signals for C4-H at 8 4.24(t) and 4.23(t) respectively.

Examples 15-is.

Using a generally similar procedure to that described in Example 8 the following compounds of formula I were obtained from the appropriate 2-aminobenzimidazole and methyl acrylate (MA) in yields of 70-90%:- (Example 15) - a 1:1 mixture of 7- and 8-butyryl-3,4-dihydropyrimido [1,2-a]- benzimidazol-2(1H)-one; obtained as a solid, m.p. 287-3000C., [crystallised from dimethyl formamide (DMF)]; microanalysis; C14H15N3O2 requires: C, 65.4; H, 5.8; N, 16.3%; found: C, 65.0; H, 5.9; N, 16.2%; NMR (TFA) shows 2 equal triplets (C4-H2) at # 4.66 and 4.70; by heating 5-butyryl-2-aminobenzimidazole with MA in ethanol under reflux for 72 hours; (Example 16) - 1:1 mixture of 7- and 8-(p-chlorobenzoyl) -3,4-dihydropyrimido[1,2-a]benzimidazo-2(1H)-one; obtained as a solid, m.p. 315-3250C:; microanalysis; CigH1aNaOCl requires: C, 62.7; H, 3.7; N, 12.9; Cl, 10.9%; found: C, 62.2; H, 3.5; N, 12.4; Cl, 10.8%; NMR (TFA): ss 3.30 (t, 2 protons, C3-Ha); 4.60 (t, 2 protons, C4-H2); 7.71 (s, 1 proton, C6-H); 7.86 (s, 1 proton, C9-H); by heating 5-(p-chlorobenzoyl)-2-aminobenzimidazole with MA in methanol under reflux for 16 hours; (Example 17) - 7,8-dichloro-3,4-dihydropyrimido [1,2-a]benzimidazol-2(1H)one; obtained as solid, m.p. > 345 C.; microanalysis, C10H7N3OCl2 requires: C, 46.9; H, 2.7; N, 16.4%; found: C, 46.9; H, 2.8; N, 16.4%; by heating 5,6-dichloro-2-aminobenzimidazole with MA in ethanol under reflux for 72 hours.

(Example 18) - a 49:1 mixture of 8,9- and 6,7-dimethyl-3,4-dihydropyrimido [1,2-a]benzimidazol-2(1H)-one; obtained as a solid, m.p. 240-244 C. (recrystallised from ethanol; microanalysis, C12H13N3O.1/4H2O requires: C, 65.5; H, 6.2 N, 19.1%; found: C, 65.5; H, 6.2; N, 19.0%; NMR (TFA) shows two triplets at # 4.42 (C4-H2 of 8,9-isomer) and 4.10 (C4-H2 of 6.7-isomer) in the ratio of 49:1 respectively; by treating 4,5-dimethyl-2-aminobenzimidazole with MA in ethanol at room temperature.

The necessary 2-aminobenzimidazole starting materials of formula VIII were obtained in a similar manner to that described in Example 8 for 5-acetyl-2-aminobenzimidazol-2(1H)-one, but starting with the appropriate 2-nitroaniline:

Starting Material for Yield Example Substituent on ring A % mep. oC.

15 5-butyryl 59 ' 235-240 16 5-(p-chlorobenzoyl) 63 235-240 17 5,6-dichloro 55 259-262 18 4;5-dimethyl 26 216-220 Example 19.

2-Amino-5-benzoylbenzimidazole (2.37g.) and methyl methacrylate (l.lg.) were heated under reflux in ethanol (20ml.) for 72 hours. More methyl methacrylate (0.8g.) was added and the reaction mixture was heated for a further 6 days. The mixture was cooled to room temperature and the solid - which deposited was collected by filtration and washed with ethanol and ether-to give a 1:1 mixture of 7- and 8-benzoyl 3,4 - dihydro - 3 - methylpyrimido [1,2-a] benzimidazol - 2(1H) - one (1.4g.), m.p.

296-321 C.; microanalysis, C18H16N3O2 requires: C, 70.8; H, 4.9; N, 13.8%; found: C, 70.4; H, 4.9; N, 13.6%; NMR (TFA) shows two doublets (C3-H) at # 4.84 and 4.93 of equal intensity.

Example 20.

2-Amino-5-benzoylbenzimidazole (2.4g.) and ethyl crotonate (1.25g.) were heated under reflux in butan-1-ol (20ml.) for 4 days. On cooling the mixture a solid separated which was recrystallised from ethanol to give a solid (0.5g.) which was shown by NMR to be a Z:I mixture of 7- and 8-benzoyl-3,4-dihydro-4-methylpyrimido [1,2-a]- benzimidazol-2(1H)-one. Evoparation of the liquors of crystallisation gave a 1:1 mixture of 7- and 8-benzoyl-3,4-dihydro-4-methylpyrimdio[1,2-a]-benzimidozol-2(1H)one (1.35g.), m.p. 250-270 C.; microanalysis, C18H15N3O2 requires: C, 70.8; H, 4.9; N, 13.8%; found: C, 71.0; H, 5.2; N, 13X9%; NMR shows two doublets (CI-CHa) at 6 1.25 and 1.31 of equal intensity.

Example 21.

A solution of 3-(2-amino-5-benzoylbenzimidazol-1-yl)-propionic acid (6.1g.) in methanol (30ml.) was treated with a saturated solution (30 ml.) of hydrogen chloride in methanol. The mixture was left at room temperature for 16 hours and then evaporated. The residue was dissolved in water. The solution obtained was adjusted to pH 8.5 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 50ml.). The extracts were dried (MgSO4) and evaporated to give methyl 3-(2 amino-5-benzoylbenzimidazol-1-yl)propionate as an oil. This oil was dissolved in methanol (60ml.) and the solution heated at reflux for 5 hours. The solid which precipitated was collected and washed successively with methanol, acetone and then ether to give 9-benzoyl-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (3.4g.), m.p.

323-330 C., microanalysis, C17H13N3O2 requires: C, 70.1; H, 4.5; N, 14.4%; found: C, 69.9; H, 4.4; N, 14.0%.

The starting material was obtained as follows: 4-Chloro-3-nitrobenzophenone (lOg.) was added to a mixture of 3-aminopropionic acid (ss-alanine) (10.lg.) and sodium hydrogen carbonate (9.6g.) in 2methoxyethanol (lOomi.) which was then heated under reflux for 4 hours. The mixture was cooled, poured into ice-water (250ml.) and brought to pH 3 by addition of concentrated hydrochloric acid. The solid obtained was filtered, washed with water and air-dried to give 3-(4-benzoyl-2-nitroanilino)propionic acid (12.lg.), m.p. 170-50C.

This acid (10g.) was dissolved in ethanol (100ml.) and hydrogenated in the presence of 10% w/w palladium-carbon (0.6g.) until uptake of hydrogen ceased.

Water (100ml.) and cyanogen bromide (3.72g.) was then added. After 16 hours at rcom temperature the mixture was evaporated. Water (50ml.) was added to the residue. The aqueous phase was separated from tarry material by decantation, and adjusted to pH 4 with concentrated aqueous ammonia to give 3-(2-amino-5-benzoylbenzimidazol-1-yl)propionic acid as a solid (6.1g.), m.p. 325,330 C.

Example 22.

Using a similar procedure to that described in Example 21, 8 - cyano - 3,4 - dihydropyrimido[1,2-a]benzimidazol - 2(1H) - one was obtained as a solid in essentially quantitative yield m.p. > 340 C., (microanalysis, C11H8N4O requires: C, 62.3; H, 3.8; N, 26.4%; found C, 61.8; H, 3.7; N, 26.0;) by thermal cyclisation of the methyl ester of 3 - (5 - cyano - 2 - aminobenzimidazol - 1 - yl)propionic acid, itself obtained as an oil of satisfactory purity by esterification of the propionic acid with methanolic hydrogen chloride.

The starting 3 - (5 - cyano - 2 - aminobenzimidazol - 1 - yl)propionic acid was prepared in a similar manner to the analogous starting material in Example 21 as a solid, m.p. > 320 C., of satisfactory purity, from 3 - (4 - cyano - 2 - nitroanilino)propionic acid, itself obtained as a solid, m.p. 200-205 C., by reaction of ss-alanine with 4-chloro-3-nitrobenzonitrile.

Example 23.

Using a similar procedure to that described in Example 1, there was obtained from methyl acrylate (2.8g.) and 2 - amino - 5 - ethylthiobenzimidazole (6.3g.), a 1:1 mixture (3.1g.) of 7- and 8 - ethylthio - 3,4 - dihydropyrimido [1,2 - a]benzimidazol - 2(1H) - one, m.p. 185-186 C.; NMR shows two tripiets (C4-H2) at # 4.22 and 4.23 of equal intensity.

The necessary, starting benzimidazole was obtained as follows:- Sodium (2.76g.) was added to dry 2-methoxyethanol (75 ml.) and the solution was cooled to 0-50C. Ethanethiol (8.72g.) in 2-methoxyethanol (lOml.) was added during 5 minutes and the subsequent solution was stirred at 0-50C. for 10 minutes and then added in portions to a solution of 5-chloro-2-nitro acetanilide (21.5g.) in boiling 2-methoxyethanol (150ml.) during 10 minutes. After 3 hours the mixture was cooled and poured into water (1 1.). The mixture was stirred and cooled to 100C.

The solid which formed was collected by filtration, washed with water, and recrystallised from ethanol to give 5-ethylthio-2-nitroaniline (16.4g.), m.p. 75-6 C.

A solution of 5-ethylthio-2-nitroaniline (8.2g.) in ethanol (100ml.) was hydrogenated over 10% w/w palladium carbon (0.8g.). Water (75ml.) was added to the mixture, maintained under an atmosphere of nitrogen, followed by cyanogen bromide (8.7g.) over a period of 10 minutes. After 3 days stirring at room temperature, the mixture was filtered and the filtrate was concentrated to a low volume. Water (75ml.) was added followed by 10% w/v sodium carbonate solution to adjust the pH to 8.

The solid which precipitated was collected by filtration, washed with water, air dried and then triturated with acetone to give 2-amino-5-ethylthiobenzimidazole (6.3g.), having characteristic absorption bands at v 3440, 3360, 1660, 1645 and 1560-1, in the IR spectrum.

Example 24. m-Chloroperbenzoic acid (1.03g.) was added to a solution of a 1:1 mixture of 7- and 8 - ethylthio - 3,4 - dihydropyrimido[1,2 - a]benzimidazol - 2(1H) - one (1.23g.) in methanol (150ml.) at 0-5 C. After 30 minutes, the mixture was evaporated to low volume. The solid obtained was separated by filtration and washed with methanol and ether to give a 1:1 mixture of 7- and 8 - ethylsulphinyl - 3,4 - dihydropyrimido[1,2 - a]benzimidazol - 2(1H) - one as its hemihydrate (0.95g.), m.p.

226-230 C.; microanalysis, C12H13N3SO2#H2O requires; C, 52.9; H, 5.1; N, 15.4%; found: C, 53.2; H, 5.0; N, 15.4%; NMR (TFA): # 1.38 (t, 3 protons, CH3); 3.38 (complex, 4 protons, C3-H2 and CH2SO); 4.71 [t, 2 protons, C4-H2 (7 isomer)]; 4.80 [t, 2 protons, C4-H2 (8 isomer)]; 7.90 (complex, 2 aromatic protons); 8.3 (s, 1 aromatic proton).

Example 25.

2 - Amino - 6,8 - dimethylbenzimidazole (2.6g.) and methyl acrylate (1.5g.) were stirred in ethanol (25ml.), at 25 C. for 5 days. The solid which formed was collected by filtration and washed with ethanol, acetone and ether to give a 9:1 mixture (2.1g.) of 7,9- and 6,8 - dimethyl - 3,4 - dihydropyrimido[1,2 - a]benzimidazol2(1H) - one, m.p. 326-32 C.; microanalysis, C12H13N3O requires: C, 67.0; H, 6.0; N, 19.5%; found: C, 66.7; H, 6.1; N, 19.5%; NMR shows 2 triplets (C4-H2) at S4.01 (7,9-isomer) and 4.32 (6,8-isomer) in the ratio of 9:1 respectively.

Example 26.

Methyl acrylate (6.1g.) was added to a solution of 2-amino-5,6-dimethoxybenz imidazole (12.2g.) in methanol (70ml.) and the mixture was stirred for 90 hours.

The crystalline precipitate was separated by filtration and washed with ethanol and then ether to give 7,8 - dimethoxy - 3,4 - dihydropyrimido[1,2 - a]benzimidazol2(1H) - one (10.3g.), m.p. 264-5 C; microanalysis, C12H13N3O2 requires: C, 58.3; H, 5.3; N, 17.0%; found: C, 58.0; H, 5.2; N, 16.8%; NMR: # 2.82 (t, 2 protons, C3-H2); 3.72 (s, 3 protons, CHaO); 3.76 (s, 3 protons, CHaO); 4.15 (t, protons C4-H2); 7.00 (s, 1 proton, C6-H); 7.04 (s, 1 proton, C9-H).

Example 27.

2-Amino-6,8-dimethylbenzimidazole (9.3g.) and methyl acrylate (5.3g.) were heated together in methanol (70ml.), under reflux for 4 hours. The crystalline precipitate which formed was filtered from the hot solution and washed with methanol to give a mixture of 7,9- and 6,8 - dimethyl - 3,4 - dihydropyrimido[1,2 - a]benzimidazole - 2(1H)one (2.4g.), m.p. 325-7 C., containing 98% of the 7,9-isomer as shown by NMR by comparison of the triplets for C4-H2 at # 4.01 ,7,9-isomer) and 4.32 (6,8-isomer).

Example 28.

A mixture of micro-crystalline cellulose (196 parts by weight) and finely divided 8 - acetyl - 3,4 - dihydropyrimido[1,2 - a]benzimidazol - 2(1H) - one (200 parts by weight) was sieved through a 30 mesh screen. Magnesium stearate (60 mesh particle size) (4 parts by weight) was added and, after thorough mixing the mixture was compressed into tablets, weighing 400mg. and containing 200mg. of active ingredient, which may be administered to man for therapeutic purposes.

In a similar manner tablets containing 150, 100 or SOmg. of active ingredient may be obtained The above active ingredient may be replaced by any compound of formula I described in any of Examples 1-11 or 13-27.

Claims (29)

WHAT WE CLAIM IS:-

1. A pyrimido[1,2-a]benzirnidazole derivative of the formula

wherein R1 is hydrogen, or a C1 C1-6-alkyl radical; R2 and R1, which may be the same or different, are hydrogen or C1-6-alkyl radicals; one, two or three of A6, A7, A8 and A9, which may be the same or different, are halogen atoms, C1-6-alkyl, C1-6-alkoxy, C2-6-alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radicals, or benzoyl radicals optionally substituted by a halogen atom, a C1-6-alkoxy or C1-6-alkyl radical, and the remainder of A6, A7, A8 and A9 are hydrogen; or an adjacent pair of A6, A7, A8 and A9 together constitute a C1-6-alkylenedioxy diradical, another of A6, A7, A8 and A9 is hydrogen, or is an atom or radical as defined above, and the remaining one of A6, A7, A8 and A9 is hydrogen; provided that when only one of A6, A7, A8 and A9 is a halogen atom, C1-6-alkyl or C1-6-alkoxy radical at least one of the remainder of A6, A7, A8 and A9 is other than hydrogen.

2. A compound as claimed in claim 1 wherein R1 is hydrogen or a methyl or ethyl radical; R2 and R3, which may be the same or different, are hydrogen or methyl or ethyl radicals; one, two or three of A6, A7, A8 and A9, which may be the same or different, are fluorine, chlorine or bromine atoms, methyl, ethyl, propyl, methoxy, ethoxy, i-propoxy, acetyl, propionyl, butyryl, hydroxymethyl, l-hydroxyethyl, 1hydroxypropyl, l-hydroxybutyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl or cyano radicals, or benzoyl radicals optionally substituted by a fluorine, chlorine or bromine atom, or by a methyl or methoxy radical and the remainder of A', A7, A8 and A9 are hydrogen; or an adjacent pair of A6, A7, A8 and A9 together constitute a methylenedioxy or isopropylidenedioxy radical, another of A6, A7, A8 and A9 is hydrogen, or is an atom or radical as defined above, and the remaining one of A', A7, A8 and A9 is hydrogen.

3. A compound as claimed in claim 1 wherein two of A6, A7, A8 and A9 are C1-6-alkyl or C1-6-alkoxy radicals, or a C1-6-alkyl radical and a halogen atom, or halogen atoms, or constitute a C1-6-alkylenedioxy diradical, and the remainder of A6, A7, A8 and A9 are hydrogen; or wherein one of A6, A7, A8 and A9 is a C2-6alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radical, or a benzoyl radical optionally substituted as defined in claim 1, and the remainder of A6, A7, A8 and A9 are hydrogen.

4. A compound as claimed in any one of claims 1 to 3 wherein two of A6, A7, A8 and A9 constitute a 6,7-, 7,8-, 8,9- or 6,9-dimethyl radical, a 7,8-dichloro, 7chloro-8-methyl, 7-methyl-8-chloro, 7,8-dimethoxy, 7-8-diisopropoxy or a 7,8methylenedioxy radical, and the remainder of A6, A', A8 and A9 are hydrogen; or wherein one of A6, A7, A8 and A9 is a 7- or 8-acetyl, -butyrl, -benzoyl, -(p-chloro)benzoyl, -methylthio, -ethylthio, -ethylsulphinyl, -cyano or -[1-(hydroxy)ethyl] radical, and the remainder of A6, A7, A8 and A9 are hydrogen.

5. A compound as claimed in claim 1 or 2 wherein one, two or three of A6, A7, A8 and A9, which may be the same or different, are halogen atoms, C1-6-alkyl, C1-6alkoxy, C1-6-alkylthio or cyano radicals and the remainder of A6, A7, A8 and A9 are hydrogen; or an adjacent pair of A6, A7, A8 and A9 together constitute a C1-6alkylenedioxy diradical another of A6, A7, A8 and A9 is hydrogen, or is an atom or radical as defined above, and the remaining one of A6, A7, A8 and A9 is hydrogen.

6. A compound as claimed in claim 1 or 2 wherein one , two or three of A6, A7, A8 and A9, which may be the same or different, are halogen atoms, C1-6-alkyl, C1-6alkoxy, C2-6-alkanoyl, 1(hydroxy)-C1-6-alkyl, C1-6-alkylthio or cyano radicals, or benzoyl radicals optionally substituted as defined in claim 1 or 2; and the remainder of A6, A7, A8 and A9 are hydrogen; or an adjacent pair of A6, A7, A8 and A9 together constitute a C1-6-alkylenedioxy radical, another of A6, A7, A8 and A9 is hydrogen, or an atom or radical as defined above, and the remaining one of A6, A7, A8 and A9 is hydrogen.

7. A compound as claimed in claim 1 or 2 wherein one of A5, A7, A9 and A9 is a halogen atom or a C1-6-alkyl or C1-6-alkoxy radical; another one or two of A6, A7, A8 and A9 is a halogen atom, or a C1-6-alkyl, C1-6-alkoxy, C2-6-alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radical, or a benzoyl radical optionally substituted as defined in claim 1, 2 or 4; or another adjacent pair of A6, A7, A8 and A9 together constitute a C1-6-alkylenedioxy diradical; and the remainder of A6, A7, A8 and A9 are hydrogen.

8. A compound as claimed in claim 1 or 2 wherein one, two or three of A6, A7, A8 and A9 are C2-6-alkanoyl, 1-(hydroxy)-C1-6-alkyl, C1-6-alkylthio, C1-6-alkylsulphinyl or cyano radicals, or benzoyl radicals optionally substituted as defined in claim 1, 2 or 4; or an adjacent pair of A6, A7, A8 and A9 together, constitute a C1-6-alkylenedioxy diradical; and the remainder of A6, A', A8 and A9 are hydrogen.

9. A compound as claimed in any one preceding claim wherein R1 is hydrogen.

10. A compound as claimed in any one of claims 1 to 8 wherein R1, R2, and R3 are hydrogen.

11. A compound as claimed in any one of claims 1, 2 or 4 wherein R1 is hydrogen, R2 and R3, which may be the same or different, are hydrogen or methyl radicals, at least two of A6, A7, A8 and A9 are hydrogen, and the remainder of A6, A7, A8 and A9 have any of the values other than hydrogen defined in claim 1, 2 or 4.

12. A compound as claimed in any one of claims 1, 2, or 4 wherein R1 is hydrogen, R2 and R3, which may be the same or different, are hydrogen or methyl radicals, A7 and one of A6, A8 and A9 have any of the values other than hydrogen defined in claim 1, 2 or 4, and the remainder of A6, A8 and A9 is hydrogen.

13. A compound as claimed in any one of claims 1, 2 or 4 wherein R1 is hydrogen, R2 and R3, which may be the same or different, are hydrogen or methyl radicals, A@ and one of A6, A' and A9 have any of the values other than hydrogen defined in claim 1, 2 or 4, and the remainder of A', A' and A9 are hydrogen.

14. A compound as claimed in any one of claims 1, 2 or 4 wherein Rl is hydrogen, R2 and R3, which may be the same or different, are hydrogen or methyl radicals, A7 and/or A8 have any of the values other than hydrogen defined in claim 1, 2 or 4, and the remainder of A6, A7, A8 and A9 are hydrogen.

15. A compound as claimed in any one of claims 11 to 14 wherein A7 or A8 is a cyano, acetyl, 1-(hydroxy)ethyl or benzoyl radical.

16. A compound as claimed in any one of claims 11 to 14 wherein A2 and A8 together constitute a methylenedioxy diradical, or are methoxy, ethoxy or isopropoxy radicals.

17. A compound selected from the group comprising 7-acetyl-, 8-acetyl-, 7benzovl-, 8-benzoyl-, 7-cyano-, 8-cyano-, 7,8-di-isopropoxy- and 7,8-methylenedioxy- 3,4-dihydropyrimido [1,2-al benzimidazol-2( 1H)-one, and 7-benzoyl-, and 8-benzoyl4-methyl-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one.

18. A process for the manufacture of a compound of formula I claimed in any one preceding claim which comprises:- (a) reacting a 2-amino-benzimidazole of the formula:

with an ethylenic acid derivative of the formula: R@-CH=CR2-CO-Z IV wherein Z is a halogen atom, or a C1-4-alkoxy radical; (b) cyclising a compound of the formula:

wherein Q is a hydroxy or C1-4-alkoxy radical; (c) for a compound of formula I wherein one of A6, A7, A8 and A9 is a 1 (hydroxy) -C16-alkyl radical, reducing a compound of formula I wherein one of A6, A', A8 and A9 is a C1-6-alkanoyl radical; or (d) for a compound of formula I wherein one of A', A7, A8 and A9 is a C1-,- alltylsulphinyl radical, oxidising a compound of formula I wherein one of A6, Av, A8 and A9 is a C1-6-alkylthio radical; and wherein R1, R2, R3, A6, A7, A8 and A9 have the meanings defined in any one preceding claim.

19. A process as claimed in part (a) of claim 18 wherein Z is chlorine or bromine atom or a methoxy or ethoxy radical and the reaction is carried out in an inert solvent or diluent at a temperature of 15 to 80"C.

20. A pharmaceutical composition which comprises a compound of formula I as claimed in any one of claims 1 to 17 together with a pharmaceutically acceptable diluent or carrier.

21. A composition as claimed in claim 20 in a form suitable for oral administration.

22. A composition as claimed in claim 20 in a form suitable for parenteral administration.

23. A composition as claimed in claim 21 which is in the form of a tablet, capsule, aqueous or oily suspensions.

24. A composition as claimed in claim 22 which is in the form of a sterile injectable suspension.

25. A composition as claimed in any one of claims 20 to 24 which contains in addition one or more agents selected from ticlopidine, clofibrate, sulfiinpyrazone, dipyridamole, acetyl salicylic acid or methyl 4-(aminoacetyl)phenoxyacetate.

26. A compound as claimed in claim 5 substantially as described in any one of Examples 1 to 7.

27. A compound as claimed in claim 6 substantially as described in any one of Examples 1 to 14.

28. A compound as claimed in claim 1 substantially as described in any one of Examples 1 to 27.

29. A composition as claimed in any one of claims 20 to 24 substantially as described in Example 28.