CH634845A5 - Pharmaceutically useful pyrimido(1,2-a)benzimidazole derivatives and corresponding preparations. - Google Patents

Abstract

The novel 3,4-tetrahydropyrimido(1,2-a)benzimidazole derivatives of formula: <IMAGE> which in the 6-, 7-, 8- or 9-position carry one or more substituents as specified in Claim 1, inhibit blood platelet agglutination. The invention also relates to preparations for the treatment or prophylaxis of thrombosis and of vascular occlusion disorders. <IMAGE>

Description

** WARNING ** Beginning of DESC field could overlap end of CLMS **.

PATENT CLAIMS 1. Pyrimido- [1s2-a] -benzimidazole derivatives of the formula:

wherein R2 and R3, which are identical or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms, one or two of A6, A7, A8 and A9, which are identical or different, halogen atoms, alkyl radicals having 1 to 6 carbon atoms, alkoxy radicals with 1 to 6 carbon atoms, alkanoyl groups with 2 to 6 carbon atoms, 1-hydroxyalkyl groups with 1 to 6 carbon atoms, alkylthio groups with 1 to 6 carbon atoms, alkylsulfinyl groups with 1 to 6 carbon atoms, cyano groups or benzoyl groups, while the rest of A6, A7, A5 and A9 are hydrogen, or an adjacent pair of A6, A7, A8 and A9 together form a divalent alkylenedioxy radical having 1 to 6 carbon atoms and the other pair of A6, A7, A8 and A9 is hydrogen, where if only one of the symbols A6 , A7, A8 and A9 denote a halogen atom, an alkyl radical having 1 to 6 carbon atoms or an alkoxy radical having 1 to 6 carbon atoms, at least one of the rest of A6, A 7, A8 and A9 is other than hydrogen.

2. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen, methyl or ethyl, one or two of A6, A7, A8 and A9, which are identical or different, fluorine, chlorine, Bromine, methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, acetyl, propionyl, butyryl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, cyano or benzoyl radicals mean, while the others of A6, A7, A8 and A9 are hydrogen, or an adjacent pair of A6, A7, As and A9 together are methylenedioxy or isopropylidenedioxy and the other pair of A6, A7, A8 and A9 are hydrogen.

3. Compounds according to claim 1, characterized in that two of A6, A7, A8, A9 6.7-, 7.8-, 8.9 or 6.9 dimethyl, 7,8-dichloro, 7-chloro-8- methyl, 7-methyl-8-chloro, 7,8-dirnethoxy, 7,8-diisopropoxy or 7,8-methylenedioxy mean, while the rest of A6, A7, A8 and A9 mean hydrogen, or one of A6, A7, A8 and A9 are 7- or 8-acetyl, butyryl, benzoyl, methylthio, ethylthio, ethylsulfinyl, cyano or -1-hydroxyethyl and the rest of A6, A7, A5 and A9 are hydrogen.

4. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, at least two of A6, A7, A8 and A9 are hydrogen and the rest of A6, A7, A8 and A9 are any have the meanings given in claim 1 with the exception of hydrogen.

5. Compounds according to claim 1, wherein R2 and R3, which are identical or different, are hydrogen or methyl radicals, A7 and one of A6, A8 and A9 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A8 and A9 represent hydrogen.

6. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, A8 and one of A6, A7 and A9 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A7 and A9 represent hydrogen.

7. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, A7 and / or A5 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A7, A8 and A9 mean hydrogen.

8. Compounds according to one of claims 4 to 7, characterized in that A7 or A8 denotes cyano, acetyl, 1-hydroxyethyl or benzoyl.

9. Compounds according to any one of claims 4 to 7, characterized in that A7 and A8 together denote methylenedioxy or denote methoxy, ethoxy or isopropoxy radicals.

10. As a compound according to claim 1, 7-acetyl, 8-acetyl, 7-benzoyl, 8-benzoyl, 7-cyano, 8-cyano, 7,8-diisopropoxy and 7,8-methylenedioxy -3, 4-dihydropyrimido- [1, 2-a] - benzimidazol-2 (1H) -one as well as 7-benzoyl- and 8-benzoyl-4-methyl3, 4-dihydropyrimido- [1, 2-a] -benzimidazole- 2 (1H) -one.

11. A pharmaceutical preparation, characterized in that it contains a compound of the formula 1 according to claim 1 together with a pharmaceutically acceptable diluent or carrier.

The present invention relates to novel pyrimido [1,2-a] benzimidazole derivatives which inhibit platelet agglutination.

Various 3,4-tetrahydropyrinudo [1,2-a] -benzimidazole derivatives have been described as diuretically active compounds (US Pat. No. 4,167,569). It has now surprisingly been found that certain 3,4-tetrahydropyrimido [1,2-a] benzimidazole derivatives which are structurally related to the above are able to inhibit the agglutination of blood platelets without, however, exhibiting any noteworthy diuretic properties.

The pyrimido [1, 2-a] benzimidazole derivatives according to the invention correspond to the formula:

wherein R2 and R3, which are identical or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms, one or two of A6, A7, A8 and A9 which are identical or different, halogen atoms, alkyl radicals having 1 to 6 carbon atoms, alkoxy radicals with 1 to 6 carbon atoms, alkanoyl groups with 2 to 6 carbon atoms, 1-hydroxyalkyl groups with 1 to 6 carbon atoms, alkylthio groups with 1 to 6 carbon atoms

atoms, alkylsulfinyl radicals with 1 to 6 carbon atoms, cyano groups or benzoyl radicals mean, while the rest of A6, A7, A8 and A9 mean hydrogen, or an adjacent pair of A6, A7, A8 and A9 together form a divalent alkylenedioxy radical with 1 to 6 carbon atoms and the other pair of A6, A7, A8 and A9 is hydrogen, if only one of the symbols A6, A7, A8 and A9 is a halogen atom, an alkyl radical having 1 to 6 carbon atoms or an alkoxy radical having 1 to 6 carbon atoms, at least one of the rest of A6, A7, A8 and A9 is other than hydrogen.

It can be seen that the compounds of the formula I are derivatives of 3,4-dihydropyrimido [1,2-a] benzimidazol-2 (1H) -one, which ring system is numbered throughout the present description as it is in the following Formula:

is shown.

It can be seen that the compounds of the formula I in which R 1 is hydrogen can exist in various tautomeric forms, one of which is shown in formula II. It goes without saying that the structural designations used in this description and the nomenclature used in this description relate to the most likely and predominant tautomeric form, but that the invention also includes compounds of the formula I in which R 1 is hydrogen, which are in any tautomeric form In the form or as a mixture of such forms.

It can also be seen that, depending on the nature of the substituents R2 and R3 and the substituents A6, A7, As and A9, a compound of the formula I can contain one or more asymmetric carbon atoms and can therefore be isolated in racemic forms or optically active forms. This description relates to any racemic or optically active forms of a compound of Formula I which have the above useful properties; it is known how to obtain an optically active form, e.g. by resolution of a racemic form or by synthesis from an optically active starting material, and how one can determine the biological properties of the optical isomers by the test described below.

A special meaning for one of the symbols R1, R2 and R3 when it denotes an alkyl radical having 1 to 6 carbon atoms is e.g. Methyl or ethyl.

Special meanings for the symbols A6, A7, A8 and A9 are given as an example: If it is a halogen atom: fluorine, chlorine or bromine; if it is an alkyl radical with 1 to 6 carbon atoms: methyl, ethyl or propyl; if it is an alkoxy radical with 1 to 6 carbon atoms: methoxy, ethoxy or isopropoxy; if it is an alkanoyl radical with 2 to 6 carbon atoms: acetyl, propionyl or butyryl; if it is a 1-hydroxyalkyl radical having 1 to 6 carbon atoms: hydroxymethyl or a 1-hydroxyalkyl radical having 2 to 6 carbon atoms, e.g. 1-hydroxyethyl, 1-hydroxypropyl or 1-hydroxybutyl; if it is an alkylthio radical having 1 to 6 carbon atoms: methylthio or ethylthio; and if it is an alkylsulfinyl radical having 1 to 6 carbon atoms: methylsulfinyl or ethylsulfinyl.

Specific meanings for specific substituents which can be present on the benzene ring of a benzoyl radical when one of the symbols A6, A7, A8 and A9 represents such a radical are merely for example: if it is a halogen atom: fluorine, chlorine or bromine; if it is an alkyl radical having 1 to 6 carbon atoms: methyl; and if it is an alkoxy radical having 1 to 6 carbon atoms: methoxy.

A specific meaning for a divalent alkylenedioxy radical having 1 to 6 carbon atoms when an adjacent pair of the symbols A6, A7, A8 and A9 forms such a radical is e.g. Methylenedioxy or isopropylidenedioxy.

Particularly suitable arrangements of meanings of the symbols A6, A7, A8 and A9 are e.g. those in which two of these symbols are alkyl radicals having 1 to 6 carbon atoms or alkoxy radicals having 1 to 6 carbon atoms or an alkyl radical having 1 to 6 carbon atoms and a halogen atom or halogen atoms or a divalent alkylenedioxy radical having 1 to 6 carbon atoms and the remainder of these symbols are hydrogen means or in which one of these symbols is an alkanoyl radical with 2 to 6 carbon atoms, a 1-hydroxyalkyl radical with 1 to 6 carbon atoms, an alkylthio radical with 1 to 6 carbon atoms, an alkylsulfinyl radical with 1 to 6 carbon atoms or cyano or a benzoyl radical, optionally as above is defined substituted, while the rest of these symbols mean hydrogen.

Specific suitable arrangements of meanings of the symbols A6, A7, A8 and A9 are e.g. those in which two of these symbols are 6,7-, 7,8-, 8,9- or 6,9-dimethyl, 7,8-dichloro, 7-chloro-8-methyl, 7-methyl-8-chloro, 7,8-dimethoxy, 7,8-diisopropoxy or 7,8-methylenedioxy mean and the remainder of these symbols mean hydrogen or in which one of these symbols 7- or 8-acetyl, -butyryl, -benzoyl, -p-chlorobenzoyl, - Methylthio, ethylthio, ethylsulfinyl, cyano or -1 hydroxyethyl and the remainder of these symbols denote hydrogen.

It will be appreciated that the above general definition encompasses various specific and individual compounds of the invention, namely those compounds of the formula I in which one of the symbols R1, R2, R3, A6, A7, A8 and A9 has one of the special or specific meanings defined above and the remainder of these symbols have any of the general, special, or specific meanings defined. However, specific groups of compounds of formula I which are of particular interest include those compounds of formula I wherein (1) R1 is hydrogen; (2) Rl is an alkyl radical having 1 to 6 carbon atoms, in particular methyl or ethyl; (3) R1, R2 and R3 all represent hydrogen; ; (4) one of the symbols A6, A7, A8 and A9 denotes a halogen atom or an alkyl group with 1 to 6 carbon atoms or an alkoxy group with 1 to 6 carbon atoms, another or two more of the symbols A6, A7, A8 and A9 denotes a halogen atom, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, an alkanoyl group with 2 to 6 carbon atoms, a 1-hydroxyalkyl group with 1 to 6 carbon atoms, an alkylthio group with 1 to 6 carbon atoms, an alkylsulfinyl group with 1 to 6 carbon atoms, Cyano or a benzoyl radical, which is optionally substituted as defined above, or a further adjacent pair of the symbols A6, A7, A8 and A9 together mean a divalent alkylenedioxy radical having 1 to 6 carbon atoms and the remainder of the symbols A6, A7, A8 and A9 is hydrogen; (5) one, two or three of the symbols A6, A7, A8 and A9 alkanoyl radicals with 2 to 6 carbon atoms, 1-hydroxyalkyl radicals with 1 to 6 carbon atoms, alkylthio radicals with 1 to 6 carbon atoms, alkylsulfinyl radicals with 1 to 6 carbon atoms, cyano groups or benzoyl radicals , which are optionally substituted as defined above, or an adjacent pair of the symbols A6, A7, A8 and A "together form a divalent alkylenedioxy radical having 1 to 6 carbon atoms and the rest of the symbols A6, A7, As and A9 are hydrogen; and in each case the remainder of the symbols A6, A7, A8, A9, R1, R2 and R3 have any of the above general, special or specific meanings.

Further specific groups of compounds according to the invention which are particularly preferred include those compounds of the formula I in which (a) R2 is hydrogen, R2 and R3, which are identical or different, are hydrogen or methyl groups, at least two of the symbols A6, A7, A8 and A9 are hydrogen and the rest of the symbols A6, A7, A8 and A9 have any of the meanings defined above other than hydrogen; (b) Rl, R2 and R3 have the meanings defined above under (a), A7 and one of the symbols A6, A8 and A9 have any of the meanings defined above with the exception of hydrogen and the remainder of the symbols A6, A5 and A9 mean hydrogen ;; (c) Rl, R2 and R3 have the meanings defined above under (a), A8 and one of the symbols A6, A7 and A9 have any of the meanings defined above with the exception of hydrogen and the rest of the symbols A6, A7 and A9 mean hydrogen ; (d) Rl, R2 and R3 have the meanings defined above under (a), A7 and / or A8 have any of the meanings defined above with the exception of hydrogen and the rest of the symbols A6, A7, A5 and A9 mean hydrogen.

Further groups of preferred compounds include those compounds which are defined in any of the above groups (a) to (d), in which furthermore (i) A7 or As is cyano, acetyl, 1-hydroxyethyl or benzoyl; or (ii) A7 and A8 together represent a divalent methylenedioxy radical, ethoxy or isopropoxy.

Specific compounds according to the invention are described in the examples, but specific preferred compounds are 7- and 8-acetyl-, 7- and 8-benzoyl-, 7- and 8-cyano-, 7,8-diisopropoxy- and 7,8-methylenedioxy- 3, 4-dihydropyrimido [1,2-a] -benzimidazol-2 (1H) -one and 7- and 8-benzoyl-4-methyl-3,4-dihydropyrimido- [1,2-a] -benzimidazole- 2 (1H) -one.

The compounds according to the invention can be obtained by any known general method for the synthesis of malogenic compounds. Processes of this kind are explained below, where R1, R2, R3, A6, A7, A8 and A9 have any of the meanings defined above: (a) Reaction of a 2-aminobenzimidazole of the formula:

with an ethylene derivative of the formula: R3-CH = CRZ-Co-Z II wherein Z is a halogen atom, e.g. Chlorine or bromine, or an alkoxy radical containing 1 to 4 carbon atoms, e.g. Methoxy or ethoxy.

The reaction can be carried out in an inert solvent or diluent, e.g. Methanol, ethanol, acetone, tetrahydrofuran or acetonitrile, and by heating, e.g.

to the reflux temperature of the reaction mixture. However, the reaction is preferably carried out at a temperature of 15 to 80 ° C., for example.

If a compound of the formula IV in which Z is a halogen atom is used, a suitable base, e.g. a tertiary amine such as triethylamine may be present.

The starting materials of the formula m can be obtained by standard methods used in benzimidazole chemistry. When Rl is hydrogen, the starting materials can thus be prepared analogously to 2-alninobemiimidazole, e.g. by converting a 1,2-diaminobenzene of the formula:

with cyanamide or cyanogen bromide or chloride, optionally in the presence of a base. When Rl is an alkyl radical, the starting materials can be obtained analogously to 2-methylaminobenzimidazole, e.g. by reacting an alkylamine with a 2-bromo- or 2-chlorobenzimidazole, which in turn is useful e.g. by reacting a compound of the formula V with urea and subsequent customary halogenation with phosphorus oxybromide or oxychloride. If Rl is an alkyl radical, the starting materials of the formula III can be prepared by reacting a compound of the formula V with a corresponding N-alkylcyanamide in the presence of base getting produced.

It will be appreciated that when the benzene ring A is asymmetrically substituted, process (a) generally provides a mixture of positional isomers. These isomers can be prepared by conventional methods of organic chemistry, e.g.

by fractional crystallization from a suitable solvent.

(b) Cyclization of a compound of the formula:

wherein Q is hydroxyl or an alkoxy radical having 1 to 4 carbon atoms.

The cyclization is preferably carried out thermally by heating a compound of formula VI to a temperature in the range of e.g. 50 to 250 "C. An inert solvent or diluent, e.g. methanol, dimethylformamide or diphenyl ether, can conveniently be present.

If Q is an alkoxy radical having 1 to 4 carbon atoms, the reaction can also conveniently be carried out in the presence of a base, e.g. Sodium ethylate or methylate, preferably in a suitable solvent or diluent, e.g.

Ethanol or methanol, and at a temperature in the range of e.g. 50 to 250 "C.

If Q is hydroxyl, the cyclization can also in Presence of a dehydrating agent, e.g. a strong one Mineral acid, such as polyphosphoric acid, or a carbodiimide, such as dicyclohexylcarbodiimide, and expediently in the presence of a suitable solvent or diluent, e.g. in the case of a carbodiimide of chloroform, and at a temperature in the range of e.g. 15 to 100 "C.

The starting materials of the formula VI can be obtained, starting from an appropriately substituted o-nitroaniline, by conventional processes, as described, for example, in the examples and in Scheme 1 below.

Reagents: (a ') base, e.g. a quaternary ammonium hydroxide (b ') hydrogen and palladium on carbon (c') CN-Br (for Rl = hydrogen) or an alkylcyanamide (for Rl = alkyl), then a strong base, e.g.

Sodium hydroxide (d ') aqueous strong base, e.g. Sodium hydroxide Alternatively and expediently, a correspondingly substituted o-nitro-chloro- or -bromobenzene can be used with a 3-aminopropionic acid of the formula:

are reacted, conveniently at a temperature in the range from 50 to 150 "C and preferably in a solvent or diluent, e.g. 2-methoxyethanol, and in the presence of an acid acceptor, e.g. sodium hydrogen carbonate. This produces an intermediate of the formula:

behavior that can be used in Scheme 1 above.

The starting materials of the formula VI can conveniently be prepared and used in situ without separate isolation and purification in process (b).

A special advantage of process (b) is that, in contrast to process (a) above, it does not produce any positional isomers if the benzene ring of the benzimidazole grouping of a compound of the formula VI is asymmetrically substituted.

(c) Reduction of a compound of the formula I in which at least one of the symbols A6, A7, A8 and A9 is an alkanoyl radical having 1 to 6 carbon atoms, for the preparation of compounds of the formula I in which at least one of the symbols A6, A7, A8 and A9 denotes a 1-hydroxyalkyl radical having 1 to 6 carbon atoms.

The reduction can be carried out by any known method that is compatible with the other residues present, e.g. by reduction with a metal hydride or similar active hydride.

Thus the reaction can e.g. using an alkali metal borohydride such as sodium or potassium borohydride, preferably in a suitable solvent, e.g. Dimethylformamide, and at a temperature in the range of e.g. 10 to 150 "C.

The required starting materials can be obtained by the processes described above or else by direct acylation or benzoylation of a corresponding compound of the formula I using an acyl or benzoyl halide in the presence of a Friedel Crafts catalyst.

(d) Oxidation of a compound of the formula I in which at least one of the symbols A6, A7, A8 and A9 is an alkylthio radical having 1 to 6 carbon atoms, for the preparation of compounds of the formula I in which at least one of the symbols A6, A7, A8 and A9 denotes an alkylsulfinyl radical having 1 to 6 carbon atoms.

The oxidation can be carried out by any known method for the preparation of sulfoxides, e.g. using hydrogen peroxide, a peracid such as peracetic acid, or an alkali metal periodate such as sodium or potassium periodate. The oxidizing agent is preferably not present in large excess, and the reaction temperature is generally best kept in the range, for example, from 5 to 35 ° C. in order to keep sulfone formation to a minimum. An inert solvent or diluent, for example water, is also preferably used. Acetic acid or aqueous methanol is used.

As indicated above, the pyrimido- [1,2-a] -benzimidazole derivatives of the formula I have the property of inhibiting platelet agglutination. This property can be demonstrated in vitro by adding a test compound, with stirring, to a sample of citrated human platelet-rich plasma and the action of the test compound to delay or reduce platelet agglutination caused by the addition of collagen or adenosine 5'-diphosphate , measures. In this test, compounds of the formula I inhibit platelet agglutination at concentrations of 10-4 molar or less.

It should only be stated for explanation that an equimolar mixture of 7- and 8-acetyl-3,4-dihydropyrimido [1,2-a] -benzimidazol-2 (1H) -one at a concentration of 10-6 molar one shows significant inhibition.

When platelets are stored for several hours and then infused into an animal or human, they tend to lose most of their hemostatic activity. Compounds which inhibit platelet agglutination in vitro are therefore useful to help stabilize platelet preparations and thereby maintain their hemostatic activity in vivo.

Such compounds can therefore conveniently be added to whole blood for longer storage in blood banks, whole blood for circulation through isolated organs before their transplantation or through heart-lumbar machines and to suspensions of blood platelets for the treatment of congenital or drug-induced thrombocytopenia are prepared, are added.

The ability of the compounds of formula I to inhibit platelet agglutination can also be demonstrated in vivo using standard tests in rats or mice in which thrombocytopenia has been produced. Thus e.g. a test compound is first administered orally to rats, followed by intravenous administration of 5 mg / kg of adenosine 5'-diphosphate after several hours. After 15 seconds, an arterial blood sample is drawn and the platelet count is determined electronically using a Coulter counter. This number is then compared to the platelet count in an arterial blood sample taken immediately prior to the administration of the adenosine 5'-diphosphate. Administration of adenosine 5'-diphosphate produces pronounced thrombocytopenia which peaks in approximately 15 seconds. Compounds that inhibit this adenosine 5'-diphosphate induced thrombocytopenia are considered active.

Another standard test is to give 8 mice orally a test compound. After 4 hours, 4 of the mice are injected intravenously with a solution of collagen (1 mg / kg) in a diluent, while the remaining mice are only injected with the diluent so that they serve as a comparison group. After one minute, arterial blood samples are taken from each mouse in each group and the platelet counts are determined using standard methods.

Again, compounds that inhibit this collagen induced thrombocytopenia are considered active.

The activity of any specific compound of formula I in vivo will necessarily vary depending on its precise chemical structure, but in general compounds of formula I will show activity in either of the above in vivo tests or both at a dose of 100 mg / kg or less, without any apparent toxicity or adverse effects being observed at the effective dose. For the sake of explanation, an equimolar mixture of 7- and 8-cyano-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one at an oral dose of 25 or 50 mg / kg in adenosine 5'-diphosphate-induced and collagen-induced thrombocytopenia showed significant activity with no evidence of toxicity or adverse effects observed.

Compounds that inhibit platelet agglutination in vivo have been used in the treatment or prophylaxis of thrombosis or vascular occlusive disease.

When a compound of the formula I is used in vivo, it is expediently administered in the form of a pharmaceutical preparation which contains a compound of the formula I together with a pharmaceutically acceptable diluent or carrier. The invention also relates to such preparations, e.g. conveniently in a form suitable for oral administration, e.g. as tablets, capsules, aqueous or oily suspensions. However, they can also be in a form suitable for parenteral administration, e.g. as a sterile injectable suspension.

Such preparations can be prepared according to conventional methods using conventional excipients. A preparation for oral administration should preferably contain 50 to 500 mg per dosage unit, while a preparation for parenteral administration should preferably contain 0.5 mg / ml to 20 mg / ml, the more dilute preparations being for infusion instead of injection suitable.

Preparations intended for the treatment or prophylaxis of thrombosis or vascular occlusive diseases may also contain one or more agents that have a beneficial effect on the disease or related conditions, e.g. Ticlopidine, clofibrate, sulfinpyrazone, dipyridamole, acetylsalicylic acid or methyl 4- (aminoacetyl) phenoxyacetate.

When a compound of Formula I is used to inhibit platelet agglutination in humans and warm-blooded animals, it can be administered in a daily intravenous dose in the range from 0.2 to 5 mg / kg. However, a compound of the formula I can also be administered at a daily oral dose in the range from 5 to 20 mg / kg.

The doses can more conveniently be administered in subdivided form. In humans, these doses are equivalent to a total daily dose of 25 to 350 mg by intravenous route or 0.35 to 1.4 g by oral route.

The invention is illustrated by the following examples in which (1) all evaporations are carried out by rotary evaporation under reduced pressure, unless otherwise specified; (2) all operations, unless otherwise specified, were carried out at room temperature, i.e. at a temperature in the range from 18 to 25 "C; (3) nuclear magnetic resonance spectra, unless otherwise stated, refer to protons and at 100 MHz in hexadeuterodimethylsulfoxide (d6-DMSO) as the solvent using tetramethylsilane (TMS) as the internal Standard; (4) TFA means trifluoroacetic acid; and (5) yields, when given, are for illustrative purposes only and should not be regarded as the maximum achievable.

Examples I to 3 15 g of methyl acrylate were added to a solution of 27.2 g of 2-amino-5,6-dimethylbenzimidazole in 100 ml of ethanol. After stirring for 2 days at room temperature, the crystalline precipitate that had formed in the reaction mixture was separated off by filtration, washed with ethanol and then with ether and gave 37.2 g of 7,8-dimethyl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one of melting point 322 to 323 "C.

Similarly, but using the corresponding 2-aminobenzimidazole of the formula:

and methyl acrylate (MA) became the following compounds of the formula:

Obtained: Example starting substituents Product in game materials on the ring A VIII (g) MA (g) Mp. ("C) From booty (g) 2 0.9 0.5 * 6,9-dimethyl 270-271 0 , 45 3 1.2 0.4 7,8-diisopropoxy 263-266 0.6 * The reaction mixture was refluxed in the absence of air for 2 days using a mixture of 10 ml of ethanol and 2 ml of methanol as a solvent .

Those of the starting materials of Formula VIII that are new were prepared as follows: (a) 2-Amino-4, 7-dimethylbenzimidazole (for Example 2) 70.0 g of a mixture of p-xylenediamines (obtained by catalytic hydrogenation of the mixture of dinitro-p-xylenes formed in the nitration of p-xylene), which contained approximately 60% 3,6-dimethyl-1,2-diaminobenzene, was converted into the monohydrochloride by adding 270 ml of aqueous 2N hydrochloric acid, whereupon it was evaporated. A mixture of 86.2 g of the monohydrochloride and 120 ml of water was heated to reflux, whereupon a solution of 23.1 g of cyanamide in 50 ml of water was added to the boiling mixture over the course of 20 minutes.

After refluxing for an additional 1 hour, the reaction mixture was made basic by adding a solution of 20.8 g of sodium hydroxide in 50 ml of water. The resulting mixture was then refluxed for 18 hours and then cooled. The oil that formed was separated by decantation and then triturated first with 250 ml of water and then three times 150 ml of chloroform. The remaining tar was partially dissolved in 150 ml of acetone, whereupon the solution obtained was purified by fractional chromatography on a column with 1.5 kg of silica gel, first using a mixture of methanol and chloroform in a volume ratio of 1: 1 and then methanol as the eluent Evaporation of the combined methanol fractions gave 13.9 g of 2-amino-4,7-dimethylbenzimidazole, which was further purified by recrystallization from ethanol to give 6.1 g of the pure material with a melting point of 164-170 "C.

(b) 2-Ambo-5, 6-diisopropoxybenzimidazole (for example 3) A solution of 2.24 g of 1,2-diamino-4,5-diisopropoxybenzene in 40 ml of methanol was added to a mixture of 1.6 g of cyanogen bromide and 40 ml of water. The mixture was stirred for 70 hours at 20-25 "C and then made basic by the addition of an excess of aqueous ammonia solution (density 0.88). The mixture was then separated by filtration and the filtrate evaporated. The residue obtained became 50 ml Water and 50 ml chloroform mixed.

The chloroform phase was separated off, dried over magnesium sulfate and evaporated. The gummy residue obtained was purified by chromatography on a column containing 40 g of silica gel, using a mixture of methanol and chloroform in a volume ratio of 1: 3 as the eluent to obtain 1.2 g of 2-amino-5,6-diisopropoxybenzimidazole as a sticky solid which had characteristic absorption bands at v = 3400, 3320, 3080, 1660 and 1565 cm 1 in the infrared spectrum.

Examples 4 and 5 Using a procedure similar to that described in Example 1, from 1.0 g of methyl acrylate and 1.75 g of 2-ammo-5-chloro-6-methylbenzimidazole, 0.8 g of a mixture 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 ] -benzimidazol-2 (1H) -one (Example 5) in a ratio of 1: 1. The mixture had a melting point of over 314 "C.

That the mixture was present in the ratio 1: 1 was shown by the magnetic proton resonance spectrum. The aromatic protons show 4 signals with o-values (ppm) of 7.72 (singlet), 7.59 (singlet) and 7.60 (singlet), 7.47 (singlet) in trifluoroacetic acid, based on tetramethylsilane as the internal standard . The integral value was the same for all signals.

The 2-amino-5-chloro-6methylbenzimidazole used as starting material was obtained in a manner analogous to the procedure used for the preparation of the 2-amino-5,6-diisopropoxybenzimidazole required in Example 3.

In this way, it was obtained in the form of 1.74 g of a solid substance with a melting point of 240 to 247 "C in the reaction of 2.43 g of cyanogen bromide with 2.4 g of 4-chloro-5-methyl-1,2-diaminobenzene.

Examples 6 and 7 Using a procedure similar to that described in Example 1, 0.77 g of methyl acrylate and 1.45 g of 2-amino-5-methylthiobenzimidazole were converted into 0.9 g of a mixture 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) in a ratio of 1: 1. The mixture had a melting point of 234 to 238 "C, and its nuclear magnetic resonance spectrum (C13, d4-acetic acid) showed 6 signals for the aromatic carbon atoms at o-values (ppm) of 108.9, 107.9, 116.0, 114.6 and 132.3, 130.9, based on tetramethylsilane as internal standard The integral values for all signals were the same.

The 2-amino-5-methylthiobenzimidazole used as starting material was obtained in a manner analogous to the procedure used for the preparation of the 2-amino-5,6-diisopropoxybenzimidazole required for Example 3. In this way it was obtained in the form of 1.45 g of a solid substance with a melting point of 195 to 210 "C, which was sufficiently pure for further use, by reacting 2.06 g of cyanogen bromide with 2 g of 4-methylthio-l, 2- received diaminoben zol.

Examples 8-11 14.5 g of methyl acrylate were added to 26.6 g of 5-acetyl-2 aminobenzimidazole in 200 ml of ethanol. The solution was refluxed for 20 hours after which the reaction mixture was allowed to cool. The crystalline precipitate was separated off by filtration and washed with ethanol and ether, 31.7 g of a solid substance being obtained which was recrystallized from dimethylformamide and 29.5 g of a mixture of 7- and 8-acetyl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one in the ratio 1: 1 (Example 8) with a melting point above 330.degree.

Microanalysis for C12HIIN302: Calculated: C62.9; H4.8; N18.3%; Found: C62.8; H4.7; N18.4% The nuclear magnetic resonance spectrum (+ TFA) showed two identical triplets at δ = 4.50, 4.55, which corresponded to the proton on carbon atom 4.

In a similar way, but using the corresponding 2-aminobenzimidazole of the formula VIII and of acrylic acid methyl ester, the following compounds of the formula IX were obtained: Example reaction substituents from mp. Microanalysis, play time on ring A booty ("C) (hours .) (%) 9 72 (7-PhCO-) 52 305-315 Found: C 70.1; (or) H 4.4; N 14.4%; (8-PhCO-) calc. for C17H13N302: (footnote A) C 70.1; H 4.5; N 14.4%.

10 24 (7-CN) 38> 320 Found: C, 62.3; (or) H3.9; N26.4%; (8-CN) Calc. for C11 H8N4O: (footnote B) C 62.3; H 3.8; N 26.4%.

11 24 7,8-methylene 60> 330 Found: C 57.0; dioxy H3.8; N 18.0%; Ber. for Cl1H9N303: C57.1, H3.9; N 18.2%.

Footnote A: Isolated as a mixture of 7- and 8-benzoyl-3,4-dihydropyrimido- [1,2-a] - benzimidazol-2 (1H) -one in a ratio of 1: 1; nuclear magnetic resonance spectrum (o values): 2.90 (triplet, 2 protons on carbon atom 3); 4.30 (triplet, 2 protons on carbon atom 4); 7.4-7.8 (complicated, 8 aromatic protons).

Footnote B: According to the nuclear magnetic resonance spectrum, a mixture of 7- and 8-cyano-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one in a ratio of 1: 1 because there are two identical singlets at = 7.89 (one proton on carbon atom 9, 8-CN isomer) and = 7.89 (one proton on carbon atom 6, 7-CN isomer).

Those starting materials of the formula VIII which are new were obtained as follows: (a) 5-Acetyl-2-aminobenzimidazole (for Example 9) 38.7 g of 4-amino-3-nitroacetophenone in one liter of ethyl acetate containing 10 mg of hydroquinone were hydrogenated at room temperature and atmospheric pressure over 10% of the palladium on carbon until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate was evaporated. The solid product was stirred in 100 ml of water, separated and dried, yielding 28.6 g of 3,4-diaminoacetophenone, melting point 131 to 134 "C.

20 g of cyanogen bromide in 400 ml of water were added with stirring to a suspension of 25 g of 3,4-diaminoacetophenone in 400 ml of methanol. The solution was kept at room temperature for 16 hours and then evaporated. The residue was dissolved in water and the solution made basic with an excess of saturated sodium carbonate solution. The resulting suspension was stirred for one hour, filtered, the residue washed with water and dried, whereby 26.6 g of 5-acetyl-2-aminobenzimidazole with a melting point of 228-234 ° C. were obtained.

(b) 2-Amino-5-cyanobenzimidazole (for Example 11) Using a procedure similar to that described above, 7.8 g of 3,4-diaminobenzonitrile and 6.9 g of cyanogen bromide were converted into 8.1 g of 2-amino-5-cyanobenzimidazole as a solid, melting point 228 to 233 "C and obtained with a satisfactory purity.

(c) 2-Amino-5,6-methylenedioxybenzimidazole (for Example 12) 3.4 g of cyanogen bromide in 60 ml of water were added to 3.8 g of 3,4-methylenedioxy-o-phenylenediamine in 60 ml of ethanol, with 4.4 g of 2-amino-5,6-methylenedioxybenzimidazole having a melting point of 230 to 243 " C.

Example 12 1.2 g of 5-acetyl-2-amino-1- (2-cyanoethyl) benzimidazole were heated to reflux in 20 ml of ethanol containing 1.2 g of potassium hydroxide for 2 hours. The mixture was concentrated to a small volume and 20 ml of water were added.

The solution was acidified with acetic acid to pH = 5 and kept at 4 "C for 16 hours. The solid substance that formed was separated off by filtration and dried by azeotropic distillation of a suspension in toluene, with 0.85 g of 5-acetyl- 2-amino-1 - (2-carboxyethyl) - benzimidazole were obtained, which were not characterized, but were heated for 5 minutes at 250 "C, whereby a tar formed, which was extracted with 3 × 10 ml of 3 normal hydrochloric acid The acidic extracts were made basic by adding an excess of saturated sodium carbonate solution, a brown solid being formed which was washed with dimethylformamide, acetone and then with ether and 0.22 g of 8-acetyl 3,4-dihydropynmido- [1, 2 -a] -benzimidazol-2 (1H) -one of melting point above 320 "C.

3 Microanalysis for C12HIIN302 H2O: Calculated: C59.4; H5.1; N17.3%; Found: C59.3; H4.7; N 17.0%.

Nuclear magnetic resonance spectrum (b values): 2.55 (singlet, 3 protons, COCH3), 3.0 (triplet, 2 protons on carbon atom 3), 4.42 (triplet, 2 protons on carbon atom 4), 7.64 ( Doublet, 1 proton on carbon atom 7) and 8.05 (singlet, 1 proton on carbon atom 9).

The 5-acetyl-2-amino-1- (2-cyanoethyl) -benzimidazole used as starting material was obtained as follows: A suspension of 10.0 g of 4-amino-3-nitroacetophenone in 25 ml of dioxane was treated with 0.5 ml of a 45% solution of choline hydrate in methanol at 32 "C. while stirring. At 32" C., 3.3 g were obtained Acrylonitrile was added in portions, whereupon the temperature was increased to 50 "C and held there for 90 minutes. 50 ml of ether were added to the thick reaction mixture. The solid was then separated off by filtration and gave 11.2 g of 4- (2nd -Cyanoäthylamino) -3-nitroacetophenone with a melting point of 138 to 142 "C.

A solution of 10.2 g of 4- (2-cyanoethylamino) -3-nitro-acetophenone in 200 ml of ethanol was hydrogenated over 1 g of 10% by weight palladium on carbon. 50 ml of 3 normal hydrochloric acid was added to the mixture after hydrogen uptake ceased. The mixture was then shaken and separated by filtration. The filtrate was made basic by adding an excess of aqueous sodium carbonate solution. The precipitated solid substance obtained was separated off by filtration, washed with water and then with acetone and gave 6.2 g of 4- (2-cyanoethylamino) -3-aminoacetophenone with a melting point of 170 to 173 "C. This was then dissolved in 200 ml of methanol and treated with 3.5 g of cyanogen bromide. The mixture was stirred overnight at room temperature and then treated with 200 ml of water and sodium carbonate solution until pH = 7, 3.6 g of 5-acetyl-2-amino-1- (2-cyano-ethyl ) -benzimidazole, the infrared spectrum of which shows bands at V 3460, 3340, 2260, 1650, 1610 cm-1.

Example 13 1.5 g of a mixture of 7- and 8-acetyl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one in a ratio of 1: 1 were in 100 ml of boiling dimethylformamide dissolved, whereupon the solution with a pure sample of 8-acetyl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one (from Example 12) was inoculated. The solution was allowed to cool to room temperature, whereupon two different crystal forms separated, i. light and heavy crystals. By comparison with the authentic 8-acetyl isomer by means of nuclear magnetic resonance spectroscopy, it was shown that the light crystals were rich in the 8-acetyl isomer and the heavy crystals were rich in the 7-acetyl isomer. The two crystal forms were separated by vortexing the mixture and then the light crystals were removed by decanting with the mother liquor. Thus 0.05 g of Sample (A) containing 80% of 7-acetyl isomer was obtained. This sample (A) was then used to inoculate a crystallizing solution of 4.0 g of a fresh sample of the mixture of the 7- and 8-isomers in the ratio 1: 1 in 300 ml of boiling dimethylformamide; this solution then gave light crystals (B) and heavy crystals (C), which were separated by decantation. The light crystals (B) were then heated with their mother liquors; the hot solution was seeded with a sample of the pure 8-acetyl isomer so that an additional amount of light crystals (D) and heavy crystals (E) were obtained. The light crystals (D) were then redissolved in their mother liquor; the solution was again inoculated with pure 8-isomers, so that a further amount of light crystals (F) and heavy crystals (G) was obtained.

The heavy crystals C, E and G were combined and recrystallized twice (without seeding) from boiling dimethylformamide, whereby 0.65 g of 7-acetyl-3,4-dihydropyrimido [1,2-a] -benzimidazole-2 (1H) - on with a melting point above 320 "C.

Microanalysis for Cl2HIIN302: Calculated: C62.9; H4.8; N18.3%; Found: C62.4; H4.8; N17.9%.

Nuclear magnetic resonance spectrum (in trifluoroacetic acid solution, values): 2.87 (singlet, 3 protons, COCH3), 3.42 (triplet, 2 protons on carbon atom 3), 4.75 (triplet, 2 protons on carbon atom 4), 7.84 (Doublet, 1 proton on carbon atom 9), 8.32 (doublet, 1 proton on carbon atom 8), 8.40 (singlet, 1 proton on carbon atom 6).

Crystallization of the light crystals F from boiling dimethylformamide in a similar manner gave a sample of 8-acetyl-3, 4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one having the same physical properties as described in Example 12 have been described.

Example 14 0.4 g of sodium borohydride were converted into 2.3 g of a mixture of 7- and 8-acetyl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one in a ratio of 1: 1 given in 10 ml of dimethylformamide. The mixture was heated to 100 ° C. for 30 minutes and then evaporated. 100 ml of water were then added. The solution was neutralized with acetic acid and then heated to 100 "C for 30 minutes. The resulting suspension was then cooled to 5" C and the solid matter was separated off by filtration, washed with cold water, acetone and then ether, yielding 1.4 g of one Mixture of 7- and 8- (1 hydroxyethyl) -3, 4-dihydropyrimido- [1, 2-a] -benzimida zol-2 (1H) -one in a ratio of 1: 1. This material was boiling by dissolving in 100 ml Purified methanol and subsequent concentration to 30 ml, whereby 0.4 g of 8- (1-hydroxyethyl) 3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one with a melting point of 270 to 278 "C. were obtained.

Microanalysis for C12H13N302: Calculated: C62.3; H5.6; N18.2%; Found: C62.1; H5.6; N 17.9%.

The nuclear magnetic resonance spectrum shows a signal at 8 = 7.38 (singlet, 1 proton on carbon atom 9).

0.74 g of a mixture of 8- and 7- (1-hydroxyethyl) 3, 4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one separated slowly from the mother liquors of the above crystallization Melting point 247 to 252 "C. It was shown by nuclear magnetic resonance spectroscopy that this mixture contained 60 parts of the 8-isomer to 40 parts of the 7-isomer by calculating the integrals of the relevant signals for the proton on carbon atom 4 at 8 = 4, 24 (triplet) and 4.23 (triplet) compared.

Examples 15-18 Using a procedure generally similar to that described in Example 8, the following compounds of Formula I were obtained from the corresponding 2-aminobenzimidazole and methyl acrylate in yields of 70 to 90%: Example 15: A mixture of 7- and 8-butyryl-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one was obtained by adding 5-butyryl-2-aminobenzimidazole in ethanol 72 Heated to reflux for hours with acrylic acid methyl ester, and was as a solid substance from melting point 287 to 300 "C (crystallized from dimethylformamide).

Microanalysis for C14H15N302: Calculated: C65.4; H5.8; N16.3%; Found: C65.0; H5.9; N16.2%.

The nuclear magnetic resonance spectrum (trifluoroacetic acid) shows two identical triplets (2 protons on carbon atom 4) at 8 = 4.66 and 4.70.

Example 16: A mixture of 7- and 8- (p-chlorobenzoyl) 3,4-dihydropyrimido- [1, 2-a] -benzimidazol-2 (1H) -one in the ratio 1: 1 was obtained by adding 5- (p-Chlorobenzyl) -2aminobenzimidazole with methyl acrylate in methanol heated to reflux for 16 hours, namely as a solid with a melting point of 315 to 325 "C.

Microanalysis for C16H12N3OCl: Calculated: C62.7; H3.7; N 12.9; Cl 10.9%; Found: C62.2; H3.5; N12.4; Cl10.8%.

Nuclear magnetic resonance spectrum (trifluoroacetic acid, 8 values): 3.30 (triplet, 2 protons on carbon atom 3); 4.60 (triplet, 2 protons on carbon atom 4); 7.71 (singlet, 1 proton on carbon atom 6); 7.86 (singlet, 1 proton on carbon atom 9).

Example 17: 7,8-Dichloro-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one was obtained by reacting 5,6-dichloro-2aminobenzimidazole with methyl acrylate in ethanol for 72 hours heated to reflux, namely as a solid with a melting point above 345 "C.

Microanalysis for CIoH7N3oCl2 Calculated: C46.9; H2.7; N16.4%; Found: C46.9; H2.8; N 16.4%.

Example 18: A mixture of 8,9- and 6,7-dimethyl-3,4 dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one in the ratio 49: 1 was obtained by adding 4, 5-Dimethyl-2-aminobenzimidazole treated with methyl acrylate in ethanol at room temperature, namely as a solid substance with a melting point of 240 to 244 "C (recrystallized from ethanol).

Microanalysis for C12H13N3O 4 4 H2O: Calculated: C65.5; H6.2; N19.1%; Found: C65.5; H6.2; N 19.0%.

The nuclear magnetic resonance spectrum (trifluoroacetic acid) shows 2 triplets at 8 = 4.42 (2 protons on carbon atom 4 of the 8,9 isomer) and 4.10 (2 protons on carbon atom 4 of the 6,7 isomer) in a ratio of 49: 1 .

The required 2-aminobenzimidazole starting materials of the formula VIII were obtained in a manner similar to that described in Example 8 for 5-acetyl-2-aminobenzimidazol-2 (1H) -one, but starting from the corresponding 2-nitroaniline: Starting substituent from m.p. (C) material on ring A yield for (%) Example 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 2.37 g of 2-amino-5-benzoylbenzimidazole and 1.1 g of methyl methacrylate were refluxed in 20 ml of ethanol for 72 hours. An additional 0.8 g of methyl methacrylate was added and the reaction mixture was heated for an additional 6 days. The mixture was cooled to room temperature and the solid that separated was isolated by filtration and washed with ethanol and ether, leaving 1.4 g of one Mixture of 7- and 8-benzoyl-3,4-dihydro-3-methylpyrimido- [1,2-a] -benzimidazol-2 (1H) -one in a ratio of 1: 1 with a melting point of 296 to 321 "C.

Microanalysis for Cl8H16N3O2: Calculated: C70.8; H4.9; N13.8%; Found: C70.4; H4.9; N 13.6%.

The nuclear magnetic resonance spectrum (trifluoroacetic acid) shows 2 doublets (1 proton on carbon atom 3) at 8 = 4.84 and 4.93 with the same intensity.

Example 20 2.4 g of 2-amino-5-benzoylbenzimidazole and 1.25 g of ethyl crotonate were refluxed for 4 days in 20 ml of butan-1-ol. On cooling the mixture, a solid separated out, which was recrystallized from methanol to give 0.5 g of a solid which, as shown by nuclear magnetic resonance, was a mixture of 7- and 8-benzoyl-3,4-dihydro- 4-methylpyrimido- [1,2-a] -benzimidazol-2 (1H) -one in the ratio 2: 1. Evaporation of the mother liquors from the crystallization gave 1.35 g of a ratio of 7- and 8-benzoyl-3,4-dihydro-4-methylpyrimido- [1,2-a] benzimidazol-2 (1H) -one 1: 1 from melting point 250 to 270 "C.

Microanalysis for C18H 15N302: Calculated: C70.8; H4.9; N13.8%; Found: C71.0; H5.2; N13.9%.

The nuclear magnetic resonance spectrum shows 2 doublets (methyl protons on carbon atom 4) at 8 = 1.25 and 1.31 with the same intensity.

Example 21 A solution of 6.1 g of 3- (2-amino-5-benzoylbenzimidazol-1-yl) propionic acid in 30 ml of methanol was treated with 30 ml of a saturated solution 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 resulting solution was brought to pH = 8.5 with aqueous sodium bicarbonate solution and then extracted 3 times with 50 ml of ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to give methyl 3- (2-amino-5-benzoylbenzimidazol-1-yl) propionate as an oil. This oil was dissolved in 60 ml of methanol and the solution refluxed for 5 hours. The solid that precipitated was isolated and washed successively with methanol, acetone and then ether to give 3.4 g of 8-benzoyl-3,4- dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) - one of melting point 323-330 "C.

Microanalysis for C17H13N302: Calculated: C70.1; H4.5; N 14.4%; Found: C69.9; H4.4; N14.0%.

The starting material was obtained as follows: 10 g of 4-chloro-3-nitrobenzophenone were added to a mixture of 10.1 g of 3-aminopropionic acid (p-alanine) and 9.6 g of sodium hydrogen carbonate in 100 ml of 2-methoxyethanol, which was then refluxed for 4 hours. The mixture was cooled, poured into 250 ml of ice water and brought to pH = 3 by adding concentrated hydrochloric acid. The solid substance obtained was filtered off, washed with water and air-dried and gave 12.1 g of 3- (4-benzoyl-2-nitroanilino) propionic acid with a melting point of 170 to 175 "C.

10 g of this acid were dissolved in 100 ml of ethanol and hydrogenated in the presence of 0.6 g of 10 percent by weight palladium on carbon until the uptake of hydrogen ceased. Then 100 ml of water and 3.72 g of cyanogen bromide were added.

After 16 hours at room temperature the mixture was evaporated. 50 ml of water was added to the residue.

The aqueous phase was separated from tarry material by decanting and adjusted to pH = 4 with concentrated aqueous ammonia, 6.1 g of 3- (2-amino-5-benzoyl benzimidazol-1-yl) propionic acid with a melting point of 325 to 330 " C.

Example 22 Using a procedure similar to that described in Example 21, 8-cyano-3,4-dihydropyrimido- [1,2-a] -benzimidazol-2 (1H) -one was obtained as a solid with a melting point above 340 "C in an essentially quantitative yield obtained by thermally cyclizing the methyl ester of 3- (5-cyano-2-aminobenzimidazol-1-yl) propionic acid, which in turn was obtained as an oil of satisfactory purity by esterification of propionic acid with methanolic hydrogen chloride.

Microanalysis for C "H8N4O: Calculated: C62.3; H3.8; N26.4%; Found: C61.8; H3.7; N26.0%.

The 3- (5-cyano-2-aminobenzimidazol-1-yl) propionic acid used as starting material was prepared in a manner similar to the analogous starting material in Example 21 from 3- (4-cyano-2-nitroanilino) propionic acid, which in turn was used as Solid substance with a melting point of 200 to 205 "C was obtained by reacting ss-alanine with 4-chloro-3-nitrobenzonitrile, obtained as a solid substance with a melting point of over 320" C in satisfactory purity.

Example 23 Using a procedure similar to that described in Example 1, 3.1 g of a mixture of 7- and 8-ethylthio-3,4-dihydropyrimido- [1,2-a] -benzimid2zol-2 (1H ) -one in a ratio of 1: 1 with a melting point of 185 to 186 "C from 2.8 g of methyl acrylate and 6.3 g of 2-amino-5-ethylthiobenzimidazole. The nuclear magnetic resonance spectrum showed 2 triplets (2 protons on carbon atom 4) at 8 = 4.22 and 4.23 of equal intensity.

The required starting material benzimidazole was obtained as follows: 2.76 g of sodium were added to 75 ml of dry 2-methoxyethanol, whereupon the solution was cooled to 0 to 5 "C. 8.72 g of ethanethiol in 10 ml of 2-methoxyethanol were added over the course of 5 minutes, followed by the addition resulting solution was stirred for 10 minutes at 0 to 5 C and then in portions of one over 10 minutes Solution of 21.5 g of 5-chloro-2-nitroacetanilide in 250 ml of boiling 2-methoxyethanol are added. After 3 hours it became Mixture cooled and poured into 1 liter of water. The mixture was cooled to 10 ° C. with stirring. The solid substance which formed was isolated by filtration, washed with water and recrystallized from ethanol to give 16.4 g of 5-ethylthio-2-nitroanlin of melting point 75 to 76 "C.

A solution of 8.2 g of 5-ethylthio-2-nitroaniline in 100 ml of ethanol was hydrogenated over 0.8 g of 10 weight percent palladium on carbon. The mixture was treated with 75% water, kept under a nitrogen atmosphere and then im 8.7 g of cyanogen bromide were added over the course of 10 minutes.

After stirring for three days at room temperature, the mixture was filtered and the filtrate was concentrated to a small volume. 75 ml of water was added and the pH was adjusted to 8 with a 10% w / v sodium carbonate solution. The solid that precipitated was isolated by filtration, washed with water, air dried and then triturated with acetone, 6.3 g of 2-amino-5-ethyl-thiobenzimidazole being obtained, the absorption bands characteristic in the infrared spectrum at, ,, = 3440.3360, 1660, 1645 and 1560 cm-1 hat.

Example 24 1.03 g of m-chloroperbenzoic acid were added at 0 to 5 ° C. to a solution of 1.23 g of a mixture of 7- and 8-ethylthio-3,4-dihydropyrimido- [1,2-a] -benzimidazole-2 (1H) -on im Ratio 1: 1 in 150 ml of methanol. After 30 minutes the mixture was evaporated to a small volume. The solid substance obtained was separated off by filtration and washed with methanol and ether, whereby 0.95 g of a Gemi cal of 7- and 8-ethylsulfinyl-3, 4-dihydropyrimido- [1, 2-a] - benzimidazole-2 (1H) -on in a ratio of 1: 1 as hemihydrate from Melting point 226 to 230 "C were obtained.

Microanalysis for C12H13N3SO2 2 H2O Calculated: C52.9; H5.1; N15.4%; Found: C53.2; H5.0; N 15.4%.

Nuclear magnetic resonance spectrum (trifluoroacetic acid, 8 values): 1.38 (triplet, 3 protons, CH3); 3.38 (complicated, 4 protons, namely 2 protons on carbon atom 3 and CH2SO); 4.71 [triplet, 2 protons on carbon 4 (7-isomer); 4.80 [triplet, 2 protons on carbon atom 4 (8-isomer)]; 7.90 [complicated, 2 aromatic protons); 8.3 (singlet, 1 aromatic proton).

Example 25 2.6 g of 2-amino-6,8-dimethylbenzimidazole and 1.5 g of methyl acrylate were added to 25 ml of ethanol for 5 days Stirred at 25 OC. The solid that formed was isolated by filtration and washed with ethanol, acetone and ether, leaving 2.1 g of a mixture of 7,9- and 6,8-dimethyl 3,4-dihyd} opyrimido [1, 2-a] -benzimidazol-2 (1H) -one in a ratio of 9: 1 with a melting point of 326 to 332 "C.

Microanalysis for C12H13N3O: Calculated: C67.0; H6.0; N 19.5%; Found: C66.7; H6.1; N19.5%.

The nuclear magnetic resonance spectrum shows 2 triplets (2 protons on carbon atom 4) at 8 = 4.01 (7.9 isomer) and 4.32 (6.8 isomer) in a ratio of 9: 1.

Example 26 6.1 g of methyl acrylate was added to a solution of 12.2 g of 2-amino-5,6-dimethoxybenzimidazole in 70 ml of methanol, and the mixture was stirred for 90 hours.

The crystalline precipitate was separated by filtration and washed with ethanol and then with ether, 10.3 g of 7, 8-dimethoxy-3, 4-dihydropyrimido- [1, 2-a] -benzimidazol- 2 (1H) -one from Melting point 264 to 265 "C were obtained.

Microanalysis for C12H13N303: Calculated: C58.3; H5.3; N 17.0%; Found: C 58.0; H 5.2; N 16.8%.

Nuclear magnetic resonance spectrum (o = values: 2.82 (triplet, 2 protons on carbon atom 3); 3.72 (singlet, 3 protons, CH3]; 3.76 (singlet, 3 protons, CH3O); 4.15 (triplet, 2 protons on carbon atom 4); 7.0 (singlet, 1 proton on carbon atom 6); 7.04 (singlet, 1 proton on carbon atom 9).

Example 27 9.3 g of 2-amino-6,8-dimethylbenzimidazole and 5.3 g of methyl acrylate were refluxed together in 70 ml of methanol for 4 hours. The crystalline precipitate that formed was filtered off from the hot solution and washed with methanol to give 2.4 g of a mixture of 7,9- and 6,8-dimethyl-3, 4-dihydro- [1, 2-a ] -benzimidazol- 2 (1H) -one with a melting point of 325 to 327 "C. As on the basis of the nuclear magnetic resonance spectrum by comparing the triplets for the 2 protons on carbon atom 4 at 8 = 4.01 (7,9 isomer) and 4, 32 (6,8-isomer), this mixture contained 98% of the 7,9-isomer.

Example 28 A mixture of 196 parts by weight of microcrystalline cellulose and 200 parts by weight of finely divided 8-acetyl-3,4-dihydropyrimido- [1,2-aj-benzimidazol-2 (1H) -one was sieved through a sieve with a mesh size of 0.500 mm. 4 parts by weight of magnesium stearate (particle size 0.251 mm) were added. After thorough mixing, the mixture was compressed into tablets which weighed 400 mg and contained 200 mg active ingredient and which can be administered to humans for therapeutic purposes.

In a similar way tablets can be obtained which contain 150, 100 or 50 mg of active ingredient.

The above active ingredient can be replaced by any compound of the formula I which has been described in one of Examples 1 to 11 or 13 to 27.

Claims (11)

PATENT CLAIMS 1. Pyrimido- [1s2-a] -benzimidazole derivatives of the formula: wherein R2 and R3, which are identical or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms, one or two of A6, A7, A8 and A9, which are identical or different, halogen atoms, alkyl radicals having 1 to 6 carbon atoms, alkoxy radicals with 1 to 6 carbon atoms, alkanoyl groups with 2 to 6 carbon atoms, 1-hydroxyalkyl groups with 1 to 6 carbon atoms, alkylthio groups with 1 to 6 carbon atoms, alkylsulfinyl groups with 1 to 6 carbon atoms, cyano groups or benzoyl groups, while the rest of A6, A7, A5 and A9 are hydrogen, or an adjacent pair of A6, A7, A8 and A9 together form a divalent alkylenedioxy radical having 1 to 6 carbon atoms and the other pair of A6, A7, A8 and A9 is hydrogen, where if only one of the symbols A6 , A7, A8 and A9 denote a halogen atom, an alkyl radical having 1 to 6 carbon atoms or an alkoxy radical having 1 to 6 carbon atoms, at least one of the rest of A6, A 7, A8 and A9 is other than hydrogen. 2. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen, methyl or ethyl, one or two of A6, A7, A8 and A9, which are identical or different, fluorine, chlorine, Bromine, methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, acetyl, propionyl, butyryl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, cyano or benzoyl radicals mean, while the others of A6, A7, A8 and A9 are hydrogen, or an adjacent pair of A6, A7, As and A9 together are methylenedioxy or isopropylidenedioxy and the other pair of A6, A7, A8 and A9 are hydrogen. 3. Compounds according to claim 1, characterized in that two of A6, A7, A8, A9 6.7-, 7.8-, 8.9 or 6.9 dimethyl, 7,8-dichloro, 7-chloro-8- methyl, 7-methyl-8-chloro, 7,8-dirnethoxy, 7,8-diisopropoxy or 7,8-methylenedioxy mean, while the rest of A6, A7, A8 and A9 mean hydrogen, or one of A6, A7, A8 and A9 are 7- or 8-acetyl, butyryl, benzoyl, methylthio, ethylthio, ethylsulfinyl, cyano or -1-hydroxyethyl and the rest of A6, A7, A5 and A9 are hydrogen. 4. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, at least two of A6, A7, A8 and A9 are hydrogen and the rest of A6, A7, A8 and A9 are any have the meanings given in claim 1 with the exception of hydrogen. 5. Compounds according to claim 1, wherein R2 and R3, which are identical or different, are hydrogen or methyl radicals, A7 and one of A6, A8 and A9 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A8 and A9 represent hydrogen. 6. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, A8 and one of A6, A7 and A9 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A7 and A9 represent hydrogen. 7. Compounds according to claim 1, characterized in that R2 and R3, which are identical or different, are hydrogen or methyl radicals, A7 and / or A5 have the meanings given in claim 1 with the exception of hydrogen and the rest of A6, A7, A8 and A9 mean hydrogen. 8. Compounds according to one of claims 4 to 7, characterized in that A7 or A8 denotes cyano, acetyl, 1-hydroxyethyl or benzoyl. 9. Compounds according to any one of claims 4 to 7, characterized in that A7 and A8 together denote methylenedioxy or denote methoxy, ethoxy or isopropoxy radicals. 10. As a compound according to claim 1, 7-acetyl, 8-acetyl, 7-benzoyl, 8-benzoyl, 7-cyano, 8-cyano, 7,8-diisopropoxy and 7,8-methylenedioxy -3, 4-dihydropyrimido- [1, 2-a] - benzimidazol-2 (1H) -one as well as 7-benzoyl- and 8-benzoyl-4-methyl3, 4-dihydropyrimido- [1, 2-a] -benzimidazole- 2 (1H) -one. 11. A pharmaceutical preparation, characterized in that it contains a compound of the formula 1 according to claim 1 together with a pharmaceutically acceptable diluent or carrier. The present invention relates to novel pyrimido [1,2-a] benzimidazole derivatives which inhibit platelet agglutination. Various 3,4-tetrahydropyrinudo [1,2-a] -benzimidazole derivatives have been described as diuretically active compounds (US Pat. No. 4,167,569). It has now surprisingly been found that certain 3,4-tetrahydropyrimido [1,2-a] benzimidazole derivatives which are structurally related to the above are able to inhibit the agglutination of blood platelets without, however, exhibiting any noteworthy diuretic properties. The pyrimido [1, 2-a] benzimidazole derivatives according to the invention correspond to the formula: wherein R2 and R3, which are identical or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms, one or two of A6, A7, A8 and A9 which are identical or different, halogen atoms, alkyl radicals having 1 to 6 carbon atoms, alkoxy radicals with 1 to 6 carbon atoms, alkanoyl groups with 2 to 6 carbon atoms, 1-hydroxyalkyl groups with 1 to 6 carbon atoms, alkylthio groups with 1 to 6 carbon atoms ** WARNING ** End of CLMS field could overlap beginning of DESC **.