CS199697B2 - Method of producing derivatives of pyrimido/1,2-a/benzimidazole - Google Patents

Description

The present invention relates to a process for the preparation of pyritaido [1,2-a] benzimidazole derivatives which inhibit platelet aggregation.

The present invention provides a process for the preparation of pyrimido [1,2-a] benzimidazole derivatives of the general formula I

wherein one or two of A ®, A ⁷ , A ⁸ and A ⁹ , which may be the same or different, represent halogen atoms, C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups, C 1 alkylthio groups up to 4 carbon atoms or cyano, and the remaining of A ⁶ , A ⁷ , A ® and A ⁹ are hydrogen, or one of A ®, A ⁷ , A ® and A ⁹ is a C 2 -C 4 alkanoyl group , a benzoyl group or a 1-hydroxy (C 1 -C 4) -alkyl group, and the remaining of A ®, A ⁷ , A ⁸ and A ⁹ are hydrogen, or an adjacent pair of A ®, A ⁷ , A ® and A ⁹ together are alkylenedioxy with 1 to 4 carbon atoms and the remaining two of A®, a ^7, a ⁸ and a ⁹ are hydrogen, with the proviso that if only one of A®, a ^7, and a ⁹ A® means halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, at least one remaining ICI symbol A®, A ^7, and A ⁹ A® is other than hydrogen, characterized by cyclising 2-aminobenzimidazoles derivative of general formula III

AND*

A®, A ^7, and A ⁹ A® have the above meanings, and

Q represents a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms.

The compounds of formula I are derivatives of 3,4-dihydropyrimido [1,2-a] benzimidazol-2 (1H) -one, the cyclic system of which will be numbered for the purposes of the present invention as in the following formula II

(II)

It will be appreciated that the compounds of formula I may exist in various tautomeric forms, one of which is represented by formula II. It should be pointed out that although the structural designations and nomenclatures used refer to the most likely and predominant tautomeric form, all tautomeric forms of the compounds of formula I as well as mixtures thereof are within the scope of the invention.

It will further be appreciated that, depending on the nature of the substituents A ⁶ , A ⁷ , A ⁸ and A ⁹ , the compounds of formula I may contain one or more asymmetric carbon atoms and may therefore be isolated in racemic forms or in optically active forms. The invention encompasses all racemic or optically active forms of the compounds of formula (I) which possess the aforementioned useful properties. It is generally known how an optically active form can be obtained - for example, by resolution of the racemic form or by synthesis using an optically active starting material - and how the biological properties of optical isomers can be determined using the assays described below.

Examples of suitable residues within the meaning of any of the symbols A ⁶ , A ⁷ , A ⁸ and A ⁹ are:

in the case of a halogen atom, a fluorine, chlorine or bromine atom, in the case of a C 1 -C 4 alkyl group, a methyl, ethyl or propyl group, in the case of a C 1 -C 4 alkoxy group a methoxy, ethoxy or isopropoxy group; up to 4 carbon atoms an acetyl, propionyl or butyryl group, in the case of a 1-hydroxy alkyl group having 1 to 4 carbon atoms, a hydroxymethyl group or a 1-hydroxyalkyl group having 2 to carbon atoms such as 1-hydroxyethyl, 1-hydroxypropyl or

1-hydroxybutyl and, in the case of C 1 -C 4 alkylthio, methylthio or ethylthio.

A suitable divalent alkylenedioxy group having from 1 to 4 carbon atoms, consisting of an adjacent pair of A ⁶ , A ⁷ , A ⁸ and A ⁹ , is, for example, methylenedioxy or isopropylidenedioxy.

Particularly preferred groups of compounds produced according to the invention are those compounds of formula (I) in which (ij A ⁷ or A ⁸ represents cyano, acetyl, 1-hydroxyl, thyl or benzoyl, or (ii) A ⁷ and A ⁸ taken together they form a divalent methylenedloxy group or both represent methoxy, ethoxy or isopropoxy groups, in which case the remaining of the symbols A ⁶ , A ⁷ , A ⁸ and A ⁹ are hydrogen atoms.

Specific preferred compounds of the invention 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.

Of these compounds, 8-cyano-3,4-dihydropyrimido [1,2-a] benzimidazol-2- (1H-one) is particularly preferred.

The cyclization of the invention is preferably carried out thermally by heating the compound of formula III to a temperature in the range, for example, from 50 to 250 ° C. Suitably, an inert solvent or diluent, for example ethanol, dimethylformamide diphenyl ether, may be present in the reaction mixture.

When Q is C1 -C4 alkoxy, the reaction may conveniently be carried out in the presence of a base such as sodium ethoxide or sodium methoxide, preferably in an inert solvent or diluent such as ethanol or methanol at a temperature of between 50 and 250, for example. ° C.

When Q is a hydroxyl group, the above cyclization can also be carried out in the presence of a dehydrating agent, for example a strong mineral acid such as polyphosphoric acid, or. a carbodiimide, such as dicyclohexylcarbodiimide, and suitably in the presence of an inert solvent or diluent, for example chloroform (in the case of carbodiimide), at a temperature of, for example, from 15 to 100 ° C.

The starting materials of formula III can be prepared by conventional procedures, for example those described in the following Scheme 1, using the appropriately substituted o-nitroaniline as the starting material.

Scheme 1

Sr. CFFcCW / CO-Q.

aebo

CWCH.CQQ,

Reagents:

(a) a base, for example, a quaternary ammonium hydroxide, (b) hydrogen, palladium on carbon, (c) broim cyanide, and then a strong base, for example sodium hydroxide, (d) a strong aqueous base, for example sodium hydroxide.

Alternatively, the appropriately substituted o-nitro-chlorobenzene or -bromobenzene can be reacted with 3-aminopropionic acid of formula IV

NH2CH2CH2CO.Q (IV) in which Q has the above meanings, conveniently at a temperature ranging from 50 to 150 ^c C, preferably in a solvent or Redi ·) by, for example 2-methoxyethanol and in the presence of an acid acceptor, e.g. sodium bicarbonate. In this way, an intermediate of formula (IIIA) is obtained

which can be used as described in Reaction Scheme 1 above.

In the process according to the invention, the starting materials of the formula III can conveniently be prepared and used in situ without separation and purification.

199897

The process of the invention is particularly advantageous in that it does not give positional isomers when the benzene ring of the benzimidazole moiety of the compound of formula (III) is asymmetrically substituted.

The pyrimido [1,2-a] benzimidazole derivatives of formula (I) above inhibit platelet aggregation. This property can be demonstrated in vitro by adding the test compound to a mixed citrate-treated human platelet-rich blood plasma sample and measuring the effect of the test compound on the delay or reduction of platelet aggregation induced by the addition of collagen or adenosine-5'-diphosphate. In this assay, compounds of Formula I significantly inhibit platelet aggregation at 10 ^-4 molar or lower concentrations.

Merely as illustrative, specifically, ekvlmolární mixture of 7- and 8-acetyl-3,4-dihydropyrimidoj 1,2-a] benzimidazol-2 (lH) -one in this test showed a significant inhibitory effect of 10 ^"6 molar concentration.

When platelets are stored for several hours and then infused into an animal or human body, they tend to lose most of their haemostatic efficacy. Compounds that inhibit platelet aggregation in vitro are therefore useful in helping to stabilize platelet preparations and thereby maintain their haemostatic activity in vivo. Such compounds may therefore be added, for example, to whole blood stored for a long time in blood banks, to whole blood intended for circulation by isolated organs prior to transplantation or to circulation in heart-lung devices, and platelet suspensions ready for use in the treatment of congenital cytopenias or cytopenias. caused by drugs. ,

The ability of the compounds of formula I to inhibit platelet aggregation can also be demonstrated in vivo by standard tests in rats or mice in which thrombocytopenia was induced. For example, the rats are first dosed orally with the test compound and, after several hours, intravenously with adenosine 5‘-diphosphate at a dose of 5 mg / kg. After 15 seconds, an arterial blood sample is collected and platelets are counted electronically (using a Coulter counter). The platelet count is compared to the platelet count in the arterial blood sample taken immediately prior to adenosine-5‘-diphosphate. Administration of adenosine-5 dif-diphosphate induces considerable thrombocytopenia, which peaks after about 15 seconds. Compounds inhibiting this thrombocytopenia induced by adenosine 5‘-diphosphate are considered to be effective.

In another standard assay, eight mice are orally administered the test compound. After 4 hours, four of these mice were injected intravenously with a 1 mg / kg collagen solution, in the diluent, and the remaining mice serving as a control group were treated with the same diluent only. After 1 minute, an arterial blood sample is taken from each mouse from both groups and platelets are counted in a standard manner. Again, collagen-induced thrombocytopenia inhibitors are considered to be effective.

The in vivo activity of the particular compounds of the formula I necessarily varies depending on their precise chemical structure, but in general the compounds of the formula I exhibit in one or both of the above-described in vivo tests efficacy at a dose of 100 mg / kg or less, without that toxicity or other harmful side effects would be observed at the effective dose. By way of illustration only, an equimolar mixture of 7- and 8-cyano-3,4-dihydropyrimido [1,2-a] benzimidazol-2 (1H) -one exhibits adenoisin-5'-diphosphate-induced thrombocytopenia, respectively. collagen efficacy when administered orally at a dose of 25, resp. 50 mg / kg without any signs of toxicity or harmful side effects.

Compounds that inhibit platelet aggregation in vivo are used in the treatment or prophylaxis of thromhosis or vascular occlusion diseases.

When used in vivo, the compounds of formula I are conveniently administered in the form of pharmaceutical compositions comprising a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

When used to inhibit platelet aggregation in warm-blooded animals, the compound of formula (I) may be administered intravenously at daily doses of from 0.2 mg / kg to 5 mg / kg. Alternatively, the compound of formula (I) may be administered orally at daily dosages of from 5 mg / kg to 20 mg / kg. These total daily doses may conveniently be administered in several divided doses. In humans, the above-mentioned dosages are equivalent to a total daily dose of from 25 mg to 350 mg when administered intravenously and resp. from 0.35 g to

1.4 g when administered orally.

The invention is illustrated by the following non-limiting examples. The following rules apply to these examples:

(i) all evaporations are carried out under reduced pressure on a rotary evaporator, unless otherwise stated;

(iij unless otherwise stated, all operations are carried out at room temperature, i.e. at a temperature in the range of 18-25 ° C;

(III) NMR spectra, unless otherwise indicated, are proton spectra and measured at 100 MHz in hexadeuterodimethylsulfoxide as solvent, using tetramethylsilane as an internal standard;

(Ivj the reported yields are merely illustrative and in no way represent the maximum achievable yields.

Example 1

1.2 g of 5-acetyl-2-amino-1- (2-cyanethyl) -benzimidazole in 20 ml of ethanol containing 1.2 g of potassium hydroxide was refluxed for 2 hours. The mixture was concentrated to a small volume and 20 mL of water was added. The resulting solution was acidified to pH 5 with acetic acid and allowed to stand at 4 ° C for 16 hours. The precipitated solid product is filtered off and dried by slurrying in toluene and azeotroping the suspension. 0.85 g of 5-acetyl-2-amino-1- (2-carboxyethyl) benzimidazole is obtained which is not characterized but is further worked up by heating to 250 ^DEG C. for 5 minutes. The tar material is extracted three times. In each case 10 ml of 3 N hydrochloric acid and acidic extracts are made alkaline by addition of an excess of saturated sodium carbonate solution. A brown solid was formed which was washed with dimethylformamide, acetone and ether to give 0.22 g of 8-acetyl-3,4-dihydropyrimidine-1,2 '[1,2-a] benzimidazol-2 (1H) -one melting above 320 ° C.

For C12H11N3O2.3 / 4 H2O calculated:

% H, 5.1%;% N, 17.3%.

% H, 4.7%; N. 17.0%.

NMR (δ values):

2.55 (singlet, 3 protons, COCHs),

3.0 (triplet, 2 protons, C3-Ha),

4.42 (triplet, 2 protons, C4-H2),

7.64 (doublet, 1 proton, Ce-H),

7.95 (multiplet, 1 proton, C7 — Ή),

8.05 (singlet, 1 proton, Cg-H).

The 5-acetyl-2-amino-1- (2-cyaneithyl) benzimidazole used as starting material is prepared as follows:

To a suspension of 10.0 g of 4-amino-3-nitroacetophenone in 25 ml of dioxane was added 0.5 ml of a 45% solution of choline hydrate in methanol with stirring at 32 ° C. To the mixture at 32 ^C; C was added portionwise 3.3 g of acrylonitrile, the temperature was raised to 50 ° C and this level is maintained for 90 minutes. Ether (50 ml) was added to the thick reaction mixture and the precipitated solid was filtered off. 11.2 g of 4- (2-cyanethylamino) -3-nitroacetopheinone of melting point 138 DEG-142 ^DEG C. are obtained.

Rofetok 10.2 g of 4- (2-cyanethylamino) -3-nitroacetophenone in 200 ml of ethanol are hydrogenated in the presence of 1 g of 10% (w / w) palladium on carbon. After the hydrogen uptake has ceased, 50 ml of 3N hydrochloric acid are added to the mixture, the mixture is shaken and filtered. The filtrate was basified by addition of an excess of aqueous sodium carbonate solution, the precipitated solid product was filtered off, washed first with water and then with acetone. There were obtained 6.2 g of 4- (2-cyanethylamino) -3-acetophenone, m.p. 170-173 ° C. This product was dissolved in 200 ml of methanol and 3.5 g of cyanogen bromide was added. The mixture was stirred at room temperature overnight, then 200 ml of water was added thereto, followed by the addition of sodium carbonate solution to pH 7. 3.6 g of 5-acetyl-2-amino-1- (2- cyanoethyl) benzimidazole, whose IR spectrum comprising bands at 3460, 3340, 2260, 1650 and 1610 cm ^1st Example 2

To a solution of 6.1 g of 3- (2-amino-5-benzoylbenzimidazol-1-yl) propionic acid in 30 ml of methanol was added 30 ml of saturated methanolic hydrogen chloride solution.

The mixture was allowed to stand for 16 hours at room temperature, then evaporated and the residue dissolved in water. The pH of the solution was adjusted to 8.5 by the addition of aqueous sodium bicarbonate solution, and the solution was extracted three times with 50 ml of ethyl acetate each time. The extracts were dried (MgSO4) and evaporated.

Oily methyl 1-3- (2-amino-5-benzoylimidazol-1-yl) propionate is obtained, which is dissolved in 60 ml of methanol and the solution is refluxed for 5 hours, and the precipitated solid product is collected and washed successively with methanol. acetone and ether to give 3.4 g of 8-benzoyl-3,4-dihydropyrimido [1,2-a] benzimidazol-2 (1H) -one, m.p. 323-330 ^° C.

Calcd for C17H13N3O2:

70.1% C, 4.5% H, 14.4% N,

69.9% C, 4.4% H, 14.0% N,

The starting material is prepared as follows:

To a mixture of 10.1 g of 3-aminopropiomic acid (S-alanine) and 9.6 g of sodium bicarbonate in 100 ml of 2-methoxyethanol was added 10 g of 4-chloro-3-nitrobenzophenone, and the resulting mixture was heated under reflux for 4 hours. The reaction mixture is cooled, poured into 250 ml of ice-water and acidified to pH 3 by addition of concentrated hydrochloric acid. The precipitated solid product is filtered off, washed with water and air-dried 12.1 g of 3- ( 170 DEG-175 DEG C. 4-benzoyl-2-nitroanilino] propionic acid.

g of this acid is dissolved in 100 ml of ethanol and hydrogenated in the presence of 0.6 g of 10% (w / w) palladium on carbon until the consumption of hydrogen ceases. After addition of 100 ml of water and 3.72 g of cyanogen bromide, the mixture was allowed to react at room temperature for 16 hours and then evaporated. 50 ml of water are added to the residue, the aqueous phase is separated from the tarry material by decantation and addition

199887 of concentrated aqueous ammonia solution is adjusted to pH 4

6.1 g of 3- (2-amino-5-benzoyl-benzimidazol-1-yl) -propionic acid as a solid, m.p. 325-330 ° C.

Example 1 a d 3

Using a procedure analogous to that of Example 2, the thermal cyclization of 3- (5-cyano-2-aminobenzimidazol-1-yl) propionate (prepared as an oil of satisfactory purity by esterification of propionic acid with methanolic hydrogen chloride) yields in virtually quantitative yield. the solid 8-cyano-3,4-dlhydropyrlmido [l, 2-a] benzimidazol-2 (lH) -one, m.p. 340 ^C centigrade.

Analysis calculated for CuHeNtO:

62.3% C, 3.8 ° / o H, 26.4% N, found:

% H, 3.7%; N. 26.0%.

In analogy to the analogous starting material in Example 2, starting 3- (5-cyano-2-aminobenzimidazol-1-yl) propionic acid was prepared in the form of a solid melting above 320 ° C from 3- (4-cyano-). 2-nitroanilino] -propioic acid, which is itself obtained by reacting 3-alanine with 4-chloro-3-nitrobenzoniltril as a solid, m.p. 200-205 ° C.

Examples 4 to 10

In analogy to Example 2, the cyclic cyclization of the corresponding methyl ethers of the general formula is carried out

in the yield of 60 to 85%, the following compounds corresponding to formula I:

Example number A® A ⁷ A® A ⁹ Melting point (C ^{) (} C) Analysis (%) found calculated 4 H CHs CH3 H 320 - 333 C12H13N3O: C: 66.9 H: 6.1 N: 20.0 C: 67.0 H: 6.0 N: 19.5 5 CH3 H H CH3 270-271 C12H13N3O: C: 67.0 H: 6.1 · N: 19.3 C: 67.0 H, 6.0 N: 19.5 6 H i-CsH7O 1-C3H7O H 263-266 C16H21N3O3: C: 63.3 H: 7.0 N: 13.5 C: 63.4 H: 6.9 N: 13.9 7 H - OCH2O— H > 330 C11H9N3O3: C: 57.0 H: 3.8 N: 18.0 C: 57.1 H: 3.9 N: 18.2 8 H H CHOH. CH3 H 270-278 C12H13N3O2: C: 62.1 H: 5.6 N: 17.9 C: 62.3 H: 5.6 N: 18.2 9 H Cl Cl H 345 C1 & H7N3OCI2: C: 46.9 H: 2.8 N: 16.4 C: 46.9 H: 2.7 N: 16.4 10 H CHsO CH3O H 264-265 C12H13N3O3: C: 58.0 C: 58.3 H: 5.2 H: 5.3 N: 16.8 N: 17.0

The necessary starting esters can be prepared by conventional procedures analogous to those used to prepare the starting materials in Examples 1 to 3.

Example 11

A solution of 0.5 g of 3- (5-cyano-2-aminobenzimidazol-1-yl) -propionic acid in 5 ml of dimethylformamide was heated to 95-100 ° C for 2 days, during which time a solid precipitated slowly. ^C to 25 C, the solid was filtered, washed with 5 ml of cold DMF and dried. 0.32 g of 8-cyano-3,4-dihydropyrimido [1,2-a] benzimidazol-2 (1 H] -one m.p. above 320 ° C, having a satisfactory analysis corresponding to the formula CnHeNaO.

Claims (5)

SUBJECT A process for the preparation of pyrimidin 1,2-a] benzimidazole derivatives of the general formula I in which one or two of A ⁸ , A ⁷ , A ⁸ and A ⁹ , which may be the same or different, represent halogen atoms, alkyl groups having (C 1 -C 4), (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio or cyano, and the remainder of A ⁶ , A ⁷ , A ⁸ and A ⁹ are hydrogen or one of A ⁸ , A ⁷ , A ⁸ and A ⁹ are C 2 -C 4 alkanoyl, benzoyl or C 1 -C 4 -alkyl, and the remainder of A ⁸ , A ⁷ , A ⁸ and A ⁹ are hydrogen or an adjacent pair of A ⁶ , A ⁷ , A ⁸ and A ⁹ together form a C 1 -C 4 alkylenedioxy group and the other two of A ⁸ , A ⁷ , A ⁸ and A ⁹ are hydrogen, provided that if only one of A ⁸ , A ⁷ , A ^8, and A ⁹ is a halogen atom, an alkyl group having an alkyl group of? C 1 -C 4 or C 1 -C 4 alkoxy, at least one of A ⁸ , A ⁷ , A ⁸ and A ⁹ is other than hydrogen, characterized by cyclizing the 2-aminobenzimazole-derivative of formula III YNALEZU And * in which A ⁶ , A ⁷ , A ⁸ and A ⁹ are as defined above, and Q represents a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms. 2. Process according to claim 1, characterized in that the starting materials of the above-mentioned general formula (III) are used in which A ⁸ is cyano, acetyl, benzoyl or 1-hydroxyethyl, A ⁸ , A ⁷ and A ⁹ are hydrogen atoms and Q is as in point 1. 3. Method according to claim 1 or 2, characterized in that the cyclization is carried out thermally at a temperature of 50-250 ^{C, and} optionally in the presence of an inert solvent or diluent. 4. Process according to claim 3, characterized in that the starting materials of the above-mentioned general formula (III) are used, in which Q is methoxy or ethoxy; and A ⁸ , A ⁷ , A ⁸ and A ⁹ are as in 3, and the cyclization is carried out in the presence of a base in an inert solvent or diluent. 5. Process according to claim 1 or 2, characterized in that the starting materials of the general formula (III) are used in which Q represents a hydroxyl group and A ⁸ , A ⁷ , A ⁸ and A ⁹ are as in 1 or 2, and the cyclization is carried out in the presence of a dehydrating agent at a temperature of 15 to 100 ° C, optionally in the presence of an inert solvent or diluent.