Method of obtaining novel pyrolobenzimidazoles

The subject of the invention is a process for the preparation of new pyrrolobenzimidazoles of the general formula I, in which R.sup.2 is a hydrogen atom, an alkyl or a cycloalkyl group, R.₂ represents a hydrogen atom, an alkyl group or R and R They represent a cycloalkylene group, X represents a valence line, an alkylene group of 1-4 carbon atoms or a vinylene group, Py represents a 2-, 3- or 4-pyridyl group, which optionally at the ring heteroatom contains an oxygen atom and or is substituted with one or more alkyl or alkoxy groups, their tauoomers, and physiologically acceptable salts with inorganic or organic acids.

Since the compounds of the general formula and in the case where Ri is different from R, have an asymmetric carbon atom, the invention also relates to a method of producing optically active variants and racemic mixtures of these compounds.

The new compounds of general formula I, prepared by the process according to the invention, have valuable pharmacological properties, in particular the strength of heart contraction, and either reduce arterial pressure and or influence thrombocyte aggregation and improve microcirculation.

In the following formulas, especially in general formula I, R5 and R2 are the same or different and represent a hydrogen atom, a linear or branched alkyl group with 1-6 or 2-6 carbon atoms.

However, for R5 and R2, in particular hydrogen, methyl or ethyl are suitable. If only R2 is hydrogen then R1 is a 1-6 carbon linear alkyl group, branched alkyl group or cycloalkyl group. *

In this sense, there are methyl, ethyl, isopropyl, isobutyl, pentyyl, cyclopeethyl and cyclohexyl groups.

R 1 and R 2 together with the carbon to which they are attached may also form a ring

148 O17 cycloalkyl having 3 to 8 carbon atoms, in particular being an apirocyclopropyl group. spiro cyclobutyl, spirocycopentyl and spirocyclohexyl group.

The alkyl or alkoxy substituents of the pyridine ring contain 1-6, especially 1-4, carbon atoms. There is a difference between the methyl and ethyl groups, or the methoxy and ethoxy groups.

If Py is a 2-, 3- or 4-pyridyl group, which optionally contains an oxygen atom on the ring heteroatom and is either substituted by one or more alkyl or alkoxy groups and X is a valence bar, then the 2-pyridyl group is , 2- (N-oxypyridyl), 3-pyridyl, 3- (N-oxypyridylvah),

3- (6-methylpyridyl), 3- (2-methoxy-6-methylpyridyl), 4-pyridyl, 4- (N-oxypyridyl) and 4- (2-methylpyridyl).

If X is an alkylene group of 1-4 carbon atoms or a vinylene group and Py is a 2-, 3- or 4-pyridyl group, then in this sense the 3-pyridylvinyl, 4-pyridylmethyl and 4-pyridyllethyl groups are particularly distinguished.

They are distinguished by the pharmacological action of pyrrolobenzimidazoles of the general formula I, in which Rj represents a hydrogen atom, a methyl, ethyl, 2-propyl, 2-methylpropyl or cyclopentyl group, represents a hydrogen atom, a methyl, ethyl group, R5 and R together with a carbon atom, to which they are attached represent a cyclpentane ring, X is a valence bar, a methylene, ethylene or vinylene group, and Py is a pyridyl N-oxide group or a pyridyl group, which is optionally substituted one or more times with methoxy or methyl.

The compounds of the general formula I are particularly distinguished in terms of pharmacology, in which X represents a valence line, R 2 represents a hydrogen atom or a methyl group

R 4 is methyl, ethyl and Py is a pyridyl N-oxide group or a pyridyl group which is optionally substituted with a methyl group.

According to the invention, the compounds of general formula I are prepared as follows: The compounds of formula II in which X and Py are as defined below are reacted with a reactive derivative of the carboxylic acid of general formula III, in particular with an acid chloride in which R R5 are as defined above to the corresponding hydrazides and these are then cyclized under alkaline conditions (Brunner * a synthesis). '

Reactive derivatives of the carboxylic acids of general formula III are especially acid chlorides, anhydrides or mesylic and tosyl esters.

In the above-mentioned cyclization to the desired compounds of the general formula, it is preferably carried out in a solvent or a mixture of solvents, such as, for example, ethanol, isopnpanol, glacial acetic acid, benzene, toluene, chlorbeezenide, glycol, ethylene glycol dimethyl ether, sulfolane (1,1). -tetrahydrophone dioxide) or dimethylformamide at a temperature of C-²²O ° C mostly but at boiling point it freezes^r r^ein the presence of a condensing agent, such as phosphorus oxychloride, terti-ionyl chloride, p-toluenesuffic acid, hydrochloric acid, sulfuric acid, phosphoric acid, polyhosoric acid, or optionally also in the presence of a base, such as sodium hydroxide, sodium methoxide or potassium tert-butoxide. However, the cyclization can also be carried out in the absence of a solvent or condensing agent.

Additional conversion of compounds of general formula I to others of general formula I involves, for example, the oxidation of a pyridyl group to the corresponding N-oxide, which is carried out predominantly with hydrogen peroxide in acetic acid, as well as hydrogenation of the unsaturated substituent. This applies in particular to the hydrogenation of a vinyl compound (X = -GH = CH-) to the corresponding ethyl compound.

In order to convert the compounds of general formula I or their tautly derivative forms into pharmacologically acceptable salts, these compounds are mainly reacted in

148 017 in an organic solvent with an equivalent amount of an inorganic or organic acid, e.g. hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, tartaric, maleic, fumaric, benzoic or cyclohexylsaminic acid.

Pharmacological studies confirm the action of the new compounds. These studies were carried out using the following methods:

Female Spragne-Bawley rats weighing from about 350 to about 450 g were anesthetized with an intraperitoneal injection of barbiturate. Because the animals were prepared for the research as follows:

- a pressure measuring catheter (Millar Nikrotip, 0.5 mm in diameter) was inserted into the left ventricle through the right carotid artery (arteria carotis dextra). The pressure in the left ventricle in the left ventricle was recorded continuously with this measuring apparatus.

- Because the jugular vein was fitted with a polypopyee catheter for the intravenous injection of the test substance.

- A polypropylene catheter was inserted through the femoral artery into the abdominal aorta for direct blood pressure measurement.

* EKG. made with a piercing electrode.

Rats were permanently attached to an electrically heated and thermostatically maintained operating table during the preparation of the animals and for the following duration of the study.

The application of the test substance was always carried out by means of intravenous claims, whereby the injection volume was 1 mL / kg body weight. Doses increasing from 0.01-30 mg were injected intravenously at intervals of 10 minutes each. In this way, dose action curves were obtained with respect to the renew parameters of the test substances.

The positive (dp / dt) effect was calculated from the measurement data by calculating regression-equipotential doses. in addition, the respective maximum effect (in terms of dp / dt) and the corresponding dose were determined as a criterion for the potency of the substance.

The following table contains the subordination of the total doses (De. C = each dose in mg / kg), which leads to an increase in the strength of heart contraction by 1.5 mHg sec.) And maximum force of action - the maximum increase in the force of contraction dp / dt - in relation to the respective initial value). .

Wyyiki:

<td>Substance (example)</td><td>DE ^ 5 m ^ sec mg kg intravenously</td><td>IN max snapshot</td>

<td>II</td><td> 0,03 '</td><td> 4,9</td>

For the production of medicaments, the compounds of general formula I are mixed in a known manner with suitable pharmaceutical carriers, aromatics, flavors and dyes, and then formed into tablets or dragees, for example, or dispersed or toe injured in water or oil after adding suitable oomoonics. such as olive oil.

In the process according to the invention, the new substances of the general formula I and their salts can be used in liquid or solid form, either in the form of a liquid or in parenteral form. Water is generally used as the injection medium, which contains additives used in injection solutions such as stabilizers, dissolution aids or buffers. This kind. extras are e.g. Calcium and citrinic buffer, ethanol, creative complex substances, such as polyethylene diamine tetaocOic acid and its non-toxic salts as well as highly4

148 017 molecular polymers like liquid polyethylene oxide for viscosity regulation. Solid carriers are, for example, starch, lactose, mairnite, meelylcellulose, talc, highly dispersed silicic acids, high-molecular-weight fatty acids such as stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and plant glycolate and solid polymers such as polyethylene glycols. Preparations suitable for oral administration may optionally contain flavoring and sweetening agents.

The compounds of general formula I prepared according to the invention are administered in an amount of 10 to 500 mg per day for a body weight of 75 kg. It is preferable to administer 1-2 tablets with an active substance content of 5 - 200 mg 2-3 times a day.Tablets can also be delayed, only 1-2 tablets with an active substance content of 10 - 500 mg are administered only once a day. can also be used by injection 1-8 times a day or by drip, usually 5-200 mg per day is sufficient.

Examples of the invention are given below:

Example 1: 7,7-Dimethyl-2- (4-pyridyl) -6.7- ^ 1) ^^ 0-3 ^ 511- ^ ^ 10 (2.3- ^) benzimidazol-6-one.

A mixture of 23 g, 0.1 mole of 5-hydrazino-2- (4-eyridyl) -benzimiazole with 8.8 g of 0.1 mole of 2-methylpropino acid is stirred for about 3 hours at 130 ° C and after cooling the mass treats with water. Pull off strongly and wash well with ether. The residue (14.3

g) mixed thoroughly with the finely pulverized 75 g of calcium oxide and heated to 180 ° C in a flask under nitrogen for about 4 hours. After cooling, it is mixed with water and, after adding 600 ml of 2 N -OL, it is boiled for about 1 hour under reflux. It is drained and the residue is treated several times with dimztylformamide until a small amount of inorganic eO2O residue is dissolved. The aqueous filtrate is extracted with dichloromethane n-butanol, all organic phases are combined and concentrated in vacuo. It is then purified by column chromatography on silica gel 60 (Merck) eluting with dichloromethane / methanol 95: 5 80:20 the desired product, which is then recrystallized from kZ ^ ^ ^.^x

Yield: 3.5 g (12% of theory) mp 285-288 ° C.

The following compounds are obtained in an analogous manner:

a) 7,7-yimeeyl-2- (2-eiryys^τIo) -θ, 7yiihydro-3H, 5-pyrolo (2,3-f) benzimidazole-one x 0.3 -₂0 from 3-hydrazino-2- (2-pyridyl) - 4-mzilidfzole and 2-metsloeinopyrin acid at a yield of 14%, mp 184-188 ° C (water). .

b) 7,7-yimethyl-2- (3-eyridyl) -6,7ydiSydro-3-, 5-pyrrole / 2,3-7 / b ^ z ^^ ddzc ^ - ^ x 3 -20 z 3- hydrfz; y10-2- (3-pyridyl) benzimifzole and 2-methyleropione / zro acid, with a specificity: 13%, mp: 33O-353 ° C (dioxane / water 2: 1).

c) 7,7-yl-2-yl-2- (4-erylyl) -6-7dihydro-3-, 3-pyrrole (2,3-f) benzimidazole-one with 5-hyyrphazine-2- (4 -pyridsylbenzimidazole and 2-methylpropionic acid, with equality: 11%, melting point: 215 ° C, ethanol / water 1: 3,

d) 7,7-dimethyl-2- / 4- (2 ^ 617 ^ 1 ^ (171-0)] -6.7- ^ 1 hydr-o - ^ -, 5—- · ρyrrole / 2,3- f / benzimidazole^-6-on x ^{0,6 -2}° z ^ bLy ^^ yno-²- / 4- (2-methylpyr^dyl)] -benzimidazole and q ^ 2^-me^withyl^aboutdilution: 13%, mp 311-313 ° C (acetone).

z) 7,7-yimethyl-2- (4-eyridylsyl o) 66_Ł7ydiSydro-3-, 3 - pyrrole / 2,3-f / bzizimidazol-6-oi x 0.6-20 with 3 “hsdrfzyno-2 (4-pyridsloztslo) bbeńzimiyazole and 2-methylpyopyino acid / zgo z / Sdfność: 12% melting point: 151 - 154 ° C (water) ^f) ⁷,^7-dime^withylo-²~ / 3- (6-mz^volyloeias^yylo) / - ^ - ^ h ^ ro ^ -, 5H-mrolo (2,3-f) benzimidazole^-6-one of ^ ^ drazine ^ (2- (6-methylpyridyl) / ^ 2-me ^ 10 ^ 001 ^ 10 ^ ^ with yield: 14%, melting point: / 36O [deg.] C (acetate ethyl) mass spectrum: m / e = 293,292,277 (100%)

148 017

g) 2- (4-pyridyl) -6.7-dUhydro-3H, 5H-pyrrolo (2,3-f) benzimidazol-6-one hydrochloride from 5-hydrazine-2- (4-pyridyl) -benzimidazole and chloride acetyl with yield: 5% melting point: 300 ° C (ethanol HCL) spectrum: m / e 466.394 (100%) 147.73

h) 7-methyl-2- (3-pyridyl) -6_&gt;7ddihydro 33H, 5H-pyrrolo (2,3-f) benzimidazole-yellow from 5-hydrapazine-2- (3-pyridyl) -benzimidazole and propionic acid, yield: 15%, melting point: 300 ° C (dioxane / methanol), mass spectrum: m / e = 264 (100%), 249.236

i) 7-meeyl-2- (4β-iridyl) -6-&gt; 7-dihydro-3H, 5H-pyrrolo (2,3-f) benzimidazol-6-one with 5-hydrazine-2- (4-pyridyl) - benzimidazole and propionic acid, yield: 13%, melting point: 315 · - 318 ° C (ethanol / water).

Example II. 7,7-dimethyl-2- (4-N-poxy-iridyl) -6,7-diihydro-3H_f5H-pyrrolopy (2,3-f) benzimiaazole 6-one x 3 ^ 0

A solution of 3.9 g (0.014 moo) of 7.7-dimethyl-2- (4-pyridyl) -6&gt; 7-didydro-3H, 5H-pyrrolo 2,3-fbenzimidazolpone in 50 ml of glacial acetic acid with 20 ml of 30 % hydrogen peroxide is stirred for 2 days at 50 ° C and then diluted with water.

The precipitated substance is filtered off under reduced ^ όηΐβ ^ βπι and recrystallized from dioxane / water 1: 1. '

Life: 1.4 g or 34% of theoretical value.

Melting point: 260 p 262 ° C.

The following compounds obtained by the process of the invention are prepared in an analogous manner:

7.7 p-dimethyl-2- (3-pytidylvinyl) -6.7aiihydro-3H, 5H-pyrrolo (2,3-f) benzimidazolp6pone, m.p. 203 p 207 ° C (water + 5% CH 3 OH),

7,7-dimethyl-2β / 3- (2-meth) xy-6-phenylpyridyl) / -6&gt; 7-ditydΓ0-3-, 5H-pyrrolo / 2,3-f) benzip midazolp6pon, melting point: 296 ^ 298 ° C,

7- (2-propyl) -2- (4-pyridyl) p6, 7-dihydro-3H, 5H-pipolo (2,3-f) benzim. D2 with &amp; lt; ^]. ^ ^ One, mp: 215 p 220 ° C ( ethanol / water),

7pcycl / pentyl / -2p (4-eiΓydyl^about) -677-diydro-3H, 5-py (l / 2,3-f) benzipidazole-6p / t, melting point: 200 p 204 ° C (dioxane / methanol)

7.7 p-diethyl-2- (4-epiyidyl) 66&gt; 7-di-diyd (O3- ^ H-pyrrolo / 2,3-f) benzipidazole-6- (t) CH, CH, mp: 216 p 219 0,

7- (2-methyleropyl) p2p (4-eΐridyl o) -6&gt; .7-diyyd / 033H, 5H-p.ir / l / / 2,3-f / benzimidazol-6-ot x 1.5 H20 Mp: 200 µL 202 ° C.