HU219479B - Imidazo[4,5-b]pyridine and benzimidazo derivatives, process for producing them and pharmaceuticals comprising the same as active agent - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to imidazo [4,5-b] pyridine and benzimidazole derivatives of formula (I), to their preparation and to pharmaceutical compositions containing them. In general formula (I), A is a straight or branched alkyl group having up to 6 carbon atoms, C3-8 cycloalkyl, or phenyl, B and D taken together to form (a) or (b), in which R2, R3 and R4 have the same or different meanings, and hydrogen, C 1-6 alkyl or halogen; T is (f), (g) or (h) wherein R 5 is hydrogen or straight or branched alkyl having up to 6 carbon atoms, R 7 is optionally substituted with 1 to 4 carbon atoms; phenyl, R9 is halogen substituted or unsubstituted phenyl, R10 is -CH2OH, -CO-NH2 or pyridyl, or T is optionally substituted with triphenylmethyl. The active substances have antihypertensive and antianterosclerotic activity. ŕ

Description

The present invention relates to novel imidazo [4,5-b] pyridine and benzimidazole derivatives, to their preparation and to pharmaceutical compositions containing them, in particular antihypertensive and antiaterosclerotic pharmaceutical compositions.

Renin, a proteolytic enzyme, is known to cleave in vivo from the angiotensinogen a decapeptide called angiotensin I, which then degrades into the angiotensin II octapeptide in the lungs, kidneys and other tissues. Various effects of angiotensin II, such as vasoconstrictor effect, retention of Na ^{+ in} the kidney, release of aldosterone in the adrenal gland, tone up of the sympathetic nervous system, act synergistically in raising blood pressure.

In addition, angiotensin II stimulates the growth and proliferation of certain cells, such as myocardial and smooth muscle cells, such that in various pathological conditions (e.g., hypertension, atherosclerosis and heart failure), these cells grow and proliferate.

One way of interfering with the renin-angiotensin system is to inhibit renin activity, another is to block the activity of the angiotensin conversion enzyme (ACE) and block the angiotensin II receptor.

EP 407 102, EP 399 731, EP 399 732, EP 324 377 and EP 253 310 disclose heterocyclic compounds which are angiotensin II antagonists.

The present invention relates to imidazo [4,5b] pyridine and benzimidazole derivatives of formula (I):

A is a straight or branched alkyl group having up to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group,

B and D together form a group of formula (a) or (b), wherein R ² , R ³ and R ^{4 are the} same or different and may be hydrogen, C 1 -C 6 alkyl or halogen,

T is (f), (g) or (h) a group wherein R ⁵ represents a hydrogen atom or a linear or branched alkyl having up to 6 carbon atoms,

R ⁷ is phenyl optionally substituted with C 1-4 alkyl,

R ⁹ is phenyl optionally substituted with one or two halogen atoms,

R ^{10 is} -CH ₂ OH, -CO-NH _2, or pyridyl, or

T is tetrazolyl optionally substituted with triphenylmethyl.

The present invention also relates to stereoisomers and salts thereof.

In the context of the present invention, physiologically tolerable salts are preferred. Physiologically acceptable salts of pyridones having a sulfonyl substituent may be formed, for example, with a mineral acid, a carboxylic acid or a sulfonic acid. The salts with the following acids are preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, malic acid, benzoic acid,.

The physiologically tolerable salts may also be metal or ammonium salts, provided that the compound of formula (I) has a carboxyl group. Particularly preferred are the sodium, potassium, magnesium or calcium salts as well as the ammonium salts or salts with organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylamino- ethanol, arginine, lysine or ethylenediamine.

The novel compounds may exist in stereoisomeric forms, enantiomers or diastereomers. The invention encompasses both enantiomers, diastereomers and mixtures thereof. Racemic forms and diastereomers can be resolved into standard stereoisomeric isomers in a known manner (E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill 1962).

The above compounds are prepared according to the invention by reacting a compound of formula II with a compound of formula II.

W is a typical leaving group such as chlorine, bromine, iodine, tosylate or mesylate, but preferably bromine, and

X is C 1 -C 6 alkoxycarbonyl or triphenylmethyl-tetrazolyl, first with a compound of formula (III), wherein A, B and D are as defined above, in an inert solvent, optionally in the presence of a base and optionally under a protective gas atmosphere and then, if desired, the resulting compound

i) hydrolyzing the R ⁵ alkyl group of formula (f) and / or ii) the T substituent of group f) with an amine of formula Va, wherein R ⁹ and R ¹⁰ have the meanings given above - ( converting h) group, or iii) present in the T substituent (f) the group (V) sulfone amine - in formula (V) ^R7 is as defined above - is converted to (g) group, and / or iv) the appropriate with a base or acid.

An embodiment of the process of the present invention is illustrated in the following Scheme A).

Suitable solvents for the process are the customary organic solvents which are not affected by the reaction conditions. Preferred are: ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, hydrocarbons such as benzene, toluene, hexane, cyclohexane or petroleum fractions; and halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Mixtures of the above may also be used. Tetrahydrofuran and dimethylformamide are preferred.

The base used in the process of the present invention may be an inorganic or organic base, preferably alkali metal hydroxides or alkaline earth metal hydroxides.

Dosages such as sodium hydroxide, potassium hydroxide or lithium hydroxide, barium hydroxide, alkali metal or alkaline earth metal carbonates, such as sodium or potassium carbonate, calcium carbonate, or alkali metal and alkaline earth metal alcoholates, - or potassium methoxide or potassium tert-butylate, or organic amines [trialkyl (C ₁ -C ₆₎ amines], such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO ), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. The base may also be an alkali metal such as sodium metal or an alkali metal hydride such as sodium hydride. Sodium hydride, potassium carbonate, triethylamine, pyridine and potassium tert-butylate, DBU and DABCO are preferred.

The base is generally used in an amount of from 0.05 to 10 moles, preferably from 1 to 2 moles, per mole of starting material (II).

In the process according to the invention, the reaction temperature is generally -80 ° C to + 100 ° C, preferably -30 ° C to + 60 ° C.

The process of the invention is generally carried out at atmospheric pressure, but it is also possible to carry out the reaction under pressure or under reduced pressure (for example, in the range of 0.5 to ^{5 5} Pa).

Commonly used bases for hydrolysis can be used. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium bicarbonate, ethanolate, potassium ethanolate or potassium tert-butylate. Lithium hydroxide, sodium hydroxide and potassium hydroxide are particularly preferred.

Suitable solvents for the hydrolysis include water or organic solvents used in the hydrolysis such as alcohols such as methanol, ethanol, propanol, isopropanol or butanol, ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Alcohols such as methanol, ethanol, propanes or isopropanol are particularly preferred. Mixtures of the above may also be used.

Hydrolysis may also be carried out, for example, with aqueous acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid. Trifluoroacetic acid is preferred.

The hydrolysis temperature is generally from 0 ° C to 100 ° C, preferably from 20 ° C to 80 ° C.

The hydrolysis is usually carried out at atmospheric pressure, but may also be carried out at elevated pressure or reduced pressure (for example 0.5-5 χ 10 ⁵ Pa).

In carrying out the hydrolysis, 1-3 moles of base, preferably 1-1.5 moles of base, are generally expected per mole of ester, preferably equimolar amounts.

During the first step, the carboxylates of the compounds of the invention are formed and can be isolated. The acids of the invention are obtained by treating the carboxylate with an inorganic acid. Suitable acids are, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid or trifluoroacetic acid. In the preparation of the carboxylic acids, it has been found advantageous not to isolate the carboxylate but to acidify the alkaline reaction mixture of the saponification and isolate the acid in a known manner. In the case of a basic heterocyclic compound, an inorganic acid salt thereof may also be prepared by treating the carboxylate solution with one of the above acids.

Sulfonamidation or amidation of compounds of formula (IV) is generally carried out in one of the solvents indicated above, tetrahydrofuran and dichloromethane being preferred.

Prior to the amidation, the acid can be activated to form an acid chloride such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride.

The amidation temperature is usually -20 ° C to 80 ° C, preferably -10 ° C to 30 ° C.

In addition to the bases mentioned above, triethylamine and / or dimethylaminopyridine, DBU or DABCO are preferably used.

The base is used in an amount of 0.5 to 10 moles, preferably 1 to 5 moles, per mole of the compound of formula (V) or (Va).

The amidating agent used during the amidation is an alkali or alkaline earth metal carbonate such as sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, or organic bases such as pyridine, triethylamine, N-methyl piperidine or bicyclic amidines such as 1,5-diazabicyclo [3.4.0] nonene-5 (DBN) or 1,5-diazabicyclo [3.4.0] undecene-5 (DBU) may be used. Potassium carbonate is preferred.

Suitable dehydrating agents include carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyloxytris (dimethylamino) phosphonium hexyl fluorophosphate or phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in the presence of a base such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide or N-hydroxysuccinimide.

The acid scavengers and water scavengers are generally employed in an amount of 0.5 to 3 moles, preferably 1 to 1.5 moles, per mole of carboxylic acid.

Most of the cyclohexane compounds of formula II are novel. They may be prepared by hydrogenating the compound of formula (VI) with a palladium-on-carbon catalyst in one of the above solvents, preferably methanol, under a hydrogen atmosphere, and the resulting compound of formula (VII) in a second step.

HU 219 479 Β

- is esterified in a conventional manner to produce a compound having a substituent other than tetrazole;

- reacting the T-tetrazolyl group with tetrazolyl, in the presence of a base, preferably?,? reacting the triphenylmethyl group in one of the solvents mentioned above in the presence of one of the above bases, preferably dichloromethane, in the presence of triethylamine;

- and finally, the methylene group is optionally brominated in the presence of a catalyst.

Reduction of the double bond at temperatures between 0 ° and 40 °, preferably 20 ° C L-10xl0 ⁵ Pa, preferably 1-3 χ done 10 ⁵ psi.

The esterification is carried out in one of the solvents indicated above, preferably in toluene or tetrahydrofuran, after the carboxylic acid is activated as described above. Preferably, the reaction is conducted through the acid chloride and the product is subsequently reacted with the appropriate alcoholate at a temperature of 0 ° C to 60 ° C, preferably 10 ° C to 35 ° C.

In preparing the cyano compound and the tetrazolyl compound, the reaction temperature is usually the boiling point of the solvent used and the reaction is carried out at atmospheric pressure.

The triphenylmethyl group is generally introduced into the tetrazole ring at 0 ° C.

The bromination is generally carried out at a temperature of 40 ° C to 100 ° C, preferably 60 ° C to 90 ° C and at atmospheric pressure, in one of the solvents mentioned above, preferably in carbon tetrachloride, with N-bromosuccinimide.

The bromination catalyst used is, for example, azo-bis-isobutyronitrile or dibenzoyl peroxide, but preferably 0.01-0.1 mol, preferably 0.01-0.05 mol, per mol of compound (VII).

The compound of formula (V) is also novel and can be prepared, for example, by reacting the compound of formula (VIII) in one of the above solvents, preferably toluene, with 1,3-butadiene in the presence of hydroquinone at a temperature of 180 ° C to 230 ° C. at a pressure of about 20 χ 10 ⁵ Pa [Eur. J. Med. Chem. 11, 493 (1976)].

The compound of formula VIII is known.

The compound of formula (VII) is novel and can be prepared, for example, by the methods described above. The same applies to the compound of formula III.

The amines of formula (V) are known and can be prepared by known methods.

The compounds of formula I according to the invention have valuable pharmacological effects which are unexpected.

The compounds have an angiotensin II antagonist activity because they inhibit the binding of angiotensin II to A-II receptors. They suppress the vasoconstrictor effect of angiotensin II and its stimulatory effect on aldosterone secretion. In addition, they inhibit the proliferation of smooth muscle cells.

Therefore, the compounds are useful in the treatment of arterial hypertension and atherosclerosis. In addition, they may be useful in coronary heart disease, heart failure, cerebral dysfunction, ischemic brain disorders, limb blood flow disorders, renal and adrenal dysfunction, bronchospasm and respiratory tract disorders, sodium.

Inhibition of agonist-induced contraction

Domestic rabbits of both sexes were anesthetized by nape percussion and bleeded, or occasionally anesthetized with non-butal (about 60-80 mg / kg iv) and killed by opening the chest. The lung aorta was removed, the adherent connective tissue was removed, dissected into 1.5 mm wide ring segments, and the rings were each suspended in 10 ml organ baths (KrebsHenseleit / Na: 2.5 mmol / l CaCl ₂ x 2 H ₂ O; 1.2 mmol KH ₂ PO ₄ ; 10 mmol / l glucose; 4.8 mmol / l KCl; 1.4 mmol / l MgSO ₄ x 7 H ₂ O; 25 mmol / L NaHCO ₃ ).

The contraction was recorded isometrically with a Statham UC2 battery, a bridge amplifier (ifd Mülheim, or DSM Aaalen) and digitized and evaluated with an analog / digital converter (A / D converter, system 570, Keithley Munich). The agonist dose response curve was plotted hourly, with each concentration plated at 3 and 4 different concentrations in baths at 4-minute intervals. Following the curve, the wash cycle (16 times 5 sec / min with the above medium) followed by a resting or incubation pause (28 min), during which the contraction usually resumes its initial value.

The height of the 3rd dose response curve is generally used as a reference. The following curves are plotted with increasing concentration of test substance (bath at the beginning of incubation time). Each aortic ring is stimulated with the same agonist throughout the day.

Agonists and their standard concentrations (one dose

100 μ 100) KC1 22.7; 32.7; 42.7; 52.7 mmol / 1 1-noradrenaline 3x10-9; 3x10-8; 3xl0- ^7; 3x10-6 g / ml serotonin ΙΟ »; 10-7; io-6 _; 10-5 g / ml B-HT 920 ΙΟ "⁷;10-6; io-5 g / ml methoxamine ΙΟ- ⁷ ; 106; io-5 g / ml Angiotensin II 3xl0- ^9; 10-8; 3x10-8; 10-7; g / ml

The IC ₅₀ concentration (the concentration at which the test substance causes 50% inhibition) was calculated by measuring the effect at 3 (submaximal) agonist concentration.

The compounds of the invention inhibit angiotensin II-induced contraction of the isolated rabbit aorta in a dose-dependent manner. Potassium depolarization or other agonist

The contraction caused by the compounds was either not inhibited or was poorly inhibited at high concentrations.

The table

Inhibition of contraction of aortic ring isolated from rabbit in vitro IC ₅₀ [nM] against contraction

Example number Ali IC ₅₀ [nM]

9. 260

30. 220

Blood pressure of angiotensin II-infused rat

Male Wistar rats (300-350 g) (Moellegaard, Copenhagen, Denmark) were anesthetized with thiopental (100 mg / kg ip). After laryngeal dissection, a catheter was inserted into the femoral artery for blood pressure measurement, and one catheter was inserted into each femoral vein, one for angiotensin II infusion and the other for administration of the compounds to be tested. After administration of the pentolinium ganglion blocking drug (5 mg / kg iv), angiotensin II infusion was started at a rate of 0.3 pg / kg / min. When the blood parameters are stable, the test compounds are administered either intravenously or in suspension or solution (0.5% in tylose). The change in blood pressure due to the active compounds is given in the table as a mean, with standard deviations.

Antihypertensive effect in non-anesthetized hypertensive rats

The antihypertensive effect of the compounds of the invention was measured (by oral administration) in non-anesthetized rats with artificially induced bilateral renal artery stenosis. For this purpose, the right renal artery was narrowed with a silver clip with an internal diameter of 0.18 mm. In the resultant hypertension, plasma renin activity was elevated in the first weeks after surgery.

The arterial blood pressure of the animals was measured at the end of a specified period after the administration of the test compound, using a so-called tail cuff. The compounds were administered intragastrically ("orally") in a suspension in a tilose suspension by gavage. The compounds of the present invention reduce the arterial blood pressure of rats at clinically acceptable doses.

In addition, the compounds of the invention inhibit the specific binding of radioactive angiotensin II in a concentration dependent manner.

Interaction between angiotensin II receptor on membrane fractions of adrenal cortex (bovine) and compounds of the invention

Freshly taken bovine adrenal cortex is carefully cleansed from the marrow and then minced into a coarse membrane homogenate in ultra-turmix (Ultra Turrax, Janke & Kunkel, Staufen, B.B.) in 0.32 M sucrose solution and centrifuged into membrane fractions.

Receptor binding assays were performed on partially purified membrane fractions as described above with radioactive angiotensin II in an assay volume of 0.25 mL containing:

50-80 µg of purified membrane, 3-5 nM ³ H-angiotensin II, test buffer (50 mM Tris, pH 7.2), 5 mM MgCl ₂ , and the test compound. The mixture is incubated at room temperature for 60 minutes, then the unbound radioactivity of the samples is removed with a moistened glass fiber filter (Whatman GF / C) and washed with ice-cold buffer (50 mM, Tris / HCl, pH 7.4, 5% PEG 6000). After that, the bound radioactivity was measured spectrophotometrically in a scintillation cocktail. The raw data are computer-processed to K _r and IC ₅₀ (Ki: the IC ₅₀ value corrected for the radioactivity used; IC ₅₀ is the concentration at which the test substance inhibits the specific binding of the radioligand to 50%).

Table B)

Example 9 K i = 47nM

Example 30 Ki = 19nM

Inhibition of smooth muscle cell proliferation

To determine the antiproliferative activity of the compounds, smooth muscle cells were obtained from the porcine aorta by media explantation [R. Ross,

J. Cell. Biol. 50, 172, 1971]. Cells were cultured in suitable culture dishes, usually 24-well plates, in medium 199 (7.5% FCS, 7.5% NCS, 2 mM Lglutamine, 15 mM HEPES, pH 7.4, 5% CO ₂ ) at 37 ° C. The serum is then withdrawn for 2 to 3 days to allow cells to synchronize. Thereafter, growth is stimulated by the addition of serum or other factors. The test compounds are administered simultaneously. After 16-20 hours, 1 pCi of ³ H-thymidine is added and after another 4 hours the incorporation of thymidine into the TCA-precipitated DNA of the cells is determined. For the calculation of IC ₅₀ values, the concentration of drug that inhibits thymidine incorporation by 10% FCS is determined.

Table C)

Example number IC ₅₀ [nM]

16. 410

17. 2

21.7

25. 26

29. 4

31. 3

The new active compounds may be formulated into pharmaceutical compositions in a known manner. Suitable formulations include tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions. For their preparation, inert, non-toxic, pharmaceutically acceptable carriers and solvents are used. The concentration of active ingredient is generally 0.5 to 90% by weight, i.e., that lower doses may be administered well.

For example, the compositions may be prepared by admixing the active ingredient with a solvent and / or carrier, optionally with emulsifiers and / or dispersants. If the diluent is water, organic solvents may be used as auxiliary solvent.

Administration is by the usual route, preferably orally or parenterally, particularly preferably perlingually or intravenously.

HU 219 479 Β

For parenteral administration, solutions of the active compounds are prepared using suitable liquid vehicles.

Generally, it is preferred that a dose of 0.0001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg, be administered intravenously. For oral administration, the dosage will be about 0.01-20 mg / kg, preferably 0.1-10 mg / kg.

However, it may be necessary to deviate from the above amounts, depending on body weight, route of administration, individual tolerance to the drug, the type of preparation and the time and interval of administration. In some cases, the amount below the minimum mentioned above may be sufficient, while in other cases the specified limit may be exceeded. For larger amounts, it may be desirable to administer the daily amount in divided doses.

Composition of heating mixtures

A = dichloromethane / methanol 10: 1

B = petroleum ether: ethyl acetate 4: 1

C = petroleum ether: ethyl acetate 1: 1

D = dichloromethane / methanol 10: 1

E = ethyl acetate: dichloromethane 1: 1

F = dichloromethane: ethanol 20: 1

G = petroleum ether: ethyl acetate 1: 2

H = dichloromethane: methanol:

aqueous concentrated ammonia 200: 20: 1

Starting materials

EXAMPLE I Trans-6- (4-Tolyl) -cyclohex-3-ene-1-carboxylic acid racemic compound k-1

Hereinafter, the term "racemic compound" is understood to include the enantiomer in the drawing and its mirror image.

275 g (1.695 moles) of 3-E- (4-tolyl) acrylic acid (commercially available) in 480 ml of toluene with 580 ml of 1,3-butadiene (measured in condensed form) are known in the art [Eur. J. Med. Chem. 11, 493 (1976)] was reacted with 3 g hydroquinone in the presence of about 220 ° C and χ in addition to 20 10 ⁵ Pa pressure for 22 hours. The crude mixture was diluted with toluene and extracted with 0.5 N aqueous sodium hydroxide. The aqueous layers were acidified with 1N hydrochloric acid and extracted with ether. The ethereal solutions were dried over anhydrous sodium sulfate, evaporated and the residue dissolved in toluene. After boiling the solution with 5 g of activated carbon for 15 minutes, suction is carried out and the solvent is evaporated to a volume of 120-160 ml; At 0 ° C, 124 g (573 mmol) of product crystallize out. The filtrate was further concentrated and cooled for post-crystallization. Repeat this to give a total of another 42 g (194 mmol) of product.

R _f = 0.39 (dichloromethane: methanol 10: 1)

II. EXAMPLE 6 Trans-2- (4-Tolyl) -cyclohexane-1-carboxylic acid racemic compound k-2

155 g (717 mmol) of compound 1 from Example I liter of methanol was hydrogenated in the presence of 10 g of 10% Pd-C in 20 ° C, a hydrogen pressure of about 10 ^5. After about 16 hours, the catalyst is filtered off and the solvent is evaporated off under vacuum.

Yield: 153 g (701 mmol).

R _f = 0.38 (dichloromethane: methanol 10: 1).

III. EXAMPLE 4 Trans-2- (4-Tolyl) -cyclohexane-1-carboxylic acid tert-butyl ester;

is a racemic compound of formula (k-3)

Method A)

45.8 g (184 mmol) of II. A solution of the compound of Example 1b in toluene (60 mL) was treated with oxalyl chloride (49.5 mL, 387 mmol) at reflux. After 2 hours, the solvent and excess reagent are evaporated off, if necessary, the carboxylic acid chloride is re-taken in toluene and the solvent is distilled off again. The product was dissolved in tetrahydrofuran (500 mL), stirred at 0 ° C with potassium tert-butylate (24.8 g, 221 mmol), and stirred at 20 ° C for 20 h. After addition of water and ether, it is extracted several times. The organic layer was dried over anhydrous sodium sulfate, evaporated and the residue was chromatographed on silica gel (Kieselgel 60, Merck, petroleum ether and ethyl acetate 20: 1).

Yield: 39.6 g.

R _f = 0.47 (petroleum ether: ethyl acetate 10: 1)

Method B

20.0 g (91.6 mmol) of II. To a suspension of the compound of Example 10a and 7 mL of concentrated sulfuric acid in 100 mL of ether was added 80 mL (713 mmol) of isobutene (autoclave) at -30 ° C. The reaction mixture was heated to 20 ° C in a sealed vessel and maintained at this temperature for 20 hours. The mixture was then cooled again to 30 ° C, the autoclave was opened and the reaction mixture was stirred at 20 ° C in a mixture of 300 ml of 3N sodium hydroxide solution and 400 ml of ether. The aqueous phase is extracted once more with ether, the organic solution is dried over anhydrous sodium sulfate and then concentrated.

Yield: 23.3 g (84.9 mmol).

ARC. EXAMPLE 4 Trans-2- [4- (Bromomethyl) phenyl] cyclohexane-1-carboxylic acid tert-butyl ester;

is a racemic compound of formula (k-4)

11.70 (42.6 mmol) III. EXAMPLE 1 Compound

To a solution of carbon tetrachloride (100 mL) was added refluxing N-bromosuccinimide (7.59 g, 42.6 mmol) and azobisisobutyronitrile (1.4 g). After 4 hours, the mixture was cooled, the precipitated succinimide precipitate was suctioned off and the filtrate was evaporated.

Yield: 14.2 g (40, 2 mmol).

Rf 0.48 (petroleum ether: ethyl acetate 10: 1).

Example V

2-Cyclopropyl-imidazo [4,5-b] pyridine;

k-5

3.27 g (30 mmol) of 2,3-diaminopyridine (Aldrich) and 2.72 g (30 mmol) of cyclopropanecarboxylic acid (Aldrich)

A mixture of toluene phosphoric acid was stirred at 120 ° C for 3 hours. The reaction mixture was poured into ice water, basified to pH 6-7 with sodium hydroxide solution and then to pH 8-9 with sodium carbonate. After repeated extraction with ethyl acetate, the combined organic phases are dried over anhydrous sodium sulfate and then concentrated under high vacuum. The crude product was chromatographed on silica gel (Kieselgel 60, Merck) with dichloromethane: methanol (50: 1).

Yield: 3.01 g (19 mmol).

R _f = 0.38 (10: 1 ethyl acetate: methanol).

VI. EXAMPLE EXAMPLE Racemic Compound of Trans-2- (4-Tolyl) -Cyclohexane-1-Carbonitrile (k-6)

100.0 g (458.0 mmol) of II. To a solution of the compound of Example 1c in dichloromethane (1 L) was added a solution of chlorosulfonyl isocyanate (84.3 g, 595.5 mmol) in dichloromethane (100 mL) at reflux, and the mixture was refluxed for 1 hour. To the cooled reaction mixture, 72 ml (938.9 mmol) of form, Ν-dimethylformamide was added dropwise and the reaction mixture was stirred for an additional 18 hours, then poured onto 350 g of ice. The organic layers were dried over potassium carbonate, evaporated and the residue was distilled.

Yield: 57.8 g (290.2 mmol) of the title product. Boiling point: 122-123 ° C / 20 Pa.

_Rf = 0.81 (dichloromethane).

VII. example

5- [Trans-2- (4-Tolyl) -cyclohex-1-yl] -tetrazole Racemic Compound (k-7)

15.34 g (69.6 mmol) of VI. example compound,

A mixture of 230 ml of anhydrous Ν, Ν-dimethylformamide, 22.6 g (348 mmol) of sodium azide and 47.9 g (348 mmol) of triethylammonium chloride is reacted at reflux under nitrogen. After 20 hours, the cooled mixture was poured into a mixture of ether and 1M sulfuric acid and extracted with 10% sodium hydroxide solution. The aqueous phase is acidified to pH 1.5 with 1N hydrochloric acid at 0 ° C, the precipitate is filtered off with suction, washed with water and dried under high vacuum with phosphorus pentoxide and sodium hydroxide.

Yield: 11.2 g (46.2 mmol).

R _f = 0.23 (dichloromethane: methanol = 20: 1).

VIII. example

5- [trans-2- (4-Tolyl) -cyclohex-l-yl] -2- (triphenylmethyl) tetrazole;

is a racemic compound of formula (k-8)

11.0 g (45.7 mmol) VII. A solution of the compound of Example 1a in dichloromethane (170 mL) was treated with triphenylmethyl chloride (13.4 g, 48.2 mmol) and triethylamine (7.57 mL, 56.6 mmol) at 0 ° C. The temperature was allowed to rise to room temperature and the mixture was stirred for a further 20 hours. It is then extracted with food and aqueous citric acid. The organic layers were dried over anhydrous sodium sulfate and evaporated.

Yield: 22.1 g (45.5 mmol).

_Rf = 0.67 (petroleum ether: ethyl acetate = 5: 1).

IX. example

5- [trans-2- (4-Bromo-phenyl) cyclohex-l-yl] -2- (triphenylmethyl) tetrazole;

is a racemic compound of formula (k-9)

22.1 g (45.5 mmol) VIII. A solution of the compound of Example 3a in 300 ml of carbon tetrachloride was refluxed with 8.1 g (45.5 mmol) of N-bromosuccinimide and 0.3 g of azo-bis-isobutyronitrile. After 3 hours, the mixture was cooled to room temperature and then to 0 ° C. The precipitate is filtered off with suction. The filtrate was evaporated; the resulting crude product is further reacted without further processing.

Yield: 26.6 g.

_Rf = 0.47 (petroleum ether: ethyl acetate = 10: 1).

Production examples

EXAMPLE 1 Trans-2-Cyclopropyl-1 - {[4- (2-tert-butoxycarbonyl / cyclohexyl) -phenyl] -methyl} -imidazo [4,5-b] pyridine racemic compound 1

Example V (0.90 g, 5.7 mmol) in dimethylformamide (15 mL) was treated with sodium hydride (80%, paraffin-stabilized, 80%, 0.17 g, 5.7 mol) at 0 ° C. After the evolution of hydrogen had ceased, the mixture was stirred for a further 20 minutes and then 2.00 g (5.7 mmol) of IV was added at 0 ° C. A solution of the compound of Example 1b in dimethylformamide (20 ml) was added dropwise. The temperature was allowed to rise to room temperature and the mixture was stirred for another 20 hours and then extracted with a mixture of water and ether. The organic layer was dried over anhydrous sodium sulfate, concentrated and the residue was chromatographed on silica gel (Merck Kieselgel 60, petroleum ether / ethyl acetate 1: 1).

Yield: 0.4 g (0.9 mmol).

R _f = 0.60 (petroleum ether: ethyl acetate = 1: 2).

Following the procedure of Example 1, the following compounds of Formula Ia are summarized in Table 1 below.

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The serial number of the example

Table 1

Z T

Rf (Running)

-CO ₂ C (CH ₃ ) ₃ 0.16 (B)

-CO ₂ C (CH ₃ ) 3 0.50 (B)

λΤΟ ^ -COaCCCH 0.21 (B) ix _ν _ _ν ^ .ηΛ γ 0.74 (G) _N _ _N , c «W, N ^ N 0.53 (G) 0.50 (0 H, O (CH _i ) ₁ ^x ^ N ^{x S} 'N' ^ CO ₂ C (CH ₃ ) ₃ 0.41 (D) U ¹ CO ₂ C (CH ₃ ) 3 0.18 (D)

EXAMPLE 10 Trans-2-Cyclopropyl-1 - {[4- (2-carboxycyclohexyl) -phenyl] -methyl} -imidazo [4,5-b] pyridine racemic compound 10

A solution of the compound of Example 1 (0.39 g, 0.9 mmol) in dioxane (10 mL) was treated with concentrated hydrochloric acid (10 mL) at 20 ° C. After 18 hours, the solution was basified to pH 13 with 2N sodium hydroxide solution and extracted once with ether. The phases are separated, the organic solvent is removed from the aqueous phase, and the aqueous solution is adjusted to pH 5 with concentrated hydrochloric acid. The precipitate was filtered off with suction, washed with water and dried under high vacuum over sodium hydroxide and phosphorus pentoxide.

Yield: 0.28 g.

R _f = 0.08 (dichloromethane: methanol = 10: 19).

In analogy to Example 10, the compounds of formula (Ib) in Table 2 were prepared.

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Table 2 Compounds of formula Ib

Example Number Z Rf (Running Mix)

CH?

0.33 (A)

0.32 (C)

0.16 (C)

0.18 (B)

0.16 (0

Examples 16 and 17 trans-2-Cyclopropyl-1 - {[4- [2 - ((2-hydroxy-2 (S) -phenylethyl) aminocarbonyl) cyclohexyl] phenyl] -methyl} imidazo (4,5-b] pyridine Compound 16

A solution of the compound of Example 10 (0.12 g, 0.32 mmol) in THF (4 mL) at -30 ° C was treated with 89.6 L of 45 (6.5 mmol) triethylamine and 26.6 μΐ (0.35 mmol). ) with methanesulfonic acid chloride. After 30 minutes, a solution of 2-phenyl-2-aminoethyl alcohol (52.6 mg, 0.38 mmol) and 4- (N, N-dimethylamino) pyridine (39 mg, 0.32 mmol) in tetrahydrofuran (3 mL) was added. The reaction mixture was added dropwise, the reaction mixture was heated to 20 ° C and stirred for an additional hour, then poured into aqueous sodium bicarbonate solution and extracted several times with ether. The ethereal extracts were dried over anhydrous sodium sulfate, evaporated and the residue was chromatographed on silica gel (Kieselgel 60, Merck: dichloromethane: methanol 50: 1).

Yield:

mg (0.12 mmol) _Rf = 0.63 (A) diastereomer A (Example 16).

mg (0.08 mmol) _Rf = 0.59 (A) diastereomer B (Example 17).

In an analogous manner, compounds of formula (Ic) in Table 3 are prepared.

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Table 3 Compounds of formula Ic

Example lot number Ζ X Rf (running mixture)

18 ΠΩ) V, ^{N <J} C "H, 0.31 (D) 19 ? A / \ / ^OH 0.27 (D) 20 CA - ^^ CON 0.37 (D) 21 CA x ^ CON 0.32 (D) 22 λΤΟ H / HCHJ, 'N CA - ^ CHjOH 0.23 (D) 23 > 0 □ HJC-ÍCHJ, CA ' ^zAk CH ₈ OH 0.15 (D) 24 CA A / ™ 0.42 (H) 25 O ^ ³ ca xA / OH X ^ S 0.40 (H) 26 O-F 0.28 (D) 27 a, A / ⁰ » 0.25 (D) 28 XtO ' ⁸ ' H / XCH,) / N ^ hT CA 0.37 (E)

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Example fate

Table 3 (continued)

X

Rf (running mixture)

Br ch ^ ch ^^ n n

OH

0.27 (E)

CHjtCHp,

0.61 (F)

CHjÍCHj)

0.56 (F)

OH

CA

0.55 (F)

0.51 (F)

0.31 (G)

0.21 (G)

Example 36 trans-2-Cyclopropyl-1 - {[4- [2 - ((4-methylphenyl) sulfonylaminocarbonyl) cyclohexyl] phenyl] methyl] imidazo [4,5-b] pyridine is a racemic compound of formula (36)

A solution of the compound of Example 10 (120 mg, 0.32 mmol) in tetrahydrofuran (4 mL) was treated with methanesulfonic acid chloride (26.6 µL, 0.35 mmol) and triethylamine (194 μΐ, 1.4 mmol) at -20 ° C. . After 2 hours, 66.0 g (0.39 mmol) of 4-toluenesulfonic acid amide and 155 mg (1.28 mmol) of 4- (N, N-diethylamino) pyridine are added and the reaction mixture is stirred for a further 20 hours. it is then poured into aqueous sodium bicarbonate solution and extracted several times with ether. The ethereal extracts were dried over anhydrous sodium sulfate, evaporated and the residue chromatographed on silica gel (Kieselgel 60, Merck, dichloromethane: methanol 50: 1).

Yield: 34 mg (0.06 mmol) of product.

R _f = 0.45 (petroleum ether: ethyl acetate = 1: 8)

EXAMPLE 37 Trans-2-Cyclopropyl-1 - {[4- (2-tetrazol-5-yl-cyclohexyl) -phenyl] -methyl} -imidazo [4,5b] pyridine Racemic Compound 37

0.64 g (1.0 mmol) IX. A solution of the compound of example 1d in tetrahydrofuran (7 ml) at 20 ° C in water (3 ml)

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Yield. 0.27 g (0.7 mmol).

_Rf: 0.35 (dichloromethane: methanol = 10: 1).

The resulting compound is reacted with 2-cyclopropylimidazo [4,5-b] pyridine to give the title compound.

In an analogous manner, the compounds of formula (ld) in Table 4 can be prepared.

and 3 ml of trifluoroacetic acid. After 2 hours, the reaction mixture was diluted with ether and extracted with aqueous sodium hydroxide solution (pH 13). The alkaline aqueous phase was adjusted to pH 4.5 with 1N hydrochloric acid and the resulting precipitate was suctioned off, washed with water and dried under high vacuum over sodium hydroxide and phosphorus pentoxide.

The serial number of the example

Table 4 Compounds of formula (ld)

Z Rf (running mixture)

Claims (3)

PATENT CLAIMS Imidazo [4,5-b] pyridine and benzimidazole derivatives of the general formula (I) A is a straight or branched alkyl group having up to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a phenyl group, B and D together form a group of formula (a) or (b), wherein R ² , R ³ and R ^{4 are the} same or different and may be hydrogen, C 1 -C 6 alkyl or halogen, T is (f), (g) or (h) a group wherein R ⁵ represents a hydrogen atom or a linear or branched alkyl having up to 6 carbon atoms, R ⁷ is phenyl optionally substituted with C 1-4 alkyl, R ⁹ is phenyl optionally substituted with one or two halogen atoms, R ^{10 is} -CH ₂ OH, -CO-NH _2, or pyridyl, or T is tetrazolyl optionally substituted with triphenylmethyl, and stereoisomers and salts thereof. 2. A process for the preparation of a compound of the formula I as claimed in claim 1, characterized in that a compound of the formula II is a compound of the formula II. W is a typical leaving group, preferably chlorine, bromine, iodine, tosylate or mesylate, particularly preferably bromine, and X is C 1 -C 6 alkoxycarbonyl or triphenylmethyl-tetrazolyl, first with a compound of formula III, wherein A, B and D are as defined in claim 1, in an inert solvent , optionally in the presence of a base and optionally under a protective gas atmosphere, and then, if desired, i) hydrolyzing the R ⁵ alkyl group in the formula (f) and / or ii) the T group substituent f) with an amine of the formula Va: in the formula Va, R ⁹ and R ¹⁰ represent 1. or (iii) converting (f), which is present as a T substituent, to a sulfonamide of formula (V), wherein R ^{7 in} formula (V) is as defined in claim I, and or iv) forming a salt with a suitable base or acid. A pharmaceutical composition comprising at least one imidazo (4,5bpyridine or benzimidazole derivative of the formula I according to claim 1 or a physiologically tolerated salt or isomer thereof together with a suitable carrier.