CS268688B2 - Method of substituted imidazopyrrole,-pyridine and-azepine derivatives production - Google Patents

Abstract

(A) Bicyclic imidazole derivs. of formula (Ia)-(Ic) and their salts are new. R1=H; alkyl opt. substd. by alkanoyl, NH2, mono- or dialkylamino, SO3H, COOH, alkoxycarbonyl, CONH2 or CN; 2-7C alkyl substd. by OH, alkoxy, halogen or alkanoyloxy; NO2, alkoxy, alkanoyl alkanoyloxy, phenylsulphonyloxy, alkylsulphonyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkanoylthio, NH2, mono- or dialkylamino, alkylenamino, morpholino, thiomorpholino, 1-piperazinyl, 4-alkyl-1-piperazinyl, trialkylammonio, SO3H, alkoxy sulphonyl, SO2NH2, mono- or dialkylsulphamoyl; iminomethyl opt. N-substd. by OH, alkoxy, alkanoyloxy, alkyl, phenyl or NH2; 2-7C alkanoyl or benzoyl; R2=H, alkyl, phenylalkyl, carboxyalkyl, alkoxycarbonylalkyl, halogen, OH, alkoxy, alkanoyloxy, SH, alkylthio, phenylalkylthio, phenylthio, alkanoylthio, COOH, alkoxycarbonyl or alkanoyl; R'1=R1, CH2OH, alkoxymethyl, halomethyl, alkanoyloxymethyl, halogen, OH, SH, CHO, COOH, alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CN, 5-tetrazolyl, 4,5-dihydro-2-oxazolyl (opt. substd. by alkyl) or CONHOH, n=0-4; R''1 =R1 or may be R'1 when n=0, 1, 3 or 4 or when n=2 and R2=phenyl alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyloxy, SH, alkylthio, phenylalkylthio, phenylthio, alkanoylthio, COOH, alkoxycarbonyl or alkanoyl; all alkyl, alkoxy and alkanoyl gps. are 'lower' unless otherwise stated; all phenyl gps. are opt. substd. by alkyl, alkoxy or halogen. - (B) The use of cpds. (Ia, R1=R, R2=R') (Ib: R'1=R, R2=R') and (Ic; R''1=R1, R2=R') for prepn. of medicaments for treating diseases responding to aromatase inhibition is claimed, where: R= H, opt. substd. alkyl, NO2, halogen, opt. etherified or esterified OH, opt. etherified, oxidised-etherified or esterified SH, NH2, mono- or disubstd. amino, ammonio, opt. functionally modified SO3H, COOH or CHO or 2-20C acyl; R'=H, opt. substd. alkyl, halogen, opt. etherified or esterified OH, opt. etherified, oxidised-etherified or esterified SH, opt. functionally modi

Description

The present invention provides substituted imidazopyrrole, -pyridine and -azepine derivatives of formula (I)

wherein n is an integer of 1, 2 or 3; and.

R 1 represents cyano, C 1 -C 4 alkyl, halogen, amino, carbamoyl, C 1 -C 4 alkylcarbamoyl or formyl, stereoisomers of the above compounds, mixtures of these stereoisomers, or salts of the above. compounds, a process for the preparation of these compounds and their use as aromatase inhibitors.

The compounds of formula I contain at least one asymmetric carbon atom and can exist as R- or S-enantiomers as well as mixtures of enantiomers, for example as racemates. The invention includes all these forms as well as other isomers and mixtures of at least two isomers, for example mixtures of diastereomers or enantiomers, as long as these isomers may exist due to the possible presence of additional or additional centers of asymmetry in the molecule.

The above-mentioned alkyl groups are, for example, n-propyl, isopropyl, n-butyl, n-butyl, sec-butyl and tert-butyl, preferably ethyl and especially methyl. .

Halogen is, for example, bromine or iodine, preferably fluorine and especially chlorine.

The compounds of the invention form acid addition salts, in particular pharmaceutically acceptable salts of β customary acids, for example in mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic acids, for example 8 aliphatic or aromatic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascoric acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, gluconic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, eulfanilic acid or cyclohexylsulfanoic acid. Salts may also be formed with amino acids such as arginine and lysine.

CS 268668 В2

If several salt-forming groups are present, mono- or poly-salts may be formed. The above-mentioned pharmaceutically acceptable salts are preferred. Salts other than therapeutically useful salts may also be used for isolation or purification, e.g.

The compounds of the invention exhibit valuable pharmacological properties, for example, aromatase inhibition in mammals, including humans. For example, these compounds inhibit the metabolic conversion of androgens to eetrogens. The compounds of formula X are therefore useful in the treatment of gynecomaathy. In addition, the compounds of formula X are useful, for example, in the treatment of estrogen-dependent diseases including estrogen-dependent mammary tumors, particularly in postmenopause, by inhibiting estrogen synthesis. These effects can be demonstrated by in vitro or in vivo tests in experimental animals, preferably using mammals such as guinea pigs, mice, rats, cats, dogs or monkeys as test animals.

In vitro inhibition of aromatase activity can be demonstrated using, for example, the method described in J. Biol. Chem., 249, 5364 (1974). In addition, kinetic enzymatic studies of inhibition of the conversion of 4- C-androstenedione to 4- ^x ^ C-estrone in human placental microsomes can be used to obtain IC ^ q values ^for aromatase inhibition. of the invention range from about 10 to about 10 moles / liter.

Specific values of the measured minimum concentrations for aromatase inhibition are given in the following table:

Example compound no. minimum inhibitory concentration (nmol / liter) 1, 2, 3, 4 and 9 7 8 2 1 18

In vivo inhibition of aromatase can be demonstrated, for example, by reducing the ovarian estrogen content of female rats first injected with serum gonadotropin in pregnant mares and, after two days, with human chorionic gonadotropin, the following day orally with the compound of the invention and after one hour with adrostenedione. The minimum effective dose of the compounds of the invention is between about 0.01 and 10 mg / kg or less. Antitumor activity, particularly in estrogen-dependent tumors, can be demonstrated in vivo, for example, in female rats - * - (Spague-Dawley) g by mammary gland-induced mammary gland. The compounds of the invention cause almost complete regression and suppression of new tumor formation when administered orally at daily doses ranging from about 1 to 20 mg / kg or even lower.

Surprisingly, it has been found that although the compounds of the invention are potent aromatase inhibitors in vitro and in vivo, they do not appear to have in vivo inhibitory activity on cholesterol side chain cleavage because they do not induce adrenal hypertrophy as verified by endocrine organ evaluation.

Owing to their pharmacological properties (aromatase inhibitors), the compounds of the invention can be used as medicaments, for example in the form of pharmaceuticals, for the treatment of hormonal diseases, such as estrogen-dependent tumors, particularly mammary carcinoma, and various anomalies such as gynecomastia animals, including humans. However, the disclosed novel compounds are also valuable intermediates for the preparation of other pharmaceutically active compounds.

CS 268688 В 2

Particularly preferred compounds within the scope of the invention are compounds of formula I wherein R 1 is cyano or halogen, especially cyano.

In particular, the invention relates to compounds of formula Ib

(Ib) where

R @ 1 represents cyano or C1 -C4 alkyl, their stereoisomers, mixtures of these stereoisomers, and salts of the above compounds;

The 5,6,7,8-tetrahydroderivatives of formula Ib contain a chiral carbon atom at the 5-position. Both the 5R- and 5S-enantiomers and the 5 (R, S) racemate are within the scope of the invention.

The general terms used to describe compounds of formula Ib preferably have the following meanings.

C1-C4alkyl is, for example, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and preferably methyl.

In particular, the invention relates to those compounds of formula (Ib) in which it is cyano and pharmaceutically acceptable acid addition salts of compounds of formula (Ib).

Most preferred are the compounds of the invention described in the Examples and their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds are also most preferred. The compounds are also best suited for use as pharmaceutical agents or for the manufacture of pharmaceutical compositions.

In accordance with the invention, the compounds of formula (I), their stereoisomers, mixtures of stereoisomers and pharmaceutically acceptable salts thereof are prepared by decarboxylating a compound of formula (I).

* 1 in which

Ry and n are as defined above, whereupon the optionally obtained compound of formula I in which it is a carbamoyl or alkylcarbamoyl group as defined above is dehydrated, or the compound of formula I in which Ry is a halogen atom is obtained by reaction with a hydrocyanic acid salt or the compound of formula X in which Ry is a formyl group, by oxidation, or the obtained compound of formula I in which R1 is an amino group, by reaction with an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula X in which R is a cyano group, and / or the salt obtained is optionally converted into a free compound or another salt, and / or the free compound is converted into a salt, and / or the mixture of isomers or racemates obtained is separated into individual isomers or racemates; a mixture of enantiomers such as the racemate. cemate, cleaves into optical isomers.

Compounds of formula (Ib) are prepared analogously, i.e. by decarboxylating a compound analogous to compound of formula (Ib) but additionally containing a carboxyl group at the 3-position, optionally converting the individual substituents into the resulting product as described above, or or to another salt, and / or the free salt-containing compound is converted to a salt, and / or the racemic mixture obtained is resolved into the individual enantiomers.

The decarboxylation reaction of the invention may be accomplished by conventional decarboxylation procedures and means, for example with acids such as hydrochloric acid, preferably at elevated temperature.

The starting materials for the process according to the invention containing a carboxyl group in the 3-position of the bicyclic ring system can be obtained, for example, by reacting a compound of formula VIII wherein

CS 268668 В 2

1 (VXII)

is as in formula I, and a lower alkyl ester halide such as ethyl chloride or a formic acid derivative, for example mixed formic anhydride and acetic anhydride, followed by ring closure with a Lewis acid such as phosphorous oxychloride.

Compounds of formula (VIII) are known or, if new, can be prepared by known methods, for example by hydrogenation of a compound of formula (XV)

»(XV) wherein it has the meaning given for formula I

The hydrogenation is preferably carried out in the presence of a catalyst such as platinum or palladium on carbon and in the presence of a mineral acid such as hydrochloric acid. *

Compounds of formula XV may be prepared, for example, by reacting a compound of formula XXI

* 1 is converted to an N-oxide by treatment with an oxidizing agent such as peracetic acid, the N-oxide is treated with a methylating agent, such as dimethylsulfate, and a cyano group is introduced at the 6e position, for example using potassium cyanide

If any of the above intermediates contain reactive groups that would be defective in a given reaction, such as a hydroxy or amino group, these groups can be advantageously temporarily protected at any of the reaction stages with easily cleavable protecting groups · The choice of protecting groups for the reaction depends several factors, such as the nature of the protected functional group, the structure and stability of the molecule containing the functional group as a substituent, and the reaction conditions. Protecting groups meeting these conditions, as well as their introduction and cleavage, are known in the art and are described, for example J. F, W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York 1973 · Protecting groups of amine and hydroxyl functions that can be cleaved under mild conditions are, for example, acyl residues such as lower alkanoyl. a radical optionally substituted by halogen, for example a formyl or trichlorobenzyl residue, or an organic silyl residue, for example a tri (lower) alkylsilyl residue, such as a trimethylsilyl residue;

Salts of the compounds of the invention can be prepared in a manner known per se. Thus, these salts can be prepared, for example, by the methods described in the Examples. Acid addition salts of the compounds of the invention 8 are obtained in a conventional manner, for example by treating the free compound with an acid or a suitable anion. - clear the way ^ a. free compounds, for example by reacting an acid addition salt with a suitable basic agent, for example an alkoxide such as potassium tert-butoxide. In contrast, the compounds of the invention which contain acidic groups, for example a carboxyl group, can be converted to salts with a base such as an alkali metal hydroxide or alkoxide, an alkali metal or alkaline earth metal salt such as sodium bicarbonate, ammonia or a suitable organic amine. Free compounds can be obtained by treating the salts with an acid. Because of the close relationship between the free compounds and the compounds in the form of salts, whenever a compound is mentioned, the corresponding salt is meant herein when it may exist or is appropriate in the circumstances ·

Depending on the choice of starting materials and methods, the novel compounds may exist in the form of one of the possible isomers or mixtures thereof, depending, for example, on the presence of chiral carbon atoms as optical isomers, e.g. antipodes, or as mixtures of optical isomers, e.g. as racemates, or as mixtures of diastereoisomers.

CS 268688 в2

The mixtures of diastereoisomers obtained can be separated on the basis of different physicochemical properties of the individual components of the mixture, for example by chromatography and / or fractional crystallization,

The obtained racemates can be resolved by known methods into optical antipodes, for example by chromatography using an optically active B phase, recrystallization from an optically active solvent, by microorganisms or by reaction of the acid intermediate or final product in an optically active base forming and racemic acid salt and separating these salts. The basic racemic products can be resolved into the antipodes in an analogous manner, for example, by separation of their diastereoisomeric salts, such as by fractional crystallization of d- or l-. tartrates.

The above reactions are carried out by standard methods, in the presence or absence of diluents, preferably those which are inert to and dissolve to the reactants, or in the presence or absence of catalysts, condensation or other reagents, and / or in an inert atmosphere at low temperatures. , at room temperature or at elevated temperature, for example at a temperature in the range of -20 ° C to +200 ° C, preferably at the boiling point of the solvent used, at atmospheric pressure or at elevated pressure. Preferred solvents, catalysts and reaction conditions are shown in the following Examples.

The compounds of the invention, including their salts, can also be obtained in the form of hydrates or eolvates with other solvents used to crystallize them.

The invention also encompasses all variants of the above-described processes, wherein the starting material is an intermediate obtained in any of the reaction steps of the process, with which the remaining reactions are then carried out, or in which the process is interrupted at any stage, or or in which the reactants are used in the form of their salts or optically pure antipodes. In particular, the starting materials which lead to the above-mentioned particularly preferred compounds are used in the above reactions. The invention also encompasses novel starting materials and methods for their preparation.

The invention further provides pharmaceutical compositions for enteral or parenteral administration, which compositions comprise a therapeutically effective amount of a compound of the invention, optionally together with a pharmaceutically acceptable carrier or mixture of carriers. As carriers, solid or liquid inorganic or organic substances are used. Suitable unit dosage forms, in particular for oral administration, for example, dragées, tablets or capsules, preferably contain about 5 to 100 mg, most preferably about 10 to 50 mg, of a compound of the invention or a pharmaceutically acceptable salt of such a salt-forming compound, together with pharmaceutically acceptable carriers. .

Daily dosages of the compounds of the invention range from about 0.1 to 100 mg / kg, preferably from 0.5 to 50 mg / kg of mammalian body weight, depending on the compound used, the age and individual condition of the patient, and method of application. When administered parenterally, for example by intramuscular or subcutaneous injection or by intravenous infusion, the doses administered are generally lower than for the enteral, i.e. oral or rectal administration. The compounds of the invention are orally or rectally administered preferably in unit dosage forms, such as tablets, dragees, capsules or suppositories, and parenterally in particular in the form of injectable solutions, emulsions or suspensions, or in the form of infusion solutions.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example normal calcium phosphate or calcium dihydrogen phosphate, as well as binders,

CS 268688 jako2 as starch pastes * for example corn paste * rice or potato starch * gelatin * tragacanth, methyloelulose and / or optionally disintegrating agents such as the aforementioned starches * and carboxymethyl starch * cross-linked polyvinylpyrrolidone * agar * alginic acid or its salts * as sodium alginate. In particular, lubricants such as silicon dioxide * talc * stearic acid or its salts * such as magnesium stearate or calcium atearate * and / or polyethylene glycol are used as additives. Dragee cores are provided with suitable coatings which may be resistant to gastric glory, using, for example, concentrated sugar solutions * which may contain gum arabic, talc * polyvinylpyrrolidone * polyethylene glycol and / or titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric-resistant coatings, solutions of suitable cellulose derivatives such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the dragee or tablet coatings, for example to identify or label different doses of the active ingredient.

Other pharmaceutical compositions for oral administration are solid filled capsules made of gelatin as well as soft sealed capsules consisting of gelatin and a sheath such as glycerol or sorbitol. The capsules and solid fill may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches, and / or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers may also be added.

Suitable pharmaceutical compositions for rectal administration are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Examples of suitable suppository bases include natural or synthetic triglycerides, paraffin, polyethylene glycols and higher alkanols. Gelatin rectal capsules may also be used which contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffins.

Especially suitable dosage forms for parenteral administration are suspensions of the active ingredient, such as corresponding oily injection solutions or suspensions, for which suitable lipophilic solvents or vehicles are used, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate. or triglycerides, or further aqueous suspensions or solutions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

г y ^ _{ar ACEU} ^ £ ^ _c means Podłęże invention are prepared, in known manner, .For example by conventional mixing, granulating, dissolving or lyophilising methods. For example, pharmaceutical compositions for oral administration can be obtained by mixing the active ingredient with solid carriers, optionally granulating the resulting mixture, and processing the granulate, optionally with suitable additives, into tablets or dragee cores.

The invention is illustrated by the following non-limiting examples. All parts refer to parts by weight. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably at a pressure of between about 2 and 13 kPa.

He did

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazole-1,5-a7-pyridine hydrochloride

A solution of 1.13 g of 5- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazolyl, 5-a7pyridine and 1.0 ml of phosphorus oxychloride in 30 ml of chloroform was heated at reflux for 15 hours, then cooled. and evaporated with toluene. The oily residue is again

Dissolve CS 268683 В 2 in 30 µl methylene chloride, cool to 0 ° C and add 30 ml of ice-cold 50% ammonium hydroxide solution. The organic phase was separated, dried and evaporated to an oily residue. The oily residue was filtered through a column of 20 g of silica gel using ethyl acetate as eluent to give the title compound as a free compound, which was dissolved in 20 ml of acetone and treated with 1.2 ml of 3N estheric hydrogen chloride. 209 DEG-210 DEG.

Example 2

5- (p-Cyanophenyl) -5,6,7,8-tetrahydroimidazole / 1,5-o7-pyridine

A mixture of 5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazole-1,5-a7-pyridine (85 mg) and specific cyanide (74 mg) in Ν, Ν-dimethylformamide (1 ml) was heated at 120 ° C for 11 h under nitrogen. The reaction mixture was cooled, diluted with 10 mL of water and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated. The oily residue is chromatographed on silica gel using ethyl acetate as the eluent to give the title compound, m.p. 117-118 ° C.

Example 3

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a7-pyridine]

To a solution of 2.01 g of 5- (p-formylphenyl) -5,6,7,8-tetrahydroimidazole / 1,5-a7pyridine and 0.96 g of hydrochloric acid in 30 ml of benzene was added dropwise while maintaining the room temperature by external cooling. , 8 ml of concentrated sulfuric acid. The reaction mixture was stirred for 2 hours and then neutralized. The organic phase is separated, dried over sodium sulphate and evaporated to an oily residue which is chromatographed on silica gel with ethyl acetate as eluent to give the title compound, m.p. 117-118 ° C.

Example 4 * (β-cyanophenyl) -5,6,7,8-1-etrahydroimide and zo 1 / 1,5- $ 7-pyridine

A solution of 2.13 g of 5- (p-eminophenyl) -5,6,7,8-tetrahydroimidazole-1,5-a] pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water was cooled in ice and a solution was slowly added thereto. 0.78 g of sodium nitrite in 2 ml of water. The resulting solution was added dropwise from a dropping funnel to a solution of 3.0 g of copper (I) cyanide in 10 ml of water, while maintaining the temperature by ice cooling between 30 and 40 ° C. The reaction mixture was heated on a steam bath for 1 hour, then cooled and adjusted to pH 9. The organic extracts were dried over sodium sulfate, evaporated and the residue chromatographed on silica gel using ethyl acetate as eluent. The title compound is obtained, m.p. 117-118 ° C.

Example 5

The following example describes the composition and preparation of 10,000 tablets each containing 10 mg of active ingredient.

CS 268668 B2 quantity

5- (p-cyanophenyl) -5 * 6, 7,8-tetrahydroimidazole-1,5-azopyridine lactose maize Starch. *

Ingredients:

component 'polyethylene glycol 6000 magnesium stearate distilled water

100.00 g 2535.00 g

125,00 g

150,00 g

40.00 g as needed

Preparation:

All powder materials are sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer, the other half of the starch is suspended in 65 cl of water and the suspension is added to the boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powder mixture and the resulting mixture is granulated, optionally with additional water. The granulate is dried at 35 ° C overnight, then sieved through a 1.2 mm sieve and pressed into a crinkled tablet using a tablet press.

Tablets containing the other compounds described above and exemplified are prepared in an analogous manner.

Example 6

This example describes the composition and preparation of 1,000 capsules, each containing 20 mg of active ingredient.

Ingredients:

quantity

Preparation:

All powder materials are sieved through a 0.6 mm sieve. The active ingredient is introduced into a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until a homogeneous mixture is obtained. This mixture is filled into a No. 2 hard gelatin capsule at 310 mg portions on a filling device.

In a similar manner, capsules are prepared containing the other compounds described above and exemplified.

Example 7

A solution of 1.25 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo [1,2-a] imidazole in 10 ml of thionyl chloride was refluxed for 1 hour, then cooled and evaporated. The residue was redissolved in 10 ml of chloroform at 0 ° C and 10 ml of ice-cold concentrated ammonium hydroxide was slowly added to the solution. The aqueous layer was separated, extracted three times with 20 ml of chloroform each, and the organic extracts were combined and dried over sodium sulfate. After filtration, evaporation and chromatography of the residue on 45 g of silica gel using 5% ammonium hydroxide in ethyl acetate

CS 268688 В 2

An oily material is obtained which, on reaction with 1 mol equivalent of ethereal hydrogen chloride, affords 0.5 8 of 5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo [1,2-a] imidazole hydrochloride, m.p. 228 ° C.

. Example 8

A solution of 1.29 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7,8,9-tetrahydroimidazole Z1,5-o-azepine in 10 ml of thionyl chloride was heated at reflux for 1 hour, then cooled and evaporated. The residue is partitioned between methylene chloride and an ice-cold sodium bicarbonate solution, the aqueous layer is separated and extracted three times with 15 ml of methylene chloride each time. The combined organic layers were dried over sodium sulfate and evaporated. The oily residue was chromatographed on 26 g of silica gel using 5% ethanol in methylene chloride as eluent. The product obtained after reaction with 1 mol equivalent of fumaric acid in ethanol was 5H-5- (4-cyanophenyl). 153-155 ° C) -6,7,8,9-tetrahydroimidazole [1,5-g] azepine fumarate.

Example 9

A solution of 1.65 g of 5- (p-yanophenyl) -3-ethoxycarbonyl-1,5,6,7,8-tetrahydroimidazole-1,2,5-pyridine in 10 ml of methanol containing 0.2 g of sodium hydroxide was stirred at room temperature for 3 hours. • A small sample is taken from the solution and acidified with 1N ammonium chloride solution. The precipitate formed is filtered off and dried. The residue consists of 5- (p-cyanophenyl) -3-carboxy-5,6,7-8-tetrahydroimidazo-1, 5-a7pyridine. IR: 1695 cm @ ^-1 (CO).

The above solution was heated to reflux and 5 ml of 1N hydrochloric acid was added. After 1 hour, the reaction mixture was cooled and evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated and, after drying over sodium sulfate, evaporated to give 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazole-1,5-a] pyridine, m.p. 117-118 ° C.

The starting material was prepared as follows.

To a solution of 2.0 g of 2-aminomethyl-6- (p-cyanophenyl) -pyridine in 20 ml of methylene chloride at -15 DEG C. under nitrogen is added 1.4 g of ethyl oxalate chloride. The reaction mixture was allowed to warm to room temperature over two hours and the solvent was evaporated. The residue was dissolved in 30 ml of phosphorus oxychloride, the reaction mixture was heated under reflux for 15 hours and then evaporated to dryness. The residue was partitioned between methylene chloride and sodium bicarbonate solution. νλ? - separated and after drying with sodium sulfate? Evaporate to an oily residue which is chromatographed. .

of silica gel using ethyl acetate as eluent gave (5- (p-cyanophenyl) -3-ethoxycarbonyl-imidazo-Z1,5-a7pyridine).

IR (KBr): 1720, 2250 cm ^1st

A solution of 1.1 g of 5- (g-cyanophenyl) -3-ethoxycarbonyl-imidazo [1,5-a] pyridine in 30 ml of ethanol is hydrogenated at 100 kPa for 2 hours in the presence of 0.1 g of 10% palladium on carbon, then filtered and evaporated to dryness. The oily residue was partitioned between water and ethyl acetate, the organic phase separated and dried over sodium sulfate and evaporated. The residue was chromatographed on 40 g of silica gel using ethyl acetate as eluent for 5- (p-cyanophenyl) -3-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo-1, 5-7-pyridine.

IR (KBr) 1720, 2240 cm @ ^-1 . .

Example 10

Racemic 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazole / η 5-α 7 -pyridine hydrochloride ae is applied in 20 mg portions to a column of ailica gel and bound β-cyclodextrin (4.6 x 250 mm) using a mixture of water and methanol (7: 3) as eluent at a flow rate of 0.8 ml / min. The separated fractions were evaporated in vacuo to give (-) - 5- (p-cyanophenyl) -5,6 , 7,8-tetrahydroimidazoZl 5-a7pyridin optical rotation -89.2 ⁰ and (+) - 5- (p-cyanophenyl) -5 _t 6.7> 8-tetrahydroimidasolZl 5-a7pyridin optical rotation = 85 * , ⁰ · 05 the two compounds were separately dissolved in acetone and treating each one molar equivalent of ethereal hydrogen chloride was converted to the hydrochloride melting at 82-83 ° C (amorphous or · 218-220 DEG C. _e.

Example 11

The following compounds can also be prepared in an analogous manner to the previous examples:

5- (p 'carbamoylphenyl) -5> 6 _t 7 _l 8-tetrahydroimidazolZl, 5-and 7-pyridine, m.p. 181-183 ° C,

5- (p-tolyl) _{-5,6> 7,8-tetrahydroimidazolZl>} 5 _a7pyridin> whose hydrochloride melts at 173-175 ° C,

5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazol-1,5-ylpyridine whose hydrochloride melts at 216 ° C,

5- (p-formylphenyl) -5>6>7> 8-tetrahydroimidazolZl _t 5? 7-pyridine, fumarate which melts at 131 ° C,

5- (p-aminophenyl) -5,6,7b-tetrahydroimidazole-1,2-apyridine,

5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo [1,2-c] imidazole, m.p. 136-139 ° C,

5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo [1,2-a] imidazole, m.p. 227-228 ° C; 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazole Z, 5- 153 DEG-155 DEG C. m.p. 153 DEG-155 DEG.

Claims (5)

A process for the preparation of substituted imidazopyrrole, -pyridine and -azepine derivatives of the general formula I * (I) wherein n is an integer of 1, 2 or 3 a. R1 represents cyano, C1-C4alkyl, halogen, amino, carbamoyl, C1-C4alkylcarbamoyl or alkyl, or stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof, characterized by: The method of claim 1 wherein the compound of formula (I *) is decarboxylated in which: R 6 and n are as defined above, whereupon the optionally obtained compound of formula I wherein R 1 is carbamoyl or an alkylcarbamoyl group as defined above is dehydrated, or the obtained compound of formula I wherein R 1 is halogen by reaction with a hydrogen cyanide salt acid, or a compound of formula I wherein R 1 is a formyl group by oxidation, or a compound of formula I wherein R 1 is amino, by reaction with an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula Where R @ 1 is cyano, and / or the salt obtained is optionally converted to the free compound or to another salt, and / or the free compound is converted to an eol, and / or the resulting mixture of isomers or racemates is separated into individual isomers or racemates and / or the mixture of enantiomers, such as the racemate, is resolved into the optical isomer ery * ’ 2. A method according to claim 1, characterized in that; using the corresponding starting materials, to give 5- (p-cyphenyl) -5,6,7,8-tetrahydroimidazol / 1,5-a] pyridine of formula Ic (Ic) its stereoisomers, a mixture of stereoisomers or pharmaceutically acceptable acid addition salts thereof. 3. A process according to claim 1, wherein the corresponding compounds are used to form 5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, stereoisomers thereof, mixtures thereof. these stereoisomers or pharmaceutically acceptable salts; 4. The process of claim 1, wherein the corresponding starting materials are used to form 5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo [1,2-c] imidazole, its stereoisomer, mixtures of these stereoisomers. or pharmaceutically acceptable salts. The method of claim 1, wherein the corresponding starting materials are used to give 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazole [1,5-a] azepine, its stereoisomers , mixtures of these stereoisomers or pharmaceutically acceptable salts;