CS268686B2 - 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)

(I) které® n is an integer 1, 2 or 3 and R ₁ louse cyano group, an alkyl group having 1 to 4 carbon atoms, halogen, amino, carbamoyl, alkylcarbamoyl having 1 to 4 carbon atoms in alkyl moieties or a formyl group, stereoisomers of the above compounds, mixtures of these stereoisomers; a process for the preparation of these compounds and their use as aromatase inhibitors.

The compounds of the 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, isobutyl, 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, and customary acids, for example mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, for example aliphatic or aromatic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid, pyrohrosic acid, phenylacetic acid, benzoic acid, acid 4-arainobenzoic acid, anthr anilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-arainosallcylic acid, pamoic acid, gluconic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid new, halobenzenesulphonic acid, toluene sulphonic acid, naphthalene sulphonic acid, sulphonic anilic acid or cyclohexyl sulpharic acid. Salts may also be formed with amino acids such as argininera and lysine.

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, for example picrates, may also be used for isolation or purification.

The compounds of the invention exhibit valuable pharecological properties, for example, aromatase inhibition in mammals, including humans. For example, these compounds inhibit metabolic

CS 268 686 B2 conversion of androgens to estrogens. Thus, the compounds of formula I are useful in the treatment of gynecomastia, i.e., the development of the mammary gland in men by inhibiting the aromatization of stereides in those men who may develop this condition. estrogen, including an estrogen-dependent mammary tumor, 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.

Inhibition of aromatase activity in vitro can be demonstrated, for example, using the method described in J. Biol. Chem. 29, 5364 (1974). In addition, ΙΟ ^ θ values for aromatase inhibition can be obtained from kinetic enzymatic studies related to inhibition of the conversion of 4- ¹ C-androstenedione to 4 C-estrone in human placental microsomes. _ICso values for compounds of the invention range from about 10 to 10 $ ^ mol / liter.

Specific values of the measured minimum concentrations for Jsu aromatase inhibition are shown in the following table: * compound of the minimum inhibitory concentration of Example No. (nmol / liter)

1, 2, 3, 4 and 9

In vivo aromatase inhibition can be demonstrated by, for example, a reduction in 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 even lower. Antitumor activity, particularly in the case of estrogen-dependent tumors, can be demonstrated in vivo, for example, in female Sprague-Dawley rats with a λλ-induced mammary gland. The compounds of the invention cause almost complete regression and suppression of new tumor formation when administered orally at daily dosages 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 exhibit cholesterol side chain cleavage inhibitory activity in vivo since 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.

Particularly preferred compounds falling within the scope of the invention are compounds obechého formula I in which R ₁ represents cyano or halogen, in particular cyano.

In particular, the invention relates to compounds of formula Ib

CS 268 685 B2

^R 1 (Ib) wherein

R 1 represents a cyano or C 1 -C 4 alkyl group, the stereoisomers thereof, 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 the compounds of formula Xb 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 all compounds of formula Ib wherein 1Ц 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. Said 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 the above general formula (X), their stereochemistry, are preferred. somers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof are prepared by producing a compound of formula IX

in which

R 1 and n are as defined above, reacted with a cyclizing agent under reductive conditions, followed by optionally obtaining a compound of formula I in which R _T is a carbamoyl or alkylcarbamoyl group as defined above by dehydration, or an obtained compound of formula I in which R _T represents a halogen atom, by reaction with a hydrocyanic acid

an acid, or a compound of formula I in which 1Ц is a foxyl group by oxidation, or a compound of formula I in which R1 is amino by reaction in an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula I, in which R | is a cyano group, and / or the salt obtained is optionally converted into a free compound or into another salt, and / or the free compound is converted into a salt, and / or the resulting isomer or racenate is separated into individual isomers or racenates, and / or enantioners, such as racemate, ros cleaves into optical isoners.

Compounds of formula (Ib) are prepared analogously, i.e. by cyclizing a compound of formula (IXb) under reductive conditions.

(IXb) whereupon the obtained salt is converted into the free compound or another salt, and / or the free compound containing the salt-forming group is converted into a salt, and / or the resulting racemic mixture is resolved into the individual enantiomers.

For example, the reductive amination of the invention is carried out by treatment with hydrogen in the presence of a conventional hydrogenation catalyst, such as Raney nickel, platinum or palladium on carbon, or using a hydrogen donating agent, for example sodium cyanoborohydride.

Starting materials of formulas IX and IXb can be prepared, for example, by the following sequence of reactions.

Oxidation of a compound of formula XIX or X1a

(XIX) (XIXa) in which n is as defined above and

R _o and R 'represent _a conventional protective group residue NH

CS 268 686 B2 using conventional oxidation procedures and reagents, for example potassium permanganate, yields the corresponding acid, which can then be converted to the corresponding lower alkyl ster. Reaction of this alkyl alkyl or free acid with a compound of formula XX

If

in which .

R @ 1 is as defined in formula I or Ib, or a suitable organometallic equivalent of this compound, and cleavage of the protecting group of the residue ## STR5 ## yields compounds of formulas IXb and IX.

If any of the above intermediates contain reactive groups which would be defective in a given reaction, for example a carboxyl, hydroxy or amino group, these groups may advantageously be temporarily protected at any stage by readily cleavable protecting groups. The choice of protecting groups for a particular reaction depends on several factors, for example 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, in J. F. W. McOmie, Protective Groups in Organic Chemists **. Plenum Press, London, New York 1973 · Protecting groups of amine and hydroxyl functions that can be cleaved under mild conditions are, for example, acyl radicals such as a lower alkanoyl radical optionally substituted by halogen, for example a formyl or tri chloroethyl radical, or an organic silyl radical, for example a tri (lower) alkyleilyl residue such as a trimethylsilyl residue.

Salts of the compounds of the invention may be prepared by methods known per se. Thus, such salts may be prepared, for example, by the methods described in the Examples. The acid addition salts of the compounds of the invention are obtained in a conventional manner, for example by treating the free compound with an acid or a suitable anion exchange resin. Salts can be converted into the free compounds in a conventional manner, for example by reacting an acid addition salt with a suitable base, for example an alkoxide such as potassium tert-butoxide. Due to the close relationship between the free compounds and the compounds in the form of salts, whenever a particular compound is mentioned, the corresponding salt is meant herein, as long as it may exist or is appropriate in the circumstances.

Depending on the choice of starting materials and methods, there may be new compounds in the form of one of the possible isomers in the form of mixtures of these isomers, and for example depending on the presence of chiral carbon atoms as optical isomers, for example antipodes, or as mixtures of optical isomers, for example as racemates or as mixtures of diastereoisomers.

The diastereoisomer mixtures obtained can be separated on the basis of different physico-chemical properties of the individual components of the mixture, for example by chromatography and / or fractional crystallization.

The racemates obtained can be resolved by known methods into optical antipodes, for example by chromatography using an optically active stationary phase, recrystallized from an optically active solvent, by microorganisms or by reacting an acid intermediate or final product with an optically active base forming a salt with racemic acid to separate these salts, e.g. by their different solubility to give individual diastereoisomers from which the appropriate antipodes can be released by treatment with appropriate agents. The basic chemical products can be resolved into the antipodes in an analogous manner, for example, by separation

CS 268 686 В2

Their diastereoisomeric salts, such as traction crystallization of d- or 1-tartrates.

The above reactions are carried out by standard methods, in the presence or absence of diluents, preferably those which are inert to the reactants and dissolve them, 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 set forth in the following Examples.

The compounds of the invention, including their salts, can also be obtained in the form of hydrates or aolvates 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, the process and which then performs the remaining reactions, or wherein the process is interrupted at any stage, or wherein the starting materials they form under the reaction conditions or in which the reactants are used in the form of their salts or optically pure antipodes. In the above reactions, in particular, starting materials are used which lead to the above-mentioned particularly preferred compounds. 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, particularly for oral administration, for example dragees, tablets or capsules, preferably contain about 5 and 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 a pharmaceutically acceptable salt. usable carriers.

Daily dosages of the compounds of the invention range from about 0.1 to 100 mg / kg, and 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 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 phosphate, for example normal calcium phosphate or calcium dihydrogen phosphate, as well as binders such as starch pastes from corn, rice or potato starch, gelatin , tragacanth, methylcellulose and / or optionally disintegrating agents, such as the aforementioned starches, and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof, such as sodium alginate. In particular, lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol, are used as additives. Dragee cores are provided with suitable coatings, which may be resistant to gastric meals, the preparation of which uses, inter alia, concentrated sugar solutions, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, Selak solutions in suitable formulations. 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.

CS 268 685 B2

Other pharmaceutical formulations for oral administration are solid-filled capsules made of gelatin, as well as soft sealed capsules consisting of gelatin and a facial sheath such as glycerol or sorbitol. The solid-filled capsules 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 rectal pharmaceutical compositions are, for example, suppositories which consist of a combination of the active ingredient with a rosehip matrix. Examples of suitable rosehip 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.

Particularly 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 which contain viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

The pharmaceutical compositions of the invention are prepared in a manner known per se, for example by conventional mixing, granulating, dissolving or lyophilizing 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 following Examples illustrate the invention but are not intended to limit the scope of the invention in any way. All parts are by weight unless otherwise indicated, all evaporations are carried out under reduced pressure, preferably at a pressure between about 2.0 and 13 kPa.

Example 1

5- (p-Cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride

A solution of 1.13 g of 5- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and 1.0 al of phosphorus oxychloride in 30 ml of chloroform was heated under reflux for 15 hours. , then cooled and evaporated with toluene. The oily residue is redissolved in 30 ml of methylene chloride, the solution is cooled to 0 ° C and 30 ml of ice-cold 50% ammonium hydroxide solution are added. The organic phase is 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 the 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 ethereal hydrogen chloride. The hydrochloride of the above free compound is obtained, m.p. 209-2 ° C.

Example 2

5- (p-Cyanophenyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine)

A mixture of 85 mg of 5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and 74 mg of cuprous cyanide in 1 ml of Ν, Ν-dimethylformamide was heated to 120 ° C under nitrogen for 11 hours. . 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 eluent to give the title compound, m.p. 117-118 ° C.

Example 3

CS 268 685 B2

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

To a solution of 2.01 g of 5- (p-formylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and 0.96 g of nitric acid in 30 ml of benzene are maintained at room temperature while maintaining 0.8 ml of concentrated sulfuric acid is added dropwise by cooling. The reaction mixture is 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 using ethyl acetate as the eluent. mp 117-118 ° C.

EXAMPLE 5- (p-cyanophenyl) -5,6 _{7,8-tetrahydro-f} [i, 5-a] pyridine

A solution of 2.13 ε 5- (p-aminophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water is cooled in ice and slowly added thereto. solution of 0.78 g of sodium nitrite in 2 ml of water. The resulting solution is added dropwise from a dropping funnel while maintaining the temperature by ice cooling between 30 and 40 ° C. to a solution of 3.0 g of copper cyanide in 10 ml of water. 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. * .Ingredients:

quantity component

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine lactose maize starch 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 powdered 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 ml of water and the suspension is added to the boiling solution of 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 overnight at 35 ° C, then sieved through a sieve β 1.2 mm and squeezed into tablets using a cambering 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

Preparation:

active substance.

Ingredients:

quantity component

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine 20.0 g lactose 207.0 g modified starch 80.0 g magnesium stearate 3.0 g

CS 268 686 B2 9

All powdered materials are passed through a 0.6 mm sieve. The active substance is placed in a suitable mixer and mixed first with magnesium stearate and then with 1 act of starch until a homogeneous mixture is formed. This mixture is filled in hard gelatine capsules # 2 at 310 mg in a filler.

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

Example? .

A solution of 1.25 g of 5H-5- (4-tert-butyleminocarbonylphenyl) -6,7-dihydropyrrolo [1,2-c] imidazole in 10 ml of thionyl chloride was heated at reflux for 1 hour, then cooled and evaporated. The residue is redissolved in 10 ml of chloroform at 0 ° C and 10 ml of ice-cold concentrated ammonium hydroxide are slowly added to the solution. The aqueous layer is separated, extracted, three times with 20 ml of chloroform each, and the organic extracts are combined and dried over sodium sulfate. Filtration, evaporation and chromatography of the residue on 45 g of silica gel using 5% ammonium hydroxide in ethyl acetate as eluent gave an oily material which, by treatment with 1 mol equivalent of ethereal hydrogen chloride, gave 0.5 g of 5H-5- (4-cyanophenyl) - 6,7-dihydropyrrolo [1,2-c] imidazole hydrochloride, m.p. 227-228 ° C.

Example 8

A solution of 1.29 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7,8,9-tetrahydroimidazo [1,5-a] azepine in 10 ml of thionyl chloride was heated under reflux for 1 hour. The residue was partitioned between methylene chloride and ice-cold sodium bicarbonate solution, the aqueous layer separated and extracted three times with 15 ml of methylene chloride each time, and the combined organic layers were dried over sodium sulfate and evaporated. 5% methanol in methylene chloride as eluent The product obtained after reaction with 1 mole equivalent of fucic acid in ethanol 5H-5- (4-cyanophenyl (-6,7,8,9-tetrahydroimidazo [1,5-a] azepine) m.p. 153-155 ° C.

Example 9

To a solution of 0.24 g of 1- (p-benzophenyl) -4- (4-imidazolyl) -1-butanone in 20 ml of methanol at room temperature was added 0.2 g of sodium cyanoborohydride. The pH is adjusted and maintained at 5.5-6.0 by addition of concentrated hydrochloric acid. The reaction mixture was stirred for 2 hours, then acidified to pH 2 and evaporated to dryness. The residue was taken up in methylene chloride, the solution was washed with saturated sodium bicarbonate solution, the organic layer was dried over sodium sulfate and evaporated. 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine is obtained, m.p. 117-118 ° C.

The starting material was prepared as follows.

6.95 g of N-tert-butyl-p-bromobenzamide are dissolved in nitrogen at -70 ° C under nitrogen.

175 ml of tetrahydrofuran and 20.1 ml of 2.7M n-butyllithium are added dropwise. After 30 minutes, a solution of 5.35 g of 4- (1-trityl-4-imidazolyl) butanoic acid in 10 ml of tetrahydrofuran was slowly added, the reaction mixture was allowed to warm slowly to room temperature, and 20 ml of aqueous ammonium chloride solution was added. The organic layer was separated and dried over sodium sulfate and evaporated to give 1- (p-N-tert-butylaminocarbonylphenyl) -4- (1-trityl-4-imidazolyl) -1-butanone.

IR (KBr) 1660, 1690 cm-4

A solution of 0.5 g of 1- (pN-tert-butylaminocarbonylphenyl) -4- (1-trityl-4-imidazolyl) -1-butanone in 20 ml of thionyl chloride was refluxed for 3 hours and then poured into 100 ml. of water with ice. The aqueous weight was extracted with ether (3 x 20 ml), adjusted to pH 10 and re-extracted with methylene chloride. The organic phase was dried and evaporated to give 1- (p-cyanophenyl) -4- (4-imidazolyl) -1-butanone.

IR (KBr): 1690, 2230 cm "

CS 268 685 B2

in 20 mg aliquots and loaded onto a silica gel column coupled with β-cyclodextrin (4.6 x 250 mm), eluting with water / methanol [7: 3 J], at a flow rate of 0.8 mL / min. The separated fractions are evaporated in vacuo to give (-) - 5- (p-cyanophenyl) -5,6,7,8-tetrahydro-imidazo [T, 5-a] pyridine with an optical rotation [ou] ^ ^S -39, 2 ⁰ and (+) - 5- (p-cyanophenyl) -5,6,7, 8-tetrahydro-imidazo 1,5-a pyridine, optical rotation [<^] p * 85.02 °. Both of these compounds are separately dissolved in acetone and converted into hydrochlorides melting at 82-83 [deg.] C. (amorphous substance), respectively, by treatment with 1 mol equivalent of ethereal hydrogen chloride. 218 až

220 DEG.

Example 11

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

181 DEG-183 DEG C. 5- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine; 5- (p-tolyl) -5,6,7,8- tetrahydroimidazo [1,5-a] pyridine, the hydrochloride of which melts at 173 ° C

whose hydrochloride melts at 216

5- (p-formylphenyl) -5 _l 6,7,8-tetrahydro-imidazo [i, 5-pyridine A, which melts at 13 fuaarát \ C, 5- (p-aminophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, 5-H-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-c] imidazole, m.p. 227-228 ° C, 5H-5- (4-cyanophenyl) -6,7> 8,9- 153 DEG-155 DEG C. tetrahydroimidazo [1,5-a] azepine;

CS 268 685 B2

Claims (5)

A process for the manufacture of substituted imidazopyrrole, -pyridine and -azepine derivatives of the general formula I wherein n is an integer of 1, 2 or 3 and R | is cyano, (C 1 -C 4) alkyl, halogen, amino, carbamoyl, (C 1 -C 4) alkylcarbamoyl or phenyl, stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof, characterized by: A compound of formula IX wherein: R 1, as defined above, is reacted with a cyclizing agent under reducing conditions, whereupon the optionally obtained compound of formula I wherein R 1 is carbymoyl or an alkylcarbamoyl group as defined above is dehydrated, or the obtained compound of formula I wherein R 1 _is is a halogen atom, by reaction with a hydrocyanic acid salt, or a compound of formula I in which R ^ is a fermyl group by oxidation, or a compound of formula I in which R а is an alkali metal nitrite by reaction with an alkali metal nitrite and with a hydrocyanic acid salt, is converted to the corresponding compound of formula I in which R R is cyano, and / or the salt 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 is separated into individual isomers or racemates, and / or the mixture of enantiomers, such as the racemate, is resolved into the optical isomers. . 2. Method according to claim 1, characterized in that the application of the corresponding starting materials to yield 5- (p-cyanophenyl) -5.6 _l 7,8-tetrahydro-imidazo [i, 5-a] pyridine of Formula Ic CS 268 686 B2 (Ic) or a pharmaceutically acceptable acid addition salt 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, its stereoisomers, mixtures of 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, stereoisomers thereof, mixtures of these stereoisomers. or pharmaceutically acceptable salts. 5. A process according to claim 1, wherein the corresponding starting materials are used to give 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo [1,5-a] azepine, its stereoisomers , mixtures of these stereoisomers or pharmaceutically acceptable salts.