CS268685B2 - 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

(57) A process for producing substituted imidazopyrrole, -pyridine and -azepine derivatives of the general formula I, in which n has the value 1, 2 or 3, R-. is ky yes group | C 1-6 alkyl, halogen, amino, carbamoyl, C 1-6 alkylcarbamoyl or forms 1 and known hydrogen, phenyl C 1-6 alkyl, halogen, amino, carbamoyl, C 1-6 alkylcarbamoyl; C 1-6 -alkylthio or C 1-6 -alkoxycarbonyl, a stereoisomer thereof and a network of stereoisomers and salts, characterized in that a compound of formula VI wherein R is a protecting group of NH or hydrogen is cyclized; is a leaving group, the radicals R ' and R ' and optionally isolating the product in the form of isomers, a mixture of isomers or salts. The compounds produced act as aromatase inhibitors and can be used as medicaments.

CS 268 684 B2

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

in which »n is a number of 1, 2 or 3,

R @ 1 represents cyano, C1 -C4 alkyl, halogen, amino, carbamoyl, C1 -C4 alkylcarbamoyl, or formyl; and.

R ₂ represents a hydrogen atom, a C 1 -C 4 phenylalkyl group, a C 1 -C 4 alkylthio group or a C 1 -C 4 alkoxycarbonyl group, stereoisomers of the above compounds, mixtures of these stereoisomers or a salt and the use of these compounds as aronatase 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, if such 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 according to the invention form acid addition salts, in particular pharmaceutically acceptable salts with customary acids, for example mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic acids such as 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, ascorbic acid, maleic acid, fuaaric acid, hydroxybutyric acid, pyruvic acid, phenylacetic acid, benzoic acid, acid 4-aninobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, panic acid, gluconic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid cyclohexylsulphonic acid. Salts can also be formed with amino acids, such as arginine and lysine.

In the case of the presence of several salt-forming groups of legs, non- or polio-salts can 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.

OS 268 685 B2 valuable pharmacological properties, e.g. inhb. Thus, for example, these compounds inhibit metabas or compounds of formula X are therefore useful

The compounds of the present invention exhibit whip aronatases in mammals, including humans, · human conversion of androgens to estrogens · in the treatment of gynecomastia, ie · development of the mammary gland in men by inhibiting steroid arcaatization in those men who may develop this condition. of formula X useful, for example in the treatment of estrogen-dependent diseases including estragon-dependent mammary tumor, particularly in postmenopause by inhibiting estrogen synthesis. These effects can be demonstrated by in vitro or in vivo tests on 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, for example, using the method described in J. Biol. Chem. 249: 5364 (1974). Further, kinetic enzymatic studies of inhibition of the conversion of 4-C-androstenedione to 4- ^T * C are possible. oestron in human placental microsomes to obtain ΧΟ ^ θ values for aromatase inhibition · IC 50 values for compounds of the invention range from about 10 * ⁶ to 10 * ^ mol (liter).

Specific values of the measured minimum concentrations for aronatase inhibition are given in the following table: Compound of Example No. Minimum Inhibitory Concentration (nnol / liter)

1, 2, 3, 5 and 7 5

In vivo inhibition of aronatase 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, human chorionic gonadotropin, the following day orally, the compound of the invention and after one hour adrostenedione. The minimum effective dose of the compounds of the invention is between about 0.01 and 10 mg / kg or less. Antitumor activity, especially in estrogen-dependent tumors, must be demonstrated in vivo, for example in female rats (Sprague-Dawley) in DMBA-induced mammary tumors. The compounds of the invention cause almost complete regression and suppression of new tumor formation by oral administration 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, do not appear to exhibit in vivo inhibitory activity on cholestrol side chain cleavage because they do not induce adrenal hypertrophy as verified by endocrine organ evaluation. .

Because of 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. warm-blooded animals including humans. However, the novel compounds described are also valuable intermediates for the production of other pharmaceutically active compounds.

Especially preferred compounds within the scope of the invention are those compounds of formula I wherein R 1 is cyano or halogen, especially cyano, and R 8 is hydrogen, phenylalkyl, alkylthio or alkoxycarbonyl, especially hydrogen.

In particular, the invention relates to compounds of formula 1b

CS 268 684 B2

(1b) wherein rJ is an acid or C1 -C4 alkyl group and R @ 1 is hydrogen, a C1 -C4 phenylalkyl group or a C1 -C4 alkyl thi group, stereoisomers thereof, mixtures of these stereoisomers and salts of the above compounds.

The 5,6,7,8-tetrahydroderivatives of sheep formula 1b contain a chiral carbon atom at the 5-position. Both the 5H- 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 1b preferably have the following meanings.

C 1 -C 4 alkyl is, for example, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl and preferably methyl.

A phenylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, R @ 1, is, for example, benzyl.

More particularly, the present invention relates to those compounds of formula (1b) wherein R 1 is cyano-acetyl and R 1 is hydrogen or C 1 -C 4 alkylthio, for example methylthioacin or ethylthio, and pharmaceutically acceptable acid addition salts of the compounds of formula (1b) with acids ·

Particularly preferred are those compounds of formula (1b) wherein R 1 is a cyano group and R 1 is ataa hydrogen, and pharmaceutically acceptable acid addition salts thereof.

The invention preferably relates to compounds of formula Ic

in which

CS 268 684 B2 represents a hydrogen atom or a (C 1 -C 4) alkylthio group, for example methylthio or ethylthioacin, and their pharmaceutically acceptable β-acid addition salts ·

Most preferred is a compound of formula (Ic) wherein R 6 is hydrogen and pharmaceutically acceptable acid addition salts thereof.

Most preferred are the compounds of the invention described in the Examples and their pharmaceutically acceptable salts, and the 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 the above general formula (I), their stereochemistry, and their stereochemistry are in accordance with the invention. Somers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof are prepared by producing a compound of formula VI

& ..

where

R 1 and n are as defined above,

R represents a protecting group _for the NH residue or a hydrogen atom and

X ₂ is a leaving group, reacted with a cyclizing agent, whereupon the optionally obtained compound of formula I wherein R p is hydrogen, is reacted with a C 1 -C 4 alkylmercaptan reagent to give the corresponding compound of formula I wherein R p is alkylthio of 1 to 4 carbon atoms, or the obtained compound of formula (I) in which Rp is hydrogen by reaction with an alkyl haloformate having from 1 to 4 carbon atoms in the alkyl moiety to be converted to the corresponding compound of formula (I) in which Rp is a (C 1 -C 4) alkoxycarbonyl group, or the compound of formula (I) in which R p is hydrogen by reaction with a C 1 -C 4 phenylalkyl halide is converted to the corresponding compound of formula (I) in which R p is represents a phenyl alkyl group having 1 to 4 atoms and / or optionally obtaining a compound of formula I wherein R ₁ is a carbamoyl or alkylcarbamoyl group as defined above, by dehydration, or an obtained compound of formula I wherein R ₁ is halo, by reaction with a hydrocyanic acid salt. or the compound of formula (I) in which R _? represents a formyl group, by oxidation, or an obtained compound of formula I wherein R is amino, by reaction with alkali metal nitrite and a salt of hydrocyanic acid, is converted to the corresponding compound of formula I wherein R ₁ is CN, and / or by optionally, converting the obtained salt into a free compound or another salt, and / or converting the free compound into a salt, and / or separating the resulting mixture of isomers or racemates into individual isomers or racemates, and / or cleaving the mixture of enantiomers such as racemate into optical isomers ·

Compounds of formula Tb are prepared analogously, i.e., by cyclizing a compound of formula VTb

CS 268 684 B2

in which

R is as defined in general formula Ib and X ₂ is a leaving group, in the presence of a base in the final product, if desired, modifying the substituents as described above and / or a resulting salt into the free compound or into another salt and / or the free the salt-containing compound is converted to a salt, and / or the racemic mixture obtained is resolved into the individual enantiomers.

The leaving group X ^ in the starting material of formula VI or VIb is preferably an esterified hydroxyl group, for example a lower alkanoyloxy group such as acetoxy or mesyloxy, benzenesulfonyloxy or toluenesulfonyloxy, or especially a halogen atom such as chlorine or bromine. The cyclization is preferably carried out using a base such as a tertiary amine as defined above, for example triethylamine, or even without using a base at all. Protecting groups of the NH radical R _{@ 8} are preferably tri (lower) alkyl silyl groups such as trimethyleilyl, lower alkanoyl groups such as acetyl, dialkylcarbamoyl groups such as dimethylcarbamoyl, or triphenylmethyl.

Compounds of formulas VI and VIb are known or, if new, can be prepared by known methods, for example by reacting another compound of formulas VI or VIb, wherein X ₂ is a hydroxyl group, as defined in formula I or 1b and an imidazole moiety NH is optionally protected with a conventional amino function protecting group, for example a tri (lower) alkyl8ilyl group such as trimethylsilyl, with a halogenating agent or esterification of the hydroxyl group with a reactive functional derivative of a sulfonic acid or carboxylic acid. The aforementioned halogenation reaction is carried out in a manner analogous to that described in U.S. Pat. No. 4,089,955. The aforementioned reaction with a reactive functional derivative of a sulfonic or carboxylic acid, e.g. acetyl chloride is carried out by known esterification methods.

Compounds of formulas VI and VIb in which X ₂ is a hydroxyl group are known or, if new, can be prepared by known methods, for example by reaction of a compound of formula XIX or XIXa

CHO (XIX)

CS 268 684 B2

(XIX а) wherein n is as defined for formula I or Ib, and βθ and preferably represents the above-defined conventional BH protecting group, for example a tri (lower) alkyl silyl group such as trimethylsilyl, with a compound of formula XX í ¹

in which it is as defined in formula (I) or (Ib) in a manner customary for the reactions of organometallic compounds;

If any of the above intermediates contain reactive groups that would be defective in a given reaction, such as a carboxyl, hydroxy or amino group, these groups may advantageously be temporarily protected at any of the reaction stages with readily cleavable protecting groups. The 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 JFW McOmle, Protective Groups in Organic Chemistry *, Plenum Press, London, New York

carbonyloxy groups are protected, for example, by esterification, for example as unsubstituted or substituted lower alkyl esters such as methyl or benzyl esters, since these ester moieties are readily cleavable under mild conditions, particularly under alkaline conditions. cleavage under mild conditions are, for example, acyl radicals, such as lower alkanoyl radicals optionally substituted by halogen, for example fomyl or trichloroacetyl radicals, or organic silyl radicals, for example tri (lower) alkylsilyl radicals, such as trimethylsilyl radicals.

Salts of the compounds according to 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 according to the invention are obtained in conventional manner. By way of the free compounds, for example by reacting an acid addition salt with a suitable basic agent, for example an alkoxide, such as potassium tert-butoxide. Because of the close relationship between the free compounds and the salt compounds, and the corresponding salt, if any, under the circumstances

OS 2 68 685 B2 ▼ good ·

Depending on the choice of starting materials and methods, there may be new compounds in the form of one or more isomers of foot isomers, for example depending on the presence of chiral carbon atoms as optical isomers, for example antipodes, or as an optical isomer, for example as racates, or as diets and atheroisoners ·

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

The obtained racenates can be resolved by known methods on optical antipodes, for example by chromatography using an optically active stationary phase, recrystallized from an optically active solvent, by microorganisms or by reaction of the acid intermediate or final product with an optically active base forming the 8 racemic acid salt. by their different solubility to give individual diastereoisomers from which the appropriate antipodes can be released by treatment with appropriate agents. Basic racemic products can be resolved into antipodes in an analogous manner, for example, by separation of their diastereoisomeric salts, such as fractional 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, 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 solvates 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 starting materials are formed under the reaction conditions or in which the reactants are used. in the form of its salts or optically pure antipodes. In particular, the above-mentioned reactions employ starting materials 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, the compositions comprising 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 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 a pharmaceutically acceptable salt. usable 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

AND

CS 268 685 B2 in the form of infusion solutions.

Suitable carriers are, in particular, fillers, such as sugars, for example 1-axis, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example normal calcium phosphate or dibasic calcium phosphate, as well as binders such as starch pastes such as corn paste, starch or potato starch, gelatin, tragacanth, methyloelulose and / or optionally disintegrating agents, such as the aforementioned starches, and carboxyethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof, such as sodium alginate. In particular, glidants, for example silicon dioxide, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol, are used as additives. Dragee cores are provided with suitable coatings which may be resistant to gastric conditions, the preparation of which uses, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or thioxydioxide, Selak solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-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 plasticizer, such as glycerol or sorbitol. Solid-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as lactose, binders such as starches, and / or glidants such as grease 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 pharmaceutical 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 employed, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate. or glycose tritium ¹ or aqueous suspensions for injection which contain substances which increase the

viscosity, 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 masterbatch 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 approximately between

2.0 and 13 kPa.

of imidazole in 50 ml of chloroform are added

CS 268 685 B2 was heated to reflux for 4 hours under nitrogen, then cooled and evaporated. The title compound is obtained, m.p. 201-203 ° C.

Preparation of starting materials

a) 4- (3-formyl-n-propyl) -1-trimethylsilylimidazole

A solution of 1.82 g of 4- (3-methoxycarbonylpropyl) -1H-imidazole in 30 ml of tetrahydrofuran was treated with 0.5 g of sodium hydride (50% oil dispersion) under nitrogen at 0 ° C for 30 minutes and then at 0 ° 1.45 ml of trimethylsilyl chloride for 3 hours. The reaction mixture was washed with cold 0.5N sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. The oily residue was redissolved at -78 ° C under nitrogen in 100 ml methylene chloride and added dropwise to the solution with 12.82 ml ( 1.56 mol) of diisobutylaluminum hydride. The reaction mixture was stirred at -78 ° C for 5 minutes, then 1 mL of methanol was added followed by 10 mL of water, and the resulting mixture was filtered through a pad of diatomaceous earth. The organic phase is separated, dried over sodium sulphate and evaporated to give the title compound (a).

b) 4- [4- (p-tert-butylaminocarbonylphenyl) -4-hydroxy-n-butyl] -1-trimethylsilylimidazole

A solution of 6.95 g of p- (tert-butylaminocarbonyl) bromobenzene in 175 ml of tetrahydrofuran was cooled to -70 ° C under nitrogen and 20.1 ml of a 2.7M solution of n-butyllithium in hexane was added dropwise. After a reaction of 30 minutes, a solution of 5> 69 g of 4- (3-formyl-n-propyl) -1-trimethylsilylimidazole in 10 ml of tetrahydrofuran is slowly added, the reaction mixture is allowed to warm slowly to room temperature and 20 ml of ammonium chloride are added. The organic layer was separated, dried over sodium sulfate and cooled. The title compound of b) is obtained.

c) 4- [4-chloro-4- (p-cyanophenyl) n-butyl] -1H-imidazole

A solution of 4.5 g of 4- [4- (p-tert-butylaminocarbonylphenyl) -4-hydroxy-n-butyl] -1-triaethylsilylimidazole in 50 ml of thionyl chloride was heated under reflux for 1 hour, then cooled and evaporated. The residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase was separated and evaporated to dryness with sodium sulfate. The title compound of paragraph c) is obtained.

Example 2

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 ml of phosphorus oxychloride in 30 ml of chloroform was heated under reflux for 15 hours. , then cooled and evaporated with toluene. The oily residue was redissolved in 30 mL of methylene chloride, cooled to 0 ° C, and 30 mL of ice-cold 50% ammonium hydroxide solution was added. The organic phase was separated, dried and evaporated to an oily residue. The oily residue was filtered through silica gel (20 g), eluting with ethyl acetate as the eluent, to afford the title 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 DEG-210 DEG.

Example 3

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 under nitrogen for 11 hours. ° C. 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. 117-188 ° C.

Example 1 a d 4

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

CS 268 685 B2 nitrates hydrogen sulphide in 30 ml of benzene and 0.8 ml of concentrated sulfuric acid is added dropwise while maintaining the room temperature by external cooling. The reaction mixture was stirred for 2 hours and then neutralized. The organic phase was separated, dried over sodium sulfate and evaporated to an oily residue which was chromatographed on silica gel using ethyl acetate as eluent to give the title compound, m.p. 117-118 ° C.

Example 5

5- (p-Cyanophenyl) -5-methylthio-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride At 0 ° C, 0.6 ml of a 2.5 M solution of n- butyllithium and 0.15 g of diisopropylamine in 5 »1 dry tetrahydrofuran prepared a solution of lithium diisopropylamide which was introduced at -78 ° C into 0.29 g of 5- (p-cyanophenyl) -5> 6,7,8-tetrshydroimidazo [1,5-a] pyridine in 10 ml tetrahydrofuran · Stir the reaction mixture for 30 min, then add 0.14 g of dimethyl disulfide dropwise · After 30 min, stop cooling, allow the reaction mixture to warm to room temperature and add 10 ml of saturated ammonium chloride solution are added. The layers are separated and the organic phase is washed with cold 1N hydrochloric acid. After neutralization, the aqueous phase is extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to an oily residue which was chromatographed on silica gel using 5% isopropanol in ethyl acetate as eluent. The oily product was redissolved in acetone and 0.1 ml of 4N ethereal hydrogen chloride was added to the solution. The title compound is obtained, m.p. 204-205 ° C.

Example 6

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

Analogous to Example 21, reaction of 5- (p-cyanophenyl (-5,6,7,8-tetrahydroimidazo [1,5-] pyridine) with ethyl chloroformate) affords the title compound. IC (KBr-technique): 1720, 2240 cm ^-1 .

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

A solution of 2.13 g of 5- (p-amnophenyl) -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 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 8

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 glyphol 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 substance, lactose, magnesium stearate and half of the starch are mixed in a suitable blender, the other half

CS 268 684 B2

Starch and · suspend т 65 ml of water and add the suspension to a 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, if necessary with additional water · The granulate is dried overnight at 35 ° C, the lever is passed through a sieve with a mesh size of 1.2 mm and s tablets are pressed with a breaking mark using a tablet press ·

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

Example 9

This example describes the composition and preparation of 1000 capsules, each containing 20 mg of the active substance.

Ingredients:

quantity component

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine 20.0g

1actose 207.0g modified Starch 80.0g magnesium stearate 3.0g

Preparation:

All the powdered materials are sieved through a 0.6 mm sieve. The active ingredient is added to a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until a homogeneous mixture is formed. the device is filled with hard gelatin capsules no. 2 ·

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

Example Ю

A solution of 3.13 g of 4- [3- (4-tert-butylaminocarbonylphenyl) -3-chloroprop-1-yl] -1-tritylimidazole in 150 ml of acetonitrile was heated under reflux for 15 hours, then cooled and added. 150 ml of methanol are added thereto. The reaction mixture was stirred for a further 15 hours and then evaporated to dryness. The residue was partitioned between ether and water, the ether layer was separated and washed twice with 15 ml of 1N hydrochloric acid each. The combined aqueous extracts were adjusted to pH 8 and extracted with methylene chloride. The organic extracts were dried over sodium sulphate and, after filtration, evaporated to a white foamy product which, after crystallization from ether, gave 1.30 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo [1,2-c] m.p. 136-139 ° C.

- ^ Starting trnaberial is prepared as follows:

a) A solution of methyl 3- (1H-imidazol-4-yl) propionate (6.0 g) and triethylamine (11 ml) in dimethylformamide (31 ml) was treated with a solution of 9.65 g of triphenylmethyl chloride in dimethylformamide (110 ml) at room temperature for 2 hours. . The reaction mixture is poured onto 700 g of ice, the precipitated solid is filtered off and recrystallized from ether. 13.83 g of methyl 3- (1-tritylimidazol-4-yl) propionate are obtained.

RMR (deuterochlorotorm, J values): 2.75 (multiplet, 4H), 3.05 (singlet, 3H), 6.5 to 7.5 multiplet, 17H).

b) A solution of 44.4 mmol of di-butyl aluminum hydride in 29 ml of toluene was added to a solution of 8.79 g of methyl 3- (1-tritylimidazol-4-yl) propionate in 175 ml of methylene chloride under nitrogen at -72 ° C. After 5 minutes, the reaction was quenched by first adding 14 mL of methanol and then 90 mL of water. The reaction mixture is allowed to warm to room temperature, filtered through diatomaceous earth, the organic phase is separated and, after drying over sodium sulphate, evaporated to a yellow oil which is chromatographed on 280 g of silica gel using ether as the eluent to give 4.13 g of oily 3- (1-tritylimidazol-4-yl) propionaldehyde.

IR (CDCl3): 2830, 2740, 1730 cm @ -1

CS 268 684 B2

о) To a solution of 3.19 g of N-tert-butyl-4-bromobenzaaside то 250 ml of tetrahydrofuran and under argon at -70 ° 0 a solution of 25 mmol of n-butyllithium in 10 ml of hexane is added dropwise. 74 g of 3- (1-tritylimidazol-4-yl) propinaldehyde in 100 ml of tetrahydrofuran, the reaction mixture is stirred at -70 ° C for 30 minutes, then allowed to warm to 25 ° C, 2.5 hours and stirred at The aqueous layer was separated and extracted twice with 100 ml of methylene chloride each time. The combined organic extracts were dried over sodium sulfate and the residue was chromatographed on 220 g of silica gel with ether. and ethyl acetate (5: 1) as eluent to give 4- [3- (4-tert-butylsainocarbonylphenyl) -3-hydroxyprop-1-yl] -1-tritylimidazole as an oil · ΐδ (dichloromethane): 1660 ca \

d) A solution of 3.21 g of 4- [3- (4-tert-butylaminocarbonylphenyl) -3-hydroxyprop-1-yl] -1-tritylimidazole and 1.5 ml of thionyl chloride in 50 ml of methylene chloride was heated at reflux for 1 hour. The organic phase is separated and, after drying with sodium sulfate, evaporated. A white foam of 4- [3- (4-tert-butylaminocarbonylphenyl) -3-chloroprop-1-yl] -1-tritylimidazole is obtained.

NMR (CDCl3): 1.45 (slnglet, 9H, 4.30 (triplet, J = 6.0Hz, 2H)) Example 11

A solution of 1.25 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo [1,2-c] 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. Filtration, evaporation and chromatography of the residue on 45 g of silica gel using 5% ammonium hydroxide in ethyl acetate as eluent yielded an oily material which, by treatment with 1 mol equivalent of ethereal hydrogen chloride, yielded 0.5 g of 5H-5- (4-cyanophenyl). 6,6-dihydropyrrolo [1,2-c] imidazole hydrochloride, m.p. 227-228 ° C.

Example 12

Solution of 1.29 g of 5-5- (4-tert-butylaminocarbonylphenyl) -6.7 _t 8,9-tetrahydro-imidazo [i, 5-azepin in 10 ml of thionyl chloride was heated for 1 hour к reflux, then cooled and evaporate. The residue was shaken between methylene chloride and an ice-cold sodium bicarbonate solution, the aqueous layer was separated and extracted three times with 15 ml of methylene chloride each time. The combined organic layers were dried over sodium sulfate and evaporated. Oily from •. The λ ** / pfrek is chromatographed on 26 g of silica gel using 5% 4 * ethanol in methylene alcohol. as eluent. The product obtained after reaction with 1 mol equivalent of fumaric acid in ethanol is 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo [1,5-a] asepine fumarate, m.p. 153-155 ° C.

The starting material was prepared from ethyl 5- (1-tritylimidazol-4-yl) -1-pentanoate in the same manner as 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dlhydropyrrolo [1,2-c] imidazole from ethyl 3- (1-tritylimidazol-4-yl) propionate. The preparation of this starting material is described below.

a) A solution of 5.6 ml of diisopropylamine in 150 ml of tetrahydrofuran was reacted at -70 ° C under nitrogen for 30 minutes and 14.5 * 1 of 2.5M n-butyllithium, and then 7.2 ml of triethylfoaphonoacetate was added dropwise. After 30 minutes, a solution of 10.09 g of 3- (1-tritylimidazol-4-yl) propionaldehyde in 50 ml of tetrahydrofuran was slowly added, the reaction mixture was allowed to warm slowly to room temperature, stirred for 15 hours, then an excess of saturated ammonium chloride solution. The aqueous layer was separated and extracted twice with 50 ml of ethyl acetate each time. The combined organic extracts were dried over sodium sulfate and evaporated to an oil (15.35 g) which was chromatographed on 430 g of silica gel with ether as the eluent to give 9.61 g of ethyl 5- (1-tritylimidazol-4-yl). Of 1-pent-2-enoate

M.p. 86-88 ° C.

(b) A solution of 9,20 g of ethyl 5- (1-triethylimidazol-4-yl) -1-pent-2-enoate in 460 µl of anhydrous ethanol in the presence of 1,88 g of 10% palladium on carbon for 20 minutes of hydrogen atmospheric pressure · The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. ·

Example 13

A solution of 0.80 mmol of lithium-diiaopropylamide prepared from 0.12 ml of diisopropyl amine and 0.32 ml of 2.5M n-butyllithium in 6 ml of tetrahydrofuran at 0 ° C and slowly added to solution 0 at -78 ° C. 17 g of 5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine in 2 ml of tetrahydrofuran. After 0.5 hours and 0.1 ml of benzyl bromide is added dropwise, the reaction mixture After stirring for 1 hour, 5 ml of water are added thereto, the mixture is acidified with 1N hydrochloric acid and after dilution with 20 ml of ether, the layers are separated. The pH of the aqueous phase is adjusted to 7, extracted three times with 15 ml of ethyl acetate. The foamed residue is reacted with 1 mol equivalent of ethereal hydrogen chloride 5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride, dried over sodium sulfate, filtered and evaporated. Melting point: 249 to 251 *

Example 14

Racemic 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride was loaded onto a β-cyclodextrin-coupled silica gel column in 20 mg portions (4.6x). 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-tetrahydroimidazo [1,5-a] pyridine with an optical rotation of -89.2 ° and (+ ) -5- (p-cyanophenyl) -5

6,7,8-tetrahydroimidazo 1,5-a pyridine with an optical rotation of [α] D = +85.02 °. Both of these compounds were dissolved separately in acetone and treated with 1 mol of etheral chloride each. The hydrogen sulfide is converted to the hydrochloride melting at 82-83 ° C (amorphous substance) and 218-220 ° C.

Example 15

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

181 DEG-183 DEG C. 5- (p-Cyrbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridines; 5-r (p-tolyl) -5> 6 _> 7, Q -tetrahydroimidazo [1,5-a] pyridine, the hydrochloride of which melts at 173 to 175 ° C,

5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine whose hydrochloride melts at 216 ° C,

5- (p-formylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine whose fumarate melts at 131 ° C; 5- (p-cyanophenyl) -5-methylthio-5,6,7, 8-tetrahydroimidazo [1,5-a] pyridine, the hydrochloride of which melts at 204 to 205 ° C;

5- (p-cyanophenyl) -5-ethoxycarbonyl-5,6,7,8-tetrahydrqimidazo [1,5-a] pyridine, 5- (p-aminophenyl) -5,6,7,8-tetrahydroimidazo [i, 5-a] pyridine, 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-c] imidazole, m.p. 227-228 ° C,

5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo [1,5-a] azepine, m.p. 153-155 ° C;

5-Benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, the hydrochloride of which melts at 249-251 ° C.

Claims (13)

A process for the manufacture of substituted inidasopyrrole, -pyridine and -asspinone derivatives of formula I (I) wherein n is a number of 1, 2 or 3, R | is cyano, (C1-C4) -alkyl, halogen, amino, carbamoyl, (C1-C4) -alkylcarbamoyl, or formyl; and R ₂ represents a hydrogen atom, phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, alkylthio having 1 to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part, their stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof, characterized in that the compound of formula (VI) wherein R, and n are as defined above, R _Q represents a protecting group or a residue NH hydrogen and X ₂ represents a leaving group _; is reacted with a cyclizing agent, whereupon the optionally obtained compound of formula I wherein R ₂ is hydrogen is converted to the corresponding compound of formula I wherein R ₂ is alkyl thio by reacting with a C 1-4 alkylmercaptan group having 1 to 4 carbon atoms, or a resulting compound of formula I wherein R ₂ is hydrogen, by reaction with an alkyl haloformate obsahuJbía ▼ alkyl moiety of 1 to 4 carbons converted to the corresponding compound of formula I in which a represents a (C 1 -C 4) alkoxycarbonyl group or a compound of formula (I) in which R ₂ is hydrogen by conversion with a C 1 -C 4 -phenyl alkyl halide into the corresponding compound of formula (I) in which: H ₂ represents a phenyl alkyl group having 1 to 4 carbon atoms in the alkyl moiety, or (a) optionally obtaining a compound of formula (I) in which R1 is a carbamoyl or alkylcarbamoyl group as defined above by dehydration, or a compound of formula (I) in which R1 is a halogen atom by reaction with a hydrocyanic acid salt or a compound of formula I, wherein R 1 is a formic group CS 268 685 B2, 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 I, wherein R 1 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 resulting mixture of isomers or racemates is separated into individual isomers or racemates, and / or mixture of enantiomers, Like racemate, cleaves into optical isomers · 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula I wherein n is an integer of 1, 2 or 3, R @ 1 represents cyano, halogen, carbamoyl or C1 -C4 alkylcarbamoyl and R 8 represents a hydrogen atom or a C 1 -C 4 phenylalkyl group, the stereoisomers thereof, mixtures of these stereoisomers, or pharmaceutically acceptable salts thereof. 3. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (X) in which: n is a number of 1, 2 or 3, R 1 is cyano or bromo; and R 8 represents a hydrogen atom or a benzyl group, stereoisomers thereof, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof. 4. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula X in which the bul n is 1, 2 or 3. R 1 is C 1 -C 4 alkyl or amino; R 8 is hydrogen, C 1 -C 4 phenylalkyl, C 1 -C 4 alkylthio or C 1 -C 4 alkoxycarbonyl or n is 1 or 3, R 1 is cyano or C 1 -C 4 alkylcarbamoyl; R 8 is as defined above, or n is 2, 'is cyano and _R² represents phenylalkyl having 1 to 4 carbon atoms in the alkyl part, alkylthio group and 1 to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part, Their stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof 5. The process of item 1, for producing compounds of formula Ib (Ib) wherein R | is cyano or C 1 -C 4 alkyl; and R ₂ represents a hydrogen atom, phenylalkyl в 1 to 4 carbon atoms in the alkyl moiety, or an alkylthio group в 1 to 4 carbon atoms, their stereoisomers, mixtures of these stereoisomers and pharmaceutically acceptable salts thereof, characterized by cyclising a compound of formula VXb ^B 1 (Vib) in which R 6 is as in formula Ib a,. X ₂ is a leaving group, in the presence of a base, whereupon the optionally obtained compound of formula I wherein R 1 is hydrogen by reaction with a C 1 -C 4 phenylalkyl halide is converted to the corresponding compound of formula Ib wherein R 1 * ₂ represents phenylalkyl в 1 to 4 carbon atoms in the alkyl part, or a resulting compound of formula Ib wherein R ₂ is hydrogen, by reaction with an agent providing an alkyl mercaptan with 1 to 4 carbon atoms is converted to the corresponding compound of formula I, wherein R ₂ is C 1 -C 4 alkylthio, or / and optionally the obtained salt is converted to a free compound or another salt, and / or the free compound is converted to a salt, and / or the resulting mixture of isomers or racemates is separated into individual isomers or racemates, and / or a mixture of enantiomers, such as a racemate, is resolved into the optical isomers. 6. A process according to claim 5, wherein the corresponding starting materials are used, CS 268 685 B2 to form compounds of formula 1b wherein: R 6 represents cy and a R 1 represents a hydrogen atom or an alkylthio group having 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition salts thereof. 7. A process according to claim 5, wherein the corresponding starting materials are used to form compounds of formula (Tb) in which cyano is: R 6 represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof. 8. A process according to claim 5, wherein the corresponding starting materials are used to form compounds of formula (Ic) ## STR3 ## in which they are hydrogen or C1 -C4 alkylthio, and their pharmaceutically acceptable acid addition salts. 9. A process according to claim 8, wherein the corresponding starting materials are used to form 5- (p-cyanophenyl) -5,6,7-e-tetrahydroimidazo [1,5-a] pyridine and pharmaceutically acceptable addition salts thereof. salts in acids. 10. 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. stereoisomers or pharmaceutically acceptable salts. ; .......- ь. . 11. 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. 12. The process of claim 1, wherein the corresponding starting materials are used to provide 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo [1,5-a] azepine, its stereoisomers , mixtures of these stereoisomers or pharmaceutically acceptable salts. 13. The process of claim 1, wherein the corresponding starting materials are used to give 5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, Its stereoisomer, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof.