CS268687B2 - Method of substituted imidazopyridine 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 imidazopyridine derivatives of formula (I)

in which

R1 represents cyano, C1-C4alkyl, halogen, amino, carbamoyl, C1-C4alkylcarbamoyl or formyl, stereoisomers of the above compounds, mixtures of these stereoisomers or salts thereof 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, 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, meleinic acid, fumaric acid, hydroxamaleic 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, sulfanilic acid or cyclohexylsulfamic acid. Salts may also be formed with amino acids such as arginine and lysine.

If several salt-forming groups are present, mono- or polysalts may be formed. Preferred are the above-mentioned pharmaceutically acceptable salts. Salts other than therapeutically useful salts, for example picrates, may also be used for isolation or purification.

Cd 268685 B2

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 esterogens. 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 steroid aromatization in those men who may develop this condition. In addition, the compounds of formula (I) 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 a copy as experimental animals.

Inhibition of aromatase activity in vitro 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 ¹⁴ C-androstenedione to 4 ¹⁴ C-stron in human placental microsomes can ^yield aromatase inhibition IC ⁵⁰ values. IC .mu.g for the compounds of the invention range from about 10 '^ 10' ⁹ moles / liter.

Specific values of the measured minimum concentrations for aromatase inhibition are shown in the following table.

Compound of Example No. Minimum Inhibitory Concentration (nmol / liter)

2, 5, 6, 7, 8 and 9.

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 with respect to estrogen-dependent tumors, can be demonstrated in vivo, for example, in female Sprague-Oawley rats with DMBA-induced mammary gland tumors. 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 in vivo inhibition of choleeterol side chain cleavage since 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 Man. However, the disclosed novel compounds are also valuable intermediates for the preparation of other pharmaceutically active compounds.

Particularly preferred compounds within the scope of the invention are those compounds of formula (I) wherein they are 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, θ-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 wherein R 1 '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 reducing the compound of formula (IA)

(IA)

In which R is as defined in formula I, or is a hydroxymethyl group, or a 7,8-dihydroderivative thereof, optionally with a simultaneous reduction of the hydroxymethyl group R R to a methyl group Rp, whereupon the optionally obtained compound of formula I wherein carbamoyl or an alkylcarbamoyl group as defined above by dehydration, or a compound of formula I wherein R 1 is halogen by reaction with a hydrocyanic acid salt, or a compound of formula I wherein R 6 is a formyl group by oxidation, or the resulting compound of formula I in which it is an amino group, by reaction with an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula I in which it is a cyano group, and / or 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 the individual isomers or racemates, and / or the enantiomer mixture, such as the racemate, is resolved into the optical isomers.

The compounds of formula Ib are prepared analogously, i.e. by reducing the compound of formula Ia

in which

R 1 'is as in formula Ib, or its 7,8-dihydroderivative.

The present invention is conveniently carried out with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium under acidic conditions such as a mineral acid such as hydrochloric acid or in the presence of palladium on carbon at atmospheric pressure in an inert solvent such as ethanol or ethyl acetate.

The starting materials of the formula IA can be prepared, for example, by:

CS 260687 B2

or a 4,5-dihydroderivative thereof, (II) to form a compound of formula IA therefor

7,8-dihydroderivative or that is

b) cyclizes the compound of formula III

(III) to form the corresponding 7,8-dihydroderivative of a compound of formula (IA), or that it is:

c) in a compound of formula IV

(IV)

Or in the 7, .alpha.-dihydroderivative of a compound of formula (IV), wherein R1 is a convertible group to a cyano group, converts a radical to a cyano group to give a compound of formula (IA) or a 7,8-dihydroderivative thereof, in which it is cyano or that is

d) decarboxylating a compound analogous to a compound of formula IA or a 7,8-dihydroderivative thereof, each of which starting material still contains a carboxyl group in the 1 or 3 position to form a compound of formula IA or a 7,8-dihydroderivative thereof.

The starting materials of the formula Ia are prepared analogously to the starting materials of the formula IA.

Another method for the preparation of 7,8-dihydroderivatives of compounds of formula IA is, for example, by cyclizing a compound of formula IXb

(XXb)

In the next section, the individual procedures described above are described in more detail.

Procedure a)

The cyclization of the formylamino compound of formula (II) is preferably carried out under the conditions described for the cyclization of 6-methyl-2-methylaminopyridine to 5-methylimidazo [1,5-a] pyridine in J. Org. Chemistry £ 0.1210 (1975). This cyclization under acidic conditions can preferably be carried out using a Lewis acid such as polyphosphoric acid, phosphorous oxychloride or polyphosphoric acid ester. ,

Procedure b)

The cyclization of the formyl derivative of the formula III is carried out, for example, under basic conditions. As the base, any base that readily receives protons such as an amine such as a tertiary amine such as a tri (lower) alkylamine such as trimethylamine or triethylamine, a cyclic tertiary amine such as N-methylmorpholine, a bicyclic amidine such as diazabicycloalkene, such as 1,5-diazabicyclo [4,3,0] nori-5-ene or 1,5-diazabicyclo [5,4,0] undec-5-ene, or, for example, a pyridine type base, for example pyridine alone. A suitable base is also an inorganic base, for example an alkali metal hydroxide or an alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide. A preferred base is an alkoxide, for example an alkali metal alkoxide, such as a methoxide, ethoxide or target, sodium or potassium butoxide.

The cyclization according to processes a) and b) is generally carried out in an inert organic solvent such as a suitable alcohol, for example methanol, ethanol or isopropanol, a ketone such as acetone, an ether such as dioxane or tetrahydrofuran, a nitrole such as acetoCS 268687 B2 nitrile, a hydrocarbon such as benzene 61 toluene, a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, an ester such as ethyl acetate, an amide such as dimethylformamide or dimethylacetamide, etc. The reaction temperature is between room temperature and temperature. the boiling point of the reaction mixture, preferably between 60 ° C and the boiling point of the reaction mixture. Preferably, the cyclization is carried out under an inert gas atmosphere, in particular under a nitrogen atmosphere.

Procedure (c)

Radicals R ^M ^ in compounds of formula IV which may be converted to cyano is for example, hydrogen, esterified hydroxy, for example halogen, especially chlorine, bromine or iodine, sulfonyloxy, for example p-toluenesulfonyloxy, benzenesulfonyloxy or mesyloxy, sulfo, amino, carboxyl, carboxyl in the form of a functional derivative, for example carbamyol, lower alkylcarbamoyl, such as tert-butylcarbamoyl or haloformyl, for example chloroformyl or bromoformyl, formyl, formyl in the form of a functional derivative, for example hydroxyiminomethyl or a halogen-magnesium group, for example an iodo, bromo or chloromethyl group. .

Compounds of formula ΙΑ wherein R R is cyano can be obtained, for example, by the following conversions.

Conversion of a compound of formula IV in which R 'is hydrogen to a compound of formula IA is carried out, for example, according to the known method of Friedel, F.M. Crafts and P. Karrer, by reaction with cyanogen chloride or cyanogen bromide or according to the method described by J. Houben and W. Fischer, by reaction with, for example, trichloroacetonitrile. Preferably, aluminum chloride is used as the standard catalyst in these reactions, and hydrogen chloride or hydrogen bromide is removed in the reaction, which can be removed from the reaction mixture by addition of a base, preferably an amine, for example triethylamine or pyridine.

Conversion of a compound of formula IV wherein R 10 is a halogen atom such as chlorine, bromine or iodine to a compound of formula IA is carried out using, for example, a hydrocyanic acid salt, especially sodium cyanide or potassium cyanide, or preferably copper (I) cyanide. Preferred solvents for this reaction are pyridine, quinoline, dimethylformamide, 1-methyl-2-pyrrolidionone and hexamethylphosphoric triamide. Higher reaction temperatures are preferred, in particular the reflux temperature of the reaction mixture.

CoQA / erosion _{in a} compound of formula IV wherein R ' the compound of formula IA proceeds in several stages. First, a diazonium salt is prepared, for example by reacting an amino compound with an alkali metal nitrite, preferably potassium nitrite. The diazonium salt may be subjected to an in situ known Sandmeyr reaction, for example with copper cyanide or a cyanide-containing cyanide complex, preferably potassium cuproammonium cyanide, or with a catalytic amount of freshly prepared precipitated copper powder in the presence of an alkali metal cyanide such as sodium cyanide or cyanide. . This reaction is described in more detail in, for example, Houben-Weyl, Methoden der Organischen Chemie, Thieme Stuttgart 1952, Vol. VIII.

The carboxyl group R ' j can be converted to the cyano group by, for example, reaction with chlorodulfonyl isocyanate according to the method described by R. Graf in Angew. Chem. 80: 183 (1968). In this reaction, the preferred solvent is dimethylformamide, releasing carbon dioxide and precipitating the chlorodulfonic acid addition salt of dimethylformamide from the reaction mixture.

Conversion of a compound of formula IV wherein R R is a carboxyl group in the form of a functional derivative, for example a carbamoyl group, a lower alkylcarbamoyl group such as a target, a butylcarbamoyl group, to a compound of formula IA is accomplished by treatment with a strong dehydrating agent such as phosphorous pentoxide , thionyl chloride, phosgene or oxalic acid chloride.

The haloformyl (halocarbonyl) group R ' p, for example a chloroformyl or bromoformyl group, is reacted with ammonia or a primary or secondary amine, for example methylamine or dimethylamine. the amide thus obtained is converted to the nitrile of formula IA optionally in situ by treatment with the dehydrating agents mentioned above, for example phosphorus pentachloride in the case of unsubstituted amide or phosphoryl chloride in the case of mono- or di (lower) alkylamide.

The hydration can preferably be carried out in the presence of a suitable base. A suitable base is, for example, an amine, such as a tertiary amine, for example tri (lower) alkylamine, such as trimethylamine, triethylamine or ethyldiisopropylamine, or N, N-di (lower) alkylaniline, for example N, N-dimethylaniline, or cyclic tertiary amine, for example N- (lower) alkyl morpholine, such as N-methylmorpholine, or pyridine type bases, for example pyridine alone or quinoline.

Conversion of the formyl group to a cyano group is accomplished, for example, by converting the formyl group into a reactive functional derivative, for example, a hydroxyiminomethyl group, and converting this group by treatment with a dehydrating agent into a cyano group. A suitable dehydrating agent is one of the inorganic dehydrating agents mentioned above, for example phosphorus pentachloride or, preferably, an organic acid anhydride, for example a lower alkanecarboxylic acid anhydride such as acetic anhydride.

Conversion of the formyl group to the hydroxyiminomethyl group is carried out by reacting a compound of formula IV wherein R 1 represents a formyl group, for example with an acid addition salt of hydroxylamine, preferably hydroxylamine hydrochloride.

A compound of formula IV wherein R 1 is a formyl group can be converted directly to a compound of formula IA, for example by reaction with O, N-bis- (trifluoroacetyl) hydroxylamine in the presence of a base such as pyridine according to the method described by DTMowry in Chem. Roar. 42, 251 (1940).

Conversion of a compound of formula IV wherein R R is a halo-magnesium group, for example an iodo, bromo or chloromethium group, to a compound of the formula IA is carried out, for example, by reaction of a magnesium halide with a halocyanate or a dicyanide. In this reaction, a magnesium halide, such as magnesium chloride, or a magnesium cyanide, such as magnesium cyanide, is formed. Grignard compound in which R * '| represents a halogeno-magnesium group, prepared by a conventional method, for example by reacting a compound of formula IV in which R 1 represents a halogen atom such as chlorine, bromine or iodine with magnesium; for example in dry ether. ·

Unless otherwise specified, the conversion of a compound of formula IV to a compound of formula IA is preferably carried out in an inert solvent, preferably in an anhydrous solvent or in a solvent mixture such as a carboxylic acid amide such as formamide such as dimethylformamide in a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, in a ketone such as acetone, a cyclic ether such as tetrahydrofuran, an ester such as ethyl acetate or a nitrile such as acetonitrile, or mixtures of these solvents, optionally in the presence of an alcohol such as methanol or ethanol or water, optionally at a reduced or elevated temperature, for example at a temperature in the range of about -40 ° C to + 100 ° C, preferably from room temperature to the boiling point of the reaction mixture and optionally under an inert gas atmosphere, for example under nitrogen. ·. 9

Preparation of intermediates

The compounds of formula (II) are either known or, if new, can be prepared by known methods, for example by reaction of a compound of formula (VIII)

(VII) ^R 1 is as defined in formula (Ia), with formic acid or a reactive functional derivative thereof, for example with mixed formic anhydride and acetic acid.

Compounds of formula III are prepared, for example, by reacting a compound of formula V

(V) wherein X 1 is a hydroxy group, for example ^, with diethyl oxide in the presence of dehydrating agents, for example acid anhydrides such as anhydrides of organic carboxylic acids, for example aliphatic or aromatic carboxylic or dicarboxylic acids, such as lower anhydrides alkanecarboxylic acids, in particular acetic anhydride, mixed anhydrides of lower alkanecarboxylic or dicarboxylic acids with mineral acids, for example acetyl chloride or oxalyl chloride, as well as anhydrides of inorganic acids, in particular phosphoric acid, such as phosphorus pentoxide. The above-mentioned anhydrides, in particular organic carboxylic acid anhydrides, for example oxalyl chloride, are preferably used in a mixture with dimethylsulfoxide in a ratio of about 1: 1. Other suitable dehydrating or water absorbing agents are carbodiimides, in particular dicyclohexylcarbodiimide, as well as diisopropylcarbodiimide, or catenimides, for example diphenyl-Nβ-tolylketenimide. These agents are preferably used in the presence of acid catalysts such as phosphoric acid, pyridinium trifluoroacetate or pyridinium phosphate. Sulfur trioxide can also be used as a dehydrating or water-absorbing agent, which is usually employed as a complex in the reaction, for example with pyridine. A base, preferably a base mentioned above in process c), for example triethylamine, is then added to the reaction mixture.

The compounds of formula (IV) are preferably prepared in a manner analogous to process (a) above.

The compounds of formula (V) are known or, if new, can be prepared by known methods, for example by reacting another compound of formula (V), where it represents a hydroxyl group, with a halogenating agent or esterification of the hydroxyl group with a reactive functional derivative of sulfonic acid or carboxylic acid. This reaction with a halogenating agent such as thionyl chloride or phosphorus pentachloride is carried out in a manner analogous to that described in U.S. Pat. No. 4,089,955. The above reaction with a reactive functional derivative of a sulfonic acid or carboxylic acid, for example a mixed anhydride of the acid with a mineral acid, such as mesyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, or acetyl chloride, is carried out by known esterification methods.

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) where the meaning of formula (IA) is as defined above.

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 V wherein X * is hydroxyl are known or, if new, can be prepared by known methods, for example by reaction of a compound of formula XVII

HO (XVII)

H in which

represents a protecting group of the NH radical, for example a group such as dimethylcarbamoyl, di (lower) alkylcarbamoyl and wherein the hydroxyl group is protected by a conventional hydroxyl function protecting group, for example trlmethylsilyl, with a compound of formula XVIII

(XVIH) where

R 1 is as in formula IA and represents a leaving group such as halogen, for example chloro or x, or p-toluenesulfonyloxy.

Compounds of formula XV may be prepared, for example, by the compound of formula XXI ^X 3, for example, an esterified hydroxyl group, bromine, or a sulfonyloxy group, for example mesylo5.

(XXI) is converted by treatment with an oxidizing agent such as peracetic acid to an N-oxide, the N-oxide, the N-oxide is treated with a methylating agent, such as dimethyl sulfate, and a cyano group is introduced at the 6-position, for example using potassium cyanide .

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 the application of J.F.W. Thus, carboxyl 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. especially under alkaline conditions. Protecting groups of amine and hydroxyl functions which can be cleaved under mild conditions are, for example, acyl radicals, such as lower alkanoyl radicals optionally substituted by halogen, for example formyl or trichloroacetyl radicals, or organic power radicals, for example tri (lower) alkylsilyl radicals such as trimethylsilyl radicals. . .

Salts of the compounds of the invention can be prepared in a manner known per se. Thus, such salts can 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. On the other hand, those compounds of the invention which contain acidic groups, for example a carboxyl group, can be converted into salts in a manner known per se by treatment with a base such as an alkali metal hydroxide or alkoxide, an alkali metal or alkaline earth metal salt such as sodium bicarbonate. or a suitable organic amine. Free compounds can be obtained by treating the salts with an acid. 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. in the form of one of the possible isomers or in the form of mixtures of these isomers, depending, for example, 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, by recrystallization from an optically active solvent, by microorganisms or by reaction of an acid intermediate or final product with an optically active base forming a 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. the products can be resolved into anitipodes in an analogous manner, for example, by separation of their diastereoisomeric salts, such as fractional crystallization of the 1-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 the reactants, or in the presence or absence of catalysts, condensation or other reagents, and / or in an inert atmosphere, at low 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 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 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, 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 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 on the method of application. For parenteral administration, for example by intramuscular or subcutaneous injection, or 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 phosphate, for example normal calcium phosphate or dihydrogen phosphate, and also binders such as starch pastes, for example corn pastes, starch 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 conditions, the preparation of which uses, inter alia, 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 coatings resistant to gastric juices, 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 with a plasticizer, such as glycerol or sorbitol. Solid fill 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 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. It is also possible to use gelatin rectal capsules 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 suitable injectable 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 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.

Example 1

5- (p-Cyanophenyl) imidazole [1,5a] pyridine

A solution of 0.1 g of 5- (p-t-butylaminocarbonylphenyl) imidazole [1,5-a] pyridine in 3 ml of toluene was reacted for 5 hours at 90 ° C with 40 µl of phosphorus oxychloride. The solvent was evaporated and the residue was redissolved in 30 ml of chloroform at 0 ° C. After addition of ice-cold ammonium hydroxide solution, the organic phase is separated and, after drying over sodium sulfate, evaporated. The residue is chromatographed on silica gel using ethyl acetate as eluent to give the title compound, m.p. 117-118 ° C, the hydrochloride of which melts at 255-257 ° C.

Example 1 a d 2

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

A solution of 1.13 g of 5- (carbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and 1.0 ml of phosphorus oxychloride in 30 µl of chloroform was heated at reflux for 15 hours, then The mixture was 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 4 ammonium hydroxide solution was added. 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 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 DEG-210 DEG. ’*

EN 26-6Θ7 02

Example 3

5- (p-tolyl) -5,6,7,4-tetrahydroimidazole [1,5-a] pyridine hydrochloride

A solution of 0.36 g of 5- (p-hydroxymethylphenyl) imidazo [1,5-a] pyridine in 25 ml of ethanol and 6.4 ml of concentrated hydrochloric acid was hydrogenated for 4 hours in the presence of 0.15 g of 10% palladium on carbon. 60 ° C under a hydrogen pressure of 276 kPa. The reaction mixture was filtered, evaporated and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phases were dried over sodium sulfate and evaporated to an oily residue which was purified by preparative thin layer silica gel chromatography using ethyl acetate as the solvent system. The hydrochloride is prepared in acetone using 1.1 mol equivalents of ethereal hydrogen chloride. The title compound is obtained, m.p. 173-175 ° C.

Example 4

5- (p-hydroxymethylphenyl) imidazo [1,5-a] pyridia Dissolve 5- (p-ethoxycarbonylphenyl) imidazo [1,5-a] pyridine in 26 ml of methylene chloride under nitrogen at -70 ° C and 6.6 ml of a toluene solution of diisobutylaluminium hydride (11.5 mmol) is added dropwise, the reaction mixture is stirred for 1 hour, then 1.5 ml of methanol are added, the cooling bath is removed and 15 ml of water are added. the organic phase was dried over sodium sulfate and evaporated to give the title compound, m.p. 137-128 ° C.

Example 5

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

A solution of 1.6 g of 5- (p-cyanophenyl) -7,8-dihydroimidazo [1,5-a] pyridine in 50 ml of ethyl acetate is hydrogenated at atmospheric pressure in the presence of 0.2 g of 5% palladium on carbon until the theoretical consumption is complete. the amount of hydrogen. The catalyst was filtered off and the solvent was evaporated, yielding the title compound, mp 117-118 ° C.

Example 1 a d 6

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

A solution of 54 mg of 5- (p-cyanophenyl) imidazo [1,5-a] pyridine hydrochloride in 5.0 ml of methanol was hydrogenated at room temperature under atmospheric pressure for 30 minutes in the presence of 0.1 g of 10% palladium on carbon. The catalyst is filtered off, 0.21 ml of 1N sodium hydroxide is added to the filtrate, the filtrate is evaporated, the residue is taken up in 10 ml of methylene chloride and the solution is filtered through a pad of diatomaceous earth. Evaporation of the filtrate yielded an oily residue which was chromatographed on silica gel using ethyl acetate as eluent to give the title compound, m.p. 117-188 ° C.

Example 7

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 copper (I) 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. Organic

AND

The 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. _E

Example 8

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

Pír-d k 1 a d 9.

5- (p-cyanophenyl) -5,6,7,8-tetrahydroiniidazofl, 5-apyridine

A solution of 2.13 g of 5- (p-aminophenyl) -5, aa, 7,8-tetrahydroimidazo [1,5-a] pyridine in 4 ml of concentrated hydrochloric acid A 10 ml of water is cooled in ice and slowly added thereto. solution of 0.78 g of sodium nitrite 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 10

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

Ingredients:

component

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine lactose maize starch polyethylene glycol 6,000 magnesium stearate distilled water quantity

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, with the addition of additional water. The granulate is dried over the nose at 35 ° C and then passed through a 1.2 mm sieve and compressed into a tablet with a breaking line using a tablet CS 268687 B2 press.

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

Example 11

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

Ingredients:.

quantity component

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

Preparation:

All powdered 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 12

Racemic 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride is applied in 20 mg portions onto a silica gel column followed by 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-tetrahydroimidazo [1,5-a] pyridine with optical rotation λ _; | ² θ = -89,2 ⁰ α (>) -5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine with optical rotation | ² ^> 85.02 °. Both of these components are separately dissolved in acetone and converted by treatment with 1 mol equivalent of ethereal hydrogen chloride to the hydrochlorides melting at 82-83 [deg.] C. (amorphous substance), respectively. Mp 218-220 ° C.

Example 13 In a logical manner as in the previous examples, the following compounds can also be prepared:

5- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, m.p.

183 ° C

5- (p-tolyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine whose hydrochloride melts at 173-175 ° C,

5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, the hydrochloride of which melts at 216 ° C; . ·

5- (p-formylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine whose fumarate melts at

131 ° C

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

Claims (6)

SUBJECT OF THE INVENTION A process for the preparation of substituted imidazopyridine derivatives of the general formula I in ^R 1 (I) which represents a cyano group, an alkyl group, a carbamoyl group, an alkylcarbamoyl group and 1 to an alkyl moiety or a formyl group. having from 1 to 4 carbon atoms, halogen atom, ami4 carbon atoms of their stereoisomers, mixtures of these stereoisomers or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula IA useful (IA) i is as R in formula I, or is a hydroxymethyl group in which ^{R 1} or its 7, θ-dihydroderivative, optionally with simultaneous reduction of the hydroxymethyl group to the Rp methyl group, whereupon the optionally obtained compound of formula I wherein R 1 is carbamoyl or an alkylcarbamoyl group as defined above, by dehydration, or a compound of formula I wherein R 1 is halogen by reaction with a hydrocyanic acid salt, or a compound of formula I wherein R 1 is a formyl group by oxidation, or the obtained compound of formula (I) in which it is an amino group, by reaction with an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula (I) in which R1 is cyano, and / or converted to the free compound or to another salt; o / a 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 the enantiomer mixture, such as the racemate, is resolved into optical isomers. . . 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R 1 is cyano, halogen, carbamoyl or C 1 -C 4 alkylcarbamoyl, stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof. 3. A method according to claim 1, wherein the corresponding starting materials are used to form compounds of formula I in which: R 1 represents a cyano group or a bromine atom, 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 I wherein: R @ 1 represents a C1 -C4 alkyl group or an amino or cyano group, stereoisomers thereof, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof. 5. The process of item 1, for producing compounds of formula 1b (1b) wherein * R 1 represents a cyano or C 1 -C 4 alkyl group, θ of their pharmaceutically acceptable salts, characterized in that the compound of formula (Ia) in which: R1 is as in formula Ib, or a 7,8-dihydroderivative thereof, reduced with hydrogen in the presence of a hydrogenation catalyst, whereupon any salt obtained is converted to the free compound or another salt, and / or the free salt-containing compound is converted to a salt, and / or cleaves the racemic mixture obtained into individual enantiomers. 6. A process according to claim 5, wherein the corresponding starting materials are used to form a compound of formula (Ib) wherein R < 6 > is cyano, and pharmaceutically acceptable acid addition salts thereof. 7. A process according to claim 5, wherein the corresponding starting materials are used to form J-C [beta] -cyanophenyl-D-S.alpha.1,1 -S-tetrahydroimdazolyl-5-alpyridine of formula Ic CN (Ic) or a pharmaceutically acceptable acid addition salt thereof. 6. A process according to claim 1, wherein the corresponding compounds are used to form 5- (p-bromophenyl) -5,6,7,8-tetrahydroimidazo-11,5-apyridine, its stereoisomer, mixtures of these stereoisomers, or pharmaceutically acceptable salts.