CS268684B2 - 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 the preparation of substituted imidazopyrrole, -pyridine or -azepine derivatives of the general formula (I) wherein n is 1, 2 or 3 »is cyano, C 1-6 -alkyl, halogen, amino, carbothioyl, C 1-6 -alkyl. alkylcaivbamoyl or formyl; represents hydrogen, phenyl-C. C 1-6 alkylthio or C 1-6 alkylthio or C 1-6 stereoisomers thereof, and mixtures of stereoisomers and salts, characterized in that the cyclized compound of formula (V) wherein X is a leaving group, into a product in which R 2 is hydrogen, optionally introducing a phenylalkyl, alkylthio or alkoxycarbonyl group, as defined above, and / or optionally modifying R radicals and optionally isolating the product in the individual isomer, isomer or salt form. The compounds produced act as aromatase inhibitors and can be used as medicines ·

(i) (V) (i

CS 268 684 82

The present invention describes substituted inidasopyrrole, -pyridine and -azepine derivatives of the general formula I

(I) in which »n is an integer equal to 1, 2 or 3, R ₁ snanená cyano, alkyl with 1-4 C atoms, Aton halogen aninoskupinu, kaxbanoylovou group alkylkarbanoylovou group having 1 to 4 carbon atoms in the alkyl moiety or a fomyl group and

R @ 1 is hydrogen, C1-C4-phenylalkyl, C1-C4-alkylthio or C1-C4-alkoxycarbonyl, stereoisomers of the above compounds, mixtures of these athero-isomers or salts of the aforementioned compounds compounds, a process for the preparation of these compounds and their use as aronatase inhibitors.

The compounds of general formula I contain at least one asynetric carbon atom and can be present as R- or S-enantioners as well as as enantiomers, for example as racenates. The invention encompasses all of these, as well as other isons and at least two, for example ate diastereoners or enantiomers if these isoners may exist in the presence of additional or additional centers of asynmetry in the molecule

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

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

The compounds of the invention form acid addition salts, including the pharmaceutically acceptable salts with customary acids such as mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids such as and formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, naleinic acid, funaric acid, hydroxymaleinic acid, pyrohrosic acid, phenylacetic acid, benzoic acid, 4-aninobensoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aninosalicylic acid, panic acid, gluconic acid, nicotinic acid, nethanesulfonic acid, ethanesulfonic acid, acid halogenated benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexysulfanoic acid. Salts can also be formed with amino acids such as arginine and lysine.

268 684 В2

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

The compounds of the present invention exhibit valuable pharmacological properties, e.g., inhibition of aronatase in mammals, including humans. For example, these compounds inhibit the non-labile conversion of androgens to estrogens. The compounds of formula I are therefore useful in the treatment of gyneconastia. Atheroids and atherosides in men »who may develop this condition · In addition, the compounds of formula I are useful, for example, in the treatment of diseases dependent on the production of ostrogen, including estragon-dependent mammary tumors, particularly in postmenopause by inhibiting eatrogen synthesis. document in vitro or in vivo tests on experimental animals »preferably with the use of mammals» for example guinea pigs »mice» cover »cats» dogs or monkeys as experimental animals ·

In vitro inhibition of aronatase activity can be demonstrated, for example, using the method described in J. Biol. Chem. In addition, kinetic enzymatic studies involving inhibition of the conversion of 4- [4-C-androstenedione to 4- [4-C] -tron in human placental microsomes can provide aronatase inhibition values. from about 10 "$ to 10" ^ nol / liter.

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

Example compound no.

minimum inhibitory concentration (nnol / liter)

1, 2, 3, 5 and 8 4

1.5

In vivo inhibition of aronatase can be demonstrated, for example, by a reduction in the ovarian eatrogen content of female rats first injected with serum gonadotropin in pregnant mares and, after two days, with human chorionic gonadotropin »the following day orally, the compound of the invention and one hour adrostenedione. of the compounds of the invention is between about 0.01 and 10 mg / kg or even lower. The antitumor activity, particularly with regard to eating-dependent tumors, can be demonstrated in vivo, for example, in female Sprague-Dawley rats with a DMBA-induced mammary gland tumor. 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 inhibitors of in vitro and in vivo aronatase »they do not appear to have in vivo inhibitory activity on cholesterol side chain cleavage» because they do not cause adrenal hypertrophy »As verified by endocrine organ evaluation

Due to their famacological properties (aronatase inhibitors), the compounds of the invention may be used as medicaments, for example in the form of pharmaceuticals, for the treatment of hormonal diseases, for example cancers dependent on the production of eatrogens, particularly mammary gland carcinoma, and various anomalies »gyneconastia» in warm-blooded animals including man. However, the novel compounds disclosed are also valuable intermediates for the production of other pharmaceutically active compounds.

CS 268 683 B2

Particularly preferred compounds within the scope of the invention are compounds of the formula I in which R1 represents a cyano group or a halogen atom, in particular a cyano group and R8 denotes a hydrogen atom, a phenylalkyl group, an alkylthio group or an alkyloxycarbonyl group, in particular a hydrogen atom.

In particular, it relates to compounds of formula Ib

where

R 1 represents a cyano group or an alkyl group having 1 to 4 carbon atoms and

R1 represents a hydrogen atom, a (C1-C4) -phenylalkyl group or a (C1-C4) alkylthio group, their stereoisomers, mixtures of these stereoisomers and salts of the abovementioned compounds; The present invention includes both the attached 5R- and 5S-enantiomers and the 5 (R, S) racemate. The general terms used to describe compounds of formula Ib 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.

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

In particular, the invention relates to those compounds of formula Ib wherein R * is cyano and Rg is hydrogen or C1-C4alkylthio, for example methylthio or ethylthio, and pharmaceutically acceptable acid addition salts of compounds of formula Ib with acids.

Particularly preferred are those compounds of formula (Ib) wherein R 6 is a cyano group and R 8 is a hydrogen atom, and their pharmaceutically acceptable acid addition salts.

The invention preferably relates to compounds of formula Ic

In which představuje represents a hydrogen atom or an alkylthio group and 1 to 4 carbon atoms, for example methylthio or ethylthio, and their pharmaceutically acceptable addition salts and acids.

Most preferred is a compound of formula (I) wherein H is a pharmaceutically acceptable acid addition salt thereof.

The compounds of the invention described in the Examples and their pharmaceutically acceptable salts are most preferred, 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 and the above-mentioned compounds of the formula I, their stereochemistry. Somer, mixtures of stereoisomers and pharmaceutically acceptable salts thereof are produced by a compound of formula V wherein:

В, and n are as defined above and

Xj is a leaving group, reacted with a cyclizing agent, whereupon an optionally unsubstituted compound of formula I wherein Rg is hydrogen is converted to the corresponding compound of formula I wherein Hg and amenate by reaction with a C1-C4 alkylmercaptan. (C1-C4) alkylthio or the obtained compound of formula (I) in which Rg 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 Rg is alkoxycarbonyl a (C 1 -C 4) alkoxy moiety, or the obtained compound of formula (I) wherein R 8 is hydrogen by reaction with a C 1 -C 4 phenylalkyl halide is converted to the corresponding compound of formula (I) wherein R 8 is phenylalkyl having 1 to 4 * atoms atoms in the alkyl moiety, and / or, if desired, the resulting compound of formula I wherein B ^ is carbamoyl or said alkylcarbamoyl group, dehydration, or an obtained compound of formula I wherein R _f represents a halogen atom, by reaction with a salt of hydrocyanic acid, , or the compound of formula X in which R 1 is a formyl group by oxidation, or the compound of formula X in which B 1 is an amino group by reaction in an alkali metal nitrite and a hydrocyanic acid salt is converted to the corresponding compound of formula X, in which R ^ is cyano, and / or the salt obtained is optionally 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 raoemates is separated into

OS 268 684 B2 5 individual isomers or racemates, and / or a mixture of enantiomers such as raoemate is resolved into optical isomers.

The compounds of general formula Ib are produced analogously, i.e. by cyclizing the compound of general formula Vb

in which

R < 4 > has the same meaning as in formula (Ib) and is a leaving group, in the presence of a base, optionally substituting the individual substituents as described above in the resulting product, and / or converting the obtained salt into free compound or other salt; the salt-forming group is converted to a salt, and / or the racemic mixture obtained is resolved into the individual enantiomers.

The leaving group X ₁ in the starting material of formula V or Vb 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.

A suitable base used for cyclization is, for example, an alkali metal or alkaline earth metal hydroxide, for example sodium, potassium or calcium hydroxide, a bicyclic or din, for example 1,5-diazabicyclo [5,4.0] undec-5-en, as preferably an alkoxide, for example sodium methoxide or potassium methoxide, sodium or potassium tert-butoxide, an alkali metal amide such as lithium diisopropylamide, or an alkali metal hydride such as sodium hydride. When R ₂ represents a functionally modified carboxyl group, the reaction proceeds much more easily and it is possible to use weaker bases such as tertiary amines such as tri (lower) alkylamines, for example triethylamine ·

The cyclization according to the invention is carried out in an aprotic and organic solvent, for example an ether such as diethyl ether, dioxane or tetrahydrofuran, a ketone such as acetone, an amide such as dimethylformamide or hexamethylphosphoric triamide, or mixtures thereof, optionally also in a mixture of the above solvents with an alkane; for example with n-hexane or petroleum ether · The reaction temperature is between about -50 ° C and 50 ° C, preferably between -10 ° C and room temperature · The reaction is preferably carried out under an inert gas atmosphere, for example under argon or nitrogen atmosphere ·

Compounds of formulas V and Vb are known or, if new, can be prepared by known methods, for example by reacting another compound of formula V or Vb wherein X _f is a hydroxyl group with a halogenating agent or esterifying a hydroxyl group with a reactive sulfonic acid functional derivative; This reaction with a halogenating agent, such as thionyl chloride or phosphorus pentachloride, is carried out in a manner analogous to the halogenation process described in U.S. Patent No. 4

089 955 · The above reaction with a reactive functional derivative of sulfonic acid or cara

Box 268, e.g. mixed with an anhydride of the acid in a mineral acid, e.g. with methyl chloride, bensenesulfonyl chloride or p-toluenesulfonyl chloride, or acetyl chloride, is carried out by means of white esterification methods.

Compounds of formula V or Vb wherein X ₁ is a hydroxyl group are known or, if new, can be prepared by known methods, for example by reaction of a compound of formula XVII or XVIIa

(XVII) (XVIIa) in which n is as defined in formula I and

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

(XVIII) in which it has the meaning as in Formula I or Ib; and

X 1 is a leaving group, for example an esterified hydroxyl group, such as halogen, for example chlorine or bromine, or a sulfonyloxy group, for example mesyloxy or p-toluenesulfonyloxy.

If any of the above intermediates contain reactive groups that would be defective in a given reaction, such as a hydroxyacid or amino group, these groups may preferably be temporarily protected at any reaction stage with easily 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 its introduction and cleavage, are known in the art and are described, for example, in J. У. Protective Groups in Organic Chemistry, Plenum Press, London, Hew York, 1973 Protecting groups of amine and hydroxyl functions that can be cleaved under mild conditions are, for example, aoyl residues such as a lower alkanoyl residue optionally substituted by halogen, for example formyl or hydroxyl. a trichloroacetyl moiety, or an organic ailyl moiety, for example a tri (lower) alkylsilyl moiety, such as a trimethylsilyl moiety.

The salts of the compounds according to 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. The salts can be converted into the free compounds in a conventional manner, for example by reacting the acid addition salt and a suitable base such as an alkoxide. potassium butoxide. Because of the close relationship between the free compounds and the compounds in the form of salts, whenever a compound is mentioned, the corresponding salt is meant herein, as long as it may exist or is appropriate in the circumstances. .

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

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

The 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 and separating such salts, 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 them, or in the presence or absence of catalysts, condensation or other reagents, and / or in an inert atmosphere at low temperatures. , at room temperature or at elevated temperature, for example at a temperature in the range of -20 ° C to +200 ° C, preferably at the boiling point of the solvent used, at atmospheric pressure or at elevated pressure. Preferred solvents, catalysts and reaction conditions are set forth in the following Examples.

The compounds of the invention, including their salts, can also be obtained in the form of hydrates or 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 those starting materials which lead to the aforementioned and particularly preferred compound (OS 268 684). The invention also encompasses novel starting materials and methods for their production.

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 and pharmaceutically acceptable carriers or mixtures of carriers · Carriers and · Using solid or liquid inorganic or organic substances Suitable unit dosage forms especially for oral administration, for example dragees, tablets or liquid, and 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 thereof, and a salt-forming compound together with pharmaceutically acceptable carriers.

Daily dosages of the compounds of the invention range from about 0.1 to 100 mg / kg, and preferably from 0.5 to 50 mg / kg of mammalian body weight, depending on the compound used, the age and individual condition of the patient, and route of administration · For parenteral administration, for example by intra-injection or acbcutaneous injection or by intravenous infusion, the doses administered are generally lower than those administered entrally, ie · oral or rectal administration · The compounds of the invention are administered orally or rectally and preferably in unit dosages in the form of 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, aacharoa, 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, rice or branbore pastes. starch, gelatin, tragacanth, methylcellulose and / or optionally deaintegrating agents, such as the above-mentioned starches, and carboxyethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof, such as sodium alginate. silicon dioxide, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores and coatings with suitable coatings, which may be resistant to gastric glory, are prepared using, 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 gastric-resistant coatings, solutions of suitable cellulose derivatives such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the dragee or tablet coatings, for example to identify or label different doses of 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. Capsules and solid fillers 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 and a basic rosehip mass. Examples of suitable rosehip bases include natural or synthetic triglycerides, paraffin, polyethylene glycols and higher alkanols. Gelatin rectal capsules containing a combination of the active ingredient and the base material may also be used. 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 the preparation of

CS 268 684 B2 uses suitable lipophilic solvents or vehicles such as fatty oils such as aesamic oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or further suitable injectable suspensions or solutions which contain viscosity enhancers such as sodium triacetate. carboxymethylcellulose, solbitol 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 add suitable ingredients to the tablets or dragee cores ·

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

Example 1

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

A solution of 8.1 g of 5- (3-chloropropyl) -1- (p-cyanophenylmethyl) -1H-imidazole in 60 ml of tetrahydrofuran is cooled to 0 ° C and 7.0 g of solid tert-butoxide are added in portions. The mixture was stirred at room temperature for 2 hours, then neutralized with 10% acetic acid and partitioned between methylene chloride and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The oily residue was dissolved in a small volume of acetone and neutralized. with ethereal hydrogen chloride. After cooling, the title compound is obtained as a white solid, m.p. 201-203 ° C.

Preparation of starting materials

a) 1-Dimethylcarbamoyl-4- (3-trimethylsilyloxypropyl) -1H-imidazole

A suspension of 51.8 g of 4- (3-hydroxy-n-propyl) -1H-imidazole [can be prepared according to 11 Farmaco, Ed. Sc., 29, 309 (1973)] in 500 ml of acetonitrile is added 50.0 g of triethylamine and 48.6 g of dimethylcarbamoyl chloride is added dropwise. After completion of the addition, the mixture is refluxed for 21 hours and the resulting solution is cooled to 0 ° C, triethylamine hydrochloride precipitated. To the mixture was first added 50.0 g of triethylamine and then 54.0 g of chlorotrimethyl silane. After the addition was complete, stirring was continued for 1 hour, then the mixture was diluted with an equal volume of ether and filtered. The filtrate was evaporated, the oily residue was triturated with ether, the mixture was filtered to remove further triethylamine hydrochloride, and the filtrate was evaporated. The title compound (a) is obtained as an oil.

b) 1- (p-cyanophenylmethyl) -5- (3-hydroxypropyl) -1H-imidazole

A solution of 97.0 g of 1-dimethylcarbamoyl-4- (3-trimethylsilyloxypropyl) -1H-2-ol. Of H-imidazole and 72.0 g of 1-bromo-4-cyano-benzene in 500 ml of acetonitrile was heated at reflux for 10 hours, then cooled to 0 ° C in ice and introduced for several minutes. ammonia gas. The resulting mixture was evaporated in vacuo to a semi-solid residue, which was dissolved in 500 mL Ш hydrochloric acid. The solution was allowed to stand at room temperature for 15 minutes and then extracted with ether. The aqueous phase was adjusted to pH 9 with 50% sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulfate and evaporated to a semi-solid residue which, by trituration with cold acetone gave the title compound b) as a white solid, m.p. 121-123 ° C. .

c) 5- (3-chloropropyl) -1- (p-cyanophenylmethyl) -1H-imidazole

8.4 g of solid 1- (p-cyanophenylmethyl) -5- (3 * hydroxypropyl) -1H-imidazole are added portionwise to a solution of 5.2 g of thionyl chloride in 80 ml of methylene chloride. The rate of addition is controlled to keep the foaming under control. After completion of the addition ae the solution

268 684 В2

Heat at reflux for 1.5 hours, then cool in ice and filter. The hydrochloride of the title compound c) is obtained as a red-yellow solid, m.p. 190-191 ° C. This salt was shaken between methylene chloride and saturated sodium bicarbonate solution. The organic extracts were washed with water, dried over sodium sulfate and evaporated to give the desired free base in oil form.

Example 2

5- (p-cyanophenyl) -5> 6,7,8-tetrahydroiaidazo [1,5-a] pyridine hydrochloride

A solution of 1.13 g of 5- (p-kaibaaoylphenyl) -5,6,7,8-tetrahydroiaidazo [1,5-a] pyridine and 1.0 al phosphorus oxychloride in 30 al chloroform was heated under reflux for 15 hours. The oily residue is redissolved in 30 [mu] l of ethylene chloride, the solution is cooled to 0 [deg.] C. and added to 30 [mu] l of an ice cold 50% ammonium hydroxide solution. Dry and evaporate to an oily residue. This oily residue, after filtration through a column of 20 g of silica gel using ethyl acetate as the eluent, affords the free title compound, which is dissolved in 20 [mu] l of acetone and treated with 1.2. HCl to give the above free compound, m.p. 209-210 ° C ·

Example 3

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

A mixture of 85g of 5- (p-bromophenyl) -5,6,7,8-tetrahydroiaidazo [1,5-a] pyridine and 74µg of copper cyanide in 1µ1 Ν, dia-diaethylfor®sald was added under nitrogen. The reaction mixture is cooled, diluted with 10 µl of water and extracted with ethyl acetate. The organic extracts are dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using ethyl acetate as the eluent. melting point 117 ee 118 ° C ·

Example 4 5- (p-Bronphenyl) -5,6,7,8-tetrahydroidazo [1,5-a] pyridine

A solution of lithium diisopropylamide, prepared at 0 ° C under nitrogen from 0.12 µl diisopropyl amine and 0.33 µl n-butyllithium (2.5M) in 2 µl tetrahydrofuran, was added to -78 ° C to solution 0. , 13 1 1 Η, Ν, Ν *, K * -tetra-ethylethylenediaine and 0.124 g of 1- (p-bronbenzyl) -5- (3-chloropropyl) -1H-iaidazole in 2 ml of tetrahydrofuran · Reaction mixture with 3.5 After stirring for 1 hour, saturated ammonium chloride solution was added thereto at -78 ° C, and the mixture was extracted three times with 10 ml each of ethylene chloride. The organic extracts were dried over sodium sulphate and evaporated to give the title compound which was purified by conversion. to hydrochloride melting at 216 ° C.

Preparation of starting materials

a) 1- (p-broabenzyl) -5- (3-hydroxypropyl) -1H-imidazole

A solution of 11.2 g of 1-dinethylkaibaaoyl-4- (3-trimethyl8-phenyloxypropyl) -1H-imidazole and 12.49 g of p-bromobenzyl bromide in 1 ml of acetonitrile was heated at reflux for 24 hours. The resulting solution was cooled to 0 ° C and ammonia gas was added over 5 minutes. The mixture is allowed to react for 45 minutes at room temperature and the solvent is evaporated. The residue is extracted with 100 µl of 1N hydrochloric acid and the solution is extracted with 50 µl of ether. The aqueous phase is adjusted to pH 8 and extracted five times with 50 µl of ethyl acetate each time. The organic extracts are washed with water and evaporated. Chromatography on 530 g of silica gel · Combines the columns with a mixture of ethyl acetate, ethanol and saturated ammonium hydroxide (90: 5: 5) to give the title compound a) as an oil ·

NMR: 5.00 (singlet, 2H)

b) 1- (p-bronbenzyl) -5- (3-chloropropyl) -1H-inidazole

CS 26В 684 B2 π

The 1- (p-bromobenzyl) -5- (3-hydroxypropyl) -1H-iodazole and analogously to Example 1o) is treated with thionyl chloride to give the title compound b).

Example 5 *

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

To a solution of 2.01 g of 5- (t -foraylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and 0.96 g of hydrochloric acid in 30 µl of benzene are maintained at room temperature. cooling · 0.8 ml of concentrated sulfuric acid is added dropwise. The reaction mixture was stirred for 2 hours and then neutralized. The organic phase is separated, dried over sodium sulphate and evaporated to an oily residue which is chromatographed on silica gel using ethyl acetate as the eluent to give the title compound, m.p. 117-118 ° C.

EXAMPLE 6 5- (p-Cyanophenyl) -5-methylthio-5,6,7,8-tetrahydroinidazo [1,5-a] pyridine hydrochloride At 0 [deg.] C., 0.6 ml of a 2.51 ml solution was added under nitrogen. n-butyllithium and 0.15 g of dilsopropylanine in 5 ml of dry tetrahydrofuran prepared a solution of lithium diiaopropylamide which was introduced at -78 ° C into 0.29 g of 5- (p-cyanophenyl) -5,6,7,8- tetrahydroinidazo [1,5-a] pyridine in 10 mL of tetrahydrofuran. The reaction mixture was stirred for 30 minutes and 0.14 g of diaethyl 1-disulfide was added dropwise. After 30 minutes, cooling is discontinued, the reaction mixture is allowed to warm to room temperature and 10 ml of saturated ammonium chloride solution are added. The layers were separated and the organic phase was 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 4K ethereal hydrogen chloride was added to the solution. The title compound is obtained, m.p. 204-205 ° C.

EXAMPLE 7 5- (p-Cyanophenyl) -5-ethoxycarbonyl-5,6,7,8-tetrahydroiaidazo [1,5-a] pyridine In an analogous manner to Example 6, by reaction of 5- (p-cyanophenyl) -5, 6,7,8-tetrahydroimidazofl, 5-a] pyridine with ethyl chloroformate yields the title compound. IC (KBr) 1720, 2240 c ^-1 .

Example 8

5- (p-cyanophenyl) -5,6,7,8-tetrahydroinidazo 1,5-a pyridine

A solution of 2.13 g of 5- (p-aminophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water is cooled in ice and slowly added thereto. solution of 0.78 g of sodium nitrite in 2 ml of water. The resulting solution was added dropwise from a dropping funnel to a solution of 3.0 g of copper (I) cyanide in 10 [mu] l of water, maintaining the reporting temperature between 30 and 40 [deg.] 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 9 The following example describes the composition and preparation of 10,000 tablets each containing 10 mg of active ingredient.

Ingredients:

folder. amount

5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine 100.00 g

1actose 2535,00 g corn starch 125,00 g polyethylene glycol 6 000 150,00 g

AND

OS 268 684 B2 magnesium stearate distilled water

40.00 g as needed

Preparation:

All active ingredients, lactose, magnesium stearate and half of the starch are mixed in a suitable blender, the other half of the starch is suspended in 65 l of water and added to the boiling polyethylene glycol solution in 260 ml. · The resulting paste is added to the powder mixture and the resulting mixture is granulated, optionally with additional water. · The granulate is dried at 35 ° C overnight, then sieved through a 1.2 mm sieve and using a tablet press. they are pressed from it to tablets with the mark ·

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

Example 10

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

Ingredients:

component

5- (p * cyanophenyl) -5,6,7,8-tetrahydroimidazo [lactose

Modified Starch Magnesium Stearate

20,0 g

207.0 g

80,0 g

3,0 g

Preparation:

All powdered materials are sieved through sieves with a mesh size of 0.6 mm. • The active substance is placed in a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until a homogeneous mixture is obtained. The device is filled with hard gelatin capsules No · 2 ·

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

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

Example 12

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

CS 268 683 B2

Example 13

A solution of lithium m-diiaopropylamide (0.80 mmol) prepared from 0.12 mL of diiaopropylamine 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 · 0.1 ml of benzyl bromide is added dropwise for 0.5 hours, the reaction mixture is stirred for 1 more After stirring for 1 hour, 5 ml of water are added thereto, the mixture is acidified with 1H hydrochloric acid and after dilution with 20 ml of ether and the layers are separated. pH of the aqueous phase is adjusted to 7, the aqueous layer is extracted three times with 15 ml of ethyl acetate. The foamed residue is treated with 1 mol equivalent of ethereal hydrogen chloride 5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine- and dried over sodium sulfate, filtered and evaporated. hydrochloride, m.p. 249-251 ° C ·

Example 14

Sacemic 5- (p-cyanophenyl) -5,6,7, θ-tetrahydroimidazo [1,5-c] pyridine hydrochloride ae is loaded in 20 mg portions onto a β-cyclodextrin-coupled silica gel column (4.6 x 250 nm), eluting with water / methanol (7: 3) at a flow rate of 0.8 ml / min. The separated fractions ae 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 +85.02 °. Both of these compounds are separately dissolved in acetone and treated with 1 mol equivalent of ethereal hydrogen chloride in each case and converted to the hydrochlorides melting at 82-83 ° C ( amorphous substance) or · 218 to 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-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine; 5- (p-tolyl) -5,6,7,8- tetrahydroinidazo [1,5-a] pyridine whose hydrochloride melts at 173-175 ° C,

5- (p-Foraylphenyl) -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 whose hydrochloride melts at 204-205 ° C; 5- (p-cyanophenyl) -5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo [1,5-a] a] pyridine, 5- (p-aminophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo [i, 2-c] emidazole, m.p. 136-139 ° C;

227 DEG-228 DEG C. 5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo [1,2-c] imidazole, 5H-5- (4-cyanophenyl) -6,7,8,9- 153 -155 ° C, 5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine, hydrochloride of tetrahydroimidazo [1,5-a] azepine melts at 249-251 ° C.

CS 268 683 B2

PREVENT THE WAY

Claims (11)

1. A process for the preparation of eubetitized iMidMopyrrole, -pyridine and -axepine derivatives of the general formula I (I) in which n is a number of 1, 2 or 3> R ₁ represents cyano, C 1 -C 4 alkyl, halogen, amino, carbamoyl, C 1 -C 4 alkylcarboyl, 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, a stereoisomer thereof, a mixture of these stereoisomers or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (V): wherein: R ₁ and n are as defined above and are a leaving group, reacted with a cyclizing agent, and then the optionally obtained compound of formula I in which it is hydrogen is converted to the corresponding compound of formula by reaction with a C1 -C4 alkylmercaptan. I wherein R p is C 1 -C 4 alkyl thio or the compound of formula I in which R 5 is hydrogen by reaction with an alkyl haloformate containing CS 268 684 B2 15 ▼ alkyl moiety with 1 to 4 carbon atoms is converted to the corresponding compound of formula I wherein R ₂ represents an alkoxycarbonyl group and 1-4 carbon atoms in the alkoxy part, or a resulting compound of formula I in which represents hydrogen by reaction with phenylalkyl halide and 1 to 4 carbon atoms in the alkyl moiety is converted to the corresponding compound of formula I in which it denotes a phenylalkyl group and 1 to 4 carbon atoms in the alkyl moiety, or R 1 is carbamoyl or an alkylcarbemoyl group as defined above, by dehydration, or a compound of formula I in which R 1 is a halogen atom by reaction with a hydrocyanic acid salt, or a compound of formula I in which R 1 is a forayl group by oxidation, or the compound of formula I obtained in which R ₁ is amino by reaction with an alkali metal nitrite and a hydrocyanic acid salt, is converted to the corresponding compound of formula (X) in which R 1 is cyano, and / or the resulting salt is optionally converted to a free compound or another salt, and / or to the salt, and / or the mixture of isomers or racemates obtained is separated into the individual isomers or racemates, and / or the mixture of enantiomers, such as the racemate, is resolved into the optical isomers. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of the formula I in which n is a number of 1, 2 or 3 » R ₁ is cyano, halogen, carbamoyl or C 1 -C 4 alkylcarbemoyl and R ₂ represents a hydrogen atom or a C 1 -C 4 phenylalkyl group, the stereoisomers thereof, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof; A process according to claim 1, characterized in that the corresponding starting materials are used to give compounds of the formula I in which n is a number of 1, 2 or 3 R ₁ is CN or Br, and R ₂ represents a hydrogen atom or a benzyl group, their stereoisomers, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof · A process according to claim 1, characterized in that the corresponding starting materials are used to give compounds of the general formula X in which the bul n has a value of 1, 2 or 3 R1 is C1-C4alkyl or amino and is hydrogen, C1-C4phenylalkyl, C1-C4alkylthio or C1-C4alkoxycarbonyl; alkoxy moiety, or n is 1 or 3 » R 1 is cyano or C 1 -C 4 alkylcarbamoyl; R ₂ is as defined above, or n is 2, R ₁ represents cyano and R ₂ represents phenylalkyl 8 1-4 carbon atoms in the alkyl moiety, alkylthio having 1 to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atoms EN 268 684 B2 ▼ alkoxyl moieties, stereoisomers thereof, mixtures of these stereoisomers or pharmaceutically acceptable salts thereof 5. A process according to item 1 for the preparation of compounds of the general formula Ib (Ib) wherein r * represents a cyano group or an alkyl group having 1 to 4 carbon atoms and R1 represents a hydrogen atom, a (C1-C4) -phenyl-alkyl or C1-C4-alkylthio group, their stereoisomers, mixtures of these stereoisomers and pharmaceutically acceptable salts of said compounds, characterized in that the compound of formula (Vb) is cyclized in which R 1 is as in formula Ib a Xj is a leaving group, in the presence of a base, whereupon the optionally obtained compound of formula Ib wherein Rg is hydrogen by reaction with a C1 -C4 phenylalkyl halide is converted to the corresponding compound of formula Ib wherein Rg is phenylalkyl a (C 1 -C 4) alkyl moiety, or a compound of formula (Ib) in which R 1 is a hydrogen atom is reacted with a C 1 -C 4 alkylmercaptan reagent to give the corresponding compound of formula (Ib) in which R 1, is C1-C4alkylthio, 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 the mixture of enantiomers, such as the racemate, is resolved into the optical isomers. CS 268 683 B2 6. A process according to claim 5, wherein the corresponding starting materials are used to form compounds of formula Ib in which: R 1 is cyano and R ₂ represents a hydrogen atom or a C 1 -C 4 alkylthio group, 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 Ib in which: R 6 is cyano and R p 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 CN in which R ₂ represents a hydrogen atom or a C 1 -C 4 alkylthio group, and pharmaceutically acceptable acid addition salts thereof. 9. A process according to claim 8, wherein the corresponding starting materials are used to form 5- (cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine and pharmaceutically acceptable addition salts thereof. 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, a stereoisomer thereof, mixtures thereof. stereoisomers or pharmaceutically acceptable salts. 11. The method of claim 1, wherein the corresponding starting materials are used to give 5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo [1,2-c] imidazole, its stereoisomer, a mixture of these stereoisomers or pharmaceutically acceptable salts.