HUT60490A - Process for producing quinoline derivatives - Google Patents

Description

The present invention relates to a novel process for the preparation of novel quinoline derivatives. The novel quinoline derivatives of the present invention at least partially antagonize one or more physiological effects of angiotensins, in particular angiotensin II (hereinafter "All"), and are therefore useful as active ingredients in pharmaceutical formulations. The present invention also relates to the preparation of clnoline derivatives which are useful as intermediates in chemical synthesis, including the above novel quinoline derivatives.

The renln - anglotenzln - eldosterone system involved in regulating the homeostasis and fluid / electrolyte balance of warm bloods (including humans) is a key mediator. From the Anglotensin I gene (a blood plasma protein) in the plasma, the enzyme renin is converted to angiotensin I, and the Anglotensin I is converted to Anglotensin 11 by the enzyme Anglotensin Converting (ACE). AH exerts a strong anticonvulsant effect primarily on the vascular system and increases vascular resistance and blood pressure. It is also known that anglotensil stimulates the release of aldosterone, which leads to hypertension and hypertension through the sodium and fluid retention mechanism. Ali inhibitors are useful for preventing or suppressing the adverse biological effects of All. Numerous All inhibitors have been described in the literature so far. Nos. 253,310 and 324,377. Substituted imidazole derivatives having AH antagonistic activity are disclosed in European Patent Application No. 4,880,804. U.S. Patent No. 5,383,841 to Alamkk-bell, U.S. Patent No. 323,841, to Alim antagonist benzimidazole derivatives. European Patent Publication No. 2,968,151, which discloses all antagonistic effects of red, pyrazole and trlazole derivatives. However, there is still a need for new AH inhibitors, and there is also a need for methods for making Ali inhibitors more advantageous than hitherto.

Compounds structurally similar to the novel quinoline derivatives of the present invention have been disclosed in EP-A-348,155. These known compounds have leukotriene D4 antagonist activity.

European Patent Publication No. 412,848 discloses quinoline derivatives of the formula I and their pharmaceutically acceptable salts.

R * is hydrogen, C 1-8 -alkyl, C 3-8 -cycloalkyl, phenylamino, or C 1-4 substituted with one or more fluorine or C 3-8 -cycloalkyl, hydroxy, C 1-4 -alkoxy, or phenyl; is an alkyl group, p

F. hydrogen or (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, (C 3 -C 8) cycloalkyl (C 1 -C 4) alkyl, carboxyl, (C 1 -C 6 alkoxy) carbonyl, cyano, denotes nitro, phenyl or phenyl (C 1 -C 4 alkyl), and P and R 4 are independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluorinated C 1 -C 4 alkoxy, halogen, hydroxy , trifluoromethyl, clano, nitro, amino, C 1-4 alkanoylamino, up to C 6 alkylamino or dialkylamino, C 3-8 dialkylaminoalkyl, 1 C4 -C4 alkanoyl, carbamoyl, up to C7 -C4 alkylcarbamoyl or di- (N-alkyl) carbamoyl, carboxy, C 1 -C 4 alkoxy-carbonyl, C 1 -C 4 alkylthio Groups, 1-6

- C4-C4 alkyl azulfinyl, C 1-6 alkylsulfonyl, or C 1-C 4 alkyl substituted with amino, hydroxy or C 1-4 alkoxy, or "1 Λ

R ^J and R together form a C 1 -C 4 alkylene dioxide group bound to adjacent carbon atoms of the benzene ring,

When and independently of one another are hydrogen, halogen or C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano or nitro,

It means methylene,

X is phenylene-isopoxtin optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, t-fluoro-methyl, cyano or nitoxy azo substituents, or

X represents a bond, and

Z is a 1 H -tetrazol-5-yl group, -CO-1 H- (1 H -tetrazol-5-yl) or -COOR 4 or -CO-NH-SO 8 R? AIT has pictures _of Iano _S! means a group in which

H represents a hydrogen atom or a biodegradable moiety of a pharmaceutically acceptable alcohol or phenol, and

C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or phenyl, and any of the phenyl groups in the groups listed may optionally be one or two C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, and / or a trifluoromethyl substituent may be attached, provided that ε 2- (methylmethoxycarbonyl-quinolin-4-yloxy) -methyl-7-benzoic acid methyl ether is of formula (I). compounds outside the cox.

Depending on the nature of the substituents, the compounds of formula (I) may optionally contain one or more asymmetric centers and may accordingly be formed as one or more optically active isomers or racemates.

The term "general alkyl group" used in connection with compounds of formula (I) includes both straight and branched chain groups. However, when designating individual alkyl groups, specific reference is made to possible chain linking Thus, for example, the term propyl refers only to the straight chain, while the term isopropyl only refers to the branched chain. The same applies to other generic terms.

Examples of R 4 and R 6 alkyl include methyl, ethyl, propyl, butyl, isobutyl, butyl, pentyl or hexyl, and the cycloalkyl group includes, for example, cyclopropyl, cyclopentyl or cyclohexyl.

R 4 is alkyl substituted with one or more fluorine atoms, for example fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl, hydroxy, cycloalkyl, C 1-4 alkoxy or phenyl. and substituted alkyl groups include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl , benzyl, 1-phenylethyl or 2-phenylethyl.

She

Examples of cycloalkylalkyl groups R include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopentylethyl ethyl, and phenylalkyl groups such as benzyl, 1-phenylethyl or 2-phenylethyl. and for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

and each of the groups which may be present or optionally substituted or optionally substituted on the X-phenylene ring include alkyl groups such as methyl and ethyl groups, alkoxy groups such as methoxyl and ethoxy groups, fluorinated alkoxy groups such as trifluoromethoxy, 2-fluoro- ethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy, halogen such as fluorine, chlorine, bromine and iodine, alkanoylamino groups such as formamido, acetamido and proplonamido, alkylamino groups, such as methylamino, ethylamino and butylamino, d-alkylamino groups such as dimethylamino, diethylamino and dipropylamino. dialkylaminoalkyl groups such as dimethyl 11-amino-raethyl 11-,

2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and 3- (ethylamino) propyl, alkanoyl groups such as formyl, acetyl and butyryl, N-alkylcarbamoyl groups such as E-methyl and K-ethylcarbamoyl groups, di- (K-alkyl) carbamoyl groups such as K, h-dimethylcarbamoyl and N, N-dlethylcarbamoyl groups, alkoxy groups. carbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups, alkylthio groups such as methylthio, ethylthio and butylthio groups, alkylsulfinyl groups such as methyl azulphonyl, ethyl azulphinyl and butyl sulphinyl, alkylsulphonyl groups, such as methylsulphonyl, ethyl azulphonyl and butylsulphonyl groups, the alkyl, substituted by the minor, hydroxy or alkoxy groups such as hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, amino-methyl, 2-amino-ethyl, 2-methoxy-ethyl and 2-ethoxy-ethyl, and slkylene dloxyl groups such as methylenedioxy and ethylene dloxyl.

- 7 het may be a non-toxic biodegradable residue derived from a pharmaceutically acceptable alcohol or phenol, such as a C 1 -C 6 alkanol (such as methanol or ethanol), phenol or glycerol.

R? alkyl, for example, methyl, ethyl, pxopyl, isopxopyl, butyl or pentyl, and cycloalkyl, for example, cyclobutyl, cyclopentyl or cyclohexyl.

The halogen substituents optionally attached to the phenyl groups include, for example, fluorine, chlorine and bromine, the alkyl azububic substituent being, for example, methyl and ethyl, and the alkoxy substituent, for example, is netoxy and ethoxy.

X is particularly preferably p-phenylene.

Preferably, R or R is hydrogen or methyl, ethyl or pxopyl, respectively.

The cited disclosure designates compounds of formula Ia as preferred representatives of the compounds of formula I wherein i iP, iP, and c 1

Ireland is as defined above, and Z is carboxyl, 1H-thiazol-5-yl, or optionally one or two halo (such as fluoro, chloro or xxo), (1-4C) alkyl (such as methyl or ethyl). ), C 1-4 alkoxy (such as methoxy or ethoxy-J, cyano, nitro and / or trifluoromethyl) benzenesulfonamido group, and pharmaceutically acceptable salts thereof.

Preferably, A or Z1 is, for example, a boxboxyl group or a la-tetxazol-5-yl group. Particular preference is given to compounds of formulas I and Ia in which Z and Z are 1H-tetrazol-5-yl groups, and this group is particularly preferably ortho to the benzene ring relative to X.

The compounds of the formula I are quinolines *.

P The port is the associated R, R, i. and R * (and optionally lia) are preferably selected from the group consisting of 2-methylquinoline, 2-ethylquinoline, 2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2- ethylquinoline, 2-ethyl-5,6,7-dimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6- (methylthio) quinoline, 2-ethyl-7- (hydroxy-methyl) -cloline, 2-ethyl-6- (2-fluoro-ethoxy) -choline, 2-ethyl-6- (2,2,2-trifluoroethoxy) -quinoline, 2-ethyl -6-quinoxamidoquinoline, 2-ethyl-6-fluoroquinoline, 2-ethyl-6-isopropoxyquinoline or 6- (aainomethyl) -2-ethylquinoline · Az-OaX- the substituent is preferably a

In position 4, it is attached to the clnolln ring.

Particularly preferred compounds mentioned in the above cited disclosure are the following compounds of formula X and their pharmaceutically acceptable salts: 2-ηιβί11-4- / Γ ² '- / 1H-tetrazol-5-yl / biphenyl-4-yl. j metoxjT'-quinoline, 2-ethyl-4- / r ² '' / l ^yl ~ ^{te tra2ol} * 5 iV-the biphenyl-4-yl-metoxj / quinoline, 2-ethyl-7- (hidxoxi- methyl) -4 - [(2 * - [(1-yl) -ethoxazol-5-yl] -biphenyl-4-yl) -methoxy] -7-quinoline, 2-ethyl-6- (2-fluoro-ethoxy) -4- [f] * - (III-Tetxazol-5-yl) -biphenyl-4-yl) -methoxy-7-quinoline, 2-e 11-6- (2,2,2-txif 1-fluoro-oxy) -4- / ² * AA-1 e TXA zol-5-yl / b 1-phenyl-4-11) -netoxi7-quinoline and 2-ethyl-6-isopropoxy-4 / C ² * · - / H-t € trazol- 5-yl / -biíenil-4-yl) -m £ '^ -toxj quinoline.

The compounds of formula (I) may form salts with acids. Compounds of formula (I) in which Z represents a group other than the ester group, or in which the cleavage is "F", represent a carboxyl group, may form salts with bases or acids, and salts thereof with pharmaceutically acceptable cation-providing bases such as alkali metal salts. sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), aluminum salts, ammonium salts and salts with organic bases (such as ethanolamine, methylamine, diethylamine or thietylamine) and pharmaceutically acceptable anion, salts with strong acids such as hydrogen halides, including hydrochloric and hydroxybenzomiddaX, sulfuric acid and phosphoric acid, and strong organic acids such as p-toxuolsulfonic acid and methanesulfonic acid. According to European Patent Application Publication No. 2, the compounds of formula I are prepared by methods known per se for the preparation of related derivatives. In our work, we have developed a novel, unisex process for the preparation of compounds of formula (I) wherein X is an optionally substituted p-phenylene group and Z is thiazolylcarbonate.

Invention therefore provides useful compounds and pharmaceutically Formula method (III), a salt thereof of the invention: - wherein h ^2, -5 g _{his son} ^ _e i _en te _{se above,} Kb is hydrogen, bslogénatomot or 1-4C-alkyl, 1 C 4 -C 4 alkoxy, trifluoxymethyl, cyano or nitoxy. According to the invention, the compounds of formula (IV) - wherein χΛ, x ² , x ^, x 3, n ^, ia and Ab are as defined above. _v is C 1 -C 6 alkyl or phenyl optionally substituted by balogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; tri-; cleave a tin group.

Λ Formula IV! in compounds o for example

C 1-4 alkyl, such as methyl, ethyl, propyl or butyl, preferably butyl.

The alkyl group optionally substituted with Rb or phenyl optionally substituted with d is, for example, methyl or ethyl, halogen is, for example, fluorine, chlorine or bromine, while alkoxy is, for example, methoxy or ethoxy.

The process of the present invention is particularly suitable for the preparation of compounds of formula (III) in which the tetrazolyl group is attached to the benzene ring in a protected position relative to the adjacent phenyl group.

For example, Sn (c) .j can be cleaved from the compounds of formula IV by acidic or basic hydrolysis. The reaction may be carried out, for example, by treating the compounds of formula IV with a mineral acid such as aqueous hydrochloric acid in the presence of a solvent or diluent. Suitable solvents or diluents are, for example, hydrocarbons such as toluene or xylene, ethers such as dioxane or trachydrofuran, water, or mixtures of the solvents listed. The reaction is usually carried out at 0-50 ° C, usually at or near room temperature.

The compounds of formula (IV) can be prepared by reacting the nitrile (V) (VI) reacts be azides of general formula: - wherein 1Λ, E ^2, R _f 1Λ, t _(a> Eb and ς is as defined above The reaction

XI is usually carried out in the presence of a solvent or diluent such as toluene or xylene at 50-150%, preferably 100-15 ° C. The azides of the formula VI are preferably used in an excess such as 1.5 to 5 equivalents. . This process is particularly suitable for the preparation of compounds of formula (IV) wherein the tetrazolyl group bearing Sn (Q) ^ is attached to the benzene ring in a precursor position relative to the adjacent phenyl group.

The compounds of formula (V) may be prepared, for example, by reacting the compounds of formula (VII) and Hb with the radicals brominated above, and the resulting bromomethyl derivatives with the quinolones of formula (VIII). in the formula r \ | _e i _x ^ _exl of the above - is alkylated. Bromination is carried out in a known manner using standard reagents; Thus, for example, compounds of formula (VII) are reacted with l-bromosuccinimide in a solvent (e.g., chlorobenzene or tetrachloride), benzoyl peroxide or azobis (isobutyronitrile). The alkylation is usually carried out in the presence of a base, in a solvent or diluent medium, at a temperature of about 11 ° C. As the base, for example, an alkali metal alkoxide (such as sodium methoxide or sodium ethoxide), an alkali metal carbonate (such as sodium carbonate or potassium carbonate) or an alkali metal hydride (such as sodium hydride), or a solvent such as 1 almanole (such as methanol or ethanol) or a polar solvent such as dimethylformamide or K-methylpyrrolidone is used. Preferably, the solvent used is 1 to 4 senatan alkanol, if the base is an alkali metal alkoxide, the λ reaction can also be carried out in the presence of quaternary ammonium hydroxide in a mixture of aqueous and non-aqueous solvents (such as water and dichloromethane).

compounds of formula (VII), e.g. European Patent Publication. however, it is also possible to form a Grignard reagent from unsubstituted or appropriately substituted 4-bromo-toluene in the presence of a solvent (such as tetrahydrofuran) at 0-25 ° C with tralkyltin halide (such as t-butyltin chloride). , an optionally substituted phenyl-trialkyltin compound is reacted with unsubstituted or substituted bromobenzonitrile in the presence of a palladium (O) catalyst such as tetracl8z (thiphenylphosphazin) palladium and azobis (isobutyronitrile). The compound of formula VII can be prepared by reacting 4-methylphenylboronic acid in the presence of a palladium catalyst such as palladium (II) chloride or tetrakis (triphenylphosphine) palladium (O) with an appropriately substituted bromobenzonitrile and azo. (bis-isobutyronitrile). Finally, the compounds of formula (VII) may also be prepared by reacting unsubstituted or substituted 4-bromo-toluene with an alkali metal alkane such as butyl lithium and zinc chloride, and then obtaining the product, tetxacis (triphenylphosphine) palladium. In the presence thereof, it is reacted with appropriately substituted bromobenzonitrile.

Compounds of the general formula (VIII) are disclosed in the literature, e.g. European Patent Publication, or by known methods, e.g. aynth. Coll., Vol. Lx, pages 374 · and 593 ·.

In accordance with the present invention, it is also possible to carry out the reaction of the compounds of formula IV directly on their reaction mixtures. In this case, the compounds of formula (V) are reacted with the azides of formula (VI) as described above, and the bn (w) 4 group is cleaved from the compounds of formula (IV) without isolation, for example, so that the reaction mixture is aqueous add acid · Sodium nitrite / hydrochloric acid may be used to acidify the reaction mixture! The excess azide that may be present is decomposed · The compounds of formula VI are commercially available or can be prepared by known methods, for example by reaction of the appropriate trialkyltin halide with an alkali metal amide.

If desired, the compounds of formula (III) may be converted into their pharmaceutically acceptable salts by reaction with pharmaceutically acceptable cation-containing bases or acids containing a pharmaceutically acceptable anion or other suitable salt-forming method.

If the compounds of formula (III) are to be prepared in the form of optically active isomers, the above process utilizes optically active starting materials. In one embodiment, the racemic compounds of formula (111) are resolved. For example, the racemic compounds of Formula III are reacted with an optically active organic base such as optically active ephedrine, R-trimethyl- (1-f (methylethyl) ammonium hydroxide or 1-phenylethylamine) to give the diastereoisomer. isolating the individual salts by fractional crystallization from a salt pair in a known manner, for example from a suitable solvent, such as a C 1 -C 4 alkanol, followed by

Treating the resulting salt with an acid, such as aqueous mineral acid, such as dilute aqueous hydrochloric acid, to provide the desired optically active compound of formula (III) · some of the starting materials and intermediates used in the process of the invention are novel compounds. For example, novel compounds of formula (XV) and (V) which are particularly preferred are those wherein the substituted tetrazolyl group is ortho-ortho to the benzene moiety ortho to the adjacent phenyl group. Our protection requirement also covers the production of new intermediates *

Antagonism of one or more physiological effects of aII, in particular inhibition of the interaction of AH with effect mediated receptors, is as follows: methods were investigated:

Test ¹ :

The assay was performed in vitro by incubating the test compound in a buffered mixture containing a known amount of radiolabeled All and an angiotensin-responsive tissue in an initial concentration of 100 micromolar (or less). λ surface cell membrane fxaction was isolated from the adrenal gland of the guinea-pig, known * to respond well to All, the interaction of radiolabeled all with the receptor (determined by rapid filtration of unbound radioactively labeled material and measured in the cell membrane). amount of bound radiolabeled substance) are antagonized by substances capable of binding to the membrane receptor sites, which displace radiolabeled AXX from the membrane under the conditions of the assay. the extent of antagonization can be simply determined by comparing the radioactivity measured in the membrane after incubation with a solution containing the compound of interest in a known concentration to that measured after incubation with a solution containing no test compound. Compounds that inhibited the binding of radiolabeled aXX at concentrations of at least 50 µCi in the above assay were re-tested at lower concentrations to evaluate the effect. The value of ΙΟ ^ θ (the concentration of active substance that suppressed the binding of radioactively labeled All by 50%) was usually measured in a concentration range of four orders of magnitude with the expected value in the center, followed by, ^ θ. The ^ visazorite is plotted against concentration ·

Compounds of formula (Xxl) generally exhibit significant inhibitory activity under Assay A conditions at concentrations of 50 micromolar or substantially lower. The assay was performed in vitro in isolated rabbit aorta held in physiological saline at 370. The degree of inhibition of hII-induced organ contraction by the given compound was investigated. To check whether this effect is based on the specific inhibition of? XI, we also tested under the same conditions whether the compound inhibited noradreaaline-induced organ contraction.

• ^! Compounds of formula (XIX) generally exhibit a report inhibitory activity under the final concentration of 50 µM or significantly less under the assay conditions of B ”assay ·

Test C:

Assays were performed in vivo in terminally anesthetized or alert rats. Prior to the study, the animals were implanted with an anesthetic catheter to measure changes in blood pressure during anesthesia. The test compound was administered orally or parenterally to the animals to determine the extent to which the parent compound was able to counteract the antihypertensive effect of the chin. To check if the observed cold is based on the specific inhibition of Ali, we also tested under the same conditions whether the drug suppresses the vasopressin-induced increase in blood pressure.

Compounds of formula (III) exhibited specific Al 1 antagonist activity in Assay C at doses of generally 50 mg / kg or less. No toxic symptoms or pharmacological effects were observed.

u Test ^H :

The studies were performed in vivo. Rats, silk monkeys and dogs were fed a low-sodium diet and animals were given a sufficient amount of frusemide (a known saluretic agent) daily. with taste, we stimulated the biosynthesis of All in the animals. Anx catheter was introduced into the body of an λζ animal under anesthesia to measure the change in blood pressure, and the animals were administered the test compound orally or palpexexally and the change in blood pressure was measured. · η (111) was generally 5 mg / kg under JA conditions. or at significantly lower doses, showing a significant antihypertensive effect, indicating the All antagonist effect of the compounds. no toxic effects or other nonxivative furmological effects were observed.

léidéként are shown that 2-methyl-4 / T ² '' / alkalization tetxazol-5-yl / biphenyl-4-yl) quinolin--metoxi7-nidroklorid pharmacological data of 'Ά, u' ¹ and O test his circumstances were:

The assay: average Ιό ^ θ 1.7 x 10 * θ mole;

Examination n: mean pAg oh, jp;

Test 0: i.v. 0.5 mg / kg.

the invention is illustrated in detail by the following non-limiting Examples. Unless otherwise stated in the Examples, (i) evaporation and concentration was carried out in a rotary evaporator under reduced pressure;

(ii) the operations were performed at room temperature (13-26 ° C);

(iii) the yield data provided are for information purposes only and are not necessarily the maximum available;

(iv) the bile spectra were recorded at a frequency of 27µHz in deutexochloroform, using tetramethylsilane as the internal standard, and chemical shift values in ppm units;

(v) ll-Tetrazol-5-yl refers to ll-1,2,3,4-thiazol-5-yl.

- 18 Fluorescent

3.3 g of tert-butyltin chloride and 1.13 g of sodium azide

A solution of 22.5 ml of water was kept at room temperature for 4 hours. The mixture is extracted with toluene and the extracts are evaporated with azeotropic distillate, while the volume of the extract is reduced to 15 ml. The resulting solution of 15 ml of toluene oil containing tributyltin azide is 0.9 g of 4 * -? quinolin-4-yloxy) -methyl-7-biphenyl-2-carbonitrile was added and the mixture was refluxed for 90 hours. The 2-ethyl-4- [t] '- [2- (tributyl-8-ethanyl) - Toluene solution containing 2H-tetrazole-5-1X-biphenyl-4-11) -methoxy-quinoxine was slowly added over a period of 1 hour with a solution of 2.5 g of sodium nitrite in 10 ml of water and 10 ml of 12% w / v D aqueous hydrochloric acid solution while maintaining the temperature below 5 °. To the mixture was added a solution of sulfuric acid (1.43 g) in water (10 ml) at a temperature below 5 ° C, and the resulting mixture was stirred for 1 hour. The suspended semi-solid is filtered off and washed three times with 10 ml of water, then with 10 ml of toluene. The semi-solid is then added to 40 ml of tatra hydrofuran. The solid dissolved and then the product precipitated as a white crystalline solid: · The mixture was cooled for 1 hour, then the solid kiszüljük, washed with 5 ml of dried tetiahidrofuránnal as sending · 2 'Ethyl 4- ^ r · * ² * - / H Tetrazol-5-yl (biphenyl-4-yl) -methoxy-7-quinoline hydrochloride was obtained in a yield of 53 µl. 179-18 ° C (dec.).

Nuclear Magnetic Resonance Spectrum (DMOO-dg) 1.46 (t, 38), 3.18 (q, 2H), 5.68 (s, 2H), 7.22 (d, 2H), 7.5-7 Δ8 (m, 7H), 7.83 (t, 1H), 8.08 (t, 1H), 8.18 (d, III), 8.32 (d, 1H).

• ·· · *.

• ♦ · ·

1.73 £ 2-ethyl-4-quinolone (compound prepared from the aniline and ethyl propionyl acetate according to the procedure described in Org. Vol. III, pp. 374 and 593), 3.1 g of 4 * - $ a mixture of 1.00 g of solid potassium carbonate and 40 ml of k-methylpyrrolidone was stirred for 36 hours under a nitrogen atmosphere, and the mixture was stirred at 15-25 ° C for 100 hours. of water was added dropwise to the reaction mixture and the resulting mixture was stirred for 30 minutes. The suspended solid is filtered off, washed with water and dried at 60 ° C under reduced pressure. The solid is recrystallized from tertiary butyl methyl ether. 1.9 g of 4 * - (2-ethyl-quinolin-4-yl-oxo) -methyl-7-biphenyl-2-carbonitrile are obtained in the form of a 1 H -urd; mp 151-153 ° C.

data for the clux spectra (Glyl) t 1.4 (t, 3H, 2.97 (q, 21H), 5.35 (s, 2H), 6.76 (s, pk), 7.4-7.6 (m, 3H), 7.6-7.8 (s, 611), 8.0 (d, 18), 0.25 ode, li).

used as starting material * ^! Compound a is prepared as follows;

(i) A mixture of 3 g of 4-methylphenylboronic acid, 36.4 g of 2-bromobenzonitrile, 0.4 g of palladium (II) chloride, 200 ml of methanol and 200 ml of toluene with stirring at 200 ° C. 2 M aqueous sodium carbonate solution was added, the temperature of the mixture rose to about 20 ° C, and a solid precipitated. r. the reaction mixture is refluxed for 2 hours. The mixture was allowed to cool and water (lml) followed by diatomaceous earth (5 g) was stirred for 15 minutes and then filtered through diatomaceous earth. The organic phase is separated from the filtrate and washed with 2M aqueous sodium bicarbonate followed by water, the organic phase is filtered and the filtrate is packed.

• * ·· ♦ «· • · · ·»

The resulting solid was recrystallized from petroleum ether (b.p. 110-120%). 4'-Ketyl-biphenyl-2-carbonitrile was obtained in a yield of 80; mp: 44-46%.

kkh spectral data (ppm: s): 2.40 (s, 34), 7.30 (d, 2d), 7.35-7.55 (m, 4), 7.60-7.65 (m, Ia), 7.75 (d, Ia).

(ii) 3.86 g of ^{4-methyl-biphenyl-2-carbonitrile,} 3.92 g of L-bromosuccinimide, 0.15 g of azobis (isobutyronitrile) and 75 ml of chlorobenzene © flies for 3 hours 7v After addition of 0.3 g of L-bromosuccinimide and 0.05 g of azobis (isobutyronitrile), stirring was continued for 15 minutes. heating was discontinued and the mixture was stirred at room temperature for 16 hours. Water (50 ml) was added and the mixture was stirred for 30 minutes. The organic layer was separated from the filtrate, washed with water (50 mL) and dried over magnesium sulfate. The solvent was evaporated and the solid residue was recrystallized from cyclohexane. solid. 3.9 g of 4 * - (biomethyl) biphenyl-2-cyanonylthiol (Compound A) are obtained.

1 H-H NMR (CDCl3): 4.55 (s, 2n), 7.4-7.85 (m, 8H).

Claims (10)

A process for the preparation of compounds of formula (111) and pharmaceutically acceptable salts thereof, wherein: hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 8) -cycloalkyl, phenyl or one or more fluorine atoms or (C 3 -C 8) -cycloalkyl, hydroxyl, C 1-4 alkyl is substituted with C 1-4 alkoxy or phenyl; h is hydrogen or C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl (C 1-4 alkyl) - , carboxyl, (C1-C4 alkoxy) carbonyl, cyano, nitro, phenyl or phenyl (C1-C4 alkyl), 12 and 12 are independently hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, fluorinated C1-C4 alkoxy, halogen, hydroxy, trifluoromethyl, cyano, nitro group, amino, C1-C4 alkanoylamino, up to C6 alkylamino or dialkylamino-oopor, C3-C8 dialkyl -aminoalkyl, C 1-4 alkanoyl, carbamoyl, up to 7 carbon atoms, h-alkylcarbamoyl or di- (L-alkyl) -carbamoyl, carboxyl, (C 1-4 -alkoxy) carbonyl C 1-6 -alkylthio, C 1-6 -alkylsulfinyl, C 1-6 -alkylsulfonyl, or C 1-4 -alkyl substituted with amino, hydroxy or C 1-4 -alkoxy, or (1) Λγ / Irish and Irish together form a C 1 -C 4 alkylenedioxy group attached to the adjacent carbon atoms of the bezol ring, and the son independently represents hydrogen, halogen or C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoro -methyl-, cyano- vag y nitiocsopoxt, and Kb hydrogen, halogen or C1-C4 alkyl, C 1 -C 4 alkoxy, trifluoxymethyl, cyano or nitro, and optionally one or two C 1 -C 4 alkyl groups on any of the phenyl groups listed above; C 1-4 alkoxy, halogen, cyano and / or trifluoromethyl substituents methyl--, characterized in that compounds of the general formula (IV) - in the formula _IIa and are as stated above and c 1-6 a C1-C4 alkyl group or a phenyl group optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or halogen substituents, and the desired product is converted into a pharmaceutically acceptable salt thereof. 2. A process according to claim 1 wherein h * is hydrogen or methyl, ethyl *, propyl, butyl, isobutyl, sec-butyl, pentyl. -, hexyl cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxy-O-yl, cyclopropyl -methyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl » R is hydrogen or methoxy, ethyl, pxopll, butyl, isobutyl, sec-butyl, pentyl hexyl, cyclopxopyl, cyclopentyl, cyclohexyl, cyclopxopylmethyl, cyclopentylaliethyl, cyclohexylmethyl , 2-cyclopentylethyl, carboxyl, methoxycarbonyl, ethoxycarbonylxopoxycarbonyl, cyano, nitro, phenyl, benzyl, 1-phenyl * ethyl or 2-phenylethyl. . R 4 and independently represent hydrogen, fluorine, chlorine, bromine, iodine or methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-Trifluoroethoxy, 3,3,3-txifluioxo-pxopoxy, hydroxy, trifluoxymethyl, clano, nitro, amino, formamido, acetamido, pxopanalido, methyl amino, ethylamino, butylamino, dinethylamino, diethylamino, dipropylamino, dimethylaminomethyl, 2- (dimethylamino) ethyl, 2- ( diethyl-amxno) -ethyl, 3- (diethylamino) -propyl, formyl, acetyl, butoxyl, carbamoyl, N-methylcarbamoyl, L-ethyl-kaxbsmoix, h, Ν-di-ethyl -carbamoyl, λ, h-diethylcarbamoyl, kaxboxyl, methoxycarbonyl, ethoxylcafenyl, pxopoxycarbonyl, methylthio, ethylthio, butylthio, methyl azulfinyl- , ethylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, butylsulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2- aminoethyl, 2-methoxyethyl or 2-ethoxyethyl, or ··· - 24 and a methylene dioxide or ethylenedioxy group attached to the adjacent carbon atoms of the benzene ring, and when and independently represent hydrogen, fluorine, chlorine, bromine, iodine or methyl, ethyl, methoxy, ethoxy, trifluoro, methyl, cyano or nitro, and hb is hydrogen, fluoxo, chloro, bxoma, iodine, or methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano or nitroceopor, and any phenyl drop in the listed groups optionally one or two methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, cyano and / or trifluoromethyl substituents may be attached. The process according to claim 1 or 2, characterized in that the compounds of formula (IV) in which ϊΛ is methyl and at the same time RΛ is hydrogen or 1Λ is ethyl and at the same time hydrogen or Y- (hydroxymethyl) ), 6- (2-fluoroethoxy), 6- (2,2,2-trifluoroethoxy) or 6-isopropoxyl, l-2, arc and xtb are hydrogen; The tetrazolyl group substituted with Sn (Q) - is attached to the benzene ring in an ortho position to the adjacent phenyl group. The process according to claim 3, characterized in that it is based on the compound weeks of the formula (IV) in which h ^{1 represents} an ethyl group and a hydrogen atom. The process according to any one of the preceding claims, characterized in that the group οη (ς) ^ * - 25.: · '* ···· .. ·' ··. ··. : '* ·. ·. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Process according to any one of the preceding claims, characterized in that it is based on a compound of formula (IV) in which it represents a C 1 -C 4 alkyl group. Process according to any one of the preceding claims, characterized in that the starting materials of formula (IV) are formed directly from the compound of formula (V) directly in the form of the compounds of formula (V): wherein ¹ , xP, ⁴ , .P,. b is as defined in any one of claims 1-4. Compounds of formula (III) according to claim 1, characterized in that they are prepared according to any one of claims 1 to 7 or which are clearly chemically equivalent thereto. 9 · Compounds of formula IV wherein a, n, xP, ⁴ , ⁴ , x, b and h are as defined in claims 1-4. and claim 6. 10 (V), analogous compounds of formula: - wherein ij, i .2, J.3 * 15 ₁ .- »5, and x is 1-4 · hb Claims defined in any of.