CS88692A3 - Process for preparing quinoline derivatives - Google Patents

Description

The present invention relates to a novel process for the preparation of novel quinoline derivatives having useful properties that antagonize at least partially one or more of the substances known as angiotensins, in particular those known as angiotensin II (hereinafter referred to as "AII"). The invention also relates to various quinoline derivatives which are valuable chemical intermediates suitable, for example, for use in the above method.

Background Art

Angiotensins are key mediators of the renin-angiotensin-aldosterone system, which is involved in the regulation of homeostasis and fluid / electrolyte balance in many warm-blooded animals, including humans. Angiotensin known as AII is produced from angiotensin I by the action of an angio-converting enzyme. . tensin (ACE), wherein angiotensin I is in turn produced from angiotensinogen, which is a blood plasma protein, by an enzyme known as renin. AII is the preferred spasmogenic agent, especially in the vasculature, and is not known to increase vascular resistance and blood pressure. In addition, angiotensins are known to stimulate release, aldosterone and therefore interfere with vascular congestion and hypertension induced by sodium and fluid retention mechanisms. Angiotensin AII inhibitors are useful in reducing or preventing angiotensin AII-mediated effects. Although there is a relatively large number of angiotensin AII inhibitors and their preparation, including, for example, some of the substituted imidazoles described in European Patent Application Publication No. 253310 and European Patent Application 324377, some of the benzimidazoles described in the patent U.S. Pat. No. 4,880,804 and some pyrroles, pyrazoles and triazoles disclosed in European Patent Application 323841, there is a continuing need to obtain 2 novel alternative inhibitors and effective synthetic methods for their preparation. European Patent Application 348155 discloses certain quinoline derivatives which are structurally similar to the quinoline derivatives which can be obtained by the process of the invention and which are said to have leukotriene D4 potency antagonism.

A number of quinoline derivatives of formula (I) are described in related European patent application No. 412848

wherein R 1 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, phenyl or C 1 -C 4 alkyl, the latter containing one or more fluorine substituents or bears a cycloalkyl substituent having from 3 to 8 carbon atoms, a hydroxy substituent, an alkoxy substituent of 1 to 4 carbon atoms or a phenyl substituent, 2 R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 'to 8 carbon atoms, the cycloalkylalkyl group in which the cycloalkyl radical contains from 3 to 8 carbon atoms and the 3 alkyl radical contains from 1 to 4 carbon atoms, carboxy, alkoxycarbonyl, in which the alkoxy radical contains from 1 to 4 carbon atoms, a group, a nitro group, a phenyl group or a phenyl-alkyl group in which the alkyl moiety contains 1 a 44 carbon atoms, and oS0U are independently selected from hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 fluoroalkoxy, halogen, hydroxy a group consisting of a trifluoromethyl group, a cyano group, a nitro group, an amino group, an alkanoylamine group having from 1 to 4 carbon atoms, an alkylamino group and a dialkylamino group having no more than 6 carbon atoms, a dialkyl amino group having from 3 to 8 carbon atoms, (C 1 -C 4) -alkanoyl, carbamoyl, N-alkylcarbamoyl and di- (N-alkylcarbamoyl) groups having not more than 7 carbon atoms, carboxyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, and the alkyl group having 1 to 4 carbon atoms, wherein the latter group bears an amino group, a hydroxyl group or an alkoxy group having 1 to 4-i-1-yl-1-i-i-phenoxy-like sub-group R1 and R2 together form an alkylenedioxy group attached to the adjacent carbon atoms of the benzene radical of Formula I,

R a and r 5 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, trifluoromethyl, cyano, nitro, and A; methylene, 4 X represents a phenylene group optionally bearing a substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, cyano and a nitro group or X is a direct bond between an adjacent phenyl group and the A group, Z is a 1H-tetrazol-7-yl group, -CO.NH- (1H-tetrazol-5-yl) group or a general group wherein R is a hydrogen atom or a non-toxic biodegradable residue of a physiologically acceptable alcohol, or R 1 is an alkyl group having 1 to 6 carbon atoms; cycloalkyl a phenyl group having from 3 to 8 carbon atoms or a phenyl group, any of which phenyl radicals may be unsubstituted or may have one or two substituents independently selected from the group consisting of (C 1 -C 4) alkyl, (C 1 -C 4), halogen, cyano trifluoromethyl, or non-toxic salts thereof except for 2 - [(3-methoxycarbonylquinolin-4-yloxy) methyl] benzoate.

It will be appreciated that, depending on the nature of the substituents, the compounds of Formula I may have one or more chiral centers and may therefore be isolated in one or more racemic or optically active forms.

In addition, in the compounds of formula (I), generic terms, such as "alkyl", include both straight and branched variants of the corresponding generic group, as long as the number of carbon atoms permits. However, when a particular group is mentioned, for example, a "propyl group", such a designation refers only to the straight-carbon chain variant, and if the corresponding branched variant is to be referred to as "isopropyl". 5

The same convention applies to other groups.

Particular values for the general substituent R 1 or when the general substituent is an alkyl group are, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl while this general substituent is a cycloalkyl group, such specific meanings are, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Particular values for R 1 when it is alkyl bearing one or more fluorine substituents are, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoro-ethyl, whereas this general substituent is an alkyl group bearing a hydroxy group, a cycloalkyl group, an alkoxy group having 1 to 4 carbon atoms, or a phenyl group as the substituent, such as the hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenyl-ethyl or 2-phenylethyl. 2

Particular values for the general substituent R when this substituent is cycloalkyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopentylethyl a group, while in the case where said general substituent is phenylalkyl, such specific meanings are, for example, benzyl, 1-phenylethyl or 2-phenylethyl. When the general substituent is an alkoxycarbonyl group, the particular meanings of this substituent are, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl. 6

Particular values for the general substituent R 1, R 6, R 6 or R a or for an optional substituent that may be present when X represents a phenylene group are, for example: for an alkyl group: methyl and ethyl; for alkoxy: methoxy and ethoxy; t for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and a, 3,3,3-trifluoropropoxy; for halogen: fluorine, chlorine, bromine and iodine; for alkanoylamino: formamide, acetaamido and propanamide; . for an alkylamino group: a methylamino group, an ethylamino group and a butylamino group; For a dialkylamino group: dimethylamino, diethylamino and dipropylamino; in: tyS? for dialkylaminoalkyl: dimethylaminomethyl, 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and 3- (diethylamino) propyl; for the alkanoyl group: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di (N-alkyl) carbamoyl: N, N-dimethylcarbamoyl and Ν, Ν-diethylcarbamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkylthio: methylthio, ethylthio and butylthio; for alkylsulfinyl: methylsulfinyl, ethylsulfinyl and butylsulfinyl; and 7 for alkylsulfonyl: methylsulfonyl, ethylsulfonyl and butylsulfonyl; for an alkyl group bearing an amide, hydroxyl or alkoxy substituent: hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, aminomethyl group, 2-aminomethyl group, 2-methoxyethyl group and 2-ethoxyethyl group; and for alkylenedioxy: methylenedioxy and ethylenedioxy.

A particular value for a general substituent when this general substituent is a non-toxic biodegradable residue of a physiologically acceptable alcohol or phenol is, for example, a residue derived from an alkanol of 1 to 6 carbon atoms, such as methanol or ethanol, or a phenol, glycerol and the like.

Particular values for the general substituent "R 7 when this general substituent is an alkyl group" are, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl, whereas when the general substituent is a cycloalkyl group, such as cyclobutyl, cyclopentyl or cyclohexyl.

Particular values for optional substituents which may be present include, for example, halogen: fluorine, chlorine and bromine, alkyl: methyl and ethyl, and for alkoxy a methoxy group and an ethoxy group.

A particular value for the general substituent X, which is particularly preferred, is, for example, a p-phenylene group. A preferred value for R or R is, for example, hydrogen and a preferred value for R @ 1 is, for example, methyl, ethyl or propyl. A preferred class of compounds described in the related application form compounds of Formula Ia

wherein R 1, R 4, R 4, and any of the foregoing are as defined above. and Z is a carboxyl, 1H-tetrazol-5-yl or benzenesulfonamide group, the latter containing one or two substituents independently selected from the group consisting of halogen, such as fluorine, chlorine or atom bromo), (C 1 -C 4) alkyl (such as methyl or ethyl), (C 1 -C 4) alkoxy (such as methoxy or ethoxy), cyano, nitro, and the like; trifluoromethyl groups, and non-toxic salts thereof. 1

For example, a carboxyl group or a 1H-tetrazol-5-yl group is preferred for the general substituent Z or Z, the latter being a particularly preferred group, especially when attached to the X group

I in ortho position.

A particularly preferred combination of meanings in any of the above definitions is a combination in which the quinoline residue together with the attached substituents R, R, RJ, and optionally Ra, if present, is any of the following: 2-methylquinoline, 2-ethylquinoline, 2- ethyl 6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl-5,6,7-trimethoxyquinoline-9-lin, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6-methylthioquinoline, 2-ethyl -7-hydroxymethylquinoline, 2-ethyl-6- (2-fluoroethoxy) quinoline, 2-ethyl-6- (2,2,2-trifluoroethoxy) quinoline, 2-ethyl-6-carboxamidoquinoline, 2-etylthio -6-fluoroquinoline, 2-ethyl-6-isopropoxy-quinoline or 6-aminomethyl-2-ethylquinoline; and wherein the substituent O.A.X- is attached at the 4-position of the quinoline ring.

Particularly preferred compounds included in said related application are: 2-methyl-4 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy / quinoline, 2-ethyl-4- (2 '-( 1H-tetrazol-5-yl) biphenyl-4-yl) methoxy / quinoline, 2-ethyl-7-hydroxymethyl-4 - [(2 ' - (1H-tetrazole-5- yl) biphenyl-4-yl) methoxy / quinoline, 2-ethyl-6- (2-fluoroethoxy) -4 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy / quinoline, 2- ethyl 6- (2,2,2-trifluoroethoxy) -4 - [(2 (1H-tetrazol-5-yl) biphenyl-4-yl) methoxy] quinoline and 2-ethyl-6-isopropoxy-4- (2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methoxy / quinoline and their non-toxic salts. Although all compounds of formula (I) may form salts with appropriate acids, it should be noted that that those compounds of formula I in which Z is other than the ester group or in which R 1 or R 4 is a carboxyl group may form salts with both the acids and the bases. she said d salts with bases providing physiologically acceptable cations formed, for example, by alkali metals (such as sodium or potassium), alkaline earth metals (such as aluminum, aluminum, or ammonium, and suitable organic bases such as alkali metals). ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, for example solis with mineral acids, in particular hydrohalides (such as hydrochloride and hydrobromide), sulphates and phosphates, and strong organic acids such as paratoluenesulfonic acid and methanesulfonic acid.

The compounds of formula I described in the cited patent application are prepared by various standard procedures well known in the art of organic chemistry for the preparation of structurally analogous compounds. A novel alternative process has now been found for the preparation of the compounds of formula (I) wherein X is optionally substituted p-phenylene and Z is tetrazolyl.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of a compound of formula III

1 2 3 4 5

wherein R, R 2, R 3, R 3, R 3 and R 6 are as defined above, and R b is a hydrogen atom or a substituent. selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a trifluoromethyl group, a cyano group and a nitro group, the principle of which is that compounds of general formula IV

3 (IV)

Removing the trisubstituted tin radical Sn (Q), i * 5 λ e ** where R, R, R, R, R, Ra and Rb have some of the meanings given above and Q represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, wherein the other of said groups is optionally substituted with C1-4 alkyl, C1-4 alkoxy or halogen.

A particular value for the general substituent Q is, for example, a C 1 -C 4 alkyl group such as a methyl group, an ethyl group or a butyl group, with a butyl group being preferred.

A particular value for the general substituent R b or an optional substituent on Q when it is a phenyl group is, for example, a fluorine, atomic or bromine atom in the case of a halogen atom, for example an alkyl or ethyl group in the case of an alkyl group, and in the case of an alkoxy group. for example methoxy or ethoxy.

The process according to the invention is particularly suitable for the preparation of compounds of formula III in which the tetrazolyl group is ortho to the adjacent phenyl group.

The trisubstituted tin residue of SiO 2 may be removed, for example, by acidic or alkaline hydrolysis.

The reaction is suitably carried out, for example, by treatment with a mineral acid such as aqueous hydrochloric acid, a compound of formula IV in the presence of a suitable solvent or diluent. A suitable solvent or diluent is, for example, a hydrocarbon such as toluene or xylene, an ether such as dioxane or tetrahydrofuran, or water or mixtures thereof. The reaction is generally carried out at a temperature of, for example, 0 to 50 ° C and suitably at a temperature close to ambient temperature.

The compounds of formula (IV) as defined above may be obtained, for example, by reacting a nitrile of formula (V 12)

with the azide of the formula VI (Q) 3.Sn.N3 (VI), wherein in the above formulas R1, R1, R2, R4, R5, R5 and Q1 have some of the abovementioned meanings. The reaction is suitably carried out in a suitable solvent or diluent such as toluene or xylene at a temperature of, for example, 50 to 150 ° C, preferably 100 to 150 ° C. Preferably an excess of azide, in particular a 1.5 to 5 equivalent equivalent, is used. In particular, this process is suitable for obtaining compounds of the formula IV in which the tetrazolyl group carrying the trisubstituted tin residue of the formula (Sn) (Q) 3 is in the ortho position to the adjacent phenyl group.

Compounds of formula (v) may be obtained, for example, by radical bromination of a nitrile of formula (VII)

wherein R- and Rb have some of the meanings given above, for 13

forming the corresponding bromomethyl derivative and subsequently alkylating the quinolone of formula VIII

wherein R 1, R 2, R 3, R 4 and R a have any of the abovementioned meanings: said bromination is carried out using known procedures and reagents, for example by reaction with N-bromosuccinimide in the presence of benzoyl peroxide or azobisisobutyronitrile in a solvent such as chlorobenzene or carbon tetrachloride and said alkylation is generally carried out in the presence of a base, for example an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali carbonate, a metal such as sodium carbonate or potassium carbonate, or an alkali hydride such as hydride. sodium, in a solvent or diluent, such as, for example, a C1 -C4 alkanol, especially ethanol or ethanol, when an alkali metal alkoxide, or a polar solvent such as N, N-dimethyl formamide or N- methylpyrrolidone, and at a temperature of, for example, 10 to 100 ° C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as a mixture of water and dichloromethane.

Compounds of formula (VII) may be obtained, for example, as described in European Patent Application No. 0253310 A2. Alternatively, thio compounds can be obtained, for example, by reacting a Grignard reagent formed from an unsubstituted or substituted 4-bromotoluene in a solvent such as tetrahydrofuran by reaction with a trialkyltin-14 halide such as tributyltin chloride at 0-25 ° C followed by (substituted) phenyltrialkyl-tin compounds with substituted or unsubstituted bromobenzonitrile in the presence of a zero-valent palladium catalyst such as tetrakis (triphenylphosphine palladium, and azo- (bisisobutyronitrile)). Another alternative method for obtaining compounds of Formula VII is to react 4-methylphenylboronic acid (4-methylphenylboronic acid) with a suitably substituted bromobenzonitrile in the presence of a palladium catalyst such as palladium chloride or tetrakis (triphenylphosphine) palladium, and azo ( bisisobutyronitrile). Yet another possibility of obtaining the compounds of the formula VII consists in the reaction of unsubstituted or substituted 4-bromotoluene with an alkane. an alkali metal such as butyllithium and zinc chloride followed by reaction with an appropriately substituted bromobenzonitrile in the presence of titetrakis (triphenylphosphine) palladium.

Compounds of formula (VIII) are either known compounds which are described, for example, in EPA 412848, or can be obtained by standard organic chemistry processes, for example as described in Org. Son., Coll. Vol. III, pp. 374 and 593. In a modified embodiment of the present invention, a compound of formula (IV) as defined above is prepared in situ from a compound of formula (V) by reaction with the above-defined azide of formula (VI). The trisubstituted tin radical of formula Sn (Q) can then be removed without isolation of the compound of formula IV, for example by addition of an aqueous solution of mineral acid to the reaction mixture. In order to remove excess azide, the reaction mixture may be acidified using a mixture of sodium nitrite and hydrochloric acid. The azides of formula (VI) are either commercially available or can be prepared by standard procedures well known in the art, for example by reacting a trialkyl halide with an alkali metal azide. If it is then desired to obtain a non-toxic salt 15 of a compound of formula (I), this salt can be obtained, for example, by reaction with a suitable base to provide a physiologically acceptable cation, or with a suitable acid providing a physiologically acceptable anion or other conventional method for salt preparation. <

Furthermore, if it is desired to obtain an optically active form of the compound of formula (I), such optically active form may be obtained by performing any of the above methods using an optically active starting product. Alternatively, the racemic form of a compound of formula (I) may be resolved, for example, by reaction with an optically active form of a suitable organic base such as ephedrine, N, N, N-trimethyl (1-phenylethyl) ammonium hydroxide or 1-phenylethylamine, followed by by conventional separation of a diastereoisomeric mixture of the salts thus obtained, for example, by fractional crystallization from a suitable solvent such as, for example, 1 to 4 carbon atoms, and the optically active form of the compound of formula (I) can be liberated by treatment with an acid using a conventional method; for example, using an aqueous solution of a mineral acid such as dilute hydrochloric acid. Some of the intermediates defined above are novel compounds, for example compounds of formula IV and formula V, and especially those compounds of formulas IV and V, wherein the tetrazolyl group and the tetrazolyl group, respectively, are present. the cyano group is ortho to the adjacent phenyl group. These new-intermediate products also form a

The antagonism of one or more physiological effects of angiotensin AII, particularly antagonism of the interaction of angiotensin AII with receptors that mediate its effects on the targeted tissue, can be determined by one or more of the following and routine laboratory tests. 16

Test A

This in vitro assay involves incubation of the test compound with a starting concentration of 100 micromolar (or lower) in a buffered mixture containing stable concentrations of angiotensin AII-labeled radiation and a cell surface membrane fraction prepared from an appropriate angiotensin targeting tissue. In this assay, guinea pig adrenal gland known to respond to angiotensin AII is the source of said membrane fraction. The interaction of the radiolabeled angiotensin AII with the Srcaptor of said adrenal gland (evaluated as the amount of radioactivity bound to the particulate membrane fraction after removal of unbound radioactivity by rapid filtration, by a standard procedure commonly used in this assay) is antagonized by the test compounds that also bind. to membrane receptor sites, the degree of which; antagonism (seen in this assay as displacement of the radioactivity that has already been bound to the membrane) is facilitated by comparing the membrane bound radioactivity in the presence of the test compound at a given test concentration with a control rate of bound radioactivity determined in the absence of the test compound. Compounds exhibiting at least 50% displacement of the radiolabeled angiotensin from its binding to the membrane receptor sites at a concentration of 10 M are tested again at lower concentrations to determine their potency. In order to determine the IC50 concentration (concentration causing 50% seal of the radiolabeled angiotensin AII from its binding to the membrane receptor sites), the concentration of the test compound is chosen to be at least four orders of magnitude, with the expected approximate concentration of θ θ, which is subsequently determined from a plot plotting the relative displacement of the radiolabeled angiotensin IIIIz binding, to the receptor sites on the concentration of the test compound.

The compounds of the general formula (17) as defined above exhibit significant test A inhibitory activity at concentrations of 50 micromolar or at much lower levels.

Test B

This in vitro assay involves measuring the antagonist effects of the test compound on angiotensin AII-induced conjugation of isolated rabbit aorta stored in physiological saline at 37 ° C. To ensure that the test compound is specifically related to angiotensin AII antagonism, the effect of the test compound on noradrenaline-induced contraction can be determined in the same formulation.

Compounds of formula (IH) generally exhibit significant B50 micron or inhibitory activity at Test B.

Test C

This in vivo test involves the use of terminally anesthetized conscious rats implanted under anesthesia with an arterial catheter to measure changes in blood pressure. The antagonizing effects of the test compound administered orally or parenterally to angiotensin AII were determined by measuring the mean of the pressure of the body of the body. it has been ensured that this effect is specifically related to kangiotensin, the effect of the test compound on pressure responses induced by vasopressin can also be determined in the same formulation.

Compounds of formula (IH) generally exhibit specific ΙΙΙΙ-antagonizing properties in test C at a dose of 50 mg / kg body weight, or at a much lower dose without apparent toxic or other undesirable pharmacological effects. 18

Test D

This in vivo test involves the stimulation of endogenous bio-synthesis of angiotensin AIX in various animal species, including rat, swine and dog, by introducing a low sodium diet and administering appropriate daily doses of a saluretic known as fru · semid. The test compound is then administered orally or parenterally to a test animal that has been implanted under anesthesia with an arterial catheter to measure changes in blood pressure.

Compounds of formula (113) exhibit D AII-antagonizing properties in the assay, which are demonstrated by significant blood pressure lowering at a dose of 50 mg / kg body weight or at a much lower dose without any apparent toxic or other undesirable effects being observed. pharmacological effects.

In order to illustrate the inhibΙΙ-inhibitory properties of compounds of formula III, it is noted that 2-methyl-4 - [(2- (1H-tertrazol-5-yl) biphenyl-4-yl) methoxy] quinoline hydrochloride provides the above following tests A, B and C the following results: in test A: mean IC 50 = 1.7 x 10 M, in test B: mean pA 2 -8.95, in test C; ED50 = 0.5 mg / kg (intravenous administration). In the following, the invention will be elucidated in more detail by means of specific examples. These examples are merely illustrative and are not intended to limit the scope of the invention, which is clearly defined by the formulation of the patent claims. In these examples, unless expressly stated otherwise i) thickening and evaporation was carried out under vacuum in a rotary evaporator; ii) individual operations were carried out at ambient temperature, i.e. at a temperature ranging from cd18 to 26 ° C; The reported yields are only indicative and do not represent the maximum yields that could be achieved by optimizing procedures; iv) 1 H-NMR spectra are normally determined at 270 MHz in CDCl 3 using thetramethylsilane as internal standard, the spectra being expressed as chemical shifts (delta values) in ppm relative to tetramethylsilane using conventional abbreviations for major peaks; s = singlet, m = multiplet, t = triplet and doublet; v) "1H-tetrazol-5-yl" means "1-H-1,2,3,4-tetra-zol."

A solution of 2-ethyl-4 - [(2 '- (2-tributylstannyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy] quinoline in toluene (15 ml) prepared in situ by heating to boiling refluxing 4 '- (2-ethylquinolin-4-yloxy) methyl / biphenyl-2-carbonitrile (0.9 g) and tributyltin azide solution (15 ml) / the latter solution was prepared by reaction of tributyltin chloride (3 , 3 g) and sodium azide (1.13 g) in water (22.5 ml) at ambient temperature for 4 hours, followed by addition of water from water. of the obtained extract to an extract volume of 15 ml / was added slowly over one hour to a solution of nitrite sodium (2.5 g) in water (10 ml) containing 12% (w / v) hydrochloric acid (10 ml), maintaining the temperature-of-the-mixture of less than 5 ° C. then a solution of sulfamic acid (1.43 g) in water (10 ml) was added while maintaining the temperature below 5 ° C and the mixture was stirred at this temperature for one hour. The semi-solid suspended was collected by filtration and washed with water (3 x 10 mL) followed by toluene (10 mL). The separated semi-solid product is then added to tetrahydrofuran (40 ml), whereby the product dissolves and later crystallizes as a white solid. After cooling for one hour, the solid product was isolated by filtration, washed with tetrahydrofuran (5 mL) and dried. There was thus obtained 2-ethyl-4 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methoxy] quinoline hydrochloride. Yield: 53%, melting point: 179-180 ° C (dec.), Nuclear magnetic resonance spectrum: (d 6 -DMSO) 1.46 (t, 3H), 3.18 (q, 2H), 5.68 (s) (2H), 7.22 (d, 2H), 7.5-7.8 (m, 7H), 7.83 (t, 1H), 8.08 (t, 1H), tri, 8.18 ( d, 1 H), 8.32 (d, 1H). Example 2

A mixture of 2-ethyl-4-quinolone (1.73 g) (prepared analogously to that described in Org. Syn., Coll. Vol. III, p. 374 and p. 593, from aniline and ethyl propionylacetate, 4-bromomethylbiphenyl-2-carbonitrile (A) (3.1 g) and solid potassium carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred under nitrogen for 36 hours. The reaction mixture was then added dropwise to water (100 mL) and stirred at 15-25 ° C for 30 minutes. The suspended solid was collected by filtration, washed with water and dried at 60 ° C under vacuum. The solid obtained is recrystallized from tert-butyl methyl ether. There was thus obtained 4- {2-ethylquinolin-4-yloxy) methyl} -biphenyl-2-carbonitrile as a solid. 151-153 [deg.] C., Nuclear Magnetic Resonance Spectrum: (CDCl3: 1.4 (t, 3H), 21 2.97 (q, 2H), 5.35 (s, 2H) , 6.76 (s, 1H), 7.4-7.6 (m, 3H), 7.6-7.8 (m, 6H), 8.0 (d, 1H), 8.25 (d). , 1H). The starting product A was obtained as follows: i) 2M sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium chloride (0%). , 4 g), methanol (200 ml) and toluene (200 ml) at 5 ° C. The temperature rises approximately 20 ° C and a solid is eliminated. The reaction mixture was then heated to reflux for 2 hours. The reaction mixture was allowed to cool and water (100 mL) was added followed by diatomaceous earth (5 g). The mixture is then stirred for 15 minutes and the diatomaceous earth is filtered off. 2 of the filtrate, the organic phase is separated off and the aqueous phase is washed with 2M sodium carbonate solution and then with water. The organic phase is then filtered and the filtrate is evaporated. The resulting solid was recrystallized from petroleum ether (b.p. 110-120 ° C). There was thus obtained 4'-methylbiphenyl-2-carbonitrile. Yield: 80%, m.p. (d, 2H), 7.35-7.55 (m, 4H), 7.60-7.65 (m, 1H), 7.75 (d, 1H); (ii) A mixture of 4'-methylbiphenyl-2-carbonitrile (3.86 g), N-bromosuccinimide (3.92 g) and azo (bis-isobutyronitrile) (0.15 g) in chlorobenzene (75 ml) is heated to 70 ° C for 3 22 hours. An additional amount of N-bromosuccinimide (0.3 g) and azo (bisisobutyronitrile) (0.05 g) were then added and the digested mixture was heated for an additional 15 minutes. The heating is stopped and the mixture is stirred at room temperature for 16 hours. Water (50 ml) was added and the mixture was stirred for 30 minutes and filtered. The organic phase was separated, washed with water (50 ml) and dried over magnesium sulfate. The solvent was removed by evaporation and the resulting solid was serecrystallized from cyclohexane. There was thus obtained 4-bromomethyl-biphenyl-2-carbonitrile as a solid. Yield. 3.9 g, Nuclear Magnetic Resonance Spectrum: (CDCl3) 4.55 (s, 2H), 7.4-7.85 (m, 8H).

Claims (10)

ΑΛ3Γ80 * λΖΉίγΝλΛ oaa avgn - 23 - PATENT CLAIMS A process for preparing quinoline derivatives of Formula III in which the hydrogen atom is an alkyl group having 1 to 8 carbon-, -cyclyl-cyclo-1-alkyl-3 to 8-carbon atoms, the phenyl group or a substituted alkyl group having 1 to 4 carbon atoms, the latter group containing one or more fluorine substituents, or having a cycloalkyl substituent of 3 to 8 carbon atoms, a hydroxy substituent, an alkoxy substituent of 1 to 4 carbon atoms, or a phenyl substituent, 2 R represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 3 -C 8 cycloalkyl group, a cycloalkylalkyl group in which the cycloalkyl radical contains 3 to 8 carbon atoms and the 24 alkyl radical contains 1 to 4 carbon atoms atoms, a carboxy group, an alkoxycarbonyl group in which the alkoxy group contains 1 to 4 carbon atoms, a cyano group, a nitro group, a phenyl group or a phenyl-alkyl group in which a the alkyl moiety contains from 1 to 4 carbon atoms, R 3 and R 4 are independently selected from the group consisting of a hydrogen atom having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a fluoroalkoxy group having from 1 to 4 carbon atoms, a halogen atom, a hydrocarbon atom; -xy-group, trifluoromethyl group, cyano group, nitro group, amine group, C1-C4 alkanoylamine group, alkylamino and dialkyl-amino group of at most 6 carbon atoms, dialkyl aminoalkyl group of 3 to 8 carbon atoms, C1 -C4 -alkanoyl, carbamoyl, N-alkylcarbamoyl and di- (N-alkylcarbamoyl having up to 7 carbon atoms, carboxyl, alkoxycarbonyl in which the alkoxy radical contains 1 to 4 carbon atoms , (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl; carbon atoms, and the latter group carries an amino group, a hydroxy group or an alkoxy group having 1 to 4 carbon atoms as a substituent, or R 3 and R 4 together form an alkylenedioxy group attached to the adjacent carbon atoms. the carbon atoms of the benzene radical of X, R a and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, trifluoromethyl, cyano is a hydrogen atom or a substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, trifluoromethyl, cyano and nitro; wherein any of said phenyl moieties may be unsubstituted or may carry one or two substituents which may be substituted are independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, cyano and trifluoromethyl, and non-toxic salts thereof, characterized in that R b R 5 removes a trisubstituted tin radical of the formula Sn (Q), 1-2-3-4-5 -; wherein R, R, R, R, R, R a and R b have some of the meanings given above and Q "C 1 -C 6 alkyl" or "phenyl", the latter of which may optionally be substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen. Process according to Claim 1, characterized in that the starting product of the general formula (IV) R 1 represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a sec-butyl group, a pentyl group , hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hydroxy. methyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl, or 2-phenylethyl; R 2 represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, an isobuyl group, a sec-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropyl group thiyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, cyano, nitro, phenyl, benzyl, 1-phenylethyl or a 2-phenyl-ethyl group, R-5 and R * are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2 -trifluoroethoxy-, 3,3,3-trifluoropropoxy, atomfluor, chlorine, bromine, iodine, hydroxy, trifluoromethyl , cyano, nitro, amine, formamide, acetamide, propanamide, methyl amine, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dimethylaminomethyl, 2- (dimethylamino) ethyl a group, 2- (diethyl-27-aminoethyl, 3- (diethylamino) propyl, formyl, acetyl, butyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl , N, N-diethylcarbamoyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylthio, ethylthio, butylthio, methylsulfinyl, ethylsulfinyl, butylsulfinyl, methylsulfonyl, phenyl, ethylsulfonyl, butylsulfonyl, hydroxymethyl, 1-hydroxyethyl the 2-aminoethyl group, the 2-hydroxyethyl group, the aminomethyl group, the 2-aminoethyl group, the 2-methoxyethyl group and the 2-ethoxyethyl group, or R 4 and R 2 together form a methylenedioxy group or an ethylenedioxy group attached to adjacent the carbon atom of the benzene radical of formula I, Ra and R are independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano a group and a nitro group, R b represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, a cyano group and a nitro group a group wherein any of said phenyl moieties may be unsubstituted or may carry one or two substituents independently selected from the group consisting of methyl, ethyl, ine, methoxy, ethoxy, atomfluor, chloro, bromo, cyano and trifluoromethyl. Process according to claim 1 or 2, characterized in that in the starting product of general formula (IV), R 1 represents a methyl group and R 4 represents a hydrogen atom or R 1 represents an ethyl group and R 4 represents a hydrogen atom, a 7-hydroxymethyl group, 6- { A 2-fluoroethoxy} group, a 6- (2,2,2-trifluoroethoxy) phenyl group or a 6-isopropoxy group, R, R, R, Ra and Rb are each hydrogen and a tetrazolyl group carrying Sn. Q 1 is in the ortho position relative to the adjacent phenyl group. 4. A process according to claim 3 wherein the starting product of formula (IV) R1 is ethyl and R is hydrogen. Process according to any one of the preceding claims, characterized in that the removal of the trisubstituted tin residue Sn (Q 1) is carried out by acid hydrolysis. A process according to any one of the preceding claims, characterized in that in the starting product of formula (II) Q is an alkyl group having 1 to 4 carbon atoms. Process according to any one of the preceding claims, characterized in that the starting product of general formula (IV) is formed in situ from a compound of formula (v) wherein R 1, R 4, R 4, R 4, R a and R b have any of the meanings 29 defined in any one of claims 1 to 4. Compound of formula (III) according to claim 1, prepared by any of the processes according to claims 1 to 7 or its obvious chemical equivalent. A compound of formula IV wherein R 1, R 2, R 3, R 45 R, R a, R b and Q have any of the meanings defined in any one of claims 1 to 6. 4 or claim 6. A compound of formula V wherein R 1, R 2, R 3, R 4, r 5, R a, and R b are as defined in any one of claims 1 to 4.