LU81814A1 - IMIDAZOLYLETHOXY DERIVATIVES OF PYRIDINE-5-METHANOLS AND QUINOLEINE-3-METHANOLS - Google Patents

Description

The present invention relates to new 2 - (1H-imidazol-1-yl) ethoxy derivatives of pyridine-5 ~ methanols and of quino-leine-3-methanols, as well as the acid addition salts of these compounds. These new compounds correspond to the following formulas: 4 1

* VNVR

/ = - »R J CH, -0-CH'CHk-N, t.

R2 X 2 \ = J ‘’ R6 and R10 W ° r * ‘_“ r8 ^ y ^ y ^ N: h2--0 “Ch-ch2 ~ n © - * s ~ R6

In the formulas I and II, as well as in all the specification below, the symbols used have the following meanings: i * The symbols a can each represent I a hydrogen atom, a hydroxy group, a halogen atom , a lower alkoxy group, a lower alkyl-thio group or: a lower alkyl group.

: * The expression "lower alkyl group" includes hydrocarbons with a straight or branched chain and containing 1 to 7 carbon atoms. Mention will be made, for example, of the methyl group, the ethyl group, the propyl group, the isopropyl group and the like. The terms "lower alkoxy group and" lower alkyl-thio "include lower alkyl groups - ύ - propoxy group, butoxy group, t-butoxy group, methylthio group, ethylthio group, propyl-thio group, group butylthio, the isobutylthio group, etc.

In all of these groups, lower alkyl groups containing 1 to 4 carbon atoms are preferred, while those containing 1 or 2 carbon atoms are particularly / n / / prereres #

The halogen atoms are the usual four halogens, chlorine and bromine, in order, being preferred ^ Preferably, all of the halogen atoms involved in a "single compound are identical.

The preferred embodiments of the present invention are compounds corresponding to formulas I and II in which the radicals R1 to R10 may each represent a hydrogen atom, a lower alkyl group containing 1 to 4 carbon atoms or an atom halogen.

The most preferred embodiments of formula I are those in which the radicals R * to R ^ each represent a hydrogen atom, a halogen atom or a lower alkyl group containing 1 to 4 carbon atoms more particularly those in which the radical R * is * a hydrogen atom or an alkyl group containing 1 to 4 atom * 2 4. ζ 6 of carbon, R, R, R · 3 and Ru each represent an atom of o chlorine and R ° is a hydrogen atom.

The preferred embodiments of the formula. - They are compounds in which the radicals R *, R ^ and R * ^ each represent a hydrogen atom or a halogen atom in particular, a hydrogen atom, R2, R ^, R ^ and R ^ each represents a hydrogen atom or a halogen atom, er particular, a halogen atom and more especially, a tone of chlorine, while the radicals R ** and R ^ are fixed respec-

On forum 1 ns imti vc.iux c orij> '),>, es fie i oimulc X par] o.s sîtï es of reactions described below,

V I

A pyridinc-5 ~ cai’boxylic acid ester of formula (III): W is reduced.

3 / ^ \ / ^ v-c_o-lower alkyl

R T II

R2 0 _ by means of a reducing agent, for example, a hydride of a metal such as lithium aluminum hydride or sodium borohydiide and the like, to obtain the alcohol of formula (XV) ί R4 N Rl -if ,.

R

The alcohol of formula IV is then transformed into a halomethyl derivative of formula (V): R4 ^ N y R1 / χ ° χ

R3 "T; CH2'X

- in which X represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, by means of a halide of an inorganic acid such as thionyl chloride, phosphorus oxybromide, etc.

The product of formula I is then prepaxed by reacting the halo compound of formula V with a substituted l- (phenyl) -2- (1H-imidazol-1-yl) ethanol of formula (Vl): N = \

N-CH - CH-OH

- RS

- 5 - s * The inorganic acid formed during the reaction is neutralized by a base, for example, an alkali metal hydroxide, a carbonate, an amine, an alcoholate or other similar agents known in the art .

The compounds of formula III used as starting materials are prepared by the methods described in C.R.

Acad. Sei. Hebd., Sci. Ser. C 275> 13 * 7 (1972); Rec. trav. chem. 65, 129 (1946); Chem. Ber. I848 (i960). The compounds of formula VI used as starting materials are prepared by the general method described in "J. Med. Chem." 1_2, 784 (1969).

The new compounds of formula II are formed by the series of reactions described below.

A quinoline-3-carboxy-acid ester of formula (Vil) is reduced: 10 C-0- lower alkyl 1 h Ti ü

R R O

by means of a reducing agent, for example, a hydride of a metal such as lithium aluminum hydride or sodium borohydride and the like to obtain the alcohol of formula (VIII): R10 9 I 1

T O T O

'7 1 2 ^

R R

The alcohol of formula VIII is transformed into a halomethyl derivative of formula (IX): 9 f R Ύ "κ1 R8 I7 * 2 *

R R

in which X represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, by means of a halide of an inorganic acid such as thionyl chloride, oxybromide phosphorus, etc.

* The product of formula II is then prepared by reacting the halo compound of formula IX with a 1- (phenyl) * - 2- (1H-imidazol-1-yl) substituted ethanol of formula (X):

N-CH.-CH-OH

"& The inorganic acid formed during the reaction is neutralized with a base, for example, an alkali metal hydroxide, carbonate, amine, alcoholate or other analogous bases known in the art.

The compounds of formula VII used as starting materials are prepared by the methods described in "Journal of Medicinal Chemistry", volume 20, 1001 (1977) î ibid., Volume 16, 875 (1973) "Tetrahedron Letters", Jj> _l , 4545 (1977) ”etc. The compounds of formula X used as starting materials are prepared by the general methods described in "Journal of Medicinal Chemistry", volume JL2, 784 (1969) ·

The compounds corresponding to formulas I and II formenl salts also forming part of the present invention.

P __--- T __- "1" ^ t ___ J! __- · __ — __ X.Z ___ 1 j l <\ s non-toxic and physiologically acceptable salts. The E \ bases corresponding to formulas I and II form salts by jj - reaction with one or more equivalents of one or the other of the various usual organic and inorganic acids ji | forming acid addition salts, for example, hydrohalides (in particular, hydrochlorides and hydrobromides • sulfates, nitrates, borates, phosphates, oxalates, maleates, citrates, acetates , ascorbates, succinates, benzene sulfonates, methane sulfonates, cyclohexane sulfamates and toluene sulfonate Acid addition salts are frequently a convenient means of isolating or purifying the product, for example ^ by forming and precipitating a salt (which is not necessarily non-toxic) in an appropriate medium in which the salt is insoluble and then, after separation of the salt, by neutralizing with a base such as 1 barium hydroxide or sodium hydroxide to obtain the free base of formula I, Other salts can then be formed from the free base by reaction with one or more equivalents of an acid containing the desired acid group.

The new compounds corresponding to formulas X and II, as well as their salts are useful as antifungal agents! . and antibacterials; they can be used to fight infections in various species of mammals, for example mice, rats, dogs, guinea pigs and the like, - in particular, infections caused by organisms such as Candida albicans, as well as organisms such as Trichomo nas vaginalis or Trichophyton mentagrophytes, For example, a compound or a mixture of compounds corresponding to formulas I and II or alternatively a physiologically acceptable acid addition salt of a compound of this type can be administered orally to an infected animal, for example, to a mouse, (inc .sc range, between about 5 and 25 mg / kg and per day in two to four subdivided doses. These doses can be formulated in the usual way in a tablet , a capsule or vm elixir containing 10 to 250 mg per dosage unit for this purpose, the active substance (s) is combined with an excipient, a vehicle, a binder, a preservative, a flavoring of conventional type, etc., according to the requirements of accepted pharmaceutical practice. Preferably, they are applied topically, for example, intravaginally in a lotion or in a conventional cream base at a concentration of about 0.01 to 2% by weight for a period of about 3 to 7 two to four times a day.

The following examples are given to illustrate the invention. The temperatures are indicated in degrees Celsius

Example 1 2,4-dichloro-5 ~ r Γ1- (2,4 ~ dichlorophenyl) -2- (1H-imidazol-1-yl) -ethoxylmethyl] pyridine, hydrochloride (1; 1) a) 2,4-dichloropyridine -5-methanol 66 g (0.3 mole) of 2,4-dichloropyridine-5-carboxylic acid ethyl ester are dissolved in 120 ml of anhydrous tetrahydrofuran. We pass nitrogen through the ball and then * while stirring and cooling to 0 °, we! add 7 × 12 g of lithium aluminum hydride in portions to maintain the reaction temperature in the range of 5 to 10 °. The stirring is continued for an additional 2 hours while cooling on the outside with water! then let the mixture sit overnight.

While stirring and cooling the mixture with ice cold water, 250 ml of hydrochloric acid are added dropwise | 3N so that the reaction temperature does not exceed | step 5 to 8 °, then evaporate the acid solution under vacuum "to dryness and extract the residual product with 500 ml ht! S of chloroform. Treat the chloroform extract with S carbon, filter it and the solvent is separated by distillation ~ to obtain 37 * 7 g of 2,4-dichloropyridine-5-methanol with a melting point of 73-77 ° ·

With sodium hydroxide, the salt formed constituting the residue is neutralized after extraction with chloroform, then the saline mixture is extracted again with

Idu chloroform in a Soxhlet apparatus and a second harvest amounting to 5 * 2 g is thus obtained. Total yield: 42 * 9 g ($ 80). After recrystallization from hexane, the 2, 4 ~ dichloropyridine-5-methanol has a melting point of 82-85 ° b) 5-chloromethyl-2,4-dichloropyridine For 19 hours, the mixture is heated to reflux 20 , 2 g of 2,4-dichloropyridine-5 ~ methanol (0.11 mole) and 150 ml of phosphorus oxychloride. Then, remove the excess phosphorus oxychloride in vacuo and add ice to the residue. The 5-chloromethyl-2,4-dichloropyridine is separated by filtration, washed with water, dried in a desiccator over water and recrystallized from hexane; yield 17 * 95 g (83 #) * melting point: 55-56 °.

! c) 2,4-dichloro-5-fT 1 - (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxylmethyl'lpyridine, hydrochloride (III)

A three-pipe flask fitted with an agitator, a reflux condenser and a gas inlet tube is introduced; 29.3 g (0.73 mole) of sodium hydroxide. And 27 ml of water. While passing nitrogen through the flask, the solution is cooled to 45 ° * and then 7 * 71 g (0.03 mole) of 1- (2,4-dichlorophenyl) -2- (1H-) are added. imidazol-1-yl) ethanol [which is prepared by the process described in "J. Med. Chem." 12, 784 (1969)) * 0.5 g of benzyltrimethylammonium chloride and 30 ml of tetrahydrofuran. To the mixture which is heated to 50 °, 5 * 9 g of 5-chloromethyl-2,4- ajoute r> li1nT'nnwr> -! F1iTiP are added. nnï ο nn a tri t “vi urmirpuBAmfinf ·. melanicre I> (nd.'mt 2 lumrcs at 6θ °. We then transfer the two-phase filtered solution in a settling funnel and extract the lower phase of aqueous sodium hydroxide with 10 ml of tetrahydrofuran. combined layers of tetrahydrofuran with charcoal and dried with sodium sulfate, then ether is added to the tetrahydrofuran extract to remove an oily by-product. To the clear solution of the free base , alcoholic hydrochloric acid is added dropwise. 3.5 g of 2,4-dichloro-5 - [[1- (2,4-dichlorophenyl) hydrochloride; 2. (1H-imidazol- 1-yl) ethoxy] methyl] pyridine precipitated from treatment with acetonitrile A second harvest is obtained by removing the mother liquor of tetrahydrofuran / alcohol and treating the residue with 3.5 g of acetonitrile .

; Melting point: 177 ° · Total yield: 7 g (52%), In I <· proceeding to recrystallization from acetonitrile, the melting point is brought to 181-182 °.

Example 2 2.4- dichloro-6-methyl-5-rfl- (2,4-dichlorophenyl) -2- (1H-imidazol ·! 1-yl) ethoxy1methyl ^ pyridine, hydrochloride

By substituting 0.3 ml of 2,4-dichloro ~ 6-methylpyridine-5-carboxylic acid ethyl ester for the ethyl ester of 2,4-dichloropyridine-5-carboxylic acid in the process of Example 1, 2,4-dichloro-6-methyl-5 - [[1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -ethoxy] methyl] pyridine is obtained. its hydrochloride at melting point: 225-260 °} nitrate, melting point ς 121-122 °. r

The following additional products of formula C are obtained by the method of Example 1 by reacting the substituted or unsubstituted l-phenyl-2- (1H-imidazol-1-yl) -ethanol of formula A with 5- substituted or unsubstituted chloromethylpyridine of formula B. The substituents apply to the respective formulas! - 11 - ..... N “= \

1 N-CH -CH-OH

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AT

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R I CH, -C1 R2

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Example 44 4,6-dichloro-3-f Γ1- (2> 4-dichlorophenyl) -2- (1H-imidazol-1-yl) -..... ethoxylmethyl] quinoline, hydrochloride (1; l) a) 4,6-dichloroquinoline-1 3-carboxylic acid ethyl ester

For 20 hours, a mixture of 45.2 g (0.18 mole) of ethyl ester of 6-chloro-4-hydroxy-quinoline-3-carboxylic acid and 250 ml of thionyl chloride is heated to reflux. Then, remove the excess thionyl chloride in vacuum, treat the residue with 200 ml of water and extract the ester with ether. After washing the ethereal extract twice with water, dried with Na2SO4 and the solvent is distilled off. The residual 4 * 6-dichloroquinoline-3-carboxylic acid ethyl ester is triturated with petroleum ether (40 ° -60 °), then filtered and dried. Yield: 45.3 g ($ 93) J melting point: 87-88 °.

b) 4,6-dichloroquinoline-3-methanol

27 g (0.1 mol) of 4,6-dichloroquinoline-5-carboxylic acid ethyl ester are dissolved in 600 ml of anhydrous tetrahydrofuran. Nitrogen is passed through the flask then, while stirring and cooling to 0 °, 2.4 g of lithium aluminum hydride are added in portions in order to maintain the reaction temperature between 0 and + 5 ° · Agitation is continued for an additional 5 hours.

- Then add 2.5 ml of water, 2 ml of aqueous sodium hydroxide ($ 20) and again 9 ml of water. By filtration, the precipitated inorganic salts are separated and the solvent is removed by means of a rotary evaporator. The oil obtained is dissolved in a small amount of benzene, then stored - A v -? tion, the crystallized 4,6-diehloroquinoline-3-methanol is separated and recrystallized from ethyl acetate. yield: 12.5 g (55%) 3 melting point: 182 °, c) 3- chloromethyl-4,6-dichloroquinoline

11.4 S (0.05 mole) of 4.6-dichloroquinoline-3-methanol are added in portions to 150 ml of thionyl chloride. The reaction mixture is allowed to stand for 24 hours at room temperature. Then, the solution is filtered and the excess thionyl chloride is removed using a rotary evaporator. The residue is triturated with water, separated by filtration, washed again with water and dried in a desiccator over P20 ^ to obtain 3-chloromethyl-4,6-dichloroquinoline j yield: Il * 5 g ($ 93.5)} melting point ï 102-105 °.

Recrystallization from cyclohexane does not modify the melting point.

d) 4,6-dichloro-3-r j ~ l- (2,4-dichlorophenyl) -2- (1H-imidazol-l ~ yl) ethoxy1methyl] quinoline, hydrochloride (1: 1)

In a three-tube flask fitted with an agitator, a reflux condenser and a ga intake tube! 14.8 g (0.37 mole) of sodium hydroxide and 25 ml of water are introduced * While passing nitrogen through the flask, the solution is cooled to 45 °, then 3 is added, 85 g (0.015 mole) of 1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethanol [prepared as described in "J. Med. Chem.", Volume 12, 784 ... ... (1969)], 0.25 g of b chloride in zyltrimethylammonium and 25 ml of tetrahydrofuran. To the mixture which is heated to 50 °, 1 · for 3 minutes, from a funnel with a preheated tap is added a solution of 3.6 g (0.015 mole) of 3 “cbloromethyl 4.6- dichloroquinoline in 10 ml of tetrahydrofuran. The mixture is vigorously stirred for 3 hours at 60 ° in hot condition in a separating funnel and the lower phase of aqueous sodium hydroxide is extracted with 10 ml of tetrahydrofuran. The combined layers of tetrahydro-furan are dried using sodium sulfate and, after removing the solvent, the residual oil is extracted with ether, then treated with charcoal and filtered. To the solution of the free base, ethereal hydrochloric acid is added dropwise. By filtration, the hydrochloride of 4,6-diehloro-3 ~ [[1- (2,4-dichlorophenyl-2- (1H-imidazol-1-yl) -ethoxyjmethyl] quinoline precipitate is separated, dried in a dessic -cator under vacuum and recrystallized from absolute ethanol Yield: 1.9 g ($ 25) J melting point! 148-150 °.

Example 45 4,7-dichloro-3-f Γ1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -ethoxy] methyllquinoline, hydrochloride (1: 2) a) Ethyl acid ester 4 "y ^ -dichloroquinoline- 3-carboxylic

For 4> 5 hours, a mixture of 30 g (0.12 mol) of 7-chloro-4-hydroxy quinoline-3-carboxylic acid ethyl ester with a melting point of 299-301 is heated to reflux. ° and 250 ml of phosphorus oxychloride. After removal of the excess phosphorus oxychloride, the residue is triturated with water and dissolved in ether. The ethereal solution is washed with aqueous sodium carbonate ($ 5) and water, then dried with sodium sulfate and the solvent is removed. The residual 4,7-dichloro-quinoline-3-carboxylic acid ethyl ester is triturated with petroleum ether (40 ° -60 °), separated by filtration and dried. Yield: 22 g ($ 68) i melting point: 81-82 °.

- X ο - b) 4> 7 ~ dichloroqu! Nolein-3-methanol

Following the method of example lb, with 21 g - (0.08 mole) of ethyl ester of 4,7-dichloroquinoline-3-carboxylic acid in 500 ml of anhydrous tetrahydrofuran and 1.9 g of hydride of lithium aluminum, we obtain 8.4 g ($ 46) of 4.7 ~ dichloroquinoline-3 ~ methanol with a melting point of 144-145 ° (ethyl acetate), c) 3 ~ cbloromethyl-4 , 7-dichloroquinoline

In accordance with the process of Example 1c, 8 g (0.035 mole) of 4 * 7-dichloroquinoline-3-methanol and 100 ml of thionyl chloride are reacted to obtain 7.1 g ($ 82.5) of 3 -chloromethyl-4j7 “dichloroquinoline; melting point î 106-107 °.

d) 4 »7-dichloro-3 ~ r Γ1- (2,4-dichlorophenyl) -2- (1H-imidazol-l-yl) -ethoxy1methyllquinoline> hydrochloride (1: 2

5.2 g (0.02 mole) of 1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -ethanol in solution are stirred for 4 hours at room temperature in 45 ml of anhydrous tetrahydrofuran, as well as 0.8 g of sodium hydride (dispersion at 55-60 $ in "mineral oil). When the formation of the sodium salt is completed, 4.9 g are added (0.02 mole) of 3 “chloromethyl ~ 4.7 ~ dichloroquinoline in solution in 25 ml of anhydrous tetrahydrofuran and the mixture is stirred at 50-60 ° (bath temperature) for 4 hours. Then, the tetrahydrofuran is eliminated, the residue is treated with water and extracted with ether, the ethereal layer is washed with water and dried with sodium sulphate by the addition of ethereal hydrochloric acid. ethereal solution of the base, the hydrochloride salt precipitates # For the purification, the hydrochloride is transformed into the free base and extraction and treatment are carried out again with hydrochloric acid. 20 / Q of 4.7 -dichloro-3 - [[1- (2,4-dichlorophenyl) - 2- (1H -imidazol-1-yl) ethoxy] methyl] quinoline, hydrochloride -. (1: 2) i melting point: I48-I490.

The additional products below of formula D are obtained by the process of 1 * example 44 by reacting l-phenyl-2- (1H -imidazol-1-yl) -ethanol substituted or unsubstituted of formula E with 3 ~ Substituted or unsubstituted cbloromethylquinoline of formula F. The substituents apply to the respective formulas.

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Claims (40)

1. Compound corresponding to one of the formulas: R JC CH2-0-CH-CH2-N J5 ^ r5 "and r6 R xA8 Τ0Τ0Τ n / S. Λ. / - = - i $ ΈΓ 7Γ cHn-O-CH-CH_ -NIT, Y ^ where. The radicals at R ^ each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, r a lower alkyl-thio group, a hydroxy group or a halogen atom, likewise as the acid addition salts of this compound. 2. Compound corresponding to formula I according to 2 A of claim 1, characterized in that R and R4 each represent a halogen atom. 3. Compound corresponding to formula I according to * 5 6- claim 1, characterized in that R and R each represent a halogen atom. 4 »Compound according to claim 2, characterized in that each halogen atom is a chlorine atom. * 5. A compound according to claim 33 characterized in that each halogen atom is a chlorine atom. 6, Compound corresponding to formula I according to claim 1, characterized in that the radicals R * - to R ^ each represent a hydrogen atom, a lower alkyl group containing 1 to 4 carbon atoms or a halo atom - 7. Compound corresponding to formula I according to 1 2 claim X, characterized in that R and R ° represent 2 To each a hydrogen atony, R and R ^ - each represent a halogen atom, R ~ * represents a 2-halo group and R ^ represents a 4-halo group, as well as the addition salts of physiologically acceptable acid of this compound. 8. Compound corresponding to formula I according to i 1 ο claim 1, characterized in that R and R represent 2 To each a hydrogen atom, R and R ^ each represent a chlorine atom, R ^ represents a 2-chloro group and R ^ represents a 4-chloro group, 9 * Compound corresponding to formula I according to claim 1 , characterized in that R ^ is a methyl group, 2 A î R and each represent a chlorine atom, RJ represents a hydrogen atom, R ~ * represents a 2-chloro group, R ^ represents a 4-chloro group, as well as the acid addition salts of this compound, 10, hydrochloride acid addition salt of the compound according to claim 8, 11, Compound corresponding to formula II according to claim 1, characterized in that R ^ is a halogen atom. 12, Compound corresponding to formula XI according to claim 1, characterized in that R is a halogen atom, 13 · Compound corresponding to formula II according to claim 1, characterized in that and each represent a halogen atom. 14 · Compound according to claim 13, characterized in that each halogen atom is a chlorine atom. 15 »Compound corresponding to formula II according to claim 1, characterized in that R ~ * is a 2-chlor group <» +. R ^ ftaf. a "rrminp. A-r.hlorn. · * J 16. Compound corresponding to formula II according to claim 1, characterized in that the radicals R to • each represent a hydrogen atom, a halogen atom or a lower alkyl group containing 1 to 4 carbon atoms " 17. Compound corresponding to formula II according to claim 1, characterized in that the radicals R ^ to R ^ each represent a hydrogen atom or a halogen atom. * l8. Compound corresponding to formula II according to claim 1, characterized in that the radicals R, R 'and R1 ^ each represent a hydrogen atom, while the radicals R, R3 and R each represent a halogen atom, as well that the acid addition salts of this compound, 19 · Compound corresponding to formula II according to claim 1 78 10 1, characterized in that R, R, R ° and R represent 2 Q each feel a hydrogen atom, R and R each represent a chlorine atom, R ~ * represents a 2-chloro group and R ^ represents a 4-chloro group. 20 “Compound corresponding to formula II according to claim 1, characterized in that R1, R ^, R ^ and R * ° represent 2 g 'each denote a hydrogen atom, R and R each represent a chlorine atom , R ^ represents a 2-chloro group and R ^ represents a 4-chloro group, 21, Compound corresponding to the formula: R4 N R1, χόχ- ^ r2 5 N ί in which the radicals R * to each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkyl-thio group , a hydroxy group or a halogen atom, as well as the acid addition salts of this compound. 22. Compound corresponding to the formula; R10 / -T * * A * 'R in which the radicals R1, R2, R ~ *, R ^, R ^, R ^, R ^ and R10 each represent a hydrogen atom, a hydroxy group, an-atom halogen, lower alkyl, lower alkoxy or lower alkyl-thio, as well as the acid addition salts of this compound. 23. Process for the preparation of a compound corresponding to the formula: γ0γ r6è> 5 in which the radicals R * to R ^ each represent a - hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkyl group -thio, a hydroxy group; or a halogen atom, as well as acid addition salts of this compound, characterized in that it consists in reacting a compound corresponding to the formula:, • / N = \ in which R “* and have the same meanings as those * defined above, with a compound corresponding to the formula; R1 R3 CH2 "XR in which X represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, while the radicals R, R, RJ and R4 have the same meanings as those defined above. 24. The method of claim 23, character- 2 Raised in that R and R ^ each represent a halogen atom. 25. The method of claim 23, characterized in that R ~ * and R ^ each represent a halogen atom. 26. The method of claim 24, characterized in that each halogen atom is a chlorine atom. · 27. The method of claim 25, characterized in that each halogen atom is a chlorine atom. 28. The method of claim 23, characterized in that the radicals R * to R ^ each represent a hydrogen atom, a lower alkyl group containing 1 to 4 carbon atoms or a halogen atom. 29, A method according to claim 23, caiac-1 2 terized in that R and R each represent a hydrogen atom. 24. s, R and R ^ each represent a halogen atom, RJ represents a group 2- halo and R ^ represents a 4-halo group, this process also being intended for the preparation of physiologically acceptable acid addition salts of a compound of this type. 30. The process as claimed in claim 23, character. * 13, wherein R and each represent a hydrogen atom 2. c R and R ^ each represent a chlorine atom, R ° represents a 2-chloro group and R ^ represents a 4-chloro group. 31. A method according to claim 23, characterized in that R is a methyl group, R and R ^ each represent a chlorine atom, R ° represents a hydrogen atom, R ^ represents a 2- group. chloro, R ^ represents a 4-chloro group, this process also being intended for the preparation of the acid addition salts of a compound of this type. 32, hydrochloride acid addition salt obtained in the process according to claim 30 · 33 · Process for the preparation of a compound corresponding to the formula: RIO r9 ^ vAynwR1 T O! Ο I / = - N in which the radicals R1, R2, R ^, R ^, R ^, R ^, R9 and R10 each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an alkyl group lower thio, a hydroxy group or a halogen atom, as well as acid addition salts of this compound, characterized in that it "consists in reacting a compound corresponding to ·· 1 I Λ Λ I— ✓ in which and R have the same meanings as those defined above, 'with a compound corresponding to the formula: R10' Yif'V RR in which X represents a halogen atom, preferably an atom of chlorine, a bromine atom or an iodine atom, while the radicals R, R, R ', R, R ”and R have the same meanings as those defined above. 34, The method of claim 33 # 8 characterized in that R is a halogen atom. 35. A method according to claim 33 # characterized in that R ^ is a halogen atom. 36. Process according to claim 33 # characterized in that R ^ and R ^ each represent a halogen atom 37 · Process according to claim 36, characterized in that each halogen atom is a chlorine atom. • 38. The method of claim 33 # characteristic 5 - rised in that R is a 2-chloro group and R is a "4-chloro group. 39. The method of claim 33 # characterized in that the radicals R ^ to R * ^ each represent a hydrogen atom, a halogen atom or a lower alkyl group I containing 1 to 4 carbon atoms. 1 - 30 - i * .¾ '· 40. Process according to claim 33 * characterized in that the radicals R * to each represent ... a hydrogen atom or a halogen atom "ij 41. Process according to claim 33 »charac-! terized in that the radicals R *, R ^ and R * ® represent I ... 25 j each a hydrogen atom, while the radicals R, RJ I and R ^ each represent a halogen atom, this process also being intended for the preparation of the acid addition salts 1 of a compound of this type, 42, A method according to claim 33 * characterized in that the radicals R *, R ^, R ^ and R * ^ each represent 2 9 each a hydrogen atom, the radicals R and R each represent a chlorine atom, R ' * represents a 2-chloro group and R represents a 4-chloro group. 43 »Process according to claim 33 * characterized in that the radicals R ^, R ^, R ^ and R ^ each represent 2 g a hydrogen atom, the radicals R and R representi each a chlorine atom, R ^ represents a 2-chloro group e1 R ^ represents a 4-chloro group. "