LU85245A1 - NOVEL AZOLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIFUNGALS AND FUNGICIDES - Google Patents

Description

? The present invention relates to new azole compounds, their preparation and their use as fungicides for combating phytopathogenic fungi and for the treatment of fungal infections in humans.

The present invention relates in particular to

azole compounds of formula I

ru q 10 I .1 (t) iu CHo -CH-N-C-Ra

ci h L

A '15 in which

Rl and R2 each represent, independently of one another, an optionally substituted aliphatic, aryl or heteroaryl group, Ri possibly also representing hydrogen, R3 and R4 represent hydrogen, a halogen, a nitro group, a optionally substituted aliphatic group which is optionally linked via S, O, SO or SO2, or an optionally substituted phenyl or phenoxy group and X represents N or CH, in the form of the free base or in the form of a salt d 'acid addition.

The invention relates more particularly to the compounds of formula I in which, R1 and R2 each represent, independently of one another, an alkyl, cycloalkyl, cycloalkylalkyl or alkenyl group, or an aralkyl, aralkenyl, heteroaryl or aryl group optionally substituted, Ri can also represent hydrogen,, 2 - R3 and R4 each represent, independently of one another, hydrogen, a halogen, a nitro group, a lower alkyl group, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or lower alkoxy optionally carrying one or more substituents chosen from halogens and the phenyl group, or an optionally substituted phenyl or phenoxy group, and X represents N or CH, in the form of free base or under form of an acid addition salt. The preferred compounds of formula I are those in which

R1 represents hydrogen or an alkyl group, R2 represents an alkyl, cycloalkyl, cycloalkylalkyl or alkenyl group, an aralkyl, aralkenyl, heteroaryl or aryl group unsubstituted or carrying one or more substituents chosen from halogens and cyano, trifluoromethyl groups , lower alkyl, lower alkynyl, lower alkoxy, optionally acylated amino, optionally acylated (lower alkyl) -amino, di (lower alkyl) amino and cyclic amino optionally carrying a second heteroatom and optionally acylated, or a phenyl, phenoxy or heteroaryl group , any cyclic amino group, phenyl, phenoxy, lower alkynyl or heteroaryl optionally present as a substituent which can in turn be substituted by another group such as R2 or R3.

R3 and R4 each represent, independently of each other. hydrogen or halogen, and X represents N or CH; in the form of a free base or in the form of an acid addition salt.

The alkyl groups and radicals present preferably contain from 1 to 10 carbon atoms, especially from 1 to 7 carbon atoms. The lower alkyl groups preferably contain s of 1 to 4 carbon atoms and the alkenyl and alkynyl groups 3; lower ones preferably contain from 2 to 4 carbon atoms. The alkyl groups forming a bridge contain, for example, from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms. The alkenyl bridge groups contain 2 to 4 carbon atoms, especially 2 carbon atoms. The cycloalkyl groups preferably contain from 3 to 6 carbon atoms. The aryl group preferably means a phenyl group. The heteroaryl group is preferably a 5 or 6-membered ring and can represent, for example, a pyridyl or thienyl group. When R2 10 signifies an unsubstituted aryl group, it may be for example. from the phenyl or naphthyl group. Unsubstituted aralkyl and aralkenyl groups preferably mean phenylalkyl and phenylalkenyl, respectively. The heteroaryl group is preferably a 5- or 6-membered ring containing one or more heteroatoms selected from S and N, and means, for example, a thienyl or pyridyl group. The aryl, aralkyl, aralkenyl and heteroaryl groups can also carry one or more substituents; examples of suitable substituents that may be mentioned are halogens such as chlorine, bromine, iodine and fluorine, and C1-C4 alkyl groups, especially methyl, friend no optionally substituted by 1 or 2 alkyl groups, especially by a methyl group, in particular dimethylamino, or phenyl. A cyclic friend group which may contain a second hetero atom, for example nitrogen, or a heterocycle may also each serve as the substituent. All these substituents (on R2) can in turn be further substituted by the aforementioned substituents.

R3 and R4 may represent, for example, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or lower alkoxy carrying one or more substituents selected from halogens and the phenyl group, or a group ^ phenyl or phenoxy optionally substituted, preferably hydrogen or halogen.

4; A particular group of compounds includes the compounds of formula I in which

Rl and R2 each represent, independently of one another, an alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkenyl, aralkenyl, heteroaryl or aryl group, the heteroaryl and aryl groups possibly being substituted, R1 can also represent the hydrogen, R3 and R4 each independently of hydrogen represent hydrogen, halogen, nitro group, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl or lower alkoxy carrying one or more halogen atoms, or an optionally substituted phenyl or phenoxy group and X represents N or CH, in the form of a free base or in the form of an acid addition salt.

The invention also includes a process for the preparation of compounds of formula I, a process in which a compound of formula II is acylated

20 Γ)

CH "- CH - NH

to 25 in which Ri, R3, R4 and X are as defined above.

The reaction is carried out according to the usual methods, for example by reacting the compound of formula II with an acid halide carrying the appropriate group R2. The operation is carried out in a solvent, for example an organic or inorganic base which can at the same time serve as an acid-binding agent, such as pyridine, and optionally with the addition of an acylation accelerator such as 4-dimethylaminopyridine. The reaction can also be carried out by reacting the compound of formula II with an activated ester of the acid carrying the group R2. The reaction can for example be carried out with a 2-pyridyl thio-ester in an inert solvent such as a di (lower alkyl) friend of a carboxylic acid such as dimethylformamide, at room temperature.

The final products can be isolated and purified according to the usual methods and can be recovered in the form of a free base or in the form of an acid addition salt.

The starting materials of formula II are partly new and can be prepared as follows: a) when R 1 is other than hydrogen, especially an alkyl group, a compound of formula III is transformed

U *

Ch2 - C = 0 (IH) ù R3 R4

into a corresponding Schiff base of formula IV

g CH, - C * NR, '2 λ 1 (IV) - »ή κ3 4 4 that Ton then reduces, or 6 - · - b) when R \ represents hydrogen, a compound of

formula V

end

O

VN

5 CH2-CH-Y (V) ù, K3 r4 with an azide, for example UN3, and the compound of formula VI thus obtained is reduced CH, - CH - N, 2 JL 3 (VI)

AT

K3 R4 X, R3 and R4 being as defined above in formulas III to VI, R11 having the same meaning as R1 except hydrogen and especially representing an alkyl group, and Y representing a halogen, in particular chlorine.

These processes are carried out according to the usual methods, for example as described in the examples. The products can be isolated and purified according to the usual methods or can be reacted directly when appropriate.

The starting materials of formulas III and V and the acylating agents are known or can be prepared according to methods analogous to the known methods and / or to those described in the following examples.

The compounds of formula I have interesting chemotherapeutic properties, in particular antimycotic properties, and can therefore be used therapeutically for 7, fighting infections and diseases caused by fungi.

This antimycotic activity has been demonstrated in in vitro tests, for example in serial dilution tests on the mycelial form of Candida albicans according to the method described by 5 J. van Cutsem et al., In Mykosen, 24, 596 -602 (1981), at concentrations between about 0.05 and 12.0 jjg / ml, and in in vivo tests, for example by systemic action, after oral administration of doses between about 1 and 25 mg / kg to rats in which intravaginal infection has been caused with Candida albicans.

Thanks to these properties, the compounds of the invention can be used as medicaments, in particular as anti-fungals.

For their therapeutic use as antifungal agents, the compounds of the invention will be administered at a daily dose of between 70 and 2000 mg, advantageously in divided doses 2 to 4 times per day in the form of unit doses each containing approximately 17 , 5 to 1000 mg of active substance, or in a delayed release form.

The compounds can be used in the form of the free base or in the form of chemically acceptable acid addition salts, for example in the form of the hydrochloride, hydrogen fumarate or naphthalene-1,5-sulfonate. These salts have the same order of activity as the free bases.

The invention therefore therefore also relates to the compounds of formula I in the form of a free base or in the form of a chemotherapeutically acceptable acid addition salt, for use as medicaments, in particular as antifungal agents. The invention also comprises a medicament containing, as active substance, a compound of formula I in the form of a free base or in the form of a chemotherapeutically acceptable acid addition salt.

As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing the active substance in association with diluents or chemotherapeutically acceptable vehicles and, optionally, with other excipients. The compounds of the invention can be administered orally, topically, intravenously or parenterally in the form of tablets, capsules, creams, tinctures or injections. Such compositions are also part of the invention.

The compounds of the invention in the form of a free base or in the form of a salt or a metal complex acceptable in agriculture are also suitable for combating phytopathogenic fungi. This fungicidal activity has been demonstrated, inter alia, in in vivo tests against Uromyces appendiculatus (bean rust) on row beans, against other rust fungi (such as Hemileia, Puccinia) on coffee, 15 wheat, flax and ornamental plants (for example geranium, snapdragon), and against Erysiphe cichoracearum on cucumber and other powdery mildew (for example E. graminis f. sp. tritici, E. gram. . sp. hordei, Podosphaera leucotricha, Uncinula recator) on wheat, barley, apples and vines.

The preferred meanings of the substituents Ri, R2, R3, R4 and X are as follows: R] _ = a) T hydrogen or b) a lower alkyl group, especially a methyl group R2 = a) a straight chain alkyl group or branched, especially having from 1 to 7 carbon atoms b) an aralkyl group, especially an optionally substituted phenylalkyl group c) an aralkenyl group, especially a phenylalkenyl group d) a heteroaryl group preferably with 5 or 6 members 30 containing 1 or several heteroatoms chosen from S and / or

NOT

e) an unsubstituted aryl group, especially a phenyl or naphthyl group 9 f) an aryl group (especially a phenyl group) carrying 1 or more substituents chosen from halogens and lower alkyl, ami no and dialkylamino groups g) an aryl group substituted by a phenyl group which may itself carry 1 or more substituents chosen from halogens, and the lower alkyl, ami no and dial kylamino groups h) an aryl group substituted by a cyclic amino group which may contain a second heteroatom, for example nitrogen, which may itself be substituted by a carbamoyl group (including mono- or dialkylcarbamoyl ,, aroyl, alkanoyl, aralkyl or alkyl i) an aryl group substituted by a heteroaryl group j) an aryl group substituted by an alkynyl group which may itself be substituted by an aryl group R3 and R4 each represent, independently of one another, a) hydrogen or b) halogen

X = a) N

B) CH.

Particularly preferred are combinations of particular meanings of the above-mentioned substituents.

A particularly preferred group of compounds is that comprising the compounds of formula I in which R 1 represents hydrogen, R 2 represents a C1-C79 alkyl group, an unsubstituted phenyl or naphthyl group, a 5 or 6-membered unsubstituted heteroaryl group containing 1 or more heteroatoms selected from S and N, a C1-C4 (phenyl) -alkyl group unsubstituted or substituted by halogen, a styryl group unsubstituted or substituted by halogen, a phenyl group bearing one or more substituents selected from halogens and lower alkyl and dialkylamino groups, a phenyl group substituted by a phenyl group itself optionally substituted by halogen, by a lower alkyl group or by a dialkylamino group, a phenyl group substituted by a cyclic amino group which may contain nitrogen as the second heteroatom and which may itself be substituted by a phenylalkyl, phenacyl, phenyl, carbamoyl group (including ris 5 mono- or dialkylcarbamoyl) or alkyl, a phenyl group substituted by a heteroaryl group or a phenylalkynyl group substituted by a phenyl group.

R3 and R4 represent hydrogen or halogen and X represents N or CH, in the form of the free base or in the form of an acid addition salt.

Particularly preferred compounds in this group are those in which R2 represents a substituted phenyl group. The following examples illustrate the invention without in any way limiting its scope. The temperatures are indicated in 15 degrees Celsius.

---- 7- / / / y y 11

Example 1 N-piva1oyl-1- (2,4-dichlorophenyl) -2- (1H-imidazole-1-yl) -ethylamine 1 g of 1- (2,4-dichlorophenyl) -2- (1H-imidazole) is dissolved -l-yl) ethylamine in pyridine, 470 mg of pivaloyl chloride and, optionally, an equivalent of 4-dimethylamino-pyridine are added and the mixture is stirred at room temperature until the reaction is complete (about 1 hour). The solvent is removed in vacuo in a rotary evaporator, the residue is partitioned between water and methylene chloride, the organic phase is washed, dried and evaporated in a rotary evaporator, which gives the composed of the raw title. The product is purified by crystallization from a mixture of isobutyl methyl ketone and di-isopropyl ether to give the title compound as colorless crystals melting at 84-88 °.

Example 2 N-C4- (4-chiorophenyl) benzoy13-1- (2,4-dichlorophenyl) -2- (1H-imidazole-1-yl) ethylamine

1.6 g of 2- (pyridyl) thio-ester of 4- (4-chlorophenyl) benzoic acid and 1.26 g of 20 l- (2,4-dichlorophenyl) -2- (1H-) are stirred at room temperature. imidazole-1-yl) ethylamine in 50 ml of dimethylformamide, until the reaction is complete (about 1 hour). The solvent is removed in vacuo and the residue is partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase is washed, dried and concentrated in vacuo. After crystallization of the residue in ethanol, the title compound is obtained in the form of colorless crystals melting at 246-250 °.

By proceeding in a manner analogous to that described in Examples 1 and 2, the following compounds can be obtained:

Ex- R, R- R, R. XP ° int de __1__2_ 3 4 fusion 3 H -C (CH3) 3 2-Cl 4-C1 N 139-140 ° 4 CH3 2-Cl 4-C1 N 144-145 ° 5 H -C6H5 2-Cl 4-C1 N 218-220 ° 6 H / - \ r1 2-Cl 4-C1 CH 188-191 ° “W // 7 CH," CH, '2-C1' 4-Cl CH oil!>> 8 H ~ CH = CH- /. \ 2-Cl 4-C1 CH 170-173 °. \ W / 9 H - /. \\ - CH, HH CH 195-196 ° \\ // 3 * · · · 10 H / - \ _ HH CH 195 ° - \ w / -F | 11 H ___ H ί H CH 205-206 °

_H II

12 H _ptr '/ = \ H! H CH 166-167 °

2 - \\ _ // I

13 H - (C ^) 2 _. ^ “\ HH CH 151-152 ° • 1 '· 14 H -CH (CH3) 2 HH CH 191-194 ° ji 15 H h H CH 152-154 ° ji ï 3 - x \ // - O- j 17 H _ /; - \\ _ ch 2-Cl 4-C1 CH 214 "

\ - / 3 I

• - * i 6 PM ___ 2-Cl 4-Cl CH 180 ° |

Ji I! i

i W I

13

Point de ^ x * ______ ^ _ * fusion 19 H if ^ 1 2-C1 4-Cl CH 219 °!

-ch = œ_L ^ Î I

8 PM 2-C1 4-Cl CH 144 ° 21 | H n-C7H15 2-Cl 4-Cl CH 105 ° {22 h _ / ΓΛ ._ // ~ \\ 2-Cl 4-Cl CH 151 ° \ - / \ - / "—MM * · · 23 'h - // \\ - F 2-Cl 4-C1 CH; 173 ° v— / - ·; :!

! _ or I I

7.! M _ // <\ _ / 3 2-C1 '4-C1 CH 228-233 ° 24. H \ _ / N j j --- 3; ! ! 25 H 1 _ // - \\ _ a 2-cl! 4-cl N 257-240 “! ''. = /! ! i 26 H <, ™),. / Γ \\ - 01 2-C1 ï 4-C ‘! CH 162-165 "! 27 H! Υ ^ j 2-C1 I; CH 162-167“! I | j! J 28 HL / AX-J i 2-Cl 1 4-Cl CH 1 228-235 ° I \ = /!! dd 29 H! _ // ~ "\\ _ Br | 2-C1 i 4-C1 i N i 241-244 ° \ - / | J i 30 H JF \\ J / ~ \! 2'C1 4-C1 N i 265-268 ° \ _ / N _ / i • · · MB ·

i. T

2-Cl 4-Cl; CH i 199-206 ° if j π j:; - * î j _ l „: H i - // \\ - Cl’ 2-Cl: 4-Cl N! 205-209 ° -! --this : ! i:; i 14 "ËxTTrT r ~ ΠΓ TrT Γχ Point de __1 | 2__3__4___fusion ._ // __ // W _ ci 33 H / \ - / 2-C1 4-Cl N 250-252 ° // \\ XJ \ j_pu _ / / \\ 34 H \ / 2 \, / '2-Cl 4-Ci CH 90-95 ° • · · - · · · - * _ CH3 35 H - // \\ - N * * N .N 2- C1 4-C1 CH 110-112 ° \ - / \ / vx \ · “· --- Ü 'CH,' 1, x 0 3 36 H jVj 2-Cl 4-C1 CH 146-160 ° 37 H // ~ \ /; ”\ N _ci HH CH 207-214 ° * · - Il · · i ... · 38 HH 4-C1 CH 216-219 ° 39 H - // Λ-Cl H 4-C1 N 181- 186 ° \ - / • · i!,!:!! J 40 H | —2-C1; 4-C1 CH 120-126 ° |? '] ~ X Cl lj, --- i // \\ "f V 11 1 i 41 H v_ / \ 2-C1 4-C1 CH 115-125 °!! · - · · - · hj. O;! 42: H - // \\ - Cl 2-C1 6-CI CH 85-87 °! I • · · - · I 43 H - //_\\-.v \\ 2-Cl 6-Cl CH 90-93 ° j II! | I {; ii> 15

Point of

Ex. Rj R2 Rj R4 X fusion 44 H _ // - \\ _ / 7 “\\ - Cl 2-Cl .6-Cl CH 195-196 ° S— / \ - / -, · 11— · · MM . »5 45 H _ // _ \\ - / fo - // V. 2-Cl 4-C1 CH 223-226 ° \ - / \ __ 'N— / 1.

m ___ »10 46 H _ · '/ V-C = C - /' V.2-C1 4-C1 CH 240-245 ° w W | ___LJ___: i___

V

15 NMR Sprectres

Ex ^ Specter 1 6.8-7.5 (m, 6H); 6.4 (d, broad; NH) · 5.56 (qua, J = 6.5 Hz, 1H); 4.4 (d, J = 6.5 Hz, 2H); 1.18 (s, 9H).

7.1-7.8 (m, 5H); 7.0 (s, 1H); 6.84 (s, 1H); 5.75 (qua, J = 6.5 Hz, 1H); 4.48 (d, J = 6.5 Hz, 2H).

7 6.9-7.7 (m, 6H); 5.5 (dd, J = 9 and 6 Hz, 1H); 4.9 (dd, J = 9 and 14 Hz, 1H); 4.4 (dd, J = 14 and 6 Hz, 1H); 2.75 (s, 3H); 2.02 (s, 3H).

25

The starting materials can be obtained as follows: „A) 1- (2,4-dichlorophenyl) -2- (1H -imidazole-1-yl) ethylamine (for examples 1,2,6,8,17 I 24 , 26 to 28, 31, 34 to 36, 40, 41 and 45). Stirred for 2 hours at 90 ° 17.6 g of 1- (2,4-dichloro-phenyl) -2- (1H-imidazole-1-yl) chloroethane and 3.8 g of lithium azide in dimethylformamide. Then water is added, the solvent is removed as much as possible under vacuum and the residue is partitioned between water and methylene chloride. The organic phase is washed, dried and concentrated under vacuum. .

The crude 1- (2,4-dichlorophenyl) -2- (1H-imidazole-1-yl) azido-ethane thus obtained (Rf value in thin layer chromatography identical to the starting product, but with a strong IR band at 2100 cm is hydrogenated under normal pressure in a hydrogenation apparatus with 1 g of Pd / C (10¾) and glacial acetic acid as solvent. The solvent is removed as much as possible under vacuum and the residue is diluted in water The acidic aqueous phase is shaken with methylene chloride, it is alkalized or dissolved with a solution of caustic soda and it is again extracted with methylene chloride. This organic phase is washed, dried and evaporated. transform the title compound „into dihydrochloride, which gives a crystallized product; mp = 227-240 ° after crystallization from an ethanol / ether mixture.

NMR spectra: 7.2-7.55 (m, 4H); 7.08 (t, J = 1Hz, 1H); 6.94 (t, J = THz, 1H); 4.72 (dd, J = 8 + 4Hz, 1H); 4.08 (AB - part of an ABX system, = 14Hz, = 4Hz, JßX = 8 Hz, 2H); l, 2-i; 9 (broad, NH ,,).

B) 1- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole-1-yl) ethylamine (for examples 3, 5, 25, 29, 30, 32 and 33)

The title product is obtained in a similar manner to that described under A); F = 107-110 °.

C) N-methyl-1- (2,4-dichlorophenyl) -2- (1H-imidazole-1-yl) ethylamine (for Examples 7 and 16).

a) 2,4-di chl oro ^ g- [l H-imi dazol e ^ l ^ yl j ^ méthy 1 açëtoghënonimi ne In an autoclave is heated for 16 hours at 90 ° 18 g of a- (lH-imidazole- l-yl) -2,4-dichloroacetophenone and 30 ml of a 30¾ solution of methylamine in alcohol. The reaction mixture is evaporated, which gives the Schiff base in the raw state which is used directly for the following reaction.

b) N-methyl-1- (2,4-dichlorophenyl] -2- [1H-i> midazo ^ e- ^ yl] ethyl-amine_ 17

18.9 g of 2,4-dichloro-a- (1H-imidazole-1-yl) -N-methylacetophenonimine are dissolved in methariol, a drop of an alcoholic solution of methyl orange and an alcoholic solution are added. hydrochloric acid up to 5 color changes. After adding 4.44 g of NaCNBHg, the mixture is stirred for one hour at room temperature and at pH 3-4 (after 2 other additions of alcoholic hydrochloric acid). The mixture is then evaporated in a rotary evaporator and the residue is distributed between methylene chloride and an aqueous solution of sodium bicarbonate.

The organic phase is dried and evaporated. The evaporation residue is chromatographed on silica gel (methylene chloride / ethanol 9/1), which gives the title compound in the form of an oil.

NMR spectrum: 7.44 (m, 2H); 7.33 (m, 2H); 7.08 (m, 1H); 6.9 (m, 1H); 3.8-4.5 (ABM system, = 14 Hz, = 4Hz, JßM = 8 Hz, 3H); 2.25 (s, 3H); 1.6-2.1 (broad, NH).

D) N-methyl-1- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole-1-yl) ethyl-amine (for example 4) The procedure is analogous to that described under C); F = 71-72 °.

NMR spectrum: 7.96 (s, 2H); 7.2-7.5 (m, 3H); 4.1-4.6 (m, 3H); 2.26 (3.3H); 2.0 (broad, NH).

E) 4- (4-Chlorophenyl) benzoic acid 2-pyridÿlio thioester (for Example 2)

A mixture of 5 g of 4- (4-chlorophenyl) benzoic acid, 10.4 g of triphenylphosphine and 8.8 g of 2,2'-dithiopyridine in 80 ml of is stirred for 2 hours at room temperature. methylene chloride. The solvent is then removed in vacuo, the residue is dissolved in a little ethanol and ether is added until cloudy. Shortly after, the product crystallizes. After spinning and drying, the title compound is obtained in the form of colorless crystals, melting at 153-160 °.

A, 18 F) 1- (4-carboxyphêny1) -4-diméthy1carbamoy1pi pêrazi ne (for example 35) a) I ”£ 4-ëthoxycarbonylghën ^ l} -4-dimëth ^ lcarbamo ^ lgigrazine To a solution of 4, 4 g of 1- (4-ethoxycarbonylphenyl) piperazine in chloroform heated to 50 °, 2.04 g of dimethylcarbamoyl chloride are added dropwise and the resulting mixture is heated for 2 hours under reflux. The solvent is removed in vacuo, 60 ml of a 30¾ aqueous solution of NaOH are added to the residue and the mixture is stirred for half an hour at room temperature with 200 ml of toluene. The organic phase is separated, washed, dried and evaporated. The residue is purified by filtration over silica gel (methylene chloride / v ethanol 9/1) to give the title compound as colorless crystals melting at 79-83 °.

2.4 g of 1- (4-ethoxycarbonylphenyl) -4-dimethylcarbamoy! Pi perrazi ne in a mixture of 70 ml of ethanol, 8 ml of water and 0.8 g are heated to reflux for 3 hours. of NaOH. The reaction mixture is then acidified, shaken with methylene chloride, the organic phase is dried and evaporated. The title compound thus obtained in the raw state is used directly for the following reaction.

G) 4-benzyl-1- (4-carboxyphenyl) piperrazine (for Example 34) a) 4-benzyl ^ 1; [4-ethoxycarbon ^ lghényl} pêrazine

For one hour, 5 g of 1- (4-ethoxycarbonyl phenyl) piperazine, 5.9 g of K2CO3 and 3.6 g of benzyl bromide in dimethylformamide are heated to 100 °. The solvent is removed in vacuo and the residue is partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase is washed, dried and evaporated in a rotary evaporator. The title compound thus obtained in the raw state is used directly 19 i * for the following reaction. Rf = 0.9 (eluent: CF ^ CI ^ A ^ HbOH = 9/1).

b) ^: ^ 0 ^ 1il: (l: £ Ê ^ 2 ^ 0! 3§0yl) PiPÊüÈ? i0Ê

The procedure is analogous to that described under Fb); F = 221-229 °.

H) 4-benzoyl-1- (4-carboxyphenyl) piperazine (for example 41)

The procedure is analogous to that described under G).

a) 4-benzoyl: 1: [§-ethoxycarbonylphenyl] pipërazin ^ 10 F = 127-132 °.

* b) 4-benzoyl: 1: [4-carboxyghényl2pigérazin ^

The product is used directly for the following reaction.

I) 1- (2,6-dichlorophenyl) -2- (1H-imidazole-1-yl) ethylamine (for Examples 42 to 44).

a) 2,6-dichloro-a-bromoacêtoph ^

50 g of 2,6-dichloroacetophenone are dissolved in 50 ml of anhydrous diethyl ether and then 0.5 g of finely pulverized aluminum chloride is added. With good stirring and under good cooling with ice, 41.6 g of bromine are then added dropwise over 15 minutes. When the addition is complete, the solvent is removed in vacuo, which gives a semi-solid yellow mass which is used directly for the following reaction.

NMR spectrum (CDCl3) = 4.44 (2H, s, CH2Br); 7.3-7.5 (3H, m, substituted phenyl).

b) a: [1H-imidazole-1-yl] -2,6-dichloroacetophenone To 30 g of crude 2,6-dichloro-a-bromoacetophenone in 50 ml of anhydrous dimethylformamide, 22.9 g of imi- 30 dazole and allowed to react for 24 hours at room temperature. For further processing, the reaction mixture is poured into about twice the amount of a saturated sodium chloride solution and extracted with ethyl acetate. The extract is dried over sodium sulfate, the solvent is removed in a rotary evaporator and the residue is chromatographed on silica gel 60 with a 7/1/4 mixture of dichloromethane, methanol and petroleum ether boiling at 60 - 80 °. A colorless viscous oil is thus obtained which is homogeneous according to thin layer chromatography.

NMR spectrum: 5.15 (2H, s, CH ^); 7.02 (1H, t); 7.14 (1H, t) + 7.58 (1H, t); imidazole nucleus; 7.40 (3H, s, substituted phenyl).

10 c) ^ {IH-lmidazole ^ l ^ ll ^ l ^ iZje ^ diçhloroghënylléthangl

20 g of a- (1H-imidazole-1-yl) -2,6-dichloro-acetophenone are dissolved in 100 ml of ethanol, 2.95 g of NaBH 4 are added at ambient temperature and with good stirring. continues to stir for a further 4 hours at room temperature. For the subsequent treatment, the excess hydride is decomposed with a few drops of dilute hydrochloric acid, diluted with water and most of the ethanol is removed in vacuo. The residue is shaken with dichloromethane and a saturated sodium bicarbonate solution, dried over NagSO 4 and evaporated. After chromatography on silica gel 60 (7/1/4 mixture of di chloromethane, methanol and petroleum ether boiling at 60-80 °), colorless crystals are obtained, melting at 137-141 °.

♦ d) 2- £ 1H-imidazoIe-1-y22zlzi.? "6-dichloropjienylJi-1-methanesulfonyloxyethane To a solution of 12.8 g of 2- (1H-imidazole-1-yl) -l- ( 2,6-dichlorophenyl) ethanol in 50 ml of anhydrous dichloromethane, 5.03 g of triethylamine and 5.7 g of methanesulfonyl chloride are successively added, under cooling with ice. After stirring for 5 hours, the mixture is shaken with dichloromethane and a saturated solution of sodium bicarbonate. The organic phase is dried over sodium sulfate, evaporated in vacuo and 21

Chromatograph the residue on silica gel 60 with the same eluent as that used under the. A viscous, colorless oil is thus obtained.

NMR spectrum: 2.70 (3H, s, CH3SO2); 4.42 + 4.50 5 (2H, dq, part AB- of an ABX system, 0Aß = 14 Hz, CH2); 5.76 (1H, dd, part X, = 14 Hz, -CH0-); 6.97 (1H, t, J = 1Hz); 7.10 (1H, t, J = 1Hz) + 7.51 (1H, t, J = 1Hz); imidazole nucleus; 7.20 - 7.45 (3H, m, substituted phenyl).

10 e) 2- {1H-imidazole = 1 = yl] -1 -_ (Z, 6-dichloroghenyl} -1-azidoethane *

With good stirring, a mixture of 12.9 g of 2- (1H-imidazole-1-yl) -1- (2,6-dichlorophenyl) -l-methanesulfonyloxyethane, of 3, is heated for 4 hours at 100 °. 77 g of sodium azide and 2.45 g of lithium chloride in 25 ml of anhydrous dimethylformamide. The mixture is then diluted with water, extracted with ether, the ethereal phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a Rotary evaporator. The colorless crystals thus obtained (F = 45-49 °) are used directly for the next reaction without further purification, f) 2- (1H-imidazole; 1; yl} -l- (2,6-dichlorophenyl} ethyl)

7 g of 2- (IH-imidazole-1-yl) -1- (2,6-di-chlorophenyl) -1-azidoethane are dissolved in 70 ml of pyridine and as much water is added so that the solution still remains clear. Then, at a temperature of 35-40 °, hydrogen sulfide is passed through for 30 minutes. After an additional two hours, the excess hydrogen sulfide is removed by bubbling nitrogen through, the pyridine is removed in vacuo and the residue is taken up in 2N hydrochloric acid. The mixture is shaken with dichloromethane and a 20% aqueous solution of NaOH, the organic phase is washed with a saturated solution of sodium chloride, it is dried over sodium sulphate and 22 is evaporated. The viscous, colorless residue thus obtained is used directly for the following reaction.

NMR spectrum: 1.96 (2H, b, -NH ^); 4.42 (2H, d, J = 7 Hz, -CH2); 5.06 (1H, t, J = 7Hz, -CH); 6.97 (1H, b), 7.04 (1H, b) + 7.50 (1H, b): imidazole ring; 7.10 - 7.40 (6H, m).

J) 1- (4-chlorophenyl) -2- (1H-imidazole-1-yl) -ethylamine (for Example 38)

The procedure is analogous to that described under I); the dihydrochloride melts at 262-270 °.

* K) 1- (4-chlorophenyl) -2- (1H-1,2,4, -triazole-1-yl) ethylamine * (for Example 39)

The procedure is analogous to that described under I; the dihydrochloride melts at 214-220 °.

* ►