LU82755A1 - NOVEL 1-PHENETHYLIMIDAZOLE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND INTERMEDIATE COMPOUND FOR THEIR PREPARATION - Google Patents

Description

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The present invention relates to certain novel 1-phenethylimidazole derivatives and their antimicrobial acid addition salts, antimicrobial compositions containing them and methods of using these derivatives, their salts and compositions containing them to inhibit the development of fungi and bacteria.

Very many antifungal and antimicrobial agents are known which contain a 1- (8-aryl) -ethyl-1H-imidazole group of formula: 10 ΛΤ

, r- '·· ‘N

O

1 CEL-CH-R

£ 2 to 15 | o 20 For example, U.S. Patent No. 3,717,655 and E. F. Godefroi et al., J. Med. Chem., 12. * 784 (1969) describe compounds of formula 1 in which R is a group of formula: -XtCH2> -! - where X represents an oxygen atom or an NH group.

30 U.S. Patent No. 3,991,201 and J. Heeres et al., J. Med. Chem. 20 ^, 1511 (1977) - describe compounds of this class in which R is a group - (CH2) n ~ Ar.

J. Heeres and colleagues describe in 35 J. Med. Chem. 2 (), 1516 (1977) of compounds of this class in which R is a group - (CH0) O-Ar.

U.S. Patents 4,055,652 and 4,039,677 describe compounds of this 2

s »V

class in which R & is a group -SR2 where R2 is a hydrogen atom, a benzyl group, a phenyl group, etc.

U.S. Patents 4,039,677 and 4,038,409 describe compounds in which Ra is a group -XC-R ^ where X and Y represent

Y

oxygen or sulfur and R ^ is a hydrogen atom or an alkyl, cycloalkyl, phenalkyl, phenalkenyl group or a group of formula -XR4 in which R ^ is an alkyl, halophenyl radical, etc.

U.S. Patent No. 4,006,243 describes compounds in which R = is a hydrogen atom

Cl or an alkyl or phenyl group.

We just discovered a class entirely

V

15 news of compounds of formula 2 which are endowed with a very good antifungal and antibacterial activity, namely compounds in which R, is a group possibly substituted on the nucleus, of formula: 20 / .....

A -x- <CH2) n-Y-! CH2) _ <^ J>;

wherein X and Y independently represent sulfur or oxygen, m is 0 or 1 and n is 1, 2 or 3, provided that when n is 1, X and Y cannot be oxygen and the phenyl nucleus linked to CH

is also substituted, where appropriate, this class containing the antimicrobial acid addition salts of these compounds.

The products of the present invention are considered to be 1- (ethyl) -iH-imidazole derivatives in which the substituents R1 and R2 are in position 2 of the ethyl side chain, as shown in formula 2 below: 3

!--NOT

i o

i12 5 CH-CH-R, 2I 1 r2 As an alternative, the products can be considered as derivatives of 1- (phenethyl) -iH-imidazole 10 in which the substituent is attached in β relative to the imidazole nucleus , as it appears in the following formula 3:

: „O

I ß 3 ΟΗ2ΟΗ-Κι \ 2 ° ^

As indicated above, one of the main features of the present invention resides in new compounds of formula _1 above in which Ra - corresponds to formula A given above and the phenyl nucleus linked to the CH group. is optionally substituted, these compounds - are also present in the form of their addition salts of antimicrobial acids, that is to say antifungal and antibacterial, in particular compounds of formula: â „4 ο R1 R2 4 CH CH-XCCH,) -ï- (CH.,) -Γ ÎJ) 5 - 2 2 n 2 m \ __ / \ ^ R3

s r4 A

Including their antimicrobial acid addition salts, the formula wherein: X and Y are, independently, sulfur or oxygen; m is zero or 1; n is 1, 2 or 3, with *** 15 provided that when n is 1, X and Y cannot both represent oxygen; R and R independently represent hydrogen, halogen or an alkyl group, or together form the atoms necessary to complete a naphthalene ring; R is CF3, SCF3, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, pyrrolidinyl, piperidinyl, piperazinyl, alkanoylpiperazinyl, morpholinyl, alkylamino, dialkylamino, alkanoylamino, amino, nitro, carboxy, carbalkoxy chosen from phenyl, benzyl, benzoyl, phenylthio, phenylsulfonyl, phenylamino and benzoylamino radicals, this aryl radical possibly being. substituted on the nucleus by one or more halogens or 4 5 6 CF 3, alkyl or alkoxy radicals; and R, R and R - independently represent hydrogen, halogen or a group CF3, alkyl, alkoxy or phenyl optionally substituted on the nucleus by one or more halogens or radicals CF ^, alkyl or alkoxy; the above-mentioned alkyl, alkoxy and alkanoyl radicals containing 1 to 6 carbon atoms, the above-mentioned alkenyl and alkynyl radicals containing 2 to 12 carbon atoms and the above-mentioned cycloalkyl radicals containing 5 to 8 carbon atoms carbon.

5 -> *

The compounds of the invention of formula A given above display an antifungal and antibacterial activity against pathogens for animals and humans as well as an antifungal activity against fungi which is of great importance for 'Agriculture. Thus, the compounds of the invention can be used as antimicrobial agents, and they have applications not only pharmaceutical, but also agricultural and industrial. Thus, another feature of the present invention relates to methods of inhibiting the development of fungi and bacteria by application to a host carrying or likely to carry fungi or bacteria, a fungicidal or bactericide of a compound of the present invention. Another characteristic of the invention resides in compositions for pharmaceutical, agricultural and industrial use, which contain compounds of formula 4 ^ of the invention in association with a suitable support or vehicle.

Another feature of the invention resides in compounds useful as intermediate compounds for the production of the compounds of formula 4 above, these intermediate compounds corresponding to the formula:

d-N

O.

CËLCH-X (CEL) -Z

2 2 n

B

R * 30 in which Z is a radical YM, halo, COO-alkyl, methanesulfonate or: -OSOj - ^ - ch3 ♦ 6 M represents a hydrogen or alkali metal atom and X, * Y, R, R , R and n have the definitions given above.

For the purposes of the present specification, "alkyl", "alkoxy" and "alkanoyl" groups each contain a saturated, branched or unbranched acyclic hydro-carbonic group having 1 to about 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl and their isomeric forms. "Alkenyl" groups include a branched or unbranched acyclic hydrocarbon group having an unsaturation formed from a carbon-to-carbon double bond and having from about 2 to about 12 carbon atoms, for example allyl, ethenyl, 2-hexenyl, 3-octenyl, 2-octenyl, 2-decenyl, 1-dodecenyl, etc. "Alkynyl" groups are similar to "alkenyl" groups, but have carbon-to-carbon triple bonds instead of double bonds. "Cycloalkyl" groups include a saturated monocyclic hydrocarbon group having from about 5 to about 8 carbon atoms, for example cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "halogen" or "halo" refers to an iodo, fluoro, bromo and especially chloro radical. The term "antimicrobial acid addition salts" refers to crystalline salts of the compounds of the invention which possess the desired antimicrobial activity and which are not biologically or otherwise undesirable. These salts are formed by bringing the compounds of the invention into contact with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids and organic acids such as fumaric, oxalic, maleic, acetic, pyruvic, citric, tartaric, methanesulfonic, ethanesulfonic, p-toluenesulfonic, hydroxyethanesulfonic, sulfamic, malic, succinic, ascorbic, levulinic, propionic, glycolic, benzoic, mandelic, salicylic, lactic, p-aminosalicylic, 2-phenoxy-35 benzoic , 2-acetoxybenzoic acid, 1,4-naphthalene-disulfonic acid, etc.

The compounds of formula 4 of the invention are organic bases, most of which are viscous oils 7 in the free form. The free bases are usually purified by chromatography on a column of silicic acid or alumina and can be converted into their solid acid addition salts by contacting one of the above acids forming a salt. , usually in a solvent such as water, ethanol, 1-propanol, ethyl acetate, acetonitrile or diethyl ether. By cooling or diluting with a less polar solvent, crystals of the acid addition salts are usually obtained.

The compounds of formula 4 have a chiral or asymmetric center, that is to say the carbon atom of the CH link which has been represented, and they can therefore exist in the form of enantiomers which can, if appropriate , be separated by known operations, for example by

'J

15 conventional means of resolution, using optically active acids such as the optically active forms of camphor-10-sulfonic, a-bromocamphor-sulfonic, camphoric, menthoxyacetic, tartaric, malic, diacetyl-tartaric, pyrrolidone-5- carboxylic, etc. It should be noted that the invention covers these optical isomers and their racemic mixtures.

The compounds of formula 4 ^ are prepared according to variants of the synthesis of ethers of Williamson (see Houben-Weyl, Methoden der Organischen Chemie, VI (part 3) 1975).

As shown in diagram I, we react. a tosylate 5 with phenylates (6, m = 0, Y = 0), thio-phenylates (6, m = 0, Y = S) or the sodium or lithium * salts of benzyl alcohols ((>, m = 1, Y = 0) or benzylmercaptans 30 (6 ,; m = 1, Y = S) to obtain the ethers 7 (Y = 0 or S, m = 0 or 1).

Similarly, the tosylate (3 was reacted with thiophenylates (9J to obtain the dithioethers Kl · "8

- CO

»* U CN _ / 5s.

\ y ’\

MM * S

3 "I

i μ ό H ~ ._! _ it! • <r · ": v CS’ ^ 3 * Γ 1

= CÎ M

S / ^ X I cl s— (v v) ·> IF "

xx_lf \ J * ". X

'X / § / = /: - "fojKjj ro j! S XX! ΧΓ J - λ. | X: · fX>! (I s Ci — I— 2 o il;

'S X

âl ·,; Λ @L ,, ’· * cr% i λ * - <U.

^ / η en s es υ 0. ; . xK, x%

H L U

1 'cvJ i c o en ιλ! w col 8 Sn "S n g * ^ -N. <* :, · l-CT i-ζΥ:

W .. V

<-r 9

Diagram I can be simplified as follows: 5 Q _ ^ f'2'3 L ™ -X-Cil2CU20S02- <Ç ^ CH3 + 6-> CR2OT-XC ^ -ï- (c ^> n - ^^ | ii | 12 10 ^ i \ R4,5,6 ^ \ R3,5,6

The ethers of formula 12. are formed by intimate contacting a solution of tosylate _1_1_ in an inert solvent such as tetrahydrofuran or a mixture of tetrahydrofuran and Ν, Ν-dimethylformamide, with an alkali metal salt (5 (sodium or lithium salt) of the desired alcohol or mercaptan, usually in the same solvent, or in a solvent supplemented with a cosolvent at temperatures of about 25 to 100 ° C and for periods ranging from about 1 hour to several days. Naturally, the optimum temperatures and durations vary according to the nucleophilic nature of the alcohol or mercaptan salt 6.

The preparation of the alkali metal salt 6 is carried out by contacting the alcohol or mercaptan with a base such as sodium hydride or the like. or n-butyl lithium in the presence of organic solvents such as tetrahydrofuran and Ν, Ν-dimethylformamide at * temperatures of -78 ° C, when using n-butyl lithium, 30 and about 0 at 100 ° C when using sodium hydride, and for periods of about 15 minutes to several hours.

Other solvents suitable for the formation of the alkali metal salts 6 as well as for carrying out the JH-12 reaction include benzene, diglyme, hexamethylphosphoramide, dimethoxyethane and toluene. Other leaving groups as variants relating to the p-toluenesulfonate anion (13, "10 Z = - ° S0f (^ / ÿ-cn3); 5 include conventional leaving groups Z such as chloro, bromo, iodo, methanesulfonate, etc.

O

10 I

CH2CH-X-CIl2CH2Z

'·> 4 5 fi 15 V- / b'b The alcohol 14_, from which the tosylate f> is obtained, has been alkylated with benzyl halides 21 as illustrated in scheme II, into ethers which therefore confirms the fact that the roles of alcohol and the alkylating compound can be interchanged in Williamson's synthesis.

The alcohol 22 from which tosylate 8_ can be alkylated with benzyl halides 21 to form the ethers 18.

Schei3 & IX

O 0 ‘Γ k2ç., Oc! I2cii2oy. 2. / = \ zc ^ raoon ^ occHj) J '\\ i 2'mi \ = / ri] * 0 ni - ^ V <5 · 6 1 = 2 ^ Bt ^^ 4,5,6 IA m = ^ - -35 - 11

Diagram II (continued) h Γ (t?} '213

Xf x- NaH ^ V! —V 5 h ^ CHSCI ^ CI ^ OH 2. 15. Cî ^ CIlSCl ^ CI ^ OCI ^ - ^ y

He | A5.6 4.5.6 R R ’10 II li

The JJ5 alkylating agents are added without diluent or in solution in a previously formed alkali metal salt (preferably a sodium salt, but it may be a lithium or potassium salt) of the alcohol in a suitable solvent, about 0 ° C. The resulting mixture is then heated to 25-100 ° to accelerate the reaction rate for periods ranging from 30 minutes to 24 hours. In the presence of the reactive benzyl halides, the reaction is completed in about 1 to 2 hours at a temperature of about 60 °. Suitable solvents or mixtures of solvents include tetrahydrofuran, Ν, Ν-dimethylformamide, hexamethylphosphoramide, benzene, toluene, diglyme, dimethoxyethane, etc. The alkali metal salts of compound _14 are formed by contacting said compound with a strong base such as sodium hydride, etc., in the solvents mentioned above at 0-100 ° for periods ranging from 15 minutes to several * hours.

The synthesis of the products 22 of the invention can be carried out according to the following scheme III.

Vr

DIAGRAM III

12 * 5 (Tù. (CO H) Γ / Τ \\ I n ---> N; /

H Cl! OI> I

Γ.Μ -msroc H 3U '· I _ ©,. © δ2 5 q% c2h.oh c “2 <rli" J> * · 2 j ô io' r - * '* · 6,; ii „12 3 P * V '' ·! A ^ fl. „1,2,3 21 -----> ---- 15 Wâ C ^ ÇHS-ÎCBJ ^ -ï-iCH;) ^ \) 0“ R4'5 US Pat. Nos. 4,038,409 and 4,039,677 describe the general methodology for the synthesis of the desired xanthate _19 and its hydrolysis to form the thiol salt which is then used in the syntheses of the invention.

The thiol salt 20 is advantageously maintained in the form of solid xanthate _19 and generated in situ as required, under a nitrogen atmosphere to minimize oxidation. The alkylating compound is then introduced and the mixture is stirred at 25-80 ° for periods of 0.5 to 24 hours to form the desired products.

The reaction of compound 20 with compound 2 / \ _ (n = 2, Z = C1, Y = S) has the result of largely eliminating HCl from 2_1 giving 23.

SCH = CH

35 R1'2'3_I

23 13 •

Compounds of type 22 in which n is equal to 2, Y is a k atom of sulfur and m is equal to 0 are therefore obtained by synthesis in the best way according to the procedure illustrated in scheme I.

5 As shown in Scheme IV, the alkylation of compound 24 with chloromethyl and phenyl sulfides (2_1_, Z = C1, n = 1, Y = S, m = 0) or benzyl and chloromethyl sulfides (22, Z = C1, n = 1, Y = S and m = 1) gives the corresponding 2J5 ethers (n = 1, Y = S, m = 0 or 1).

10 DIAGRAM IV

O O i’2.3 15 L ^ u- <n; a® * a ·> C> · "5'6. Ö li.

TL \ 4'5'6 20

Ethers of general formula 25, in which n is equal to 2, Y is oxygen and m is equal to 0, are preferably prepared by synthesis in accordance with the procedure illustrated by scheme I.

The preparation of compounds is described below. intermediaries.

Alcohols and tosylates

Starting from the known alcohol 26, the new ester 28 ^ is prepared, the alcohol and its corresponding tosylate 5 as indicated in diagram V below:

DIAGRAM V

5 Ç Ö ÜÎÎÜU. CJ

I 1. Hall, THF-n; · '? I> · jf

CU2 ^ 0H T BrCII ^ C ^ CH2Ci: 0CH2C02C2H5 CI ^ CHOCH ^ H

^ 1 Q. ‘Q.

10 V / 5.6 \> Λ5'6 / V4.5.6 26 ü y ^ Yjr / T ~ V \; ΪΕΛ · cu2012 Xîï / 15 l / ~ Λ CH2CHOCîI2C * [2OSO, -V / ~ CH3 ril ^ Λι4'5'5 20

Treatment of the anion of compound 2 (3 (see U.S. Patent No. 3,717,655 and Godefroi et al., With respect to this alcohol as well as other suitable alcohols) with bromacetate ethyl 27 is carried out without difficulty giving the ester 28. This ester can be isolated and purified in the form of solid nitrate, or it can be reduced, in the raw state, with lithium hydride and aluminum giving the starting alcohol 14.

Other reducing hydrides such as aluminum hydride, diisobutylaluminum hydride and sodium- bis- (2-methoxyethoxy) -aluminum hydride, etc. can be used. Diethyl ether, tetrahydrofuran, diglyme and benzene are suitable solvents.

35 JA alcohol is a viscous gum and is isolated, purified and stored as its solid nitrate. Nitrate can also be used in the Williamson synthesis, provided that an additional base equivalent is used, for example NaH.

9 15

Treatment of a solution of H. alcohol or its nitrate in methylene chloride containing triethylamine with p-toluenesulfonyl chloride gives tosylate 5 in good yield. T5 Js tosylate is a viscous oil and is usually used shortly after preparation. If necessary, the tosylate can be purified by filtration on alumina with methylene chloride, but the raw material is satisfactory. The tosylate should be stored in a refrigerator.

Alcohol _14 can be activated by other reactants. For example, it can be mesylated with methanesulfonyl chloride or perhaps even chlorinated with thionyl chloride to form additional alcohol derivatives for the synthesis of Williamson.

15 The sodium thiolate 20 ^ (see diagram III) has been alkylated with chlorethanol or bromethanol (29, Z = C1 or Br) so as to obtain alcohol 17. · The latter is then converted into its corresponding tosylate 8 as illustrated by diagram VI.

20 DIAGRAM VI

ο o c "3O50 * cicj | 6®. Y ch2ci2, tea Y '

25 CH ^ IISfîa + ZCh2CI! 20H ^ CI ^ CHSCt ^ C ^ OH --—> CH ^ HSCI ^ Cl ^ OSO ^ VcH

Q 11 Ô G

20. 17 30

Topsylate £ is also a viscous oil and is used without rigorous purification. The alcohol 1-7 can be purified by chromatography on silicic acid or it can be isolated and purified in the form of its acid fumarate.

A large number of phenols, thiophenols, benzyl alcohols, benzylmercaptans and benzyl halides with which the invention can be used are <16 available commercially or are known in the literature and easy to prepare synthetically.

For example, p-trifluoromethyl-5 thiobenzyl chloride 31 and benzyl alcohol 3J) can be prepared according to the following scheme: / = \ Bit -THF / T “\\ S0C12 / ^ \ 29a 22. 3Ί- .

Alcohol 3 £ and its chloride 21 are suitable substrates for the synthesis of Williamson. Many benzo acids or esters are available for such reactions.

Alkylating agents which can be used can be prepared as indicated below. These agents are used to alkylate compound 2J0 (see scheme III).

Cl 'Cl 20 / ~ \ 1 * Wall, diglyr.a / = \ <\ /) “011 -u A-0CH? CHC1.

y // 2. TsOGH2CH2C1 V V Z

V uo ° \ 1

Cl Cl 32 / · rl 33

Ci / 25 _ / 1. lfeH, DMF _ /

Ci-A-OH 1 2 · Ts0CII2CK2C1 ^ Cl — 0CH2CH2C1

34 DD

30

Cl ïîaOEt, E fcOK __ / 34 -----> 2

Br (CH2) 3Cl C1- / A-OCCïl2) 3Cl

reflux v — U

35 ^

f / ^ 1. HaOSt, EtOH

C1 SU 2. BrCH2CH2CH2Cl> Cl / S (CH ^ 3C1 reflux 3T 38 "17

Likewise, thiophenols are easily prepared, ”as illustrated by the synthesis of the following known compounds 40 and 42 which are used to prepare the antimicrobial agents of the invention.

5 Cl cl / ^ Λ 1. MO ,, KC1 / = \ 2 2 · KS | <j0C2H5 s 10 -3. KaOH ü 3 ("yry * / = \ / = v 41 il From the indications given above, it can be seen that, in general, the compounds of formula £ can be prepared, for example, by one of the following variants:

Scheme VII, reaction of a compound of formula: o N N '43, χ

CH2CHW

^ -4.5.6 3 ° i [^ r with an equimolar amount of a compound of formula: R1'2'3 35 2

44 W (CH2) n Y (CH2) m - </ J

"18

AT

formulas in which W represents r (a) an XM group, M being a hydrogen atom or an alkali metal atom such as Na, K or Li, or (b) a leaving group reacting with M, for example Cl, Br, OSC ^ p-tolyle or OSC ^ CH. ^, And represents the other of the two options (a) and (b), or

Scheme VIII, by reaction of a compound of formula: 10 r-N ·

O

NOT

- 15 45 CH2CHHX (CH2) nW1 —r4.5.6 20 with an equimolar amount of a compound of formula: pli2.3 î formulas in which W represents: 30 (c) a group YM in which M has the definition given for Scheme VII or (d) a leaving group as defined in Scheme VII, and represents the other of the two options (c) and (d), 1 6 35 X, Y, m, n and R - R having the definitions given for the formula

Table I below only illustrates some of the compounds of formula £ which have been prepared.

19 TABLE I General formula f \\ i * \ _ /. Ih ^ CH — A — fl \ —R9

Rr 11 \ io

V

C1 - ÎABLBàU I 1 H'0 3'®1 addition. '* ~] of 7 s q T n i Ί comp. acid * A R RR Rlü R11

1 1.5 c4h4o4 -sch2s- H H "" "ci H H

2 C4H4 ° 4 -SCH2CH2S- H H Cl HH

3 HN03 -SCH2CH2S- Cl H Cl HH

4 C4H4 ° 4 ~ SCE2CE2S ~ H H ~ C6H5 H H

5 C4H4 ° 4 -30¾ ° ¾ ° ¾3- H H Cl HH

6 HNG3 -0CH2CH20- H CF3 H HH

7 HN03 -CCH2CH20- Cl H Cl HH

8 hno3 -och2ch2o- Cl H H H Cl

9 HN03 -0CH2CH20- Cl H Cl Cl H

1 ° C2H204 -0CH2CH20- h h tertio- H H

butyl

11 c2h2o4 -och2ch2o- h h -c6h5 H H

12 C2H204 -0CH2CH20- Cl H -CgH5 H H

13 C2H2 ° 4 -0CH2CH20- ~ c6h5 H H HH

L4 C2H204 -0CH2CH20- ~ c6H5 H Cl HH

15 1.5 C2H204 -0CH2CH20- H H -CH ^ gHg H H

L6 C2H204 -0CH2CH20- H H -SO ^^ H H

---— J -—------------- 20 TABLE All I (continued),. - Add salt. .

A R7 R8 R9 -plO 11! comp. at * acid · * R K R R R:

O

17 C2H2 ° 4 “0CH2CH2 °" H H “COgH5 H H

18 C4H4 ° 4 -SCH2CH20- H H H HH

19 C4H4 ° 4 -SCH2CH20- Cl H H H Cl

20 C4H4 ° 4 -SCH2CH2CH20- Cl H Cl HH

21 C2H204 -OCH2CH2S- H H P HH

22 HN03 -OCH2CH2S- H H Cl HH

23 HN03 -OCH2CH2S- Cl H Cl HH

24 C2H204 -OCH2CH2S- Cl H Cl Cl H

25 C2H2 ° 4 -OCH2CH2S- H H -CgHg H H

26 C2H204 -OCH2CH2SCH2- H H Cl HH!

27 C2H204 -OCH2CH2SCH2- Cl H Cl HH

28 HN03 -OCH2CH2SCH2- H H CH3 H H

29 C2H204 -OCH2CH2OCH2- H H Cl HH

30 C2H204 -OCH2CH2OCH2- Cl H Cl H H

31 free base -OCH2CH2OCH2- H H SCF3 H H

32 C2H204 -OCH2CH2OCH2- H H OCH3 H H

33 C4H404 -SCH2S- Cl H Cl HH

34 C2H2 ° 4 -0CH2CH20 ~ H H -NHCgHj. H H j

O

/-\ He

35 bas® libre -0CH2CH20- H H _ ^, N-CCH3 H H

36 HN03 -OCH2CH2SCH2- H H OCH3 H H

37 HNO- -OCH „CH0OCH„ - H H C.H- H H

£ TO To 6 D y.

38 HN03 -0CH2CH20- H H Cl ** / \

\ J

39 C4H404 -SCH2S- Cl H H H Cl

40 C4H4 ° 4 -OCH2S- H H Cl HH

41 1.5 C4H404 -SCH20- H H Cl HH

42 C4H4 ° 4 -SCH2SCH2- H H Cl HH

43 C2H2 ° 4 "OCH2SCH2" H H Cl d H H

* C4H40 = fumaric acid, C2H204 = oxalic acid 10 11 ** R and R together form and with the benzene group a naphthalene nucleus 9 21 The antifungal activity of compounds of general formula 4 ^ was determined according to a technique using dilution of a broth, with regard to the various following strains of fungi pathogenic for humans and animals: Candida albicans, Candida tropicalis, Candida krusei, Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum canis.

Double dilutions were made in series with the Sabouraud liquid medium starting from stock solutions of the test compounds, usually in dimethyl sulfoxide, Ν, Ν-dimethylformamide or water. The minimum inhibitory concentrations, which are considered to be the minimum concentrations of the test compounds in. micrograms per milliliter which prevent appreciable development of the test organisms, are then determined after inoculation of the broths supplemented with active substance with the test organisms, and incubation at the appropriate temperature and for the appropriate time interval .

The species belonging to the genus Candida were incubated for 24 hours at 37 ° C., while the incubation was carried out for 5 days at 28 ° for the dermatophytes, namely Tr ichophyton rubrum, Tr ichophyton mentagrophytes and Microsporum canis.

The determined minimum antifungal inhibitory concentrations of the compounds 1 to 32 of table I * are indicated in the following table II.

! f v 22 *

’*? · CO

O Lft tfl VO U *) LO

“* 3" CM CM O CM CM ΙΛ, (Λ CM ^ K ^> * · rs 1 • Γ- CM O O ”- O CO I“ ο Ο I— ^ CO r- o | fl

3 U

B

3 S.

O

a en O **. <n co i- cmn id eo eo eo

U r · ** f— CM VO CM ΙΛΟ Ifl li) ic O

• J "00 *" · ** · "* v c" · **, · rv · ".. rv" V.

SO ^ OOO p— O eO r- OO ^ -CMeOOOOCM O

I— - »r * ΙΛ 1 0) 4->> J = i

Cl O

s.

in

fl -K CO

-ΡΟνΟίΛΐΛ Irt 00 in ΙΛ CO

CP ^ OCMCM CM LO r- CM in CM r— C (U CO ** · V · "“> »V r * ^ Λ ** v“ V Λ.

O £ en O O O CM CM O O 03 r— O OO ”- COCMOCOCMr— O

v 4J

ï - B o -C ............. "......... ........... —......... ..

^ £ tüD y _ J, .j r- E ”^ s- en in in in

-O CM O. CM r— “M

H 3 1 · ^ - "S * -s H ω. i- H · O O O O r— I—

H

te & s .................

<4 .H -—-----------

H B

§ b: * in "r" r S s

‘H

y I, J ^ -P <u cm m en lo w in m cm m cm in cm in en, Q 3 O · “" »^ ^ · - · * k. · -— # **.

^ 5-tOi — OCM CM ΙΟ O CM r— CM OO CM OOOO CO CM ^ r— s _! _ I_i__ 'H * en est cm fl * r ri m vr 5 ”- cm £“ ^ -PO Ht to T- r— B a in +3 oo ri 1- Ul “J“ “BN <tMtOe '-' t <ÛW <tW> Î <ÛN'ÛCO“ Î S -P 'r- r— en rr- r- en r -

o - * --—- —--- 1 ---- S

Ö to "u) min mm m o O fl en *". "V · * _. "X ·". in ^ rv Ο Ό O O O CM O · - Or— CMf-OO ^ T O n

f- in S

“O I— w c fl * # O er” in Q) * 3 * in in in in cm “3

O · »« v »S IS

tninOCMCM O CM CVJ M <t r— p— O O O

§ ^ o (J * 3 • t- O in in in in J3 "S-lf) CM lO CM CM CM * p— in ·" rv * \

"O O CM r- O" S- CM f— r-r— Or— CMi— O O <3 "* i— i— O

__vJ _________—--- * '0) 3 Ö R o X * Q.

H r-CMM ^ flOlOrvOOCtOf— “MrO ^ lOlOr ^ COOCr — CM Q o f— * - | - t— f— i— r— 1— f— i— CM CM CM

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O c'jc \ icj <\ ic \ i <\ ic \ jmmm o ü 3 24 The antibacterial activity of compounds of - general formula 4 has also been established. Table III shows the antibacterial activity expressed by the minimum inhibitory concentration of some of the compounds shown in Table I with respect to Gram-positive organisms.

TABLE III

10 ^ ° of the Inhibitory Concentration sinisaie ^ g / ml) contp. Steop tococcus - Staphylococcus: aureus pneumoniae pyogenes faecalis A9585 * __ A9604 * A206SS *. Λ9537 * Λ9606 * 41509 ^: 7 63 63 2 2 2 2 15 8 | 63 63 4 2 2; . 2 9; 63 63 2 1 1 1 11 125 125 8 .8 8 8 18 125 125 32 16 16 16 2q 20 125 125 2 1 1 '2 l 21 63-63 2 2 2 2 22 125 125 2 2 2 1 24 125 125 4 1 2 2 d 26> 125> 125 2 · 2 2 2 25 29> 125 "> 125 4 2 2 2 30 63 63 1 1 1 .1 31> 125> 125 8 4 4 4 ——-- l · '- --------- 1 - - - - - * 1 30 i H ° of strain A. pneumoniae and S _; _ pyogenes were tested in a mixture containing 50% of Mueller-Hinton broth , 45% antibiotic broth and 35% human serum, while S ^ faecalis and S ^ _ aureus were subjected to the agar dilution test in Mueller-Hinton medium.

x 25

The following examples only illustrate * certain preferred embodiments of the intermediate compounds and antimicrobial compounds of the invention, the structures of which are disclosed in the present specification 5 are based on satisfactory spectral data (infrared spectrum and resonance spectrum magnetic of the protons). All the quantities and all the proportions indicated in this specification are expressed by weight, unless otherwise specified, the temperatures are expressed in degrees 10 Celsius and the melting and boiling points are not corrected.

Example 1 2- [1- (2,4-dichlorophenyl) -2- (1H-1-imidazolyl) ethyl ethoxyjacetate (Scheme V, 28 ^, R ^ '5 = 2,4-dichloro)

A solution of 3.0 g (0.0118 mole) of 1- (2,4-dichlorophenyl) -2- (1H-1-imidazolyl) ethanol * in 7 ml of Ν, Ν-dimethylformamide (DMF) is added to a suspension with stirring in mineral oil, cooled with ice water, of 0.55 g (0.013 mole) of 57% sodium hydride in 15 ml of tetrahydrofuran (THF). The mixture is refluxed for 1.25 hours until complete formation of the salt. The cooling bath is removed and a solution of 1.5 ml (0.014 mole) of ethyl bromacetate in 5 ml of THF is added dropwise over 10 minutes. The mixture is refluxed for 18 hours, cooled and diluted with diethyl ether. The ether solution is washed with water "(3 times), then brine and dried over sodium sulfate. After removal of the ether, the residue is dissolved in acetonitrile and the mineral oil is removed by two washes with n-pentane. Removal of acetonitrile leaves 2.55 g of the desired ester in the form of a clear oil which is suitable for reduction. Addition of 0.5 ml of 70% nitric acid (d = 1.42) to a solution of 2.55 g of the ester in 50 ml of diethyl ether containing 10 ml of ethanol gives 2.1 g of colorless nitrate crystals melting at 82-87 °. By recrystallization from ethyl acetate, the analytical sample is obtained, melting at 102-104 ° C.

26

Analysis:

- C% HS Cl S NS

Calculated for C15H16C12N203.HN03: 44.35 4.22 17.45 10.34 5 Found: 44.38 4.15 17.12 10.72 * U.S. Patent No. 3,717,655 and Godefrei and collaborators, see above.

Example 2

1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) -10 ethyl] -1H-imidazole nitrate (Scheme V, compound 14 'R4'5 = 2,4- dichloro)

A solution of 6.4 g (0.019 mole) of 2- (1- (2,4-dichlorophenyl) -2- (1H-1-i, 15 imidazolyl) ethoxy ethyl Jacetate in 100 is rapidly added dropwise ml of diethyl ether to a stirred mixture, cooled with ice water, of 0.76 g (0.02 mole) of lithium aluminum hydride in 150 ml of diethyl ether. reflux the mixture for 16 hours, it is cooled with ice water and the excess of complex aluminum hydride is decomposed by successive additions, drop by drop, of 5 ml of water in 50 ml of THF, 10 ml of 15% aqueous sodium hydroxide and 5 ml of water The mixture is stirred for a further 30 minutes and introduced by filtering through a dropping funnel. The aqueous phase is extracted with ether of diethyl (3 times) and the combined ether phases are washed with water, then with brine (2 times). After dehydration over sodium sulfate and elimination of the ether, 5.12 g remain. desired alcohol, in the form of a viscous oil se.

Treatment of a solution of the free base in ether with 70% nitric acid gives the nitrate which melts at 97.5-98.5 ° after recrystallization from a mixture of acetonitrile and ether .

Analysis: 35 C% H% Cl% N%

Calculated for C13H14C12N202.HN03: 42.87 4.15 19.47 11.54

Found: 43.02 4.13 19.29 11.57 27

Example 3 r 1- (2- (2,4-Dichlorophenyl) -2- (2-hydroxyethoxy) - ethyl J-1H-imidazole Tosylate (Schemes I and V, 5, R ^ '5 = 2,4-dichloro) 5 The nitric acid salt of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethylJ-iH-imidazole (6.0 g) is partitioned between methylene chloride (CH2ci2 ) and 40 ml of 0.5N sodium hydroxide The chloromethylenic phase is washed (brine) and dehydrated (Na2SO4). The removal of 10 CH2Cl2 leaves the base free (5.02 g) of the alcohol. 3.50 g (0.0184 mole) of p-toluenesulfonyl chloride is added to a cooled solution (ice water), with stirring, of 5.02 g • (0.0167 mole) of the alcohol in 60 ml of methylene chloride containing 2.56 ml (0.0167 mol) of triethylamine, stirring is continued at ice bath temperature (1 hour), then at 25 ° (1 hour), the mixture is washed successively with cold water, a cold aqueous solution of Na2CO3 (2 times), water and brine. The chloromethylenic solution is dried over sulphate of sodium 20 and concentrated to dryness giving 7.15 g of the tosylate in the form of a viscous oil. If necessary, a solution of the tosylate in CH2C12 can be filtered through alumina to remove traces of starting alcohol. This latter operation is not, however, necessary for the subsequent reactions.

The nitric acid salt of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethyl) -H-imidazole can be used directly in the formation of tosylate, provided that add an additional equivalent of triethyl-30 amine.

Example 4

1- (2- (4-biphenylyloxyethoxy) -2- (2,4-dichlorophenyl) ethyl] -1H-imidazole acid oxalate (Table I, compound No. 11) 35 A solution of 2.42 g (0 0.0142 mole) of 4-hydroxybiphenyl in 15 ml of DMF is added dropwise to a suspension in 57% NaH mineral oil (0.658 g, 0.0156 mole) in 25 ml of DMF, cooled to ice water and with stirring. Stirring is continued, at 70 ° 28 (20 minutes), then at 100 ° (10 minutes) to complete the formation of the salt. The cooling bath is again placed and a solution of the 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethyl J-1H-imidazole tosylate 5 (6.47 g, 0.0142 mole) in 15 ml THF. Stir the mixture for 18 hours at an oil bath temperature of 75 ° under a nitrogen atmosphere and concentrated to dryness. The residue is partitioned between diethyl ether and water. The ether phase is washed with water (2 times), then with brine and dried (Na2SO4). After removal of the ether, di ssout the residue in acetonitrile and the mineral oil is removed by two washes with normal pentane. The elimination of acetonitrile leaves 5.2 g of crude free base in the form of a viscous oil, which gives 4.2 g of pure base after chromatography on 150 g of silicic acid with a mixture of chloride. 10: 1 methylene and acetone.

A solution of 4.0 g (0.00882 mole) of the free base in 100 ml of ethyl acetate is treated with a solution of 0.794 g (0.00882 mole) of oxalic acid in 50 ml of ethyl acetate to obtain, on cooling, 4.28 g of the acid oxalate, melting at 122-124 ° (decomposition). Analysis: C% H% Cl% N% 25 Calculated for C25H22C12 ° 2N2, C2H2 ° 4: 59.67 4.45 13.04 5.16

Found: 59.39 4.51 13.24 5.16

By replacing 4-hydroxybiphenyl in the above procedure with 4-chloro-2-phenylphenol, 2-30 chloro-4-phenylphenol, 2-phenylphenol, 4-benzylphenol, 2,6-dichlorophenol, 4-fluorothiophenol, 4-mercapto-biphenyl, 4-chlorobenzylmercaptan and 4-methylbenzyl-mercaptan and using the appropriate salt-forming acid, the addition salts of crystalline acids are obtained, respectively following: 1- (2- (4-chloro-2-phenylphenoxy-ethoxy) -2- (2,4-dichlorophenyl) ethyl] -1H-imidazole oxalate acid melting at 88-91 ° (Table I, compound No. 14).

29

Analysis: C% H% N%

Calculated for C25H21C13N2 ° 2'C2H2 ° 4: 56'12 4'01 4'85 5 Found: 56.24 4.19 5.01

1- (2- (2-chloro-4-phenylphenoxy-ethoxy) -2- (2,4-dichlorophenyl) ethyl] -1H-imidazole acid oxalate, melting at 93-95 ° (Table I, compound No. 12 ).

Analysis: 10 C% H% N%

Calculated for C25H21C13N2 ° 2-C2H2 ° 4: 56'12 4 '° 1 4'85

Found: 56.00 4.15 5.16

V

1- (2- (2,4-dichlorophenyl) -2- (2-, phenylphenoxethoxy) ethyl J-1H-imidazole acid oxalate, melting at 140-141 ° (Table I, Compound No. 13).

Analysis: C% H% Cl% N%

Calculated for 20 C25H22C12N2 ° 2-C2H2 ° 4! 59'68 4'45 13'05 5'16

Found: 59.28 4.55 12.86 5.27

1- (2- (4-Benzylphenoxyethoxy) -2- (2,4-dichlorophenyl) ethyl) -1H-imidazole acid oxalate, melting at 117-118 ° (Table I, compound No. 15).

25 Analysis: C% H% Cl% N%

Calculated for C26H24C12N2 ° 2 · 1.5 {C2E20 ^: 57'82 4'52 11 ^ 77 4.65

Found: 57.58 4.62 11.43 4.56 30 1- (2- (2,6-dichlorophenoxyethoxy) -2- (2,4-dichlorophenyl) ethyl] -1H-imidazole nitrate, melting at 106- 108 ° (Table I, compound No. 8).

Analysis: C% H% Cl% N% 35 Calculated for C19H16C14N202.HN03: 44.82 3.37 27.85 8.25

Found: 44.84 3.38 27.47 8.28

1- [2- (2,4-Dichlorophenyl) -2- (4-fluorothiophenoxyethoxy) ethyl] -1H-imidazole acid oxalate, melting at 107-108 ° (Table I, Compound No. 21).

30

Analysis: C% H% Cl% N% S%

Calculated for C19H17C12FN20S.C2H204: 50.31 3.82 14.14 5.59 6.40 5 Found: 50.38 3.93 14.01 5.78 6.88

Acid oxalate of 1- (2- (2,4-dichlorophenylJ-2- ((4-biphenylthio) ethoxy Jethyl) -1H-imidazole (Table I, compound No. 25).

Analysis: 10 C% H% N% S%

Calculated for C25H20C12N2OS, C2H2 ° 4: 57.96 4.32 5.01 5.73

Found: 57.68 4.35 5.15 5.25

Acid oxalate of 1- (2- ((4-chlorobenzylthio) -15 ethoxyJ-2- (2,4-dichlorophenyljethyl) -iH-imidazole, melting at 98-100 ° (Table I, compound No. 26).

Analysis: C% H% Cl% N% S%

Calculated for 20 C20H19C13N2OS, C2H2 ° 4 1 49.68 3.98 20.00 5.27 6.03

Found: 49.94 3.95 19.81 5.38 6.37

1- (2- (2,4-DichlorophenylJ-2 - ((4-methylbenzylthio) ethoxyJethyl) -iH-imidazole nitrate, melting at 107-108 ° (Table I, Compound No. 28).

25 Analysis: C% H% Cl% N% S%

Calculated for C21H22C12N20S * HN03: 52.07 4.79 14.64 8.67 6.62

Found: 51.85 4.68 14.71 8.64 6.49 30 Example 5

1- (2- (2,4-dichlorophenyl) -2- (2,4,5-trichloro-phenoxyethoxy) ethyl J-1H-imidazole nitrate (Table X), compound No. 9

A solution of 3.41 g (0.0173 mole) of 2,4,5-trichlorophenol in 10 ml of DMF is added dropwise over 5 minutes to a cooled mixture (ice water), with stirring, of hydride. sodium 57% in mineral oil (0.727 g, 0.0173 mole) in 25 ml of DMF. Stirring is continued at 50-120 ° for half an hour to complete the salt formation. The ice bath is replaced and a solution of 7.15 g (0.0157 mole) of 1- (2- (2,4-dichlorophenyl) -2- tosylate) is added dropwise over 5 minutes. (2-hydroxyethoxy) ethyl) -1H-imidazole in 25 ml of THF. The mixture was heated at moderate reflux for 18 hours and concentrated to dryness. The residue is partitioned between diethyl ether and water. The ether phase is washed (water, brine) and dried over sodium sulfate. After removing the ether, the residue is dissolved in acetonitrile and the solution washed twice with n-pentane to remove the mineral oil. The elimination of acetonitrile leaves 6.23 g of a gum which is dissolved in a mixture of 100 ml of diethyl ether and 25 ml of ethyl acetate. The addition of 70% nitric acid (d = 1.42) causes the nitrate indicated in the title to separate, melting at 100-15 110 °. Two recrystallizations from ethyl acetate, the second with the addition of bleaching charcoal, give beige crystals of the analytical sample melting at 143-144.5 °.

Analysis: 20 C% H% N%

Calculated for C19H15C15N202.HN03: 41.98 2.97 7.73

Found: 42.27 3.06 7.64

Following the procedure described above and replacing 2,4,5-trichlorophenol with 4-tert-butylphenol, 4-phenylsulfonylphenol (Szmant and Suld, J. Amer. Chem. Soc., 7! 8 , 3400 (1956)), 4-hydroxybenzophenone, 2,4,5-trichlorothiophenol and 4-methoxy-benzyl alcohol, the following compounds are prepared, which are respectively characterized in the form of acid oxalates.

1- [2- (4-tert-butylphenoxyethoxy) -2- (2,4-di-chlorophenyl) ethyl J-1H-imidazole, melting at 141-143 ° (decomposition) (Table I, compound No. 10).

Analysis: 35 C% H% Cl% N%

Calculated for C23H26C12N2 ° 2 * C2H2 ° 4: 57.37 5.39 13.55 5.35

Found: 56.71 5.06 13.47 5.06 32 1- (2- (2,4-dichlorophenyl) -2- (4-phenylsulfonyl-, phenoxyethoxy) ethyl J-1H-imidazole, melting at 169-171 ° (breakdown) (Table I, compound No. 16).

Analysis: 5 C% H% Cl% N% S%

Calculated for C25H22C12N2 ° 4S'C2H2 ° 4: 53'39 3'98 11/67 4.61 5.28

Found: 53.39 3.98 11.70 4.83 5.42 1- (2- (4-benzoylphenoxyethoxy) -2- (2,4-dichloro-10 phenyl) -ethyl] -1H-imidazole melting at 118 -124 ° (Table I, compound N ° 17).

Analysis: C% H% Cl% N%

Calculated for 15 C26H22C12N2 ° 3 * C2H2 ° 4: 57'72 4'37 12.19 4'89

Found 58.09 4.46 12.41 4.85 1- (2- (2,4-dichlorophenyl) -2- (2,4,5-trichlorothio-phenoxyethoxy) ethyl J-1H-imidazole, melting at 108, 5-109.5 ° (Table I, compound No. 24) 20 Analysis: C% H% Cl% N% S%

Calculated for C19H15C15N20S.C2H204: 42.99 2.92 30.31 4.77 5.47

Found: 42.90 2.78 30.08 5.10 5.30 25 1- (2- (2,4-dichlorophenyl) -2- (4-methoxybenzyloxyethoxy) ethyl J-1H-imidazole, melting at 155, 5-157.5 ° (Table I, compound No. 32).

Analysis:

C% HS Cl% NS

. 30 Calculated for C91H „Cl, N, 0o.C9H, 04: 54.02 4.73 13.87 5.48

Found: 53.90 4.78 13.82 5.77

Example 6

1- (2- (4-chlorothiophenoxyethoxy) -2- (2,4-dichloro-phenyl) ethyl] -1H-imidazole nitrate (Table I, compound No. 22)

A 50% dispersion of sodium hydride in mineral oil (0.21 g, 4.4 mmol) is added to a stirred solution of 0.64 g (4.4 mmol) of 4-chloro-thiophenol in 25 ml of DMF at 20 °. Stirring is continued at 33 ° room temperature for 1 hour and a half, then at 50-60 ° for half an hour. The solution is cooled to 20 ° and a solution of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethyl] -1H-imidazole tosylate (2.0 g, 5 4.4 mmol) in 10 ml of DMF The mixture is heated to an oil bath temperature of 75 ° for 3 hours and concentrated to dryness. The residue is partitioned between methylene chloride and water and the aqueous phase is extracted with methylene chloride. The combined chloromethylenic phases are evaporated to dryness and the residue is dissolved in acetonitrile. The mineral oil is removed by two washes with n-pentane. acetonitrile leaves 2 g of a viscous oil which gives 0.87 g of the pure base after chromatography on 50 g of neutral alumina with methylene chloride. A solution of 0.87 g of the free base in 100 ml of diethyl ether is converted into nitrate by adding 70% nitric acid (d = 1.42) until precipitation is complete. By recrystallization from a mixture of ketonitrile and ether, an analytical sample of the title compound is obtained, melting at 98-99 °.

Analysis: C% H% Cl% N% S%

Calculated for 25 C19H17C13N20S.HN03: 46.49 3.70 21.67 8.56 6.53

Found: 46.76 3.65 21.58 8.42 6.56

By following a similar procedure and by replacing 4-chlorothiophenol with 2,4-dichlorothio-phenol, 2,4-dichlorophenol and 3-trifluoromethylphenol, the following compounds are prepared, which are characterized in the form of nitrates: 1- (2- (2,4-dichlorophenyl) -2- (2,4-dichlorothio-phenoxyethoxy) ethyl J-1H-imidazole, melting at 172-173 ° (Table I, compound No. 23).

35 Analysis: C% H% N% S%

Calculated for C1gH16Cl4N20S.HN03: 43.44 3.26 8.00 6.10

Found: 43.75 3.24 8.14 6.00 34 î 1- (2- (2,4-dichlorophenoxyethoxy) -2- (2,4-dichloro-, phenyl) ethyl] -1H-imidazole, melting at 173.5-174.5 ° (Compound If table N ° 7).

Analysis: 5 C% H% N%

Calculated for C19H16C14N202.HN03: 44.81 3.17 8.25

Found: 44.86 3.36 8.47 1- (2- (2,4-dichlorophenyl) -2- (3-trifluoromethyl-10 phenoxyethoxy) ethyl] -1H-imidazole, melting at 105.5-107.5 ° (Table I, compound N ° 6).

Analysis:> C% H% N%

Calculated for 15 C20H17Cl2F3N2 ° 2 * HNO3: 47.26 3.57 8.27

Found: 46.98 3.48 8.53

Example 7

1- (2 - [(2,4-dichlorobenzylthio) ethoxy) -2- (2,4-dichlorophenyl] ethyl) -1H-imidazole acid oxalate (Table I, compound 20 No. 27)

A 1.6 M solution of n-butyl lithium in hexane (6.3 ml, 0.01 mole) is added dropwise to a stirred solution of 1.93 g (0.01 mole) of 2 , 4-di-25 chlorobenzylmercaptan in 65 ml of THF at -78 °. Stirring is continued at -78 ° for half an hour and a solution of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethyl J-iH-imidazole tosylate is added dropwise (4.55 g, 0.01 mole) in 35 ml of THF The mixture is stirred for a further half an hour at -78 °, then for 1.5 hours at room temperature. vacuum and a mixture of the residue is extracted with methylene chloride (3 times) with water The combined chloromethylenic extracts are washed three times with brine, then with water and they are dried over sulphate The removal of the solvent, after treatment with bleaching charcoal, gives 4.8 g of an oil which produces 2.99 g of pure free base after chromatography on 100 g of silicic acid, with a mixture of sodium chloride. 35 "methylene and 20: 1 acetone. Adding oxalic acid to a solution of the free base in ethyl acetate gives 2.77 g of the title salt, melting at 8 5-88 °. Analysis: 5 C% H% N%

Calculated for C20H18C14N2OS * C2H2 ° 4: 46.66 3.56 4.95

Found: 46.49 3.55 5.17

Example 8 10 Acid oxalate of 1- (2- (4-chlorobenzyloxyethoxy) -2- (2,4-di-chlorophenyl) ethyl J-1H-imidazole (Table I, compound No. 29) 4 A solution of 2.5 g (6.87 mmol) of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethyl] -1H- nitrate. 15 imidazole in 15 ml of DMF is added dropwise over 15 minutes to a suspension in mineral oil, stirred and cooled with ice water, 57% sodium hydride (0.61 g, 14.4 mmol) in a mixture of 10 ml of DMP and 10 ml of THF under nitrogen atmosphere. Stirring is continued for half an hour at 25 ° and for 0.25 hours at 50 °. The cooling bath is replaced and the 4-chlorobenzyl chloride is quickly added ( 1.22 g, 7.56 mmol) The mixture is stirred at room temperature for 35 minutes, then at an oil bath temperature of 65 ° for 1.5 hours. The mixture is concentrated to dryness and partition the residue between diethyl ether and water. The ether phase is washed with water and brine, it is dried over * sodium sulfate and concentrated to dryness. The residue is dissolved in acetonitrile and the mineral oil is removed by washing with n-pentane (three times). The residue (2.35 g) is chromatographed on 130 g of alumina with a mixture of methylene chloride and ethanol at 25: 1 to obtain 1.26 g of the pure free base, in the form of an oil yellow. By treating a solution of 1.2 g of the free base in ethyl acetate with 0.254 g of oxalic acid, the title compound is obtained, melting at 103-105 °.

36 a

Analysis: 7 C% H% Cl% N%

Calculated for C20H19Cl3N2O2.C2H4O4: 51.23 4.10 20.62 5.43 5 Found: 51.35 4.02 20.60 5.68

By proceeding in a similar manner and replacing the chlorinated 4-chlorobenzyl with 2,4-dichlorobenzyl chloride and 4-trifluoromethylthiobenzyl chloride, the following are obtained, respectively: 10 The acid oxalate of 1- (2- ( 2,4-dichlorobenzyloxyethoxy) -2- (2,4-dichlorophenyl) ethyl] -1H-imidazole, melting at 100-103 ° (Table I, compound No. 30).

5 Analysis: C% H% Cl% N% • 15 Calculated for C20H18C14N2 ° 2, C2H2 ° 4: 48.02 3.66 25.77 5.09

Found: 48.10 3.65 25.66 5.34

1- (2- (2,4-dichlorophenyl) -2- (4-trifluoro-methylthiobenzyloxyethoxy) ethyl J-1H-imidazole, melting at 51-20 52 ° (Table I, compound No. 31).

Analysis: C% H% Cl% N%

Calculated for C21H19C12F3N202S î 51.33 3.90 14.43 5.70 25 Found: 51.60 3.75 14.38 5.80

Example 9

4-trifluoromethylthiobenzyl alcohol (30)

A 1.02 M solution of borane in tetrahydrofuran (56.9 ml, 0.058 mole) is added dropwise over 0.25 hours to a stirred solution of 10.0 g (0.045 mole) of 4- sulfide. carboxyphenyltrifluoromethyl in 25 ml of THF at -5 °. The cooling bath is removed and the stirring is continued for 3 hours at 25 °. The cooling bath is replaced and 30 ml of 1: 1 mixture of water and THF are carefully added. The aqueous phase is saturated with potassium carbonate and the phases are separated. The aqueous phase is extracted with four times 25 ml of diethyl ether. The ether extraction phases 40 are combined with the THF phase and the mixture is washed 37 * with water and dried over sodium sulfate. Elimination * of the solvents gives an oil which crystallizes by trituration with 6N hydrochloric acid. By recrystallization from "Skellysolve-B", 6.5 g of the alcohol melting at 52-53 ° are obtained.

Analysis: C% H%

Calculated for C8H? F3OS: 46.15 3.39 10 Found: 46.44 3.51

Example 10

4-trifluoromethylthiobenzyl chloride (31) a ---- ------ - - -. _ _. —11 .....-, -

2.48 g (0.0208 mole) of is added dropwise. 15 thionyl chloride to a stirred solution of 4.0 g (0.0192 mole) of 4-trifluoromethylthiobenzyl alcohol in 40 ml of 5 ° methylene chloride. A drop of DMF is then added and the solution is stirred for 18 hours at 25 °. It is concentrated and the residue is triturated with ice water, then extracted with methylene chloride. The chloromethylenic solution is washed with water and dried over sodium sulfate. Removal of the solvent leaves 4.0 g of the title product in the form of a mobile oil.

25 Analysis: C% H% Cl%

Calculated for * CgHgClFgS: 42.39 2.67 15.65

Found: 42.31 2.76 15.26 38

Example 11 = Acid fumarate of 1- [2- (2,4-dichlorophenyl) -2- (2-hydroxy-ethylthio) ethylJ-ethylj-1H-imidazole (Schemes II and VI, 17., R4 / 5 = 2, 3-dichloro) 5 -

13.1 g (0.029 mole) of 1- (2- (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethylj-1H-imidazole oxalate are added (see United States Patent No. 4,038,409 and No. 4,039,677) to a stirred solution of 5.8 g (0.145 mole) of sodium hydroxide in 650 ml of ethanol at 25 ° under a nitrogen atmosphere. 0.75 hours at 25 °, a solution of 3.87 g (0.031 mole) of 2-bromethanol in 10 ml of ethanol is added, stirring is continued for 1 hour and the ethanol is removed. the residue between diethyl ether and water.

The aqueous phase is extracted with several portions of ether and the combined ether phases are washed with water, then with brine. Removal of the ether, after dehydration over sodium sulfate, leaves 9.3 g of the free base in the form of a viscous oil. The addition of 3.40 g of fumaric acid to a solution of 9.3 g of the free base in 30 ml of 1-propanol gives, after removal of the 1-propanol and after two recrystallizations from acetonitrile, 8, 8 g of colorless crystals of the salt indicated in the title, melting at 124-125 ° (foaming).

Analysis î C% H% Cl% N% S%

Calculated for C13H14Cl2N2OS * C4H4 ° 4: 47.12 4.19 16.37 6.47 7.40 30 Found: 47.07 4.00 16.31 6.80 7.40

A similar operation carried out using 2-chlorethanol in place of 2-bromethanol gives the free base in the form of a viscous oil after chromatography on silicic acid, with a mixture of chloroform and acetone at 1. : 1.

39

Example 12. Acid fumarate of 1- (2- (4-chlorothiophenoxyethylthio) -2- (2,4-dichlorophenyl) ethyl) -1H-imidazole (Table I, compound No. 2) 530 930 mg (4.9 mmol) of p-toluenesulfonyl chloride to a solution cooled with ice water, with stirring, of 1.4 g (4.41 mmol) of 1- (2- (2,4-di-chlorophenyl) -2- (2- hydroxyethylthio) ethyl J-1H-imidazole in 20 ml of methylene chloride containing 0.61 ml (4.41 mmol) of triethylamine. Stirring is continued at ice bath temperature (0.75 hours), then at 25 ° (0.75 hours) The mixture is then washed successively with the following cold aqueous solutions: water (2 times), mixture of water and 2% K2CO3 (2 times), water (2 times) and 15 Removal of the solvent after dehydration with sodium sulfate leaves 2.03 g of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethylthio) ethyl J-1H-imidazole tosylate in the form of 'a viscous oil.

A solution of 0.67 g (4.66 mmol) of 4-chlorothiophenol in 3 ml of DMF is added over 5 minutes to a suspension cooled with ice water, with stirring, of 57% sodium hydride in mineral oil (196 mg, 4.66 mmol) in 8 ml of DMF. The mixture is then heated to an oil bath temperature of 110 ° for half an hour. The cooling bath is replaced and a solution of the above-mentioned tosylate (2.03 g, 4.31 mmol) in 8 ml of THF is added over 5 minutes. The mixture is refluxed moderately for 6 hours and concentrated to dryness under vacuum. The resulting oil is diluted with water and the mixture is extracted with several portions of diethyl ether. After having combined the extraction phases with ether, they are washed with water and brine, they are dried over sodium sulphate and concentrated to obtain an oil which is dissolved in 35 l 'acetonitrile (CH ^ CN). The acetonitrile solution is washed twice with n-pentane. Removal of acetonitrile leaves the free base (1.29 g) of the title compound. A solution of the free base (1.29) in CH3CN is treated with 0.31 g of fumaric acid to give 0.85 g of the "compound indicated in the title, melting at 95-98 ° (formation of a foam). By recrystallization from acetonitrile, colorless crystals are obtained from the analytical sample, melting at 96-98 °.

Analysis: C% H% Cl% N% S%

Calculated for C19H17C13N2S2.C4H404: 49.33 3.78 19.00 5.40 11.45 10 Found: 49.47 3.86 18.72 5.08 11.48 Similarly, replacing the 4- chlorothiophenol by 2,4-dichlorothiophenol and 4- * mercaptobiphenyl and the use of the suitable salt-forming acid give, respectively: * 15 1- [2- (2,4-dichlorothiophenoxyethylthio) nitrate - 2- (2,4-dichlorophenyl) ethyl J-1H-imidazole melting at 104-105 ° (Table I, compound No. 3).

Analysis: C% H% Cl% N% 20 Calculated for C19H16C14N2S2.HN03: 42.15 3.17 26.20 7.76

Found: 42.34 2.78 25.97 8.12

1- (2- (4-biphenylylthio-ethylthio) -2- (2,4-dichlorophenyl) ethyl) -H-imidazole fumarate acid, melting at 116-119 ° (Table I, Compound No. 4).

Analysis:

Cl% N% S%

Calculated for C25H22C12N2S2 * C4H4 ° 4: 11.79 4.66 10.66, 30 Found: 12.20 5.00 10.38 41

Example 13 Acid fumarate of 1- (2- (2,4-dichlorophenyl) -2- (4-chlorophenylthiopropylthio) ethyl J-1H-imidazole (Table I, compound No. 5) 5 -

3.5 g (7.7 mmol) of 1- (2- (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethyl J-1H-imidazole oxalate (as in Example 11) are added to a stirred solution of 1.55 g (0.0388 mol) of sodium hydroxide in 176 ml of ethanol at 25 ° under a nitrogen atmosphere After stirring at 25 ° for 45 minutes, is added dropwise in 5 minutes 1.8 g (8.1 mmol) of 4-chlorophenyl * and 3-chloropropyl sulphide, the mixture is refluxed for 18 hours and concentrated to dryness. The residue is diluted with water and the mixture is extracted with several portions of diethyl ether. The combined ether phases are washed with water and dried over sodium sulfate. The elimination of the ether leaves 3.8 g of a viscous oil. 0.96 g of fumaric acid is added to a hot solution of the oil in 10 ml of CH3CN. On cooling, colorless crystals (3.3 g) of the title compound separate ; these crystals melt at 116-117 ° .

Analysis: C% H% Cl% N% 25 Calculated for C20H19C13N2S2, C4H4 ° 4: 50.22 4.04 18.53 4.88

Found: 50.19 4.06 18.66 5.05 Similarly, replacing 4-chlorophenyl and 3-chloropropyl sulfide with chloromethyl and 4-chlorophenyl sulfide and the ether of 2 , 4-dichlorophenyl and 3-chloropropyl, respectively:

1- (2- (4-chlorothiophenoxy-methylthio) -2- (2,4-dichlorophenyl) ethyl J-1H-imidazole sesquifumarate melting at 125-126 ° (foaming) (Table I, compound N ° 1).

42 't.

Analysis: * C% H% Cl% N% S%

Calculated for C18H15C13N2S2.1,5C4H404: 47.73 3.51 17.61 4.64 10.62 5 Found: 47.64 3.59 17.41 4.92 10.29

1- [2- (2,4-dichlorophenoxy-propylthio) -2- (2,4-dichlorophenyl) ethyl) -1H-imidazole fumarate acid, melting at 138-139.5 ° (Table I, compound No. 20).

Analysis: 10 C% H% Cl% N% S%

Calculated for C20H18Cl4N2OS.C4H4O4: 48.66 3.74 23.95 4.73 5.41

Found: 49.04 3.75 23.41 4.90 5.60

Example 14. 1- (2- (2,4-Dichlorophenyl) -2- (phenoxyethylthio) ethyl J-1H-imidazole acid fumarate (Table I, Compound No. 18)

1.1 g (2.45 mmol) of 1- [2- (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethyl J-1H-20 imidazole oxalate are added to a stirred solution, cooled to ice water, 0.49 g (0.0123 mol) of sodium hydroxide in 60 ml of methanol under a nitrogen atmosphere. The ice bath is removed after stirring for 0.25 hours. Stirring is continued at 25 ° for half an hour and a solution of 0.49 g (2.42 mmol) of β-bromophenetole in 10 ml of methanol is added. The mixture is stirred at room temperature for 1 hour and then refluxed for 2 hours. The methanol is removed and a mixture of the residue in water is extracted with two portions of diethyl ether.

After having combined the extraction phases with ether, they are washed three times with a 5% aqueous solution of K2CO3 'and then with water. The ether phase is then extracted with dilute hydrochloric acid and the aqueous phase is washed with several portions of ether. The aqueous phase is made basic by addition of an aqueous solution of sodium hydroxide and the free base is extracted with ether. The ether phase is dried over sodium sulphate and concentrated to give 700 mg of a viscous oil, a 520 mg portion of which is chromatographed on 20 g of 43 * silicic acid with a mixture of methylene chloride and = d acetone at 100: 15, gives 260 mg of purified free base. By treating a solution of the free base in acetonitrile with fumaric acid, colorless crystals of the title compound are obtained, melting at 116-117 °.

Analysis: C% H% N%

Calculated for 10 C19H18Cl2N2OS, C4H4 ° 4 s 54.23 4.35 5.50

Found: 53.48 4.36 5.51 Similarly, by replacing 8- * bromophenetole with 2-chloroethyl and 2,6-dichlorophenyl ether, the acid fumarate of 1- (2- (2,6-dichlorophenoxyethylthio) -2- (2,4-dichlorophenyl) ethyl J-1H-imidazole melting at 107-108 ° (Table I, Compound No. 19).

Analysis: C% H% N%

Calculated for 20 C19H16C14N20S * C4H4 ° 4: 47.76 3.49 4.84

Found: 47.87 3.50 4.81

Example 15

3-chloropropyl and 2,4-dichlorophenyl ether (36) (Netherlands Patent No. 94,934 (1960)) 25 -

60 g (0.38 mole) of 1-bromo-3-chloro-propane are added to a solution of 40.8 g (0.25 mole) of 2,4-dichlorophenol in 500 ml of sodium ethylate in 0.5 M ethanolic solution. The mixture is refluxed for 2 hours, cooled and diluted with 500 ml of water.

It is then extracted with methylene chloride. The chloromethylenic phase is washed (aqueous NaHCO 4 solution), concentrated, and the resulting oil is distilled, giving 40.5 g of the title compound, boiling at 114-115 ° 35 (0.2 mm).

Similarly, treatment of 1-bromo-3-chloropropane with 4-chlorothiophenol gives 3-chloropropyl and 4-chlorophenyl sulfide (see Bird and Stirling, J. Chem. Soc. (B), 111 (1968)) (Diagram VI, 41), 40 boiling at 107-108 ° (0.2 mm).

44 h

Example 16 - 2-Chlorethyl and 2,6-dichlorophenyl ether (33)

A solution of 32.6 g (0.20 mole) of 2,6-dichlorophenol in 65 ml of diglyme is added to a suspension in mineral oil, cooled with ice water and with stirring, of hydride. 57% sodium (9.3 g, 0.22 mole) in 90 ml of diglyme containing 5 ml of DMP. The mixture is stirred for 5 minutes at 40 ° and the cooling bath is replaced. Then a solution of 47 g (0.020 mole) of 2-chloroethyl p-toluenesulfonate in 20 ml of diglyme is added over 20 minutes. The mixture is heated to an oil bath temperature of 110 ° for 19 hours and partially concentrated. The mixture is diluted with cold water and extracted with twice 125 ml of diethyl ether. After the ether extraction phases have been combined, they are washed successively with ice-cold 1 N sodium hydroxide, water and brine. The ether solution is dried over sodium sulfate, concentrated and the residue is distilled to give 35.5 g of the title compound, boiling at 79-81 ° (13.3 Pa).

2-Chloro-2,4-dichloro-phenyl ether (3J5) (see Foldeak et al., Acta Phys. Chem. 9, 134 (1963)) boiling at 107-111 ° (100 Pa) is prepared in the same way.

Example 17

1- (2- (4-chloronaphthoxyethoxy) -2- (2,4-dichloro-phenyl) ethyl J-1H-imidazole nitrate (Table I, compound No. 38) 30 A solution of 1.68 g (9.4 mmol) of 4-chloro-1-naphthol in 5 ml of DMF is rapidly added to a suspension in mineral oil, cooled with ice water and with stirring, of sodium hydride at 57% (435 mg, 10 , 3 moles) in 15 ml of DMF. The cooling bath is removed and the stirring is continued for 5 minutes at 5-35 ° to complete the formation of the salt. The cooling bath is replaced and add a solution of 1- [2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) -ethyl] -1H-imidazole tosylate (4.28 g, 9.4 mmol) in 15 ml of THF.

t 45

The mixture is stirred under moderate reflux for 18 hours and concentrated to dryness. The residue is partitioned between diethyl ether and water. The ether phase is washed successively with 1N sodium hydroxide, water, brine and dried over sodium sulfate. After removal of the ether, the residue is dissolved in acetonitrile and the mineral oil is removed by two washes with n-pentane. Removal of acetonitrile leaves 3.30 g of the crude free base in the form of a viscous brown oil, which gives 2.18 g of pure base after chromatography on 120 g of silicic acid with a mixture 10: 1 methylene chloride and acetone.

Addition of 0.3 ml of 70% nitric acid (d = 1.42) to a solution of 2.18 g of the purified free base in ethyl acetate gives the nitrate melting at 88- 95 °. By recrystallization from ethyl acetate, peach-colored crystals are obtained from the analytical sample, melting at 154-156 °.

Analysis: 20 C% H% Cl% N%

Calculated for C23H19C13N2 ° 2 * HN03! 52.64 3.84 20.27 8.01

Find ; 52.45 3.92 20.30 7.79 Similarly, the replacement of 4-25 chloro-1-naphthol in the above test with p-hydroxydi-phenylamine, 4- (4- acetyl-1-piperazinyl) phenol (patent application of the Federal Republic of Germany DOS No. 2 804 096) and p-methoxybenzylmercaptan and the use of the suitable salt-forming acid give the following respective products:

1- (2- (4-anilinophenoxyethoxy) - 2- (2,4-dichlorophenyl) ethyl] -1H-imidazole oxalate acid, melting at 131-135 ° (Table I, compound No. 34).

Analysis: 35 C% H% Cl% N%

Calculated for C25H23C12N302.C2H204: 58.07 4.51 12.70 7.52

Found: 51.71 4.53 12.45 7.57 46 1- (2- (4- (4-acetyl-1-piperazinyl) phenoxyethoxyJ- »2- (2,4-dichlorophenylJethyl) -1H-imidazole, flux at 128-130 ° (Table I, compound No. 35).

Analysis: 5 C% H% Cl% N%

Calculated for C25H28C12N4 ° 3: 59'65 5.61 14.08 11.13

Found: 59.90 5.64 13.88 10.92

1- (2- (2,4-DichlorophenylJ-2- ((4-10 methoxybenzylthio) ethoxyjethyl) -iH-imidazole nitrate, melting at 86-88 ° (Table I, compound No. 36).

Analysis:; C% H% Cl% N% S%

Calculated for α91Η99αΐ, Ν, 0.33.ΗΝ0-: 50.40 4.63 14.17 8.40 6.41

Found: 50.23 4.63 14.27 8.34 6.46

Example 18

1- (2- (2,4-dichlorophenyl) -2- (2,4-dichloro-thiophenoxymethylthio) ethyl J-1H-imidazole acid fumarate (Table I, Compound No. 33)

4.51 g (0.01 mole) of 1- (2- (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethyl} -1H-imidazole oxalate acid is added to a stirred solution of 2.02 g 25 (0.050 mole) of sodium hydroxide in 180 ml of ethanol at 25 ° under a nitrogen atmosphere After stirring at 25 ° for 0.75 hours, 2.5 g (0.011 mole) of sodium sulfide are added chloromethyl and 2,4-dichlorophenyl, the mixture is refluxed for 18 hours and concentrated to dryness, the residue is diluted with water and the mixture is extracted with two portions of diethyl ether. having combined the extraction phases with ether, they are washed successively with dilute sodium hydroxide, water, brine and dried over sodium sulphate. ether leaves 4.2 g of a cloudy oil which gives 3.8 g of pure free base after chromatography on 100 g of silicic acid with a mixture of methylene chloride and acetone at 10: 1.

47

The oily free base (3.8 g) is treated with »950 mg of fumaric acid, giving, after dilution with acetonitrile, the fumarate which melts at 117-120 ° after two recrystallizations from acetonitrile.

5 Analysis: C% H% Cl% N% S%

Calculated for C18H14C14N2S2.C4H404: 45.53 3.13 24.44 4.83 11.05

Found: 45.35 3.09 24.10 4.68 11.04 10 Example 19

1- (2- (4-biphenylylmethoxyethoxy) -2- (2,4-dichloro-phenyl) ethyl J-1H-imidazole nitrate (Table I, compound No. 37)

A solution of 3.64 g (0.01 mole) of 1— [2— (2,4-di- chlorophenyl) -2- (2-hydroxyethoxy) ethyl J-1H solution is added dropwise over 10 minutes. -imidazole in 22 ml of dimethylformamide in a suspension in mineral oil with stirring, cooled with ice water, of sodium hydride at 57% (926 mg, 0.022 mole) in 15 ml of DMF under 20 atmosphere nitrogen. Stirring is continued at 40-45 ° for 20 minutes to complete the formation of the salt. The cooling bath is replaced and a solution of 2.03 g (0.01 mole) of 4-chloromethylbiphenyl in 10 ml of THF is added. The mixture is then heated to an oil bath temperature of 65 ° for 3 hours and concentrated to dryness. The residue is partitioned between diethyl ether and water. The ether phase is washed with brine, dried over sodium sulfate and the ether is removed. The residue is dissolved in acetonitrile and the mineral oil is washed off with n-pentane (twice). The acetonitrile is removed and the residue is chromatographed on 120 g of silicic acid with a mixture of methylene chloride and acetone at 10: 1, and 1.56 g of the free base are thus obtained in the form of a yellow oil. A solution of 1.56 g of the free base in ethyl acetate is treated with 300 mg of oxalic acid to give the acid oxalate which melts at 113-121 ° after recrystallization from ethyl acetate , then recrystallization from nitromethane. The acid oxalate is distributed between diethyl ether and a dilute aqueous solution 48 of sodium hydroxide. The ether phase is washed with water and brine, dried over sodium sulfate and concentrated. By treating a solution of the resulting free base in ethyl acetate with 70% nitric acid (d = 1.42), the nitrate indicated in the title is obtained, melting at 114-116 , 5 °. By recrystallization from ethyl acetate, colorless crystals are obtained from the analytical sample, melting at 115-118.5 °.

Analysis: 10 C% H% Cl% N%

Calculated for C9fiH94C19N9 ° 9 * HN0 ·}: 58.88 4.75 13.37 7.92

Found: 58.67 4.98 12.89 7.73

Example 20 Chloromethyl and 2,6-dichlorophenyl sulfide (Scheme III, 21_, Z = C1, n = 1, Y = S, m = 0, R1,2 = 2,6-dichloro)

Following the general procedure of Goralski and Burk (J. Or g. Chem., 42, 3094 (1977)), 0.6 g (2.2 mmol) of benzyltriethylammonium bromide is added to a mixture with stirring. 12.0 g (0.067 mole) of 2,6-dichlorothiophenol and 4.42 g (0.067 mole) of 85% powdered potassium hydroxide in 300 ml of 22 ° bromochloromethane. An immediate exothermic reaction ensues, the temperature rising to 38 °. Stirring is continued at room temperature for 2 hours. The mixture is filtered and the excess bromochloromethane is removed in a rotary evaporator to obtain an amber colored oil.

A solution of the oil in diethyl ether is dried over sodium sulfate and concentrated to give the crude product as a crystalline solid. By recrystallization from "Skellysolve-B", 11.9 g of large crystals of the title compound are obtained, melting at 52.5-55.5 °.

49 *

Example 21 * Acid fumarate of 1- (2- (2,4-dichlorophenyl) -2- (2,6-dichlorophenylthiomethylthio) ethyl] -1H-imidazole (Table I, compound No. 39) 5 -

4.51 g (0.01 mole) of 1 - [2 - (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethyl) -1H-imidazole acid oxalate is added to a stirred solution of 2.02 g (0.050 mole) of sodium hydroxide in 180 ml of ethanol at 25 ° under a nitrogen atmosphere. After stirring at 25 ° for 0.75 hour, 2.5 g (0.011 mol) of chloromethyl and 2,6-dichlorophenyl sulfide are added. The mixture is refluxed for 18 hours and concentrated to dryness. The residue is diluted with water and the mixture is extracted with two portions of diethyl ether. After having combined the extraction phases with ether, they are washed successively with dilute sodium hydroxide, water, brine and dried over sodium sulfate. Removal of the ether leaves 4.4 g of a cloudy oil which gives 2.56 g of the pure free base after chromatography on 150 g of silicic acid with a mixture of methylene chloride and acetone at 10: 1.

A 2.56 g solution of the free base in acetonitrile is treated with 632 mg of fumaric acid to give 2.22 g of colorless crystals of acid fumarate melting at 134-136 °. By recrystallization from acetonitrile, the analytical sample melting at 133-136 ° is obtained.

Analysis: 30 C% H% Cl% N% S%

Calculated for C18H14C14N2S2.C4H404: 45.53 3.13 24.44 4.83 11.05

Found: 45.36 3.02 24.29 5.00 11.03 50

Example 22 1- (2- (4-chlorophenoxymethylthio) -2- (2,4-dichlorophenyl) ethylj-1H-imidazole sesquifumarate acid (Table I, compound No. 41) 5 ---

Following the procedure of Example 21r and replacing the chloromethyl and 2,6-dichlorophenyl sulfide with chloromethyl and 4-chlorophenyl ether, the compound indicated in the title is obtained, melting at 158 -10 160 °.

Analysis: C% H% Cl% N% S%

Calculated for C18H15C13N20S.1.5 (C4H404): 49.04 3.60 18.09 4.77 5.45 15 Found: 49.28 3.74 17.74 4.85 5.51

Example 23

1- {-2 - [(4-chlorophenylthio) methoxy] -2- (2,4-dichlorophenylJethyl] -1H-imidazole acid fumarate (Table I, compound No. 40) 20 -

2.57 g (0.01 mole) of 1- (2,4-dichlorophenyl) -2- (1H-1-imidazolyl) ethanol are added (United States Patent No. 3,717,655 and Godefroi et al., See above) to a stirred mixture of a suspension in 57% sodium hydride mineral oil (463 mg, 0.011 mole) in 15 ml of DMF and 10 ml of THF, under a nitrogen atmosphere. The mixture is heated at moderate reflux for 0.75 hours to complete the formation of the salt. The mixture is cooled in an ice-water bath and a solution of 1.93 g (0.01 mole) of chloromethyl and 4-chlorophenyl sulfide in 3 ml of THF is added thereto. The mixture is heated at moderate reflux for 18 hours and concentrated. A solution of the residue in diethyl ether is washed successively with water, an aqueous solution of sodium carbonate, brine, then it is dried over sodium sulfate and concentrated. The residue is dissolved in acetonitrile and the mineral oil is removed by washing with n-pentane (2 times). Removal of acetonitrile leaves a dark colored oil which is chromatographed on 120 g of silicic acid with a mixture of methylene chloride and acetone at 20: 1 to obtain 1.79 g of a brown oil that crystallizes. By recrystallization from cyclohexane, 1.5 g of the free base 5, melting at 95-97 °, are obtained.

Treatment of a solution of the free base in acetonitrile with fumaric acid gives the acid fumarate melting at 128-130 °. Two recrystallizations from a mixture of ethyl acetate and "Skellysolve-B" give the analytical sample melting at 129-133 °.

Analysis: C% H% Cl% N% S%

Calculated for C18H15C13N20S.C4H404: 49.87 3.61 20.07 5.29 6.05 15 Found: 49.80 3.60 19.99 5.17 6.20

Example 24

1- (2- (4-chlorobenzylthiomethylthio) -2- (2,4-dichlorophenyl) ethyl J-1H-imidazole acid fumarate (Table I, compound No. 42) 20 -

4.51 g (0.01 mole) of 1- [2- (2,4-dichlorophenyl) -2- (ethoxythiocarbonylthio) ethyl J-1H-imidazole oxalate is added to a stirred solution of 2.02 g (0.05 mole) of sodium hydroxide in 180 ml of ethanol at 25 ° under a nitrogen atmosphere. After stirring at 25 ° for 0.75 hour, a solution of 2.07 g (0.01 mole) of 4-chlorobenzyl sulfide and chloromethyl in 2 ml of ethanol is added. The mixture is refluxed for 20 hours and concentrated to dryness. The residue is partitioned between diethyl ether and water. The ether phase is washed successively with water, an aqueous solution of sodium carbonate, water and brine, then it is dried over sodium sulfate. Removal of the ether leaves 3.3 g of the free base in the form of a viscous brown oil. By treating a solution of 3.3 g of the free base in acetonitrile with 0.78 g of fumaric acid, 2.5 g of the title compound are obtained, melting at 120-125 °.

By recrystallization from ethyl acetate, colorless crystals are obtained from the analytical sample, melting at 40 121-123 °.

52

Analysis: C% H% Cl% N% S%

Calculated for C19H17C13N2S2.C4H404 î 49.34 3.78 19.00 5.00 11.45 5 Found: 49.70 3.90 18.94 5.24 11.39

Example 25

1- (2- ((4-chlorobenzylthio) methoxy) -2- (2,4-dichlorophenyl Jethyl) -iH-imidazole oxalate acid (Table I, compound No. 43) io -: -

2.57 g (0.01 mole) of 1- (2- (2,4-dichlorophenyl) -2- (2-hydroxyethoxy) ethylJ-1H-imidazole is added to a suspension in mineral oil, under stirring, 57% sodium hydride (463 mg, 0.011 mole) in a mixture of 15 ml of DMF and 10 ml of THF The mixture is heated at moderate reflux for half an hour to complete the formation of Add a solution of 2.07 g (0.01 mole) of 4-chlorobenzyl sulfide and chloromethyl and heat the mixture at moderate reflux for 20 hours.

It is partitioned between diethyl ether and water. The ether phase is filtered to remove the starting alcohol (1.3 g). The ether filtrate is concentrated. A solution of the residue in acetonitrile is washed twice with n-pentane to remove the mineral oil. The acetonitrile is removed and the residue is chromatographed on 30 g of silicic acid with a mixture of methylene chloride and acetone at 25: 3 to give 190 mg of free base in the form of a viscous brown oil . By treating a solution of 190 mg of the free base in ethyl acetate with 40 mg of oxalic acid, colorless crystals of the title compound are obtained, melting at 148-150 °. The product melts at 153.5-154 ° after recrystallization from acetonitrile.

Analysis: C% H% Cl% N% S% 35 Calculated for C19H17C13N20S.C2H204: 48.71 3.70 20.54 5.41 6.19

Found: 49.21 3.71 19.95 5.30 6.73

The antimicrobial compounds of the invention display antifungal and antibacterial activity against a wide variety of pathogens for humans and animals, in addition to those indicated in Tables II and III above, and they are therefore useful not only in pharmaceutical applications, but also in agricultural, industrial, household and other applications which require such activity. Generally, the antimicrobial compositions can contain these compounds in any concentrations, that is to say from approximately 0.1 to approximately 99.9% in a conventional suitable carrier or vehicle suitable for the intended purpose. For example, concentrates of about 10 to 90% can be prepared for dilution by the user at concentrations generally between about 0.1 and 10%.

In the case of pharmaceutical formulations, the compositions may be in the solid, semi-solid or liquid form, for example tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions, gels, ointments, etc. Pharmaceutically acceptable non-toxic carriers or excipients normally used for solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin, lactose, starch, etc. ; for semi-solid formulations, there may be mentioned, for example, polyalkylene glycols, various forms of petroleum jelly and other cream bases; for liquid formulations, it can be mentioned. for example water, vegetable oils and low boiling solvents such as isopropanol, hydrogenated naphthalenes, etc. The pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical operations such as sterilization and may contain conventional pharmaceutical excipients such as preservatives, stabilizers, emulsifiers, salts for the regulation of osmotic pressure and buffers. The compositions can also contain other substances endowed with therapeutic activity.

54

The pharmaceutical compositions of the invention * normally contain a non-toxic pharmaceutically acceptable carrier in association with one or more compounds represented by formula 4 in an amount effective to combat or prevent the particular condition being treated. Since the active compounds of the invention display antifungal and antibacterial activity over a wide range of concentrations, the effective amount can be varied. For example, in topical formulations, the amount can range from about 0.1 to about 10% of the total pharmaceutical formulation, while in other formulations, the amount can range from 5 to "95% or more. Preferably, the pharmaceutical compositions of the invention are formulated in unit doses to facilitate administration (a unit dose representing the amount of active ingredients administered in one dose).

In pharmaceutical applications, the compounds and compositions of the invention can be administered to humans and animals by conventional methods, for example topically, orally, parenterally, etc. "Topical" administration includes intravaginal application, while parenteral administration involves intramuscular injection as well as subcutaneous and intravenous injection. - An intravenous injection of imidazole derivatives has been shown to be effective for - certain systemic conditions (see, for example

Drugs 9_, 419-420 (1975) which describes the intravenous administration of Miconazole, i.e. Ι- ΒΟ (2,4-dichloro-ß- (2 ', 4'-dichlorobenzyloxy) phenethyl) nitrate ] imidazole to patients with systemic candidiasis). Topical application is the preferred mode of administration in pharmaceutical applications. For such treatment, an area which is the site of a fungal or bacterial development or which must be protected from attack by fungi or bacteria can be treated with the compounds of formula 4 ^ of the invention or with compositions containing it, for example by dusting, 55; sprinkling, spraying, rinsing, brushing, immersion, * coating, coating, impregnation, etc.

The exact pharmaceutical administration regime for the compounds and compositions described herein necessarily depends on the needs of the individual being treated, on the type of treatment, for example depending on whether it is a preventive or curative treatment. , the type of organism involved and of course the appreciation of the attending physician. In general, for systemic administration (eg, oral or parenteral), the active ingredient should be administered in amounts of between about 1 and 100 mg / kg of body weight per "day (preferably between about 5 and 50 mg / kg body weight per day), which are divided into several applications (for example 3 individual doses) in order to obtain effective results. However, for localized (e.g. topical) administration, less of the active ingredient should be used proportionately.

In agricultural applications, the compounds of the invention can be applied directly to plants (eg seeds, foliage) or to the soil. Compounds of the present invention may, for example, be applied to seeds, alone or in admixture with a solid powder carrier. Representative examples of powdered supports include various mineral silicates such as mica, talc, pyrophyllite and clays. The compounds of the invention can also be applied to seeds in a mixture with a conventional surface-active wetting agent, with or without additional solid support. Surfactant wetting agents which can be used include all agents of the conventional anionic, nonionic, amphoteric or cationic types. For the treatment of a soil containing fungi, etc., the compounds of the invention can be applied in the form of a powder mixed with sand, earth or a solid support in powder form such as mineral silicate, with or without addition of surface-active agent, or the compounds of the invention can be applied in the form of an aqueous sprayable solution containing 56 tî i optionally a surface-active dispersing agent and a support =, solid powder. For the treatment of foliage, the compounds of the invention can be applied to growing plants in the form of an aqueous sprayable composition which contains a surface-active dispersing agent with or without the addition of powdered solid support and hydrocarbon solvents.

In industrial applications, the compounds of the invention can be used to combat bacteria and fungi by contact of pathogens with the compounds in any known manner. Materials capable of supporting bacteria and fungi can be protected by contact, mixing or

M

impregnation of these materials with the compounds of the invention. In order to increase their effect, the compounds of the invention can be combined with other pesticides such as fungicides, bactericides, insecticides, acaricides, etc. A particularly important application of the compounds of the invention in the industrial and agricultural field lies in their use as food preservatives against bacteria and fungi which spoil and contaminate food.

It goes without saying that the present invention has only been described by way of explanation, but in no way limiting, and that numerous modifications can be made without departing from its scope.

"*

Claims (12)

57 &? CLAIMS> 1. A compound of formula: 5 O R1 r2 CH2CH-X CCH2) n-ï- CCH2) m — r3 r4V. R5-fS Λ m (as well as its antimicrobial acid addition salts), formula wherein X and Y are, independently, sulfur or oxygen; m is zero or 1; n is 1, 2 or 3, provided that when n is 1, X and Y cannot both represent oxygen; R and R independently represent hydrogen, halogen or an alkyl group, or together form the atoms necessary to complete a naphthalene ring; R is a group CF ^, SCFg, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, pyrrolidinyl, piperidinyl, piperazinyl, alkanoylpiperazinyl, morpholinyl, alkylamino, dialkyl-25 amino, alkanoylamino, amino, nitro, carboxy, carbalkoxy alkyl chosen from phenyl, benzyl, benzoyl, phenylthio, phenylsulfonyl, phenylamino and * benzoylamino radicals, this aryl radical being optionally * substituted on the nucleus by one or more halogens or 4 or CF radicals, alkyl or alkoxy; and R, R and R independently represent hydrogen, a halogen or a CFgr alkyl, alkoxy or phenyl group optionally substituted on the nucleus by one or more halogens or radicals CF ^, alkyl or alkoxy; the above-mentioned alkyl, alkoxy and alkanoyl radicals containing 1 to 6 carbon atoms, the above-mentioned alkenyl and alkynyl radicals containing 2 to 12 carbon atoms and the above-mentioned cycloalkyl radicals containing 5 to 8 carbon atoms carbon. 58 k î 2. Compound according to Claim 1,,, 4 5 - characterized in that R is a 2-chloro radical, R is a 4-chloro radical and R6 is a hydrogen atom. 3. A compound according to claim 1, characterized in that R is a trifluoromethyl, alkyl, phenyl, phenylsulfonyl, benzyl, benzoyl, f 2 3 phenylamino or 4-acetylpiperazinyl group and R and R are hydrogen atoms. 4. Compound according to claim 1, 10 characterized in that R is a chloro radical. 5. Compound according to claim 1, O characterized in that R is a chloro or phenyl radical. . 6. Compound according to claim 1, 4 characterized in that R and R are chloro radicals. 7. Compound according to claim 1, characterized in that R and R occupy positions 2 and 3 3 and combine to complete a naphthalene nucleus and R is a 4-chloro radical. 8. Composition useful for inhibiting the development of fungi or bacteria, characterized in that it comprises an antimicrobial amount of a compound according to any one of the preceding claims, in mixture with a suitable support. 9. A composition for pharmaceutical use according to claim 8, characterized in that the support is a non-toxic support acceptable from the pharraaceu point of view. tick. * 10. A composition according to claim 9, * intended for topical administration, characterized in that the compound is present in an amount of from about 0.1 to about 10% by weight. 11. Compound useful as an intermediate compound for the production of the compound according to claim 1, characterized in that it corresponds to the formula: 59 ’· / -N O 5 I CH0CH-X (CH0) -Z 2. n R \ R- £ g6 10 i ^ e6 in which Z is a radical YM, halo, COO-alkyl, methanesulfonate or: J. i * 15 oso 2 "@ ~ CH3 4 M is a hydrogen or alkali metal atom and X, Y, R, e / r R, R and n have the definitions given in claim 1. 12. Compound according to any one of claims 1 or 2, characterized in that X and Y are both sulfur, preferably in that n, and ni are both equal to 1 and more particularly still in that 12, 3 R and R both represent hydrogen and R is a 4-chloro radical. "