HU193633B - Process for production of new benzo /b/ tiofenes and tiocromates - Google Patents

Abstract

The present invention relates to novel benzothiophenes of the formula I and thiochromes and their acid addition salts. In formula I, n is 1-4, p is 0 or 1, q is 0, 1 or 2, R and R1 are hydrogen or halogen, alkyl or haloalkyl, or R and R1 form a carbocyclic ring; X is sulfur, sulfinyl or sulfonyl; Y imidazolyl; Z is an alkenyl group or a heterocyclic aromatic group which may be substituted and, if n is 1-4, Z, alkylthio, phenyl or phenoxy, and the latter two are optionally substituted. The novel compounds have antimicrobial activity. -1-

Description

The present invention relates to novel benzo [b] thiophene and thiochroman derivatives having antimicrobial activity and to antimicrobial compositions containing such compounds.

The present invention provides compounds of the formula I and their acid addition salts wherein π is an integer from 0 to 1 to 4; p is 0 or 1;

q is 0, 1 or 2;

R and R 'are independently hydrogen, halogen, C1-4 alkyl, or represents, C 1-4 haloalkyl having 1-3 halogen atoms or the adjacent positions of R and R' together C5-7 ^L condensation polymerized, saturated or forms an unsaturated carbocyclic ring;

X represents a sulfur atom or a sulfinyl or sulfonyl group;

Ύ 1-imidazolyl,

Z is C 2 -C 4 alkenyl or thienyl, quinolyl, benzothienyl, pyridyl, thiazolyl, pyrazolyl, thiadiazolyl or isoxazolyl, and said heterocyclic groups optionally substituted in one to three positions by halogen, C 1 -C 4 alkyl, Substituted with C4 alkylenedioxy, phenyl or -C1-4 alkanoyl-piperazino, with the proviso that when n is an integer from 1 to 4, Z is a C 1-4 alkylthio group or a phenyl or it may also represent a phenoxy group substituted at one to three positions by halogen, C 1-4 alkyl, C 1-4 alkylenedioxy, or Ν- (C 1-4 alkanoyl) piperazino, and the dotted line is single or represents a double bond with the proviso that it represents a double bond only when p is 0 and X is sulfur.

The term "halogen" means fluorine, chlorine, bromine and iodine. Alkyl groups contain from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl. In Z, alkyl, alkylthio and alkenyl can be straight or branched. These groups include the aforementioned alkyl groups, methylthio, ethylthio, 1-propenyl, 2-propenyl.

Substituted phenyl in Z is especially mono-, di- and tri-halophenyl and mono-, di- and tri-lower alkylphenyl, such as 4-chlorophenyl, 2,4-dichlorophenyl, 2,5- dichlorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, tolyl, xylyl and mesityl.

In the N-alkanoylpiperazino group, the alkanoyl group may be straight or branched and may have up to 4 carbon atoms, such as formyl, acetyl or butyryl.

The aromatic heterohydric radicals in Z are optionally substituted with at least one halogen or alkyl, especially 2-thienyl, 3-thienyl, 2-chloro-3-thienyl, 5-chloro-2-thienyl, 2,5-dichloro. 3-thienyl, pyridyl, quinolyl and thiazolyl.

The compounds of formula I wherein the dashed line represents a single bond may exist in the form of cis and trans isomers (2,3-cis and 2,3-trans isomers when p is 0 and 3,4-cis). - and 3,4-trans isomer, when p is 1), from which the racemates can be resolved by salt formation with optically active acid and fractional crystallization. The invention encompasses all isomers; in general, the cis isomers are preferred over the trans isomers because of their greater antimicrobial activity.

A preferred group of compounds of formula I are those wherein X, Y, n and p are as defined above, q is 1, R and R ¹ are each independently hydrogen or halo, lower alkyl, lower haloalkyl,

Z is lower alkyl, alkenyl, or said heterocyclic aromatic group optionally substituted with at least one halogen or lower alkyl, with the proviso that when n is an integer from 1 to 4, Z is alkylthio, phenyl, phenoxy or may also be phenyl substituted with halogen, lower alkyl, or N- (lower alkanoyl) piperazino, "the lower term denotes C 1-4 groups and the dotted line represents a single bond.

In these compounds, X is particularly sulfur and p is 0, another preferred group of such compounds being compounds of formula II, wherein R, R ¹ and n are as defined above. In compounds of formula II, Z is preferably a phenyl or heterocyclic aromatic group optionally substituted with halogen or lower alkyl, such as thienyl or 2-chlorothienyl. In another preferred group of compounds of formula II, n is 1, Z is chlorophenyl or dichlorophenyl, R and R ^{1 are} hydrogen or halogen.

Particularly preferred compounds of formula I for their favorable antimicrobial activity (number in parentheses indicate mass spectrum; M ⁺ ) are: cis-6-chloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro -2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 99-101 ° C, cis-6-chloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 98-100 ° C,

-2193633 cis-6-fluoro (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 76-78 ° C, cis-5-fluoro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. . 109— ITPC

Other preferred compounds of formula I are: cis-6-chloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene-1. -oxides, mp. 125 ° C, cis-5-chloro-3- (2'-chloro-3'-phenyl) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene -1 oxide (rubber),

6-chloro-3- (2'-chloro-3'-phenoxy) -2- (1 '-imidazolylmethyl) -benzo [b] thiophene, m.p. 84 ° C

5-chloro-3- (2'-chloro-3'-thenyloxy) -2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 124 ° C, cis-6-chloro-3- (6'-chloro-3'4'-methyleridioxybenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene , op. 130-132 ° C, cis-6-chloro-3- (2'-chloro-6'-fluorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene , op. 140 ° C, cis-6-chloro-3 - ((5'-chloro-3'-methyl-1'-phenylpyrazol-4'-yl) methoxy) -2,3-dihydro-2- (1 "-Imidazolylmethyl) benzo [b] thiophene, [468], cis-6-chloro-3- (2'-chlorobenzo [b] thienyl-3'-methoxy) -2,3-dihydro-2 - (1'-imidazolylmethyl) = benzo [b] thiophene, m.p. 129-130 ° C, cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazole) benzo [b] thiophene, op. 77 ° C, cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolyl) -benzo [b] thiophene oxide,

6-chloro-3- (2'-chloro-3'-thenyloxy) -2- (1 '-imidazolyl) -benzo [b] thiophene, m.p. 115 ° C, cis-3- (2'-chloro-3'-thenyloxy) -2,3,5,6,7,8-hexahydro-2- (1'-imidazolylmethyl) naphtho [2,3 -b] thiophene, op. 87-88 ° C, cis-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) naphtho [1,2-b] thiophene, m.p. . 165-166 ° C (HCl), cis-3- (2'-chloro-3'-thenyloxy) -2,3,4,5,6,7-hexahydro-2- (1 "-imidazolylmethyl) - naphtho [3,4-b] thiophene, m.p. 106-108 ° C, cis-6-chloro-3-allyloxy-2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, (oil), [306]; cis-6-chloro-3- (quinoline-2'-methoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, [407]; cis-6-chloro-3- (4'-thiazolylmethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 92-93 ° C, cis-6-chloro-2,3-dihydro-3- (4'- (5'-methyl-3'-phenylisoxazolyl) methoxy) -2- (1 '- imidazolylmethyl) benzo [b] thiophene, m.p. 134-135 ° C, cis-6-chloro-3- [8'-chloro-1,3'-dioxolo [4 ', 5'; g] quinolin-7'-ylmethoxy) -2,3-dihydro -2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 212-214 ° C, cis-6-chloro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, cis-6-chloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, [390], cis-6- chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 122-124 ° C, cis-5-chloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, m.p. . 95-97 ° C, cis-7-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, op. 86-87 ° C, cis-5,6-dichloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene , op. 128-129 ° C, cis-5,7-dichloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, cis-6-trifluoromethyl-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 112-114 ° C, cis-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1-imidazol-1-yl) benzo [b] thiophene, cis-5-chloro- 3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 157-158 ° C (nitrate), cis-5-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, op. 96-97 ° C, cis-4,6-dichloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, op. 147-149 ° C, cis-4,6-dichloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene , op. 122-124 ° C, cis-5,6-dichloro-3- (2'4'-dichlorobenzoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, cis-5-chloro-3- (2 ', 6'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, cis-6-chloro -3- (2'-chloro-5'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 94-95 ° C, cis-5-chloro-3- [2'- (4 '- (1-acetyl-4' '- piperazinyl) phenoxy) ethoxy] -2,3-dihydro-2- ( 1 "" imidazolylmethyl) benzo [b] thiophene [478] and cis-6-chloro-3- (3'-pyridylmethoxy) -2,3-dihydro-2- (1 "imidazolyl) methyl) benzo [b] thiophene, [358] (diHCl).

Other typical compounds of formula I:

cis-7-chloro-3- (methylthiomethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, [326] _; cis-7-chloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman, m.p. Γ35-137 ° C (nitrate), cis-7-chloro-4- (2'-chloro-3'-phenoxy) -3- (1'-imidazolylmethyl) thiochroman, [378]

The compounds of the formula I are bases and can be converted into acid addition salts with acids, in particular by at least neutralizing the free bases of the formula I, preferably by addition of the acid to pH 5. Particularly suitable acids for this purpose are hydrochloric, sulfuric, phosphoric, hydrobromic and nitric acids.

The compounds of formula I and their acid addition salts may be prepared by any of the methods for the preparation of compounds of similar structure.

The compounds of the formula I according to the invention or their acid addition salts are prepared by reacting a compound of the formula III

-3193633 is reacted with a compound of formula IV wherein R, R ', Y, Ζ η, p and q are as defined for formula I, X' sulfur and Q ¹ and Q ^{2 are} hydroxy and the other is a reactive ester group. in the presence of an organic solvent and an alkali metal base such as X, sulfur containing compounds are obtained and optionally

i) for the preparation of compounds of formula I wherein X-SO or -SO ₂ represents a resulting compound in which X is a sulfur atom, and ii) for the preparation of compounds of formula I in which the dashed line represents a double bond, the compound of formula I wherein X-SO is dehydrated and the resulting compound of formula I is isolated as the free base or acid addition salt.

The reactive ester group at the Q or more preferably Q ₂ site may be a hydrogensulfonyloxy group, but preferably a halogen atom, especially a chlorine or bromine atom.

This process is preferably carried out by reacting a compound of formula III in which Q, hydroxy, with an alkali metal base, such as an alkali metal hydride, or an alkali metal hydroxide, such as potassium hydroxide, or an alkali metal salt, adding the halide of formula IV, in which Q is ² halogen atoms. The organic solvent may be an amide (e.g. dimethylformamide or hexamethylphosphoric triamide), an aromatic hydrocarbon (e.g. benzene or toluene), an ether (e.g. diethyl ether, dioxane, tetrahydrofuran or ethylene glycol methyl ether), a ketone (e.g. acetone) or, if the base is an alkali metal alcohol methanol or ethanol). The reaction with the halide of formula IV can be carried out at 0 to 100 ° C, preferably at 20 to 60 ° C, for example at room temperature.

An excess of the alkali metal base and the halide can be used to improve the yield of the product of formula I.

In a particularly preferred method of preparing compounds of formula I wherein X is sulfur, sodium hydride is added at 0-5 ° C to a solution of the compound of formula III wherein Q ¹ is hydroxy at 0-5 ° C and at ambient temperature ca. After reacting for 1 hour, the compound of formula IV (wherein Q ² is bromo or chloro and n and Z are as defined in formula I) is added to the reaction mixture which is maintained at ambient temperature for a further approximately 1 hour. The resulting compound of formula I is isolated and purified by known methods such as extraction, chromatography and recrystallization.

Compounds of formula I wherein X is -SO or -SO ₂ (sulfoxide or sulfone) are formed from compounds of formula I wherein X is sulfur by oxidation, preferably organic peracid, in an inert organic solvent, in particular m-chloroperbenzoic acid (approximately equimolar). the sulfoxide and twice the sulfone) is prepared in a halogenated hydrocarbon such as chloroform or dichloromethane at ambient or lower temperatures, for example 0-5 ° C. Compounds wherein X is a sulfur atom and the dotted line is a double bond are prepared from compounds of formula I wherein X is -SO, p Ot and the dashed line represents a single bond, for example, with an anhydride such as acetic anhydride or especially trifluoroacetic anhydride, e.g. temperature in an inert organic solvent such as an aromatic hydrocarbon, especially benzene or toluene, and preferably at the reflux temperature of the mixture.

The halide starting materials of formula IV wherein Q ^{2 is} halogen and n and Z are as described above are known compounds or may be prepared by known methods. Halides which may be used in this first process of the invention include allyl chloride, methylthioethyl chloride, p-chlorophenoxymethyl chloride, a-chlorophenylthiomethyl chloride and 1 - {(4 '(1' -acetyl-4 '-piperazinyl)) -phenoxy (- 2-bromoethane.

The starting materials of formula III wherein X is sulfur can be prepared by any of the following known reaction sequences:

a) A thiochroman-4-one substituted in the benzene ring with R and R ^{1 is} first converted to the corresponding alpha-bromo ketone with bromine, in a solvent such as ether, chloroform or carbon tetrachloride. The resulting alpha-bromo ketone is then reduced to the corresponding bromohydrin, for example sodium borohydride, in a solvent such as a lower alcohol, especially methanol or ethanol. This bromohydrin is then reacted with a compound of formula YH, where Y is as defined above, in a solvent such as dimethylformamide, hexamethylphosphoric triamide, lower alcohol or acetonitrile to give a compound of formula III wherein q is 1 and p is 0, e.g. -imidazolylmethyl-benzo [b] thiophene, i.e. the six-membered thiochroman heterocycle is reduced to five members.

b) An aqueous solution of a compound of formula YH wherein Y is as defined above is reacted with 3-dimethylamino- (CH ₂ ) - thiochroman-4-one, where q is 1. The resulting 3-Y- (CH ₂ ) ₉ - is obtained. thiochroman-4-one, for example, with sodium borohydride in a lower alcohol, reduced to a compound of formula III, a mixture of cis and trans isomers; this compound may be used in the form of a mixture of the invention

-4193633

In the above reaction, or to the pure cis and trans isomer, it can be separated by standard techniques such as chromatography.

Process b) is preferred for the preparation of compounds wherein p is 1.

reacted with a N- [tri (lower alkyl) silyl] imidazole, preferably at the reflux temperature, and a VIII to the compound of formula obtained, in which Y - c) A VII the compound of formula - in which R and R ¹ are as defined above , R and R ¹ are as defined above. This compound can then be reduced to a compound of formula III wherein X is sulfur and p and q are 0; for example sodium borohydride in methanol.

Other compounds of formula III may be prepared in a similar manner or by known methods.

The invention also provides for the preparation of formula I compounds or an acid addition salt of Formula A process - in this formula, X, -SO- and p and q are both 0 - in such a way that a V compound having formula - wherein, R, R ^1, Z and n are as defined above, by reaction with a compound of formula VI, wherein Y is as defined above, and each lower alkyl group contains from 1 to 4 carbon atoms, preferably ethyl or especially methyl, and then i) for the preparation of a compound of formula -SO ₂ , the resulting product is oxidized, and ii) dehydrating the product of formula I wherein the dashed line represents a double bond, and the compound of formula I is free base or in the form of an acid addition salt.

The reaction of the compounds of the formulas V and VI can be carried out at elevated temperature, for example by heating the reaction partners with or without a solvent, in particular without solvent and by boiling.

The oxidation of a compound of formula I wherein X is sulfur to a compound of formula I wherein X is -SO- or -SOj - may be carried out, if desired, according to the first process described above.

Compounds of formula I and their salts show broad antimicrobial activity, including active against human and animal pathogenic fungi such as Aspergillus, Caudida, Epidermophyton, Geotrichum, Microsporum, Monosporum, Pityrosporum, Rhodotorula, Saccharomyces, Trichophyton, Trichosporon protozoa such as Trichomonas and also against human and animal pathogenic bacteria such as Actinomyces, Bacillus, Bacteroides, Clostridium, Escherichia, Mycobacterium, Mocardia, Propionibacterium, Sarcina, Staphylococcus, Streptococcus and Streptomyces. Mainly fungi of agricultural importance, such as Cladosporium, Colletotrichum,

Erysiphe, Fusarium, Helminthosporium, Penicillium, Peronospora, Phytophthora, Pithomyces, Polyspora, Puccina, Rhizoctonia, Solerotium, Uromyces and Venturia, and primarily act against agriculturally important bacteria such as Agrobacterium, Erwinia and Xanthemonas.

The following Examples A-D illustrate the preparation of the starting compounds required for the process of the invention (in particular of formula III):

EXAMPLE Cis-2,3-Dihydro-3-hydroxy-2- (1'-imidazolylmethyl) -benzo [b] thiophenes

AA) cis-6-Chloro-2,3-dihydro-3-hydroxy-2- (Γ-imidazolylmethyl) -benzo [b] thiophene

1) 3-Bromo-7-chlorothiochroman-4-one '10 g (50.3 mmol) of 7-chlorothiochroman-4-one are dissolved in 100 ml of chloroform and the solution is cooled to 0-5 ° C. Bromine (3.60 mL, 50.3 mmol) was added dropwise over 10 min. After stirring at room temperature for 1 hour, 100 ml of chloroform was added and the mixture was extracted with 10% aqueous sodium sulfate solution and then with 200 ml of water. The chloroform solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from cyclohexane

3-bromo-7-chlorothiochroman-4-one is obtained, m.p. 109-110 ° C.

2) 3-Bromo-7-chlorothiochroman-4-ol

3-Bromo-7-chlorothiochroman-4-one (59.6 h, 215 mmol) was suspended in methanol (500 mL), cooled to 0-5 ° C, and sodium borohydride (8.18 g, 215 mmol) was added in 3 portions. . After stirring for 3 hours at room temperature, the reaction mixture was poured into 4 L of ice water and extracted with 2 L of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was treated with a mixture of chloroform and hexane to give 3-bromo-7-chlorothiochroman-4-ol, m.p. 141-142 ° C.

3) cis-6-Chloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) -benzo [b] thiophene

5.27 g (18.8 mmol) of 3-bromo-7-chlorothiochroman-4-ol and 12.8 g (188 mmol) of imidazole are added to 100 ml of acetonitrile and the mixture is refluxed for 4 hours and then poured into 500 ml of water. and extracted with 500 ml of chloroform. The organic layer was washed with water (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with anhydrous ether, filtered and recrystallized from acetonitrile to give cis-6-chloro-2,3-dihydro-3-hydroxy-2- (Γ-imidazole 1-methyl) -benzo [b] thiophene.

AB) In Example AA (1-3) above, 7-chlorothiochroman-4-one is displaced with equivalent amounts of the following compounds:

(a) thiochroman-4-one,

b) 6-chlorothiochroman-4-one,

c) 8-chloro-thiochroman-4-one,

d) 5,7-dichlorothiochroman-4-one,

e) 6,7-dichlorothiochroman-4-one,

-5193633

f) 6,8-dichlorothiochroman-4-one,

g) 7-Trifluoromethylthiochroman-4-one to give the following compounds:

a) cis-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) benzo [b] thiophene;

b) cis-5-chloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) benzo [b] thiophene,

c) cis-7-chloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) benzo [b] thiophene,

d) cis-4,6-dichloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

e) cis-5,6-dichloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

f) cis-5,7-dichloro-2,3-dihydro-3-hydroxy-2- (Γ-imidazolylmethyl) -benzo [b] thiophene;

g) cis-6-trifluoromethyl-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) -benzo [b] thiophene.

Example B

3- (1 '-imidazolylmethyl) thiochromanols

BA) 7-Chloro-3- (1'-imidazolylmethyl) -thiochroman-4-ol

1) 7-Chloro-3- (1'-imidazolylmethyl) -thiochroman-4-one

Imidazole (25.8 g, 380 mmol) was dissolved in water (100 mL) and 7-chloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride (11.1 g, 38.0 mmol) was added. After stirring at room temperature overnight, water (1 L) was added and the mixture was extracted with chloroform (500 mL). The chloroform solution was washed in portions with a total of 2 liters of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

The residue was chromatographed on a silica gel column, eluting with chloroform. The eluates found to be identical by TLC were combined and concentrated in vacuo to give 7-chloro-3- (1-imidazolylmethyl) thiochroman-4-one. The product was further purified by crystallization from chloroform-hexane, m.p. 104-105 ° C.

2) 5.0 g (17.9 mmol) of 7-chloro-3- (1'-imidazolylmethyl) thiochroman-4-one are dissolved in 100 ml of methanol, cooled to 0-5 ° C and stirred 0.51 g (13.4 mmol) of sodium borohydride is added. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. Water (100 mL) was added to the residue and stirred at room temperature for 30 minutes. The residue was then filtered and washed with water (2 x 200 mL) and chromatographed on a silica gel column using chloroform: methanol: ammonium hydroxide (97: 3: 0.1) as eluent. The fractions found to be identical by thin layer chromatography were combined, evaporated to give two products, namely

a) cis-7-chloro-3- (1'-imidazolylmethyl) thiochroman-4-ol, m.p. 210-212 ° C (from ethanol) and

b) trans-7-chloro-3- (1'-imidazolylmethyl) thiochroman-4-ol, m.p. 135 ° C (from ethanol). BB / In Example BA, 7-chloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride is replaced by equivalent amounts of the following 6:

(a) 3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

b) 6-chloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

c) 8-chloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

d) 5,7-dichloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

e) 6,7-dichloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

f) 6,8-dichloro-3- (dimethylaminomethyl) thiochroman-4-one hydrochloride,

g) 7-Trifluoromethyl-3- (dimethylaminomethyl) -thiochroman-4-one hydrochloride, and the corresponding 3- (1'-imidazolylmethyl) -thiochroman-4-one derivative according to reaction BA / 1 with imidazole which is reacted with sodium borohydride according to BA / 2) to give the corresponding 4-hydroxy derivative, which is separated by chromatographic purification into the cis and trans isomers, i.e., the following compounds:

a) cis and trans-3- (r-imidazolylmethyl) thiochroman-4-ol,

b) cis and trans-6-chloro-3- (1'-imidazolylmethyl) thiochroman-4-ol,

c) cis and trans-8-chloro-3- (1'-imidazolylmethyl) thiochroman-4-ol,

d) cis and trans-5,7-dichloro-3- (1'-imidazolylmethyl) thiochroman-4-ol,

e) cis and trans-6,7-dichloro-3- (1'-imidazolylmethyl) thiochroman-4-ol,

f) cis and trans-6,8-dichloro-3- (1'-imidazolylmethyl) thiochroman-4-ol; and

g) cis and trans-7-trifluoromethyl-3- (1'-imidazolylmethyl) -thiochroman-4-ol,

Example C

- {(4 '- (1 "-Acetyl-4" -piperazinyl)) -phenoxy} -2-bromomethane

15.0 g (58.5 mmol) of 1-acetyl-4- (4'-hydroxyphenyl) piperazine and 3.28 g (58.5 mmol) of potassium hydroxide are dissolved in 500 ml of absolute ethanol. Ethylene dibromide (50.4 mL, 585 mmol) was added and the mixture was refluxed for 2 hours. An additional 3.28 g (58.5 mmol) of potassium hydroxide was added and refluxed again for 2 hours. This last step is repeated twice more. The ethanol was removed in vacuo. The residue was dissolved in 1 liter of chloroform and extracted with 1 liter of water. The chloroform solution was dried over anhydrous magnesium sulfate, concentrated and the residue was chromatographed on silica gel using chloroform as eluent. The fractions found to be identical by TLC were combined, evaporated to give 1 - {(4 '- (1' -acetyl-4 '-piperazinyl)) -phenoxy) -2-bromomethane. Example D

Using equivalent amounts of 7-fluorothiochroman-4-one and 8-fluorothiochroman-4-one in Examples AA (1-3), cis-6-fluoro-2,3-dihydro-3-hydroxy-2- ( Α-imidazole 1-methyl) -6193633 zo [b] thiophene and cis-7-fluoro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) benzo [b] thiophene are obtained. .

The following examples illustrate the preparation of compounds of formula I and their acid addition salts; numbers in square brackets, e.g. [390] represent the characteristic molecular ion (M ⁺ ) peak of the mass spectrum.

Example 1 Cis-3- (Chlorotenyloxy) or (-chlorobenzyloxy) -2,3-dihydro-2- (1 H -imidazolylmethyl) -benzo [b] thiophenes

N-cis-6-Chloro-3- (2'-chloro-3-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene

A solution of cis-6-chloro-2,3-dihydro-3-hydroxy-2- (1-imidazolylmethyl) benzo [b] thiophene (2.0 g, 7.50 mmol) in dry dimethylformamide (20 ml) was added. Cool to 0-5 ° C and add 0.40 g (8.25 mmol) of a 50% sodium hydride dispersion and stir at room temperature for 1 hour. Subsequently, 1.75 g (8.25 mmol) of 2-chloro-3-tenylbromide are added and the mixture is stirred for an additional 1 hour at room temperature. It was then poured into 500 ml of ether and extracted three times with 500 ml of water. The ethereal solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using chloroform as eluent. The fractions found to be identical by thin layer chromatography were combined, concentrated in vacuo and the residue recrystallized from cyclohexane to give cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 "imidazolylmethyl). Benzo [b] thiophene is obtained, m.p. 99-101 ° C.

B / Equivalent amounts of the following compounds are used instead of 2-chloro-3-thienyl bromide in Example 1A:

a) 2,5-Dichloro-3-tenenium bromide

b) 4-chlorobenzyl chloride

c) 2,4-Dichlorobenzyl chloride, and the following derivatives are obtained: cis-6-chloro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (1 " -imidazolylmethyl) benzo [b] thiophene, cis-6-chloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1 '-imidazolylmethylbenzo [b] thiophene [390] and cis-6-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 122-124 ° C.

C) The cis-2,3-dihydro-3-hydroxy-2- (1 '-imidazolylmethyl) benzo [b] thiophenes prepared in Example AB are reacted with 2-chloro-3-thienyl bromide according to Example 1A and the following: compounds are obtained:

a) cis-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p.

101-102 ° C,

b) cis-5-chloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1 "-imidazol-1-ylmethyl) benzo [b ] thiophene, op. 95-97 ° C

c) cis-7-chloro-3- (2'-k 1 h-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 86-87 ° C

d) cis-4,6-dichloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

e) cis-5,6-dichloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 128-129 ° C,

f) cis-5,7-dichloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

g) cis-6-trifluoromethyl-3- (2'-chloro-3'-thenyloxy) 2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 112-114 ° C.

D / Similarly, when all of the cis-2,3-dihydro-3-hydroxy- (1'-imidazolylmethyl) benzo [b] thiophene prepared in Example AB is reacted with each of the three reagents listed in Example 1B, the following compounds are prepared: we get:

a) 1) cis-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (Γ-imidazolylmethyl) -benzo [b] thiophene [356],

2) cis-3- (4'-chlorobenzene loxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene,

3) cis-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1 "-imidazolylmethyl) -benzo [b] thiophene,

b) 1) cis-5-chloro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,

3-dihydro- (1'-imidazolylmethyl) -benzo [b] thiophene,

2) cis-5-chloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, m.p. 157-158 ° C (nitrate),

3) cis-5-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 96-97 ° C

c) 1) cis-7-chloro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,

3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

2) cis-7-chloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene,

3) cis-7-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

d) 1) cis-4,6-dichloro-3- (2 ', 5'-dichloro-3'-tenyloxy) ~

-2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

2) cis-4,6-dichloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 147-149 ° C,

3) cis-4,6-dichloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, m.p. . 122-124 ° C.

e) 1) cis-5,6-dichloro-3- (2 ', 5'-dichloro-3'-tenyloxy)

-2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

2) cis-5,6-dichloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene,

3) cis-5,6-dichloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b] thiophene,

f) 1) cis-5,7-dichloro-3- (2 ', 5'-dichloro-3'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b ] thiophene,

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2) cis-5,7-dichloro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

3) cis-5,7-dichloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b] thiophene,

g) 1) cis-6-trifluoromethyl-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (1 "-imidazolylmethyl) -benzo [b] thiophene,

2) cis-6-trifluoromethyl-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

3) cis-6-trifluoromethyl-3- (2 ', 4'-dichlorobenzoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene.

E) If the cis-6-fluoro-2,3-dihydro-3-hydroxy-2- (Γ-imidazolylmethyl) benzo [b] thiophene obtained in Example D and the cis-7-fluoro-2,3 -dihydro-3-hydroxy-2- (1'-imidazolylmethyl) · benzo [b] thiophene was reacted as in Examples 1A and 1B to give the following compounds:

a) 1) cis-6-fluoro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 76-78 ° C

2) cis-6-fluoro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene,

3) cis-6-fluoro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene;

4) cis-6-fluoro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene,

b) 1) cis-7-fluoro-4- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 109-111 ° C,

2) cis-7-fluoro-3- (2 ', 5'-dichloro-3'-thenyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b] thiophene,

3) cis-7-fluoro-3- (4'-chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene;

4) cis-7-fluoro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene.

Example 2

4- (Chlorobenzyloxy) (or 2-chloro-3-thenyloxy) -3- (1'-imidazolylmethyl) -thiochromans

N-cis-7-Chloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochromane was prepared as in Example 1A, 1.59 g (5.66 mmol) of cis-7. of chloro-3- (1'-imidazolylmethyl) thiochroman-4-ol, 1.13 g (7.0 mmol) of p-chlorobenzyl chloride 0.34 g (7.0 mmol) in 50% yield; sodium hydride in 10 ml of dry dimethylformamide, except that the reaction mixture was poured into 100 ml of chloroform. To prepare the nitrate salt, the free base (gum-like residue) is dissolved in 250 ml of anhydrous ether and added dropwise to a solution of nitric acid in isopropanol until precipitation is complete. The excellent cis-7-chloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman nitrates are filtered off and recrystallized from ethyl acetate-hexane, m.p. 135-137 ° C.

"8

B / trans-7-Chloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman [404] likewise 0.5 g (1.78 mmol) of trans-7-chloro. From -3- (1'-imidazolylmethyl) thiochroman-4-ol, 0.36 g (2.23 mmol) of p-chlorobenzyl chloride, 0.11 g (2.29 mmol) of 50% hydride dispersion in 10 ml of dimethylformamide.

C) In Examples 2A and 2B, p-chlorobenzyl chloride is replaced by an equivalent amount of 2-chloro-3-thienyl bromide and cis-7-chloro-4- (2'-chloro-3'-thenyloxy) -3- (1 " -imidazolylmethyl) thiochroman [378] and trans-7-chloro-4- (2'-chloro-3'-thenyloxy) -3- (1'-imidazolylmethyl) thiochroman are obtained.

D / Reaction of 3- (1'-imidazolylmethyl) thiochroman-4-ol prepared in Example BB with Examples 2A and 2B or with 2-chloro-3-thienyl bromide as in Example 2C gives the following compounds:

cis-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman, m.p. 136-138 ° C (nitrate), cis -4- (2'-chloro-3'-thenyloxy) -3- (1'-imidazolylmethyl) thiochroman, cis-6-chloro-4- (4 ' -chlorobenzyloxy) -3- (1 "-imidazolylmethyl) -thiochroman [390], cis-6-chloro-4- (2'-chloro-3'-thenyloxy) -3- (1" -imidazclyl), methyl) thiochroman, cis-8-chloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman, cis-8-chloro-4- (2'-chloro-3) '-thenyloxy) -3- (1'-imidazolylmethyl) thiochroman, cis-5,7-dichloro-3- (4'-chlorobenzyloxy) -3- (1-imidazolylmethyl) thiochroman, cis -5,7-dichloro-4- (2'-chloro-3'-thenyloxy) -3- (1-imidazolylmethyl) thiochroman, cis-6,7-dichloro-4- (4'-chlorobenzyloxy) ) -3- (1'-imidazolylmethyl) thiochroman, cis-6,7-dichloro-4- (2'-chloro-3'-thenyloxy) -3- (1-imidazolylmethyl) thiochroman, cis -6,8-dichloro-4- (4'-chlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman, cis-6,8-dichloro-4- (2'-chloro-3'- tenyloxy) -3- (1-imidazolylmethyl) thiochroman, cis-7-trifluoromethyl-4- (4'-chlorobenzyloxy) -3- (1'-imine) dazolylmethyl) thiochroman, cis-7-trifluoromethyl-4- (2'-chloro-3'-thenyloxy) -3- (1'-imidazolylmethyl) thiochroman, and the trans isomers corresponding to the compounds listed above .

F) If the 3- (1'-imidazolylmethyl) thiochroman-4-ol prepared in Example BB is treated as in Examples 2A and 2B, except that 2,5-dichloro-3 is substituted for p-chlorobenzyl chloride. Equivalent amounts of -tenyl bromide, 2,4-dichlorobenzyl chloride and 2,6-dichlorobenzyl chloride are used to give the following compounds:

a) 1) cis-4- (2 ', 5'-dichloro-3'-thenyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

2) cis-4- (2 ', 4'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman,

3) cis ^: 4- (2 ', 6'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman,

b) 1) cis-6-chloro-4- (2 ', 5'-dichloro-3'-thenyloxy) -3 (1 "-imidazolylmethyl) thiochroman,

2) cis-6-chloro-4- (2 ', 4'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman,

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3) cis-6-chloro-4- (2 ', 6'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) trichroman,

c) 1) cis-8-chloro-4- (2 ', 5'-dichloro-3'-thenyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

2) cis-8-chloro-4- (2 ', 4'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman,

3) cis-8-chloro-4- (2 ', 6'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman,

d) 1) cis-5,7-dichloro-4- (2 ', 5'-dichloro-3'-thenyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

2) cis-5,7-dichloro-4- (2 ', 4'-dichlorobenzyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

3) cis-5,7-dichloro-4- (2 ', 6'-dichlorobenzyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

e) 1) cis-6,7-dichloro-4- (2 ', 5'-dichloro-3'-thienoxy) -3- (1 "-imidazolylmethyl) thiochroman;

2) cis-6,7-dichloro-4- (2 ', 4'-dichlorobenzyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

3) cis-6,7-dichloro-4- (2 ', 6'-dichlorobenzyloxy) -3- (1' -imidazolylmethyl) thiochroman,

f) 1) cis-6,8-dichloro-4- (2 ', 5'-dichloro-3'-thenyloxy) -3- (1'-imidazolylmethyl) thiochroman,

2) cis-6,8-dichloro-4- (2 ', 4'-dichlorobenzyloxy) -3- (1' -imidazolylmethyl) thiochroman,

3) cis-6,8-dichloro-4- (2 ', 6'-dichlorobenzyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

g) 1) title-7-trifluoromethyl-4- (2 ', 5'-dichloro-3'-thenyloxy) -3- (1 "-imidazolylmethyl) thiochroman,

2) cis-7-trifluoromethyl-4- (2 ', 4'-dichlorobenzyloxy) -3- (1' -imidazolylmethyl) thiochroman;

3) cis-7-trifluoromethyl-4- (2 ', 6'-dichlorobenzyloxy) -3- (1'-imidazolylmethyl) thiochroman and trans isomers of the listed compounds.

Example 3 Cis-5-Chloro-3- {2 '- (4' - (r '-acetyl-4' '- piperazinyl) -phenoxy) -ethoxy-2,3-dihydro-2- (1' -imidazolyl) -methyl) benzo [b] thiophene

A) 0.5 g (1.87 mmol) of cis-5-chloro-2,3-dihydro-3-hydroxy-2- (1'-imidazolylmethyl) benzo [b] thiophene and 0.15 g A mixture of potassium hydroxide (2.2 mmol) in acetone (10 mL) was stirred at room temperature for 1 hour. 1 - {(4'- (1 "-acetyl-4" -piperazinyl)) -phenoxy} -2-bromomethane was added and stirred overnight at room temperature. Potassium hydroxide (0.15 g, 2.2 mmol) was added again and stirred overnight. This is repeated a third time. The mixture was poured into 500 ml of chloroform and extracted with 500 ml of water. The chloroform solution was dried over magnesium sulfate and concentrated in vacuo. The residue obtained is chromatographed on a silica gel column, eluting with 2% methanol in chloroform. The fractions found to be identical by thin layer chromatography were combined and evaporated to give cis-5-chloro-3- {2'- (4 "- (1" '-acetyl-4 "' - piperazinyl) phenoxy) ethoxy) -2,3- dihydro-2- (1 '' - imidazolylmethyl) -benzo [b] thiophene is obtained [478J.

B) The product obtained in Step A is dissolved in a mixture of chloroform (10 ml) and methanol (10 ml), acidified with isopropanolic hydrochloric acid to pH 2 and evaporated to give 5-chloro-3- {2'- (4 "- (1) '' -Acetyl-4 '' - piperazinyl) -phenoxy) -ethoxy} -2,3-dihydro-2- (1 '' -imidazolylmethyl) -benzo [b] thiophene dihydrochloride is obtained.

Example 4

3- (Chlorotenyloxy) (or chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene-1-oxide

A) 6-Chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b [thiophene-1-oxide]

0.20 g (0.5 mmol) of 6-chloro-3- (2 ', 4'-dichlorobenzoxy) -2,3-dihydro-2- (1'-imidazole 1-methyl) benzo [. A solution of b] thiophene in 10 ml of dichloromethane was cooled to 0-5 ° C and m-chloroperbenzoic acid (0.0812 g, 0.47 mmol) was added and the mixture was stirred for 1 hour, (40 mmol) in sodium sulfate for an additional 30 minutes. Dichloromethane (25 mL) was added and the mixture was extracted with 25 mL of 10% aqueous sodium carbonate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was subjected to silica gel column chromatography. Elution with 5% methanol in chloroform. The fractions found to be identical by thin layer chromatography were combined and evaporated to give 6-chloro-3- (2 ', 4'-dichlorobenzyloxy) 2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b] thiophene. -1-oxide is obtained, m.p. 60C.

B) The cis-3- (chlorotenyloxy) - (or chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene prepared according to Example 1 4- (chlorobenzyloxy) - (or 2-chloro-3-thenyloxy) -3- (1'-imidazolylmethyl) thiochromans prepared according to example 3 and cis-3- (2'- (4 '- (1' '- Acetyl-4' '- piperazinyl) phenoxy) ethoxy [-2,3-dihydro-2- (1-imidazolylmethyl) benzo [b] thiophene was reacted as in Example 4A. the corresponding 1-oxides are obtained.

Example 5

3- (Chlorotenyloxy) (or chlorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene-1,1-dioxide

A) 6-Chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -berlo [b] thiophene-1,1-dioxide

0.20 g (0.5 mmol) of 6-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1' -imidazolylmethyl) -benzo [b] thiophene A solution of 10 ml of dichloromethane was cooled to 0-5 ° C, m-chloroperbenzoic acid (0.1624 g, 0.94 mmol) was added and stirred for 1 hour. The solution was warmed to room temperature and stirred overnight. Dichloromethane (25 mL) was added and extracted with 25 mL of 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give 6-chloro-3- (2 ', 4'-dichlorobenzyloxy) -2,3-dihydro-2- (1-imidazolylmethyl) benzo [b] of thiophene-1,1-dioxide, m.p. 182 ° C.

B) The cis-3- (chloro-thenyloxy) (or chlorobenzyloxy) -2,3-dihydro-2- (1-

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imidazolylmethyl) benzo [b] thiophenes, 4- (chlorobenzyloxy) (or chlorophenoxy) -3- (1-imidazolylmethyl) thiochromans of Example 2, and Example 3 Cis-3-N '- (4' - (1-acetyl-4 '' - piperazinyl) phenoxy) ethoxy) -2,3-dihydro-2- (1-imidazolylmethyl) benzo [b] Thiophene was treated as in Example 5A to give the corresponding 1,1-dioxide.

Example 6 'cis-7-Chloro-3- (methylthiomethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene [326]

The compound was prepared according to Example IA from 2.67 g (10 mmol) of cis-7-chloro-3-hydroxy-2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene and From 06 g (11 mmol) of (chloromethyl) methylsulfide, 0.53 g (11 mmol) of a 50% solution of sodium hydride in oil is prepared in 30 ml of dry dimethylformamide, except that the product is charged with two using purified by high pressure liquid chromatography and eluted with ethyl acetate.

Example 7 Cis-6-Chloro-3- (2'-chloro-5'-phenoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene

The compound was prepared as in Example IIA from 2.67 g (10 mmol) of cis-6-chloro-2,3-dihydro-3-hydroxy-2- (Γ-imidazolylmethyl) -benzo [b] thiophene, 2.33 g. (11 mmol) from 2-chloro-5-tenyl bromide in 0.53 g (11 mmol) of a 50% sodium hydride in oil solution in 27 ml of dimethylformamide. 94-95 ° C.

Example 8 cis-6-Chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene-1-oxide)

5.0 g (12.5 mmol) of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] ] thiophene was dissolved in 100 ml of dichloromethane and cooled to 0-5 ° C. 2.65 g (15.4 mmol) of m-chloroperbenzoic acid are added and the mixture is stirred for 1 hour. The solution was diluted with dichloromethane (100 mL), washed with 10% aqueous sodium carbonate (2 x 150 mL) and water (2 x 150 mL). The organic layer was separated, dried over magnesium sulfate and filtered. The solvent was distilled off and 4.8 g of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 "imidazolylmethyl) -benzo [b] thiophene were obtained. l-oxide is obtained in the form of white crystals. After recrystallization from ethyl acetate, the melting point is 125 ° C.

Calcd for C ', ₇ H _I4 C1 ₂ N ₂ O ₂ S ₂ O: C, 49.35; H, 3.38; N, 6.8; S, 15.48;

Cl, 17.17%;

Found: C, 48.74; H, 3.4; N, 6.9; S, 15.25;

Cl, 17.29%.

Example 9

6-Chloro-3- (2'-chloro-3'-thenyloxy) -2- (1 '-imidazolylmethyl) -benzo [b] thiophene

4.5 g (10.9 mmol) of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] Thiophene-1-oxide was treated with trifluoroacetic anhydride (6.86 g, 32.7 mmol) in toluene (100 mL) for half an hour. The solution was diluted with 200 ml of dichloromethane and washed with 150 ml of aqueous sodium bicarbonate solution and 150 ml of water. The organic extract was dried over anhydrous magnesium sulfate and filtered to give 3.2 g of 6-chloro-3- (2'-chloro-3'-thenyloxy) -2- (1'-imidazolylmethyl) -benzo [b] thiophene as a solvent. mp 84 ° C (white needles, dioxane).

Elemental Analysis C _I7 H | After ₂ C1 ₂ N ₂ O ₂ S ₂ Found Calculated: C, 51.58; H, 3.03; N, 7.08; S, 16.18; Cl, 17.7%;

Found: C, 51.52; H, 2.97; N, 7.26; S, 15.95;

Cl, 17.9%.

The corresponding 5-chloro isomer can be similarly prepared, m.p. 124 ° C.

Example 10

6-Chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolyl) -benzo [b] thiophene A) 6-Chloro-3- (2'- chloro-3'-thenyloxy) -2,3-dihydro-benzo [b] thiophene

A solution of 1.0 g (5.35 mmol) of 6-chloro-3-hydroxy-2,3-dihydro-benzo [b] thiophene (Chem. Abs. 54, 11494d) in 10 ml of dimethylformamide was added at 0-5 ° C. cooled. Sodium hydride (0.283 g, 5.89 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then 1.25 g (5.89 mmol) of 2-chloro-3-bromomethylthiophene are added and the reaction mixture is stirred at room temperature for 2 hours and then diluted with 500 ml of ether. The solution was washed with water (4 x 500 mL), dried over magnesium sulfate, and evaporated to give 0.959 g of 6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-benzo [b] thiophene as an oil.

B) 6-Chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-benzo [b] thiophene-1-oxide

The compound was obtained from 4.0 g (13 mmol) of 6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-benzo [b] thiophene with 2.59 g (15 mmol) of m-chloroperbenzoic acid. In 50 ml of dichloromethane according to the procedure of Example 8. 4.2 g of product are obtained in the form of a gum.

C) 6-Chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolyl) -benzo [b] thiophene

4.0 g (14.2 mmol) of 6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-benzo [b] thiophene-1-oxide and 5.92 g ( (5 mmol) of trimethylsilylimidazole was refluxed for 1 hour, cooled to room temperature and diluted with 20 mL of methanol. The product was extracted into chloroform (100 mL) and washed with water (3 x 100 mL). The solvent was evaporated and the resulting oil was chromatographed on a silica gel column; eluting with 1% methanol-chloroform and 550 mg of trans-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolyl) benzo [b] thiophene. (m.p. 160 ° C) and 450 g of the corresponding cis isomer (m.p. 77 ° C) are obtained.

Example 11 Cis-6-Chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolyl) -benzo [b] thiophene-1-oxide

The compound was 412 mg of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolyl) -10193633

From benzo [b] thiophene, 240 mg (1.4 mmol) of m-chloroperbenzoic acid was prepared in 25 ml of dichloromethane according to Example 8.

Example 12

6-Chloro-3- (2'-chloro-3'-thenyloxy) -2- (1 '-imidazolyl) -benzo [b] thiophene

400 mg (1 mmol) of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 "-imidazolyl) -benzo [b] thiophene-1-oxide and 620 mg (3 mmol) of trifluoroacetic anhydride in 10 ml of toluene was refluxed for 2 hours. The reaction mixture was evaporated to dryness and the product was extracted into 100 ml of chloroform. The solution was washed with 10% aqueous sodium bicarbonate (2 x 50 mL) and water (2 x 50 mL), dried over magnesium sulfate and evaporated to give 190 mg of 6-chloro-3- (2'-chloro) m.p. 3'-Thenyloxy) -2- (1'-imidazolyl) -benzo [b] thiophene is obtained.

Example 13

A) cis-3- (2'-Chloro-3'-thenyloxy) -2,3,5,6,7,8-hexahydro-2- (1'-imidazolylmethyl) naphtho [2,3-b] ] thiophene

The compound was prepared according to Example 1 from cis-3-hydroxy-2,3,5,6,7,8-hexahydro-2- (1'-imidazolylmethyl) naphtho [2,3-b] thiophene (m.p. 193-195 ° C), which may be prepared from 2,3,6,7,8,9-hexahydro-4H-naphtho [2,3-b] thiopyran / 4-one (KrolIpfeifer and Schultze, Chem. Bert. 56, 1819-1924 (1923) (Compound V) az

As described in Example A). The title compound melts at 87-88 ° C.

B) cis-3- (2'-Chloro-3'-phenoxy) -2,3-dihydro-2- (t '-imidazolylmethyl) naphtho [1,2-b] thiophene

The compound was prepared according to Example 1 from cis-3-hydroxy-2,3-dihydro-2- (1'-imidazolylmethyl) -naphtho [1,2-b] thiophene (m.p. 162-165 ° C). may be prepared from 2,3-dihydro-4H-naphtho [1,2-b] thiopyran-4-one (Krollpfeifer and SchuLtze, Chem. Ber. 56 (1923) 1819-1924, Compound II). according to. The hydrochloride of the title compound melts at 165-166 ° C.

C) cis-3- (2'-Chloro-3'-thenyloxy) -2,3,4,5,6,7-hexahydro-2- (1'-imidazolylmethyl) naphtho [3,4-b] ] thiophene

The compound was prepared according to Example 1 from cis-3-hydroxy-2,3,4,5,6,7-hexahydro-2- (1'-imidazolylmethyl) naphtho [3,4-b] thiophene (m.p. 180-181 ° C) from 2,3,5,6,7,8-hexahydro-4H-naphtho [3,4-b] thiopyran-4-one (Krollpfeifer and Schulze, Chem. 56, 1819-1924 (1923) (Compound VI) may be prepared as described in Example A). The title compound melts at 106-108 ° C.

Example 14

A) Cis-6-Chloro-3-allyloxy-2,3-dihydro-2- (1 '-imidazolylmethyl) -benzo [b] thiophene

3.0 g (0.011 mmol) cis-6-chloro-3-hydroxy-2- (1'-imidazolylmethyl) -2,3-dihydrobenzo [b] thiophene, 3.44 g (0.045 mmol) allyl chloride and a mixture of 1 ml of methyl tricaprylammonium chloride in 10 ml of 50% aqueous sodium hydroxide and 25 ml of tetrahydrofuran for 2 hours.

The reaction mixture was diluted with dichloromethane (200 mL) and washed with water (4 x 200 mL). The extract was dried over magnesium sulfate and evaporated to give 3.2 g of cis-6-chloro-3-allyloxy-2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [t]] thiophene as an oil. [306]

B) Cis-6-Chloro-3- (quinolyl-2'-methoxy) -2,3-dihydro-2- (1 "-imidazolylmethyl) -benzo [b] thiophene may be prepared in a similar manner if in Process A) the allyl chloride is replaced by 2-chloromethylquinoline. The compound [407] is obtained in the form of a gum.

C) cis-6-Chloro-3- (2'-chlorobenzo [b] thiene-3'-methoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene

The compound can be prepared according to Method A by replacing the allyl chloride with 3-bromomethyl-2-chlorobenzo [b] thiophene. 129-130 ° C.

3-Bromomethyl-2-chlorobenzo [b] thiophene can be prepared as follows:

A mixture of 21.9 g (0.12 mmol) of 2-chloro-3-methylbenzo [b] thiophene, 21.4 g (0.12 mmol) of N-bromosuccinimide and 1.0 g of dibenzoyl peroxide is heated in 200 ml of carbon tetrachloride for 8 hours. length. The succinimide is filtered off and the carbon tetrachloride is distilled off. The residue is crystallized from methanol by decarbonation to give 3-bromomethyl-2-chlorobenzo (b) thiophene, m.p. 69-70 ° C.

D) cis-6-Chloro-3- (4'-thiazolylmethoxy) -2,3-dihydro-2- (1 '-imidazolylmethyl) -benzo [b] thiophene

Process A may be prepared by substituting 4-chloromethyl-thiazole (Caldwell and Fox, J.Am.Chem.Soc. 73, 2395-6 (1951)) for the α-chloride. 92-93 ° C.

E) The following compounds may be prepared in a similar manner:

cis-6-chloro-3- (6'-chloro-3 ', 4'-methylenedioxybenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, m.p. . 130-132 ° C;

cis-6-chloro-3- (2'-chloro-6'-fluorobenzyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 140 ° C;

cis-6-chloro-3 - ((5'-chloro-3'-methyl-1'-phenylpyrazol-4-yl) methoxy) -2,3-dihydro-2- (1 '-imidazolylmethyl) ) benzo [b] thiophene rubber, [468]; cis-6-chloro-2,3-dihydro-3'- (4'- (5'-methyl-3'-phenylisoxazolyl) methoxy) -2- (1'-imidazolylmethyl) benzo [ b] thiophene, op. 134-134 ° C and cis-6-chloro-3- {8'-chloro-1 ', 3'-dioxolo [4', 5'-g] quinolin-7'-1-methoxy) -2,3 -dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, m.p. 212-214 ° C.

Example 15 Cis-3- (3'-Tenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene

A) In Example 1A, 2-chloro-3-thienyl bromide is replaced by an equivalent amount of 3-thienyl bromide and cis-6-chloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolyl) is added. methyl) benzo [b] thiophene, m.p. 98-100 ° C.

B) Similarly, cis-2,3-dihydro-3-hydroxy-2- (1 '-imid

-11193633 azolylmethyl) benzo [b] thiophene (3-thienyl bromide) is reacted to give the following compounds:

a) cis-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazole 1-methyl) -benzo [b] thiophene;

b) cis-5-chloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

c) cis-7-chloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene;

d) cis-4,6-dichloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

e) cis-5,6-dichloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo (b) thiophene;

f) cis-5,7-dichloro-3- (3 '-thienoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

g) cis-6-trifluoromethyl-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene;

h) cis-6-fluoro-3- (3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolylmethyl) -benzo [b] thiophene;

l) cis-7-fluoro-3- (3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene.

Example 16 Cis-6-Chloro-3- (3'-pyridylmethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene

As described in Example 2, 4.0 g (15.0 mmol) of cis-6-chloro-2,3-dihydro-3-hydroxy-2- (2-imidazolylmethyl) benzo [b] thiophene and , From 71 g (16.5 mmol) of 3-pyridylmethyl chloride hydrochloride in 1.51 g (31.5 mmol) of a 50% dispersion of sodium hydride in 40 ml of dry dimethylformamide, except that 1% as eluent chloroform containing methanol and 0.2% concentrated ammonium hydroxide was used.

The free base (gum) was dissolved in a mixture of 500 ml of anhydrous ether and 10 ml of isopropanol. Hydrogen chloride gas-saturated isopropanol is added dropwise until the precipitation is complete. The solution was filtered and the residue was dried. Redissolved in water and lyophilized to give cis-6-chloro-3- (3'-pyridylmethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene dihydrochloride, [ 358].

Example 17 Cis-6-Chloro-3- (2'-chloro-3'-phenoxy) -2,3-dihydro-2- (1 '-imidazolylmethyl) -benzo [b] thiophene hydrochloride

2.0 g of cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene are dissolved in 400 ml of ether. Hydrogen chloride gas-saturated isopropanol is added dropwise until the precipitation is complete. The mixture was filtered and the residue was dried to give the title compound.

In the examples above, especially Figures 1B-7 and 15-16. The free bases obtained in Examples 1 to 8 are treated in a similar manner to give the corresponding hydrochloride salts.

By the methods described in the previous examples, the following compounds can be prepared:

cis-5-tert-butyl-3- (2'-chloro-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, [417];

cis-5-tert-butyl-3- (2'-chloro-3'-pyridylmethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene dihydrochloride, [434 ];

cis-5-tert-butyl-3 - ((5'- (4 '-acetyl-1' -piperazinyl) -1 ', 2', 4'-thiadiazolyl) -3'-methoxy] -2,3-dihydro -2- (1 '' -imidazolylmethyl) -benzo [b] thiophene, [512];

cis-6-chloro-3- (2'-chloro-3'-pyridomethoxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene, [391] ;

cis-6-fluoro-2,3-dihydro-2- (1'-imidazolylmethyl) -3- (3-thenyloxy) -benzo [b] thiophene, [346];

5-chloro-3- (2'-chloro-3'-thenyloxy) -2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 124 ° C;

6-chloro-3- (2'-chloro-3'-thenyloxy) -2- (1'-imidazolylmethyl) -benzo [b] thiophene, m.p. 84 ° C.

Compounds of formula I, in particular compounds of formula II, and their acid addition salts are valuable antifungal agents, as shown by in vivo animal studies such as the hamster Candida infection model, a guinea pig dermatophyta infection model and a mouse systemic Candida infection model. These studies indicate that the compounds of the present invention are a broad spectrum antifungal drug for topical, oral or parenteral application against topical dermatophytes and vaginal and systemic fungal / yeast infections.

Generally, the amount of compound of formula I used to eliminate a particular fungal infection is similar to that required for miconazole, clotrimazole and ketoconazole, but the preferred dosage level and route of administration will depend upon the host and the type and degree of infection.

The compounds of the invention can be used in industry and agriculture. They can be applied directly to crops and soil in agriculture. The carriers may be powders such as talc, mica or clay, or sprays such as aqueous solutions, with or without a solid carrier and wetting agent. Industrially, the compounds can be used to disinfect glassware, medical equipment and the like by rinsing, contacting or impregnating the infected surface with a compound in a suitable carrier. In addition, the compounds are useful for preventing fungal growth, for example in paints or other industrial materials which are prone to fungal growth.

The present invention therefore provides compositions having antimicrobial activity which comprises a compound of Formula I or an acid addition salt thereof. The carrier may be, for example, an industrial material (such as a dye) which is intended to be protected from microbial contamination; under these circumstances, the acid addition salt need not be pharmaceutically acceptable and anions of antimicrobial acids may be used to enhance the antimicrobial activity or broaden the spectrum of the compounds of formula I to 12193633. However, the acid addition salt is generally pharmaceutically acceptable, especially when the compounds are used as medicaments.

The pharmaceutical compositions contain an antifungal, antibacterial or antiprotozoal effective amount of a compound of Formula I or an acid addition salt thereof, together with a pharmaceutically acceptable non-toxic carrier or excipient, in particular for topical, oral or parenteral administration.

Dosage forms for topical administration may be prepared in a manner well known in the art and may contain various substances as carriers. Formulations suitable for topical administration include ointments, creams, solutions, powders, aerosols and sprays. Ointments, solutions and creams may contain water, oils, fats, waxes, polyesters, alcohols or polyols and perfumes, emulsifiers and preservatives. Powders are prepared by mixing the active ingredient with readily available inert, powdered diluents such as talc, calcium carbonate, tricalcium phosphate or boric acid. Aqueous suspensions may be prepared from the above powders. For solutions or emulsions, inert solvents such as vegetable oils, isopropanol, dimethylsulfoxide, hydrogenated or alkylated naphthalenes are used, which are preferably non-flammable, odorless, colorless and non-toxic. Similarly, the aerosol or non-aerosol spray may be prepared using a solution or suspension in a suitable solvent, such as dichlorodifluoromethane, suitable for aerosol production.

Formulations for topical administration such as ointments, creams, solutions, powders or sprays generally contain from 0.1 to 3 g of a compound of formula I per 100 g of carrier. Dosage units contain from 2 to 250 mg, preferably from 5 to 125 mg of active ingredient.

Oral forms include elixirs, suspensions and unit dosage forms such as tablets and capsules. The tablets contain starch or lactose as an excipient;

coloring and flavoring agents may be added to the liquid forms.

Parenteral formulations may be administered intravenously, intramuscularly or subcutaneously, usually in the form of a sterile solution, and these solutions may be rendered isotonic with salts or glucose.

The following examples illustrate compositions containing the antimicrobial agents of the present invention. The term "active ingredient" may mean any compound of the invention, but in particular one of the following: cis-6-fluoro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1 "-imidazolyl). methyl) benzo [b] thiophene, cis-5-fluoro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-30 -2- (1 '-imidazolylmethyl) benzo [b] ] thiophene, cis-5-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, and cis-S- chloro-3- (2'-thenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) -benzo [b] thiophene.

The compositions are prepared by known methods

7.50 mg tablets

Preparation I The tablet

agent 7.50 mg Lactose, anhydrous 114.14 mg Starch (Sta-Rx- -1500) 54.66 mg Sodium lauryl sulfonate wood 5.00 mg Microcrystalline target- pulp 16.44 mg Silica gel 0.41 mg Magnesium stearate 1.85 mg Water (evaporates) (0.05 mg) Preparation II B tablets 125 mg agent 1 25 mg Polyethylene-glycolic until 6,000 100.0 mg Sodium lauryl sulfonate wood 6.25 mg corn starch 30.00 mg Lactose, anhydrous 87.25 mg Magnesium stearate 1.50 mg

-13193633

Preparations III and IV III ARC Capsule 25 mg capsules 5.0 mg capsule agent 25.00 mg 5.00 mg Microcrystalline cellulose 312.00 mg - Sodium laureth sulfate 5.00 mg 25.00 mg cornstarch 90.00 mg 310.00 mg Hydroxymethyl cellulose 13.50 mg - Magnesium stearate 4.50 mg - Water (evaporates) Preparation V. Injection mg / ml agent 10.0 Methyl p-hydroxybenzoate 1, 30 Propyl p-hydroxybenzoate 0.20 Sodium hydrogensulfite 3.20

Ethylenediaminetetraacetic acid disodium salt 0.10

Sodium sulfate 2.60

Water for injections up to 1 ml

Preparation VI

Injectable suspension

agent

Benzyl alcohol

Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Sodium carboxymethyl cellulose Polyethylene elicol 4000 Povidone

Sodium citrate

Ethylenediaminetetraacetic acid, disodium salt

Water for Injection mg / ml

10.00

9.0

1.8

0.2

5.0

10.0

5.0

15.0

0.1

To 1.0 ml

Preparation VII

Sterile powder for injection

Active ingredient (sterile powder) 20.0 mg

Water for Injection Use 10-200 ml of sterile or bacteriostatic water for injection, USP Water for Injection.

Preparation VIII

Cream THE B C agent 0.5 mg 5.0 mg 10.0 mg Sorbitan monostearate 20.0 20.0 20.0 Polysorbate 60 15.0 15.0 15.0 Spermaceti is synthetic 30.0 30.0 30.0 Octyldodecanol 135.0 135.0 135.0 Benzyl alcohol 10.0 10.0 10.0

Purified water up to 1 g

193 633 27 28 Preparation IX Gel THE B C agent Butylated hydroxy 0.5 mg 5.0 mg 10.0 -toluene 5.0 5.0 5.0 Carbomer 940 15.0 15.0 15.0 Propylene glycol 300.0 300.0 300.0 Sodium hydroxide Polyethylene glycol 400 to 1 g 0.6 0.6 0.6 Preparation X Ointment THE B C agent Mineral oil White petroleum jelly up to 1 g 0.5 mg 5.0 mg 10.0 50.0 50.0 50.0

Preparation XI

Solution

agent

Sorbitan monosztea_A_

0.50 mg _B_

5.0 mg

Ra 2.0 2.0 Polysorbate 60 30.0 30.0 Cetyl esters (wax) 30.0 30.0 Sub-Cetoszterail alcohol 40.0 40.0 octyldodecanol 40.0 40.0 Benzyl alcohol 20.0 20.0 Purified water to g Preparation XII spray liquor THE B agent 0.5 mg 5.0 Propylene glycol 200.0 200.0 Lanoxol AWS 5.0 5.0 Alcohol 300.0 300.0

Purified water up to 1 g

C_

10.0 mg

2.0

30.0

30.0

40.0

40.0

20.0

C_

10.0 mg 200.0

5.0

300.0

Preparation XIII Powder A

Active ingredient 0.5

Starch 100.0

Talc up to 1 g

The biological activity of the compounds of the formula I was tested in vivo and in vitro on Candida albicans, yeasts and dermatophytes.

Hamsters infected with Candida albicans were treated with the compounds of the invention and sampled from their vaginal discharge on days 2, 4, 6, 8 and 11 after treatment,

B C_

5.0 10.0

100.0 100.0 and grown on agar plates. Cultures were evaluated as follows:

θθ 4 = turbidity equal to control, = less turbid than control, = no visible turbidity but cells visible under microscope, = cells not visible under microscope but

The 0.2 ml aliquot can be expanded on agar, 0 = negative agar plate.

-15193633

The group values obtained from the samples collected at five time points are summarized. The amount obtained was multiplied by the number of last samples giving positive results (days 2, 4, 6, 8 or 1).

The value obtained was divided by the value obtained from the untreated control and then subtracted from 100 to obtain the inhibition value expressed as a percentage of the control.

The minimum inhibitory concentration (MIC) was determined on Sabourand dextrose medium (SDB) and Eagle's minimum essential medium (EMEM). In the first case, the culture was continued for 48/72 hours at 37/28 ° C and in the second case for 48 hours at 37 ° C.

The values given are the geometric mean values of the lowest inhibition concentrations observed. The experiments were performed with 6 Candida and 4 dermatophytes. Data for the known miconazole selected for comparison are the mean values from 12 different assays on Sabourand dextrose medium and 5 on Eagle's minimal medium.

Particularly important are the results obtained on Eagle's minimal medium because it is presumed that in vivo the fungus is more active in the mycelial phase than in the yeast phase. The results obtained show that the active ingredients inhibit the transition from the yeast phase to the mycelium phase. The results obtained with cis-2,3-dihydro-2- (imidazolyl-1-methyl) benzo [b] thiophenes (X sulfur, R hydrogen, n = 1, p = 0, q = 1, dashed single bond) as shown in the following table.

Abbreviations given for Z represent the following groups: a 2-chloro-6-fluorophenyl b 2,4-dichlorophenyl c 2,6-dichlorophenyl d 2-fluorophenyl e 4-fluorophenyl f 3,4-dichlorophenyl g 2,4-difluorophenyl h 2,5-difluorophenyl 2,6-difluorophenyl j 3-fluorophenyl k 2-chloro-5-fluorophenyl 14 chloro-2-fluorophenyl

Starred results were tested on C. albicans strain C43 and other data were obtained on strain C60.

0p .: (° C) R ¹ . z Candida dose (%) inhibition index (7) MIC SDB yeast EMEM dermatophyte yeast 6-Cl the 0.5 99 5 ^X 0.05 * 92 96-98 5-F b 4.5 0.13 141-142 5-F c 0.05 84 ^X 8.0 0.09 152-154 5-F the 0.5 * 99 0.04 0,016 0.05 ⁹⁷ x 123-125 5-F d 0.5 99 0,025 0.05 72 ^x 6-Cl c 7.1 0.18 6-Cl d 0.05 99 ^X 0,016 6-Cl e 0.05 65 ^X 6.4 0,016 6-Cl f - 6.4 81-83 5-F f 0.11 94-95 5-F g - 0,016 94-96 5-F h - 0,016 167-168 5-F í 0, 05 94 0.21 0.02 0,025 82 .0125 62 94-96 6-Cl j - 0,025 97-100 6-Cl g - 0,020 97-100 6-Cl h 0.1 83 128-130 6-Cl i 0.05 97 0.08 0,016 103-105 5-F k - 0,016 82-84 5-F 1 - 0,016 106-108 6-Cl 1 - 6.4 0,016 125-127 6-F the 0.05 86 0.08 0,016 0,025 93 .0125 47 124-126 6-CFj the 0.05 65 6-F d 0.05 ⁸⁷ x 0,016 miconazole 0.25 99 ^X 8.8 0.36 0.053 (known) 0.1 90 ^X 0.05 * 62 0.1 69 0.05 51

Claims (30)

PATENT CLAIMS A process for the preparation of benzo [b] thiophenes and thiochromans of the formula I in which n is 0 or an integer from 1 to 4; p is 0 or 1; q is 0, 1 or 2; R ¹ and R ¹ each independently represent hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl containing 1 to 3 halogens, or the adjacent R 5 and C ¹ -C 5 fused, saturated or unsaturated carbocyclic forms a ring; X represents a sulfur atom or a sulfinyl or sulfonyl group; Y is 1-imidazolyl, Z is C2-C4 alkenyl or thienyl, quinolyl, benzothienyl, pyridyl, thiazolyl, pyrazolyl, thiadiazolyl or isoxazolyl, and said heterocyclic aromatic groups optionally have one to three positions with halogen, C1-C4 alkyl or Substituted with C 1-4 alkylenedioxy, phenyl or N- (C 1-4 alkanoyl) piperazino and when π is An integer of from 1 to 4, Z may also represent a C 1-4 alkylthio group or a phenyl or phenoxy group which may be substituted with one to three halogens, C 1-4 alkyl, C 1-4 alkylenedioxy or N- (I). C4 alkanoyl) piperazino group and the dotted line represents a single or double bond, provided that it represents a double bond only when p is 0 and X is sulfur - their cis and trans isomers and their acid addition salts characterized in that a) for the preparation of compounds of the formula I in which X is a sulfur atom, a compound of the formula III and a compound of formula IV in which R, R ¹ , Y, Z, n, p and q are the same as above and X 'is sulfur; is, one of Q ¹ and Q ² is a hydroxy group and the other reactive ester group is reacted in the presence of an inert organic solvent and an alkali metal base, or b) for the preparation of compounds of formula I wherein p and q are 0, X is a sulfinyl group and the other symbols are as defined above, a compound of formula V wherein R, R ¹ , Z and n are as defined above Reacting a compound of formula VI wherein Y is as defined above and each alkyl group contains from 1 to 4 carbon atoms and then optionally a compound of formula I obtained by a) or b) i) oxidizing to produce a compound of formula I wherein X is -SO or -SO ₂ ; and, if desired, ii) producing a compound of formula I wherein the dashed line represents a double bond; dehydrating the compound of formula I and recovering the compound of formula I in the form of the free base or an acid addition salt or a cis or trans isomer thereof. A process according to claim 1 for the preparation of compounds of the formula I and their acid addition salts wherein X is sulfur, n, p, q, R, R ¹ , Y and Z are as defined in claim 1, nogy a compound III of the formula - R, ^R1, Y, p and q is defined above, X 'is sulfur and Q ¹ hydroxy group - with a compound of general formula IV - Z and n as defined above, Q ₂ reactive ester group - is reacted, and the resulting formula I The compound of Formula I is isolated as the free base or as an acid addition salt. 3. A method according to claim 2, characterized by reacting compounds of formula III and IV, wherein Q ¹ and Q ² hydroxyl organic sulfonyloxy or halogen. A process according to claim 1 for the preparation of compounds of formula I, their cis and trans isomers and acid addition salts thereof, wherein X is sulfur, π is 0 or 1-4, p is 0, q is 1, R and R ¹ are each independently hydrogen or halogen, C 1-4 alkyl or 1-3 halogen, C 1-4 haloalkyl, C 2 -C 4 alkenyl or a heterocyclic aromatic group as defined in claim 1 which may be substituted with 1 to 3 halogens or C 1 -C 4 alkyl and when n is 1 to 4, Z is C 1 -C 4 alkylthio; may also represent a phenyl group substituted with 1 to 3 halogens, C 1 -C 4 alkyl or N- (C 1 -C 4 alkanoyl) piperazino, and the dotted line is a single bond, characterized in that a compound of formula III wherein Q the other symbols are reacted with the above compound of formula IV wherein Q ^{2 is} chlorine or bromine, and the other symbols are as defined above. 5. A process according to claim 4, wherein the compound of formula III wherein Q ^{1 is} hydroxy is reacted with an alkali metal base in an inert organic solvent followed by the addition of a halide of formula IV wherein Q ^{2 is} chlorine or bromine. -17193633 The process according to claim 5, wherein the alkali metal base is an alkali metal hydride, an alkali metal hydroxide, an alkali metal amide or an alkali metal alcoholate. 7. Process according to any one of claims 1 to 3, characterized in that the organic solvent is an amide, an aromatic hydrocarbon, an ether or a ketone. 8. In steps 3-7. Process according to claims 1 to 3, characterized in that the reaction is carried out at a temperature of 0 to 100 ° C. 9. A process for the preparation of compounds of formula I wherein X is sulfur according to claim 2, wherein a solution of a compound of formula III wherein Q ^{1 is a} hydroxyl group at 0-5 ° C in dimethylformamide solution is added at room temperature for 1 hour. After an hour's reaction, a compound of formula IV wherein Q ^{2 is} chlorine or bromine, n and Z are as defined in claim 2 is added and the components are reacted for an additional 1 hour at room temperature. 10. The process of FIGS. Process for the preparation of the compounds of the formula I and their acid addition salts according to any one of claims 1 to 3, wherein Z is a mono-, di- or tri-halophenyl group, R, R ¹ , X, Y, n, p and qa and reacting a compound of formula III as defined in claim 4 with a compound of formula IV wherein Z is a mono-, di- or tri-halophenyl, Q ¹ and Q ^{2 are} as defined in claim 4. 11. A 4-8. A process for the preparation of the cis isomers of the compounds of formula I and their acid addition salts according to any one of claims 1 to 5, wherein Z is a mono-, di- or tri-halophenyl group, R, R ', X, Y, n, p and qa characterized in that a compound of formula III wherein Q ¹ and - (CH ₂ ) - Y are cis relative to one another is reacted with a compound of formula IV wherein Z is a mono-, di- or tri-halophenyl group , Q ¹ and Q ^{2 are} as defined in claim 4. 12. A process for the preparation of a compound of formula I or an acid addition salt thereof according to any one of claims 1 to 3, wherein Z is a heterocyclic aromatic group as defined in claim 4, R, R ¹ , X, Y, n, p and qa as defined in claim 4, reacting a compound of formula III as defined in claim 4 with a compound of formula IV wherein Z is a heterocyclic aromatic group as defined in claim 4, Q ¹ and Q ^{2 are} as defined in claim 4. 13. Figures 4-8. A process according to any one of claims 18 to 18, which is a compound of formula I as defined in claim 18 II acompound of general formula: - wherein R, R ^1, Z and n as defined in claim 4, characterized in that a IIIA compound of the formula with a compound of the formula IV - R, ^R1, η, Z, Q ¹ and Q ^{2 a as} defined in claim 4 -. A process according to claim 13 for the preparation of a compound of formula II and acid addition salts thereof wherein R and R ^{1 are} hydrogen or halogen, n is 1, Z is phenyl or a heterocyclic aromatic group as defined in claim 4 which is halogen or It may be substituted with 1 to 4 carbon atoms, characterized in that a IIIA compound of the formula with a compound IV, wherein R, ^R1, n and Z are as defined in this claim and Q 'is a hydroxyl group and Q ² is chlorine or bromine . 15. A process according to claim 13 for the preparation of compounds of formula II and their acid addition salts wherein R and R ^{1 are} hydrogen or halogen, n is 1, Z is thienyl, 2-chlorothienyl, chlorophenyl or dichloro. -phenyl, wherein a compound of formula IIIA is reacted with a compound of formula IV wherein R, R ¹ , Z and n are as defined in this claim, and Q ^{1 is a} hydroxy group and Q ^{2 is a} chlorine or bromine atom. The process of claim 13, wherein cis-6-chloro-3- (2'-chloro-3'-thenyloxy) -2,3-dihydro-2'-imidazolylmethyl) benzo [b] thiophene is present. cis-6-chloro-3- (3'-thenyloxy) -2,3-dihydro-2- (1 '-imidazolylmethyl) -benzo [b] thiophene, cis-6-fluoro-3- (2') -chloro-3'-thenyloxy) -2,3-dihydro-2- (1'-imidazole 11-methyl) -benzo [b] thiophene or cis-7-fluoro-3- (2'-chloro-3'- tenyloxy) -2,3-dihydro-2- (1'-imidazolylmethyl) benzo [b] thiophene, characterized in that cis-6-chloro-3-hydroxy-2,3-dihydro-2- ( 1 ”-imidazolylmethyl) benzo [b] thiophene, cis-6-fluoro-3-hydroxy-2,3-dihydro-2- (1” -imidazolylmethyl) benzo [b] thiophene, or cis-7 -fluoro-3-hydroxy-2,3-dihydro-2- (1'-imidazol-1-yl) benzo [b] thiophene 2-chloro-3-chloromethylthiophene, 3-bromomethylthiophene, 2 chloro-3-bromomethylthiophene, respectively Reaction with 3-chloromethylthiophene. Process according to any one of claims 1 to 16, characterized in that the compound of formula 1 is obtained as the free base. 18. A process according to any one of claims 1 to 6, wherein the compound of formula I is obtained as a pharmaceutically acceptable acid addition salt. 19. The process of claim 18, wherein the compound of Formula I is obtained as an acid addition salt with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or nitric acid. -18193633 Process b) according to claim 1 for the preparation of compounds of the formula I and their acid addition salts wherein X is a sulfinyl group, p and q are 0, the other symbols are defined within the scope of claim 1, characterized in that reacting compound R, R, Z and n as defined in claim 1 with a compound of formula VI - Y as defined in claim 1, wherein the alkyl groups have from 1 to 4 carbon atoms - and then obtaining the compound of formula I as the free base or acid addition salt separated. 21. The process of claim 20, wherein the compounds of formulas V and VI are heated together with or without an inert organic solvent. 22. The process of claim 21, wherein the compounds of formulas V and VI are boiled without solvent. 23, pp. 20-22. A process according to any one of claims 1 to 5, wherein all alkyl in the compound of formula VI is methyl. The process of claim 1, wherein the oxidation of a compound of formula I wherein X is sulfur to a compound of formula I wherein X is -SO or -SO ₂ is carried out with an organic peracid in an inert organic solvent. The process of claim 1, wherein the oxidation in the halogenated hydrocarbon to produce a compound containing X is -SO _{2 is} approximately equimolar, and the equimolar amount is approximately two to five times the equimolar amount. -perbenzoic acid. 26. The process of claim 1, wherein dehydration of a compound of Formula I wherein X is -SO 2 and the dotted line is a single bond is carried out with acetic anhydride or trifluoroacetic anhydride in an inert solvent under heating. 27. A process for the preparation of a pharmaceutical composition comprising the steps of 1-26. An antifungal, antibacterial or antiprotozoal effective amount of a compound of formula I or an acid addition salt thereof according to any one of claims 1 to 6, in admixture with a pharmaceutically acceptable nontoxic carrier or excipient, into a pharmaceutical composition. 28. The method of claim 27, wherein the formulation is a topical, oral or parenteral formulation containing 0.1 to 3 g of active ingredient per 100 g of carrier. The method of claim 27, wherein the composition is in a dosage unit It is prepared in 3Q form. 30. The method of claim 29, wherein the composition comprises a compound of the formula I or an acid addition salt thereof in a unit dose of 2 to 250 µg.