NL8601189A - NEW AZOLIC DERIVATIVES, METHODS FOR PREPARING THESE DERIVATIVES AND FOR THEIR USE - Google Patents

Description

* *

New oil derivatives, methods for preparing these derivatives and for their use.

The present invention relates to azod derivatives of formula 1, wherein R 1 and R 1 independently of one another, a hydrogen atom, a nitro group, halogen atom or a lower alkenyl, lower alkyl-5 thio, lower alkyl sulfinyl, lower alkyl sulfonyl, lower alkyl or lower alkoxy group, each optionally mono- or poly-substituted by halogen, R 3 a lower alkyl, lower alkenyl or lower alkynyl group, each optionally mono- or poly-substituted by halogen pen carbo-10 xyl, lower alkoxycarbonyl lower alkoxy, lower alkylthio, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino attenuated dialkylamino group or a phenyl group optionally containing halogen, lower alkyl, lower alkoxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino, lower dialkylamino, 1-piperazinyl and / or 4-lower alkanoyl-1-piperazinyl is substituted, any alkyl, alkenyl or alkynyl group present in R 1 may be halogen mono- or poly-substituted, XN or CH and n ee represent an integer of 2-5, in an enantiomeric or racemic form, for methods of their preparation and for their use as pharmaceuticals, for example, antimycotic agents or as agrochemicals, for example, fungicides.

The lower alkyl groups in particular contain 1-5, preferably 1-4, for example 1 or 2, carbon atoms. This also applies to lower alkyl groups that are present in other groups. The lower alkenyl and lower alkynyl groups contain in particular 3-6, in particular 3 or 4, carbon atoms. Halogen in particular represents a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom. The cycloalkyl groups present in the compounds of the invention suitably have 3-6 members, preferably 3 (n-2).

The compounds of formula I according to the invention can be in free form or in the form of a salt, for example in the form I 2 - 2 - of an addition salt with an organic or inorganic acid, in the form of an ethanolate salt or in the form of a metal complex, for example, with a metal from the periodic table's Ib, Ila, lib, Vlb, Vllb or VIII group, such as copper or zinc with an anion, such as chloride, sulfate or nitrate. The salt forms and metal complexes can be obtained in a conventional manner from the corresponding free forms and vice versa.

According to the invention, the compounds of formula 1 can be prepared by a) reaction of a compound of formula 2, or a compound of formula 2a, wherein R 1, R 2, R 1 and n have the meanings indicated above and R 1 a represents a cleavable group, with a compound of formula 3, wherein X has a meaning as defined above and M is a hydrogen atom or a metal equivalent, or b) a reaction of a compound of formula 4, wherein, R2 and n are the values indicated above have meanings, with a previously defined compound of formula 3 and dimethylsulfoniummethylide or dimethyloxosulfoniummethylide, or a precursor thereof, wherein any amino groups present may be protected by corresponding protecting groups, which groups are removed after the completion of the reaction and the compounds thus obtained in free form or in the form of a salt.

Process a) can be carried out, for example, by reacting a compound of formula 2 or 2 a) with an azole of formula 3 as such (M = H) or in the form of its metal compound (M = metal), in the especially in the form of the alka-1 metal compound, for example the sodium salt, in an inert solvent, such as dimethylformamide, between room temperature and the boiling point of the reaction mixture.

Method b) can be carried out in a conventional manner, for example as described in JACS 84/3782 (1982), Heterocycles 8/397 (1977) and JACS 87/1353 (1965).

Λ M

• v .. i - f V Λ - 3 -

The protecting star groups and cleavable groups used are those commonly used in this type of reaction. Protective groups can be introduced and removed in a usual manner.

The compounds of formula 1 have an asymmetric carbon atom and can therefore exist in the form of enantiomers or mixtures thereof, which can be separated in a usual manner. The use of optically active starting materials leads to corresponding end products. The invention relates to both near-pure enantiomers and mixtures thereof, wherein if = Cl or Br, = H, = CH 2 and n = 2, the (+) - enantiomer is recommended.

Recommended meanings are:

For R 1 and R 1 a) hydrogen 15 b) halogen

For R3 lower alkyl / especially methyl For X a) N

b) CE and

For n = 2.

Preferred compounds of formula 1 contain for combinations of these meanings of the substituents.

The compounds of formula 2 are new and can be obtained from compounds of formula 4, analogous to method b). For example, compounds of formula 2a can be conventionally obtained from compounds of formula 2.

The compounds of formula IV are partly new and can be prepared in a conventional manner, for example by a) reaction of a compound of formula 5, wherein R, and n have the meanings indicated above and hal represents a halogen atom, with a thiol of formula 6, wherein R 2 has the meaning indicated above, in free form, suitably in the presence of a base, or in salt form, or b) reaction of a compound of formula 9, wherein R 2, R 2, - 4 - n and hal have the meanings indicated above, with a halogen, for example bromine, in a mixture of ether and dioxane, to give a compound of formula 8, wherein, R 1 / n and hal have the meanings indicated above and reacting this compound with thiol of formula 6, in free form, suitably in the presence of a base, or in salt form, whereby a compound of formula 7 is obtained and closing this ring.

Insofar as the preparation of the starting materials has not been described, these compounds are known or can be prepared analogously to known methods or methods described herein.

The final products and starting materials can be separated and purified in a usual manner.

The compounds of the invention have interesting biological properties, in particular antimycotic properties and are therefore indicated for use as pharmaceuticals, in particular as antimycotics. The antimycotic activity can be determined by in vitro tests, for example the in vitro series dilution test on different families and species of mycetes, such as yeasts, terrestrial fungi and dermatophytes in concentrations from about 0.6 to about 50 µg / ral and also according to in vivo tests, for example by systemic use of doses of about 0.1-10 mg / kg body weight (2 times daily) to rats infected intravaginally with Candida albicans.

For example, an indicated appropriate daily dose is between 40 and 700 mg, administered in divided doses 1 to 4 times daily or in a controlled release form, with the dosage forms suitable for oral administration being 10-700 mg of active ingredient contain.

The compounds according to the invention can be used both in the form of the free base and in the form of pharmaceutically acceptable salts (acid addition salts or ethanolates). In general, the salt forms exhibit a similar degree of activity as the free base forms. Examples of such acid addition salts are, for example, hydrochloride, hydrogen fumarate and naphthalene 1,5-disulfonate.

The compounds can be mixed with conventional pharmaceutically acceptable diluents and carriers and optionally other excipients and orally, topically, i.v. or administered parenterally, in forms such as tablets, capsules, creams, tinctures or injectable preparations.

Such preparations are also part of the invention.

The invention therefore also relates to a method for combating infections and conditions caused by mycetes, which method comprises administering one or more compounds of the formula 1, in free base form and / or in the form of a pharmaceutically acceptable salt thereof, to a patient in need of such treatment and to compounds for use as pharmaceuticals, particularly as anti-mycotic agents.

Thus, the compounds of the invention, in free form or in the form of an agriculture-acceptable salt, or metal complex form, are suitable for controlling phytopathogenic fungi. This fungicidal activity can be demonstrated by, for example, in vivo tests against Uromyces appendiculatus (bean rust) on climbing beans, as well as against other rust fungi (eg Hemileia, Puccinia) on coffee, wheat, flax and ornamental plants (eg pelargonium and snapdragons) and against Erysiphe cichoracearum on cucumber, as well as against powdery fungi (eg E. graminis f. sp. tritici. S. gram. f, sp. hordei, Podosphaera leucotricha, Unicinula recator) on wheat, barley, apples and vine.

„** - 6 -

Example I: α- (4-chlorophenyl) -α- (1-methylthio) cyclopropyl-1H-1,2,4-triazole-1-ethanol (proc. B)): _

To a suspension of 3.2 g of sodium hydride (50%) in 120 ml of absolute dimethylformamide, 14.8 g of trimethylsulfoxonium iodide were added in portions and stirred for an additional 45 minutes. Simultaneously. a solution of 3.2 g of sodium hydride (50%), 120 ml of absolute dimethylformamide and 4.6 g of 1,2,4-triazole, added in portions, which solution was also stirred for 45 minutes and with the aforementioned suspension was unified. A solution of 10.6 g of 4-chlorophenyl-1-methylthiocyclopropyl ketone in 50 ml of absolute dimethylformamide was then added dropwise to this mixture at room temperature. The reaction mixture was stirred at room temperature for 7 days and the solvent was removed under the reduced pressure of 1 Torr / 50 °. The oily residue was partitioned between chloroform and water and the combined organic phases were washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The title compound was obtained as colorless crystals after column chromatography on silica gel (ethyl acetate). Melting point: 131-133 ° C.

Example II: a- (4-bromophenyl) -a- (1-methylthio) cyclopropyl-1H-1,2,4-triazole-1-ethanol (proc. B)) _

Obtained analogously to Example I, melting point: 125-127 ° C.

Example III: (+) - a- (4-chlorophenyl) -a- (1-methylthio) cyclopropyl-1H-1,2,4-triazole-1-ethanol (proc. A)): Stirred a mixture of 129 mg (+) - 4-chloro-a- (1-methylthio) -cyclopropyl-a-methyloxymethyl-benzyl alcohol, 53 mg 1,2,4-triazole, 105 mg potassium carbonate and 10 ml dry dimethylformamide 4 hours at 70 ° C. The mixture was then poured onto water, extracted with ethyl acetate, the organic phase dried over magnesium sulfate and concentrated by evaporation. The residue was chromatographed on silica gel with ethyl acetate. Colorless crystals of melting point 112-114 ° C, -20 / a, (acetate) = + 40.2 °, were obtained.

"D

Example IV: (-) - (4-chlorophenyl) -a- (1-methylthio) cyclopropyl-1H-1,2,4-triazole-1-ethanol (groc. A)) - 20 Analogous to example III obtained, / α / (acetone) = -40 °.

For example, the starting materials can be prepared as follows: A) 4-chlorophenyl-1-methylthiocyclopropyl ketone (for Example I) 10 a) 4-chlorophenyl-3-chloro-1-bromopropyl ketone.

65.1 g of 4-chlorophenyl-3-chloropropyl ketone were dissolved in a mixture of 120 ml of absolute ether and 60 ml of absolute dioxane, this solution was brought to a boil and 48 g of bromine was added thereto. After stirring for 30 minutes at room temperature. the reaction mixture is poured onto 300 ml of ice and then extracted with ether.

The combined organic phases were dried over sodium sulfate, concentrated and the solid residue was crystallized from petroleum ether, mp: 67-69 ° C.

b) 4-chlorophenyl-3-chloro-1-methylthiopropyl ketone. A suspension of 10.6 g of sodium methanethiolate in 200 ml of absolute 1,2-dimethoxyethane was added dropwise with stirring 45.25 g of 4-chlorophenyl-3-chloro-1- Bromopropyl ketone in 100 ml of absolute 1,2-dimethoxyethane, while keeping the temperature below 30 ° C. The reaction mixture was stirred at room temperature for 2 hours and was diluted gently with 150 ml of water and 250 ml of ether. The organic phase was washed with water, dried and concentrated. The title Ter bond was purified by column chromatography over silica gel (a mixture of n-hexane and ethyl acetate: 98: 2). A colorless oil was obtained, Rf = 0.12 (a mixture of n-hexane and ethyl acetate = 98: 2).

- 8 - c) 4-chlorophenyl-1-methylthiocyclopropyl ketone

A solution of 10.86 g of potassium hydroxide in 45 ml of methanol was added dropwise to a solution of 24.3 g of 4-chlorophenyl-3-chloro-1-methylthiopropyl ketone in 45 ml of methanol. The reaction mixture was stirred at room temperature for 1 hour, concentrated with a rotary evaporator, partitioned between toluene and water, washed the combined organic phases with water, dried and concentrated by evaporation. The resulting oily residue was crystallized from petroleum ether. Colorless crystals: melting point: 30-32 ° C.

B) 4-bromophenyl-1-methylthiocyclopropyl ketone (for examples) __

Analogous to A).

a) 4-bromophenyl-3-chloro-1-methylthiopropylketone 15 melting point: 92-94 ° b) 4-bromophenyl-3-chloro-1-methylthiopropylketone Rf = 0.13 (n-hexane / ethyl acetate = 98/2) c ) 4-bromophenyl-1-methylthiocyclopropylketone melting point: 43-45 ° C) 4-chloro-α- (1-methylthio) cyclopropyl-α-mesyloxymethylbenzyl alcohol (for examples III and IV) a) 1- (4-chlorophenyl) -1- (1-methylthio) cyclopropyl oxiran

To a suspension of 0.73 g of sodium hydride (80%) in 50 ml of dry dimethylformamide, 5.34 g of tri-25 methylsulfoxonium iodide were added in portions and the mixture was stirred for 45 minutes. A solution of 5 g of 4-chloro-phenyl-1-methylthiocyclopropyl ketone in 25 ml of dimethylformamide was then added dropwise and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure (1 Torr) and the resulting residue was taken up in a mixture of ethyl> 9 acetate and water. The organic phase was separated, dried over magnesium sulfate and concentrated by evaporation. A colorless oil was thus obtained.

1 H NMR: 7.1-7.6 (m, 4H); 2.76-3-0 (AB system, 2H); 1.98 (s, 3H); 0.7-1.3 (m. 4H).

b) 4-chloro-a-hydroxymethyl-a- (1-methylthio) cyclopropylbenzyl alcohol.

0.2 g of 1- (4-chlorophenyl) -1- (1-methylthio) cyclopropyl oxiran was stirred with a 0.3 molar potassium hydroxide solution in a mixture of dimethyl sulfoxide and water (4: 1) for 20 hours. 30 ° C. The mixture was then diluted with 50 ml of water and extracted with ethyl acetate. The extract solution was dried over sodium sulfate and concentrated by evaporation. The crude product can be purified by chromatography on silica gel with a mixture of hexane and ethyl acetate (4: 1). Colorless crystals with a melting point of 86-91 ° C were obtained.

c) Separation of the optical anti-pods.

2.67 g of camphoric acid chloride was added to 2.65 g of the racemic product in 50 ml of pyridine in portions and with cooling with ice water and the mixture was stirred at room temperature for 20 hours. The mixture was poured onto ice-cooled, dilute sulfuric acid, extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate and concentrated by evaporation. The mixture of diastereoisomeric esters was separated by chromatography on silica gel with a mixture of hexane and ethyl acetate (4: 1).

—20

Diastereomer A: mp .: 122-124 °, / <& '(acetone) = + 28 °.

"--20

Diastereomer 3: mp: 125-127 °, t / LfΏ (acetone) = -43.6 °.

2 g of diastereoisomer A was stirred under reflux for 15 hours and with 3 g of a strongly basic ion exchanger in a mixture of methanol and water. After filtration and concentration by evaporation, the right-turning enantiomer was obtained as a colorant. : si - 10 - empty crystals.

mp .: 60-62 °.

/ a7D (acetone) = + 79.7 °.

d) (+) - 4-chloro-a- (1-methylthio) cyclopropyl-a-mesyloxy-5-thyl-benzyl alcohol

1.27 g of (+) - 4-chloro-α-hydroxymethyl-α- (1-methylthio) cycloprcpyl-benzyl alcohol are added dropwise, 0.88 g of mesyl chloride with cooling water to subcool with ice water. Then stirring with the mixture for 2.5 hours at a temperature between 10-5 ° C, poured on ice-cold dilute sulfuric acid, extracted with ethyl acetate, dried the organic phase over magnesium sulfate and concentrated by evaporation to a colorless oil.

1 H-NMR: 7.2-7.65 (m, 4H); 4.5-5.22 (AB system, 2H); 3.0 (s, 3H); 1.52 (s. 3H); 0.5-1.4 (m. 4H).

- - 20 / et / ... = + 57.4 °.

~: “D

The (-) antipode can be obtained in a similar manner.

Claims (12)

Azole derivatives of the formula I, wherein R 1 and R 2 independently are one another, a hydrogen or halogen atom, a nitro group, low alkenyl group, low alkyl group, low alkyl sulfenyl group, low alkysulfonyl group, low alkyl or low alkoxy-5 group each optionally mono- or polysubstituted by halogen, represent a lower alkyl, low alkenyl or lower alkynyl group, each optionally mono- or polysubstituted by halogen, carboxyl, lower alkoxycarbonyl, lower alkoxy, lower alkylthio, 10 amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkyl-amino and lower dialkylamino, or a phenyl group optionally substituted by halogen, lower alkyl, lower alkoxy, amino lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino low dialkylamino, l-piperazinyls> èf4 alkanoyl-1-piperazinyl, wherein any alkyl, alkenyl or alkynyl group present in it may be mono or polysubstituted by halogen, XN or CH n is an integer from 2 to 5, in enantiomeric or racemic form. 20 A compound according to claim 1, wherein R 1 and R 1 r independently, a hydrogen or halogen atom, R 3 represents a lower alkyl group and n 2. 3. Azole derivatives of formula 1, wherein R 1 and R 2} independently of one another, a hydrogen or halogen atom, a nitro, lower alkenyl, lower alkylthio, lower alkylsulfinyl, lower alleylsulfony 1, lower alkyl or lower alkoxy group, each optionally mono- or polysubstituted by halogen, R3 represent a lower alkyl, lower alkenyl or γ1-alkynyl group, each optionally mono- or poly-substituted by halogen, carboxyl, lower alkoxycarbonyl, lower alkoxy , lower alkylthio, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino and / or - 13 - i has indicated meanings and M is a hydrogen atom or a metal equivalent, or b) a compound of formula 4, wherein, R ^, R ^ and n have the meanings indicated above, to react with a previously defined compound of formula 3 and dimethylsulfonium methylide or dimethyl oxosulfonium methylide, or a precursor thereof, wherein any amino groups present by corresponding protective groups bars can be protected, which groups are removed after the completion of the reaction and recover the compounds thus obtained in free form or in the form of a salt. 11. Method as described in the description and / or examples. 4r'-t-12 - low dialkylamino, or a phenyl group, optionally substituted by halogen, low alkyl, low alkoxy, amino, low alkanoyl amino, low alkoxycarbonylamine, low alkylamino, low dialkyl amino, 1-piperazinyl and / or 4-lower alkanoyl-5-piperazinyl, represents, XN or CH represents n is an integer of 2-5, in an enantiomeric or racemic form. A compound according to any one of claims 1 to 3 in free form. A compound according to any one of claims 1 to 3 in salt form. 5. (+) - α · {4-chlorophenyl) -a- / 7l-methylthio) cyclopropy1 / 1H-1,2,4-triazole-1-ethanol in free form or in the form of a salt. 7. A pharmaceutical preparation containing one or more compounds according to any one of claims 1-6, in free form and / or in the form of a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent and / or carrier . A compound according to any one of claims 1-6, in free form and / or in the form of a pharmaceutically acceptable salt, for use as a pharmaceutical. A compound according to any one of claims 1-6, 25 in free form and / or in the form of a pharmaceutically acceptable salt, for use as an anti-micotic. 10. Process for preparing a heterocyclic compound, characterized in that a compound of formula 1 according to claim 1, in free form or in the form of a salt, is prepared by A) a compound of formula 2, or reacting a compound of formula 2a, wherein, R ^ / R ^ and n have the meanings indicated above and R ^ is a cleavable group with a compound of formula 3, wherein X represents the above '' • v - J - i II SR; C ^ _> ° lAs I N xV T U f ~ cACH ^ o cut-c-c ^ mi A '' N 3 Λ w M 2 0. Ri R * R1 R1 SR3 hall OH SRj, l | A H s "'1. c — cv (CHk c - C (CH ^ Ri | CHj — C C (CHe ^ 1 1 0. a ώ 5 k * 2a r, Rt * Rf X Ri R2 0 SR. 11! , HS-R3 C —CH - (CH ^ —hal 'h 0 ha! R' Rl Α „-, fM,., - A · A 9 R1 Ri · <* · '· 1 .1 · Λ' SANDOZ AG Basel Switzerland