HU212424B - New propan-2-ol derivatives substituted with triazole or imidazole and process for producing them - Google Patents

Abstract

The invention relates to novel substituted propane-2-ol derivatives of formula (I), wherein R<1> represents a C1-10alkyl group, a phenyl group or a phenyl-C1-6alkyl group, and the phenyl moiety of the two latter groups may carry at least one substituent selected from the group consisting of a halogen atom, C1-6alkoxy group, phenyl group, phenoxy group and trifluoromethyl group; X represents a hydrogen or halogen atom; and Y<1> represents a -N= atom or a group of the formula --CH=, and optical antipodes and racemates thereof, further to pharmaceutical compositions of fungicidal action, containing such compounds, processes for the preparation of these compounds and compositions, finally to a method of treatment by using these compounds and compositions.

Description

The present invention relates to novel propan-2-ol derivatives of formula I wherein:

R ¹ is phenyl substituted with one or more halogen atoms,

X is hydrogen or halogen,

Y ^{1 is} a group of the formula -N = or -CH =, a fungicidal pharmaceutical composition containing them as an active ingredient, and processes for the preparation of the active compounds and compositions. The compounds of the present invention may be used to control fungi which are harmful to the body by administering to the mammal to be treated, including man, one or more effective doses of the compounds of formula I, either alone or in a pharmaceutical composition.

British Patent No. 2,078,719 A discloses high potency fungicidal compounds which also have significant plant growth regulating activity. The compounds described are represented by formula (A) wherein R is alkyl, cycloalkyl, aryl or aralkyl, or a derivative thereof containing one or two halogen atoms, or further alkoxy, phenyl on the aryl and benzyl groups. , there are also phenoxy or trifluoromethyl substituents, Y ¹ and Y ^{2 being} as defined above.

British Patent No. 2,099,818 A discloses that 2- (2,4-difluorophenyl) -1,3-bis (1,2,4-triazol-1-yl) propan-2-ol is human. as a lingicide. The molecule is marketed as Fluconasole or Diflucan as an outstanding human fugicidal drug.

According to British Patent No. 2,078,719 A, the propan-2-ol derivatives represented by the general formula (A) are prepared by reacting a Grignard compound of the formula RMg-Halogen with dichloroacetone. The resulting 1,3-dichloropropan-2-ol derivatives of formula (ΙΠ) are reacted with an imidazole or triazole salt, such as sodium, in an protic or aprotic medium (dimethylformamide). The reaction may also be carried out with epoxy derivatives which are formed in situ by the elimination of the dihalo compound by the action of a base with hydrochloric acid. The target compounds may also be prepared by reacting the corresponding 1,3-bisimidazolyl or 1,3-bis (1,2,4-triazol-1-yl) acetone with a Grignard compound of the formula R-Mg-Halogen. In another embodiment, the compounds of formula (IV) are prepared with dimethyl oxosulfonium methylide to form compounds of formula (V), which are reacted with the sodium salt of imidazole or triazole in the same manner as in the preceding procedure. The starting compounds are prepared by reactions known per se.

The process described in British Patent No. 2,099,818 A for the preparation of the active ingredient of Fluconasole also utilizes the starting compounds of formula (III) and (V), but with a base instead of 1,2,4-triazol-1-yl sodium. triazole is used as reaction partners.

A common feature of the processes described in both patents is that the products obtained in the reaction are isolated by extraction after mixing the reaction mixture with water and the product is purified and isolated by column chromatography, fractionation in vacuo or other methods. The yield obtained ranges from 30% to 50%.

British Patent 2,078,719 A discloses that the esters and ethers of the target compound are prepared by reacting the sodium hydride salt of the alcohol with a suitable acylating or alkylating agent.

According to Spanish Patent Specification ES 549 020 A1, 1,3-dichloroacetone is reacted with 2 moles of 1,2,4-triazole per mole and then 1,3-bis (1,2,4-triazol-1-yl) is obtained in very poor yield. ) -propan-2-one is reacted with 2,4-difluorophenyl magnesium bromide to give fluconazole. The yield is about 45% based on the Grignard reagent.

A common feature of the processes described in Spanish Patents ES 549 021 A1, ES 549 022 A1 and ES 549 684 A1 is that one or both of the triazolyl groups of fluconazole is (1,2,4-triazol-1-yl) - is introduced into the molecule with methyl magnesium halide. Yields of about 45-55% are described. Grignand reagents containing the triazolyl group are known to be unstable and sometimes inactive, so they can only be reacted with poor efficiency. Reproductions of the processes described in the patents yielded yields below 10% in each case.

A more favorable process than that described is described in Spanish Patent Specification ES 2026 416. According to this, 1- (1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-halopropan-2-ol is reacted with 4-amino-1,2,4-triazole. then the resulting 1- (1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3- (4-amino-1,2,4-triazol-1-yl) ) -propan-2-ol is diazolized to remove the amino group and the resulting diazonium salt is decomposed. The first step yields 78% and the second step 85%. The process has several significant drawbacks to industrial production. The first is that the epoxide derivative of formula (V) must be refluxed in a highly corrosive halohydrogen medium to produce the 3-halopropan-2-ol starting material. A further disadvantage is that the reagent 4-amino-1,2,4-triazole is difficult to obtain as a fine glass. The diazotization reaction followed by the decomposition of the diazonium salt is a very dangerous operation under industrial conditions. Finally, the overall yield of the highly laborious multi-step process is barely 42-43%.

Due to its high potency, known for its broad spectrum of action, the high-volume Fluconasole active ingredient, due to its very high human fungicidal activity, revealed that it has a relatively weak activity against the very common Candida albicans pathogenic fungal strain. It is mainly this resistant fungal strain that causes the very difficult to control fungal disease called widespread candidiasis. In vitro studies have shown that while Fluconasole is active at very low concentrations in other Candida strains and other pathogenic fungi2

Whole inhibition (0.1-10 pg / ml) is complete, whereas in Candida albicans this inhibitory effect occurs only at 2500 pg / ml.

In our research to produce more potent fungicides with a broader spectrum of activity, we have surprisingly discovered that the propan-2-ol derivatives of formula (I) have surprising fungicidal activity. This is a broad spectrum of action along with plant fungi, especially human fungal strains.

The present invention is based on the discovery that the silyl ethers of formula II, which can be prepared, for example, by reacting epoxide derivatives of formula VI with a silyl triazole of formula VII or silyl imidazole in the presence of a strong base catalyst or can be hydrolyzed quantitatively in alkaline aqueous medium to the propanol derivatives of formula (I).

According to the present invention, the substituted propan-2-ol derivatives of formula I are prepared by reacting a silyl ether derivative of formula II wherein R ¹ , X and Y ¹ are as defined above, R ^{2 is} a 1- C 7 -alkyl, R ³ and R ⁴ each independently represent a C 1 -C 10 -alkyl or a phenyl, being hydrolyzed in a solution containing less than 3 or more than 8 pH.

Hydrolysis proceeds rapidly. The trimethylsilyl ethers are completely hydrolysed at room temperature over 10 minutes in dimethylformamide solution containing 10% water at pH> 10. The hydrolysis is carried out in the same medium and temperature, but under pH = 2, over a period of 0.5 to 1 hour.

The hydrolysis is conveniently carried out in a homogeneous phase in a mixture of a water-miscible protic or aprotic dipolar solvent and water at the pH range indicated above.

The compounds of formula (I) formed during the reaction are conveniently isolated by diluting the reaction mixture with water and then cooling. The resulting compounds of formula I are precipitated from the reaction mixture in high purity and can be isolated, for example, by filtration.

The hydrolysis process of the present invention may also be carried out by not separating the silyl ether derivatives of formula (Π) from the reaction mixture used for their preparation, but adding to the homogeneous reaction mixture about 5 volumes of water and stirring. In this case, the base catalyst used in the preparation of the silyl ether derivative provides a pH above 8 for the hydrolysis reaction. After hydrolysis is complete, if desired, a portion of the organic solvent is removed from the reaction mixture and the residue is diluted with water. Upon cooling, the resulting compounds of formula I are precipitated from the reaction mixture and can be isolated, for example, by filtration.

Compounds of formula VI used as starting materials for the preparation of silyl ethers of formula II are known or can be prepared in a manner known per se. They are reacted with a silyl derivative of formula (VII) to give the starting compounds of formula (II). For the silylation, trimethylsilyl derivatives of the readily available trimethylchlorosilane and imidazole or triazole are preferably used as the compound of formula VII.

The fungicidal activity of the compounds of formula I was investigated by the following in vitro test:

Densitometry of yeast proliferation:

A BIOSCREEN Type C (LABSYSTEMS, Helsinki, Finland) microbiological analyzer was used for measurement. The test compounds were diluted in 50 mg / ml stock solution with dimethyl sulfoxide followed by a 15 step batch dilution. 10-10 μ-10 of the dilution steps were measured into the cells of the device. Subsequently, 390 μΐ of the medium was pipetted into the cells in which cells of the test yeast (e.g., Candida albicans) were suspended so that the optical density of the suspension was approximately 0.1. The suspension was prepared by shaking a young culture for about 12 hours at 30 ° C. The composition of the aqueous medium is: 1% glucose, 0.5% yeast extract (yeast extract, product L21 from OXOID Ltd., UK) and 0.5% nutrient broth (OXOID Ltd., UK). CM 1/2 product). The concentrations of test compounds in the cells corresponded to 1250, 625, 312, 156, 78, 39, 19, 9, 4, 2, 1, 0.6,0,3,0,15 and 0.07 pg / ml, respectively. . The densitometry of the culture was performed by incubation at 37 ° C for 30 hours. The change in turbidity in the culture, which could be followed optically, is proportional to the growth of the yeast.

In the assay, the minimum inhibitory concentration (MIC) was determined as the minimum concentration of active ingredient that was still fully capable of inhibiting fungal growth. The results are shown in the table.

Spreadsheet

MIC values in each assay / pg / ml]:

Active ingredient: Candida albicans

Example 5 625

Example 6 19

Example 7 150

Fluconasole 2500

Therapeutic use of compounds of formula I may be contemplated in any disease where the target is controlling pathogenic fungi. The active compounds can be used to treat both the animal and the human body.

In therapeutic use, the compounds of the formula I are administered in a daily dose of from 0.1 to 10 mg / kg body weight, once or several times daily by oral or parenteral administration.

The active compounds of the formula I are formulated into pharmaceutical compositions by admixing with non-toxic inert solid or liquid carriers and / or excipients suitable for parenteral or enteral administration in the pharmaceutical field. Hoidozó3

As the substance B, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, talc, vegetable oils may be used.

The active compounds may be prepared in the form of conventional pharmaceutical compositions, in particular solid forms such as rounded or bevelled tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like.

The amount of solid active ingredient may vary over a wide range, preferably from about 25 mg to about 1 g per tablet. The formulations may also contain conventional pharmaceutical excipients, such as preservatives. They are prepared by conventional techniques such as sieving, mixing, granulating and optionally pressing the components in the case of solid preparations. The compositions may also be subjected to standard pharmaceutical technology treatments (e.g., sterilization by injection).

Further details of the invention are illustrated by the following non-limiting examples.

Example 1

1.2-Epoxy-2- (2,4-difluorophenyl) -3-chloropmpane

32.5 g (0.135 mol) of 2- (2,4-difluorophenyl) -1,3-dichloropropan-2-ol, prepared according to British Patent 2,078,719 A, are dissolved in 200 ml of dichloromethane. then add a solution of 8 g of sodium hydroxide (0.2 mol) in 40 ml of water at room temperature and 1 ml of a 40% solution of tetrabutylammonium hydroxide in water. After stirring at room temperature for half an hour, the organic layer was separated, washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, washed with dichloromethane (2 x 5 mL), and the organic layers were combined and evaporated to a solvent. The title compound was obtained as a light yellow oil (26 g, 93.7%). n ²⁰ D = 1.4978.

Example 2

1.2-Epoxy-2- (2,4-difluorophenyl) propane

All proceed as in Example 1, but instead of 2- (2,4-difluorophenyl) -1,3-dichloropropan-2-ol, 27.88 g (0.135 mole), also in the high-purity process of 2,078,719 A. 2- (2,4-difluorophenyl) -1-chloropropan-2-ol, prepared according to British Patent Specification No. 4,684,198, is used. This gave 20.7 g (90.2%) of the title compound as a light yellow oil. n ²⁵ D = 1.5264.

Example 3

2- (2,4-Difluorophenyl) -1-chloro-3- (1,2,4-triazol-1-yl) -2 (trimethylsilyloxy) propane

1,2.11 g (0.02 mol) of 1,2-epoxy-3-chloro-2- (2,4-difluorophenyl) -propane in 50 ml of dimethylformamide are 4.23 g (0.03 mol) of 1- (trimethylsilyl) -1,2,4-triazole and 0.1 g (0.001 mol) of 1,2,4-triazol-1-yl potassium at 50 ° C for 2 hours. The reaction mixture was then quenched with glacial acetic acid, mixed with water (250 mL) at room temperature and extracted with dichloromethane (2 x 50 mL). The combined dichloromethane layer was washed with water (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography. (Merck, Kieselgel 40, 70-230 mesh, ethyl acetate: methanol 20: 1, by volume). The pure fractions by TLC were combined and de-solvented to give a residue which was crystallized from n-heptane. g (71.5%) of the title product is obtained, m.p.

Example 4

2- (2,4-Difluorophenyl) -3- (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) propane

5.13 g (0.03 mol) of 1,2-epoxy-2- (2,4-difluorophenyl) -propane in 40 ml of dimethylformamide 6.35 g (0.045 mol) of 1-trimethylsilyl-1 With 2,4-triazole and 0.14 g (0.0015 mol)

1,2,4-Triazol-1-yl sodium was reacted at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature, neutralized with glacial acetic acid, diluted with water (200 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and dried over anhydrous sodium sulfate. Separation on a column of Example 3, removal of solvent and crystallization of the residue from n-heptane gave 6.0 g (64.5%) of the title compound. Mp .: 51-53 ° C.

1-4. Other starting materials of the formula (II) used in the process of the invention may also be prepared according to the Examples.

Example 5

2- (2,4-Difluorophenyl) -3- (l, 2,4-triazol-l-yl) -propan-2-ol

6.22 g (0.02 mol) of 2- (2,4-difluorophenyl) -3- (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) propane 30 of methanol and 2 ml of water in the presence of 0.06 g (0.015 mol) of sodium hydroxide for 1 hour at room temperature. Water (300 ml) was added and the mixture was cooled to 0 ° C. The precipitated material is filtered off and dried. 4.54 g (95%) of the title compound are obtained. Mp .: 84-85 'C.

Example 6

1-Chloro-2- (2,4-difluorophenyl) -3- (imidazol-1-yl) propro-2-ol

3.44 g (0.01 mol) of 1-chloro-2- (2,4-difluorophenyl) -3 (imidazol-1-yl) -2- (trimethylsilyloxy) propane (18 ml) in methanol and 2 ml water (0.04 g, 1 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to 6 ml and water (50 ml) was added to the residue. The precipitated material was filtered at 0 'C. 2.4 g (88%) of the title compound are obtained. Mp .: 142-144 'C.

Example 7 1-Chloro-2- (2,4-difluorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol

3.45 g (0.01 mol) of 1-chloro-2- (2,4-difluorophenyl) -3- (1,2,4-triazol-1-yl) -2- (trimethylsilyloxy) -propane are obtained. of ethanol, 20 ml of water and 0.1 ml of concentrated hydrochloric acid were stirred at room temperature for 1 hour. The reaction mixture was stripped of solvent by distillation, water (10 ml) and dichloromethane (20 ml) were added, followed by 10% sodium hydroxide solution.

The solution is made alkaline to pH = 8 with xid solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from n-hexane. This gave 2.54 g (93%) of the title compound. Mp .: 67-69 'C.

Example 8

-Chloro-2- (2,4-difluorophenyl) -3- (imidazol-1-yl) propro-2-ol

1,2.11 g (0.02 mol) of 1,2-epoxy-3-chloro-2- (2,4-difluorophenyl) -propane in 40 ml of dimethylformamide were 4.20 g (0.03 mol) of 1- (trimethyl) silyl) imidazole and 0.09 g (1 mmol) of imidazol-1-yl sodium at 60 ° C for 2 hours. Water (0.5 mL) was added to the reaction mixture, stirred for an additional half hour at 30 ° C, and then concentrated in vacuo. The residue was partitioned between water (80 mL) and dichloromethane (60 mL), the organic layer was separated and chromatographed as in Example 3. 3.61 g (66%) of the title compound are obtained. Mp .: 142-144 'C.

Example 9

100 mg tablets with 10 mg active ingredient

50.0 g of active ingredient,

285.0 g lactose,

100.0 g potato starch,

2.5 g of sodium dodecyl sulfate,

5.0 g of polyvinylpyrrolidone (Kollidon-K 90 ^R ),

50.0 g microcrystalline cellulose (Avicel ^R ),

7.5 g of vegetable oil (Sterotex ^R ) is pressed into 100 mg tablets by wet granulation and compression in the usual way. Each contains 10 mg of the active ingredient.

Example 10

125 mg dragees with 10 mg active ingredient

Tablets prepared in the above manner are coated in a known manner with a layer of sugar and talc. The dragees are polished with a mixture of beeswax and kamauba wax.

Example 11 Capsules containing mg of active ingredient

40.0 g of active ingredient,

12.0 g of sodium lauryl sulfate,

102.0 g lactose,

102.0 g potato starch,

2.4 g of magnesium stearate and

1.6 g of colloidal silica are thoroughly mixed and the resulting mixture is filled into hard gelatin capsules. Each capsule contains 20 mg of the active substance.

Claims (10)

PATENT CLAIMS Novel propan-2-ol derivatives of the general formula (I) - wherein R ¹ is phenyl substituted with one or more halogen atoms, X is hydrogen or halogen, Y ^{1 is} a group of the formula -N = or -CH =. (Priority: 09/20/1994) 2- (2,4-Difluorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol according to claim 1. (Priority: 9/9/1994 20.) The 1-chloro-2- (2,4-difluorophenyl) -3-imidazol-1-yl) propan-2-ol of claim 1. (Priority: 09/20/1994) The 1-chloro-2- (2,4-difluorophenyl) -3- (1,2,4-triazol-1-yl) propan-2-ol of claim 1. (Priority: 09/20/1994) 5. A fungicidal pharmaceutical composition comprising, as active ingredient, a therapeutically effective dose of one or more novel substituted propan-2-ol derivatives of formula (I) wherein R ¹ , X, Y ¹ are as defined in claim 1. in addition to the excipients commonly used in the preparation of formulations. (Priority: 09/20/1994) A process for the preparation of new propan-2-ol derivatives of the formula I wherein: R ¹ is phenyl substituted with one or more halogen atoms, X is hydrogen or halogen, Y * for preparing a group of the formula -N = or -CH =, wherein a silyl ether derivative of the formula II - wherein R ¹ , X and Y ¹ are as defined above, R ^{2 is} a C 1-7 alkyl R ³ and R ⁴ are each independently hydrolyzed in a solution containing water having a pH of less than 3 or greater than 8 and a C 1-10 alkyl or phenyl group. (Priority: 23/09/1993) The process according to claim 6, wherein the hydrolysis is carried out in an aqueous medium containing dimethylformamide in the presence of sodium hydroxide. (Priority: 23/09/1993) The process according to claim 6, wherein the hydrolysis is carried out in an aqueous methanolic medium in the presence of potassium hydroxide. (Priority: September 23, 1993) 9. A process according to claim 6, wherein the hydrolysis of the compound of formula II wherein R ¹ , R ² , R ³ , R ⁴ , X and Y ¹ is as defined above, without isolation from the reaction mixture used for its preparation. , water is added to the reaction mixture. (Priority: 23/09/1993) 10. A process for the preparation of a fungicidal pharmaceutical composition, characterized in that one or more compounds of formula (I), wherein R ¹ , X and Y ¹ are as defined in claim 6, are conventionally used in the preparation of pharmaceutical compositions, and mixed with facilitating excipients to form a pharmaceutical composition. (Priority: 23/09/1993)