DD246296A5 - PROCESS FOR THE PREPARATION OF NEW BIS-TRIAZOL DERIVATIVES - Google Patents

Abstract

A process for the preparation of antifungal compounds of formula I wherein R is phenyl optionally substituted with 1 to 3 substituents each independently selected from F, Cl, Br, J, CF 3, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, or R 5 chloropyridine 2-yl, and their O-esters, O-ethers and their pharmaceutically and agriculturally acceptable salts. The compounds are useful as antifungal agents in humans and in agriculture. Formula I

Description

R. CH ₃

wherein X and X ^{1 are} each an leaving group and R is as defined above, reacted with 1,2,4-triazole or a base salt thereof and then optionally the product in an O-ester, O-ether or a pharmaceutically or agriculturally acceptable Salt is converted.

2. Method according to item I, characterized in that X and X ^{1 are} each Br.

.3. Process according to any one of the preceding claims, characterized in that it is carried out using 1,2,4-triazole in the presence of potassium carbonate.

4. The method according to any one of items 1 and 2, characterized in that it is carried out using an alkali metal salt of 1,2,4-triazole.

5. The method according to any one of the preceding points, characterized in that R 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl or 5-chloropyrid-2-yl.

6. The method according to item 5, characterized in that R is 2,4-difluorophenyl or 4-chlorophenyl.

Field of application of the invention

The invention relates to methods of preparing novel bis-triazole derivatives having antifungal activity and useful in the treatment of fungal infections in animals, including humans, and as agricultural fungicides.

Characteristic of the known technical solutions

The following publications were considered for the invention: EP-A 0069442 and EP-A 0044605. EP-A 0044605 discloses fungicidally active bis-azolyl compounds. EP-A 0069442 discloses fungicidally active bis-triazole derivatives.

Object of the invention

The compounds prepared by the process according to the invention are characterized by an activity against Aspergillus fungi which is unexpected compared with the known structure-like compounds.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of new bis-triazole derivatives available. According to the invention, compounds of the formula

tf-CH _o -C - ΟΧ w / j! Oh

OH H _χΝ

_ T \ T "NT

(I)

wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, J, CF ₃ , C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or R 5 chloropyridine-2 -yl, and its O-esters, O-ethers and pharmaceutically and agriculturally acceptable salts

C ₃ and C ₄ alkyl and alkoxy groups may be straight-chain or branched.

When R is the optionally substituted phenyl group, it is preferably substituted by 1 to 3 substituents, more preferably 1 or 2 substituents, substituted phenyl, each substituent independently selected from F, Cl, Br, J and CF ₃ . The preferred single R groups are 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2 Fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl and 5-chloropyrid-2-yl. The most preferred R groups are 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl, 4-chlorophenyl and 5-chloropyrid-2-yl

 In the most preferred single compound, R is 4-chlorophenyl.

According to the invention, a process for the preparation of the compounds of the formula (I) is provided, in which a compound of the formula

, OH. ,

X-CH ₀ -C-CH-X ¹ (V)

R CH ₃

wherein X and X ^{1 are} each an leaving group, preferably Cl, Br or J, and R is as defined for formula (I), with either 1,2,4-triazole, preferably in the presence of a base, e.g. As potassium carbonate, or with a base salt, preferably an alkali metal salt, is reacted by 1,2,4-triazole.

Preferably, X and X ^{1 are the} same and most preferably Br. Typically, the compound (V), 1,2,4-triazole and potassium carbonate are taken together to e.g. B. 40-120 ⁰ C in a suitable organic solvent, for. As dimethylformamide, heated until the reaction is complete. The product can then be isolated and purified in a conventional manner.

The starting materials (V) are obtained in a conventional manner, e.g.

ί τ

R.ttgBr + Br-CH-CH-Br ₀ -C Br.CH ₀ -C-CH-Br (VA).

² I ² II

CH. R CH

It is not necessary to isolate the intermediate (V). It can be used directly.

The O-esters and O-ethers may be prepared in a conventional manner, typically by reacting an alkali metal salt of a compound (I) with the appropriate chloro or bromo compound, e.g. An alkanoyl or benzoyl chloride or alkyl, alkenyl, benzyl or phenyl chloride or bromide.

Pharmaceutically acceptable acid addition salts of the compounds of formula (I) are those with strong acids which form non-toxic acid addition salts, such as hydrochloric, hydrobromic, sulfuric, oxalic and methanesulfonic acid. The salts can be obtained by conventional procedures, e.g. By mixing solutions containing about equimolar amounts of the free base and the desired acid, and the desired salt is recovered by filtration if insoluble or by evaporation of the solvent.

The compounds of the invention have been found to have unexpectedly good activities against infections caused by the clinically important Aspergillus fungi.

The compounds of formula (I) and their O-esters, O-ethers and salts are antifungal agents useful for controlling fungal infections in animals, including humans. They are useful, for example, in the treatment of topical fungal infections in humans, causing, i.a. a. of Candida, Trichophyton, Microsporum or Epidermophyton, or of mucosal infections caused by Candida albicans (ζ B. candidiasis of the throat and vagina). They may also be used in the treatment of systemic fungal infections, e.g. of Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces. The in vitro determination of the antifungal activity of the compounds can be carried out by determining the minimum inhibitory concentration (MIC) of the test compounds in a suitable medium in which growth of the specific microorganism no longer occurs. In practice, a series of agar plates, each containing the test compound incorporated in a particular concentration, are incubated with a standard culture of e.g. B. Candida albicans and each plate • then incubated for 48h at 37 ° C. The plates are then checked for the presence or absence of growth of the fungus and the corresponding MIC value noted. Other microorganisms used in such assays may include Candida albicans, Aspergillus fumigatus, Trichophyton spp, Microsporum spp, Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata. , · ·

The in vivo evaluation of the compounds may be carried out at a range of dose levels by intraperitoneal or intravenous injection or by oral administration to mice, e.g. B. in a strain of Candida albicans or Aspergillus flavus are inoculated. The activity is due to the excess of a treated group of mice after entering an untreated group of mice. The dose value at which the compound provides 50% protection against the lethal effect of the infection (PD ₅₀ ) is noted.

For human use, the antifungal compounds of formula (I) and their salts, O-ethers and O-esters may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier with regard to the intended route of administration and standard pharmaceutical practice is selected. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or egg-shaped tablets either alone or in admixture with excipients or in the form of elixirs or suspensions containing flavoring or coloring agents , You can parenteral, z. B. injected intravenously, intramuscularly, or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution containing other substances, e.g. For example, enough salts or glucose to render the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dose of the antifungal compounds of formula (1) and their salts, O-ethers and O-esters is 0.1 to 10 mg / kg (in divided doses) by oral or parenteral administration. Thus, tablets or capsules of the compounds contain 5 mg to 0.5 g of the active compound for administration singly or two or more simultaneously, as appropriate. The doctor will in any case determine the actual dosage that is most appropriate for a single patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there may of course be isolated cases where higher or lower dosage ranges are beneficial, and they are within the scope of the invention.

Alternatively, the antifungal compounds of formula (I) may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or powder. For example, they may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they may be incorporated at a concentration between 1 and 10% in an ointment consisting of a white wax or white soft paraffin base, together with such stabilizers and preservatives as may be necessary.

The compounds of formula (I) and their O-ethers, O-esters and salts also possess activity against a variety of phytopathogenic fungi, including e.g. Various types of rust, mildew and mold, and are thus useful for treating plants and seeds for eradicating or preventing such diseases. The in vitro determination of the activity of the compounds against plant fungal can be accomplished by measuring the minimum inhibitory concentrations in the same manner as described above, except that the plates are incubated at 30 ° C for 48 hours or longer before being tested for the presence or absence of growth become. Microorganisms used in such assays include Cochliobolus carbonum, Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoctonia solani.

For agricultural and horticultural purposes, the compounds and their agriculturally acceptable salts are preferably used in the form of a composition suitable for the particular use and purpose desired. Thus, the compounds may be applied in the form of dusting powders, granules, seed sauces, aqueous solutions, dispersions or emulsions, dipping solutions, spraying agents, aerosols or smoking agents. Compositions may also be supplied in the form of dispersible powders, granules or granules or concentrates for dilution prior to use. Such compositions may thus contain conventional carriers, diluents or adjuvants as known and acceptable in agriculture and horticulture, and are prepared according to conventional procedures. The compositions may also contain incorporated other active ingredients, e.g. B. Compounds with herbicidal or insecticidal activity or another fungicide. The compounds and compositions can be applied to a variety of ways, e.g. Directly on the foliage, stalks, twigs, seeds or roots of the plants or on the soil or other growth medium, and may be used not only to eradicate the disease but also prophylactically to protect the plants or seed from infestation , The following examples illustrate the invention. All temperatures are in ° C.

example 1

Preparation of 1,3-bis- (1H-1,2,4-triazol-1-yl) -2- (4-chlorophenyl) -butan-2-ol

MgBr

+ BrCH ₂ COCH (CH ₁ ) Br - - ^. BrCH ₂ -C-CH (CH) Br

1,2,4-triazole, N, N-CH-C-CH (CH,) N

K ₂ CO ₃

4-Chlorophenyl magnesium bromide in ether (80 ml) (prepared from 4-chlorobromobenzene [15.2 g] and magnesium turnings [2.8 g]) was added to a solution of 1,3-dibromobutane-2 under a nitrogen atmosphere for 30 minutes via a double-ended needle -on (9.2g) (Org. Synthesis, 53.123) in dry ether (50ml) at -78 °. After stirring for one hour at -78 °, the resulting mixture was quenched with saturated ammonium chloride solution and allowed to reach room temperature. The ether layer was separated, the aqueous layer extracted with ether (3 × 20 ml) and the combined ether extracts washed with brine and dried over MgSO 4 The residue obtained after removal of the ether was added to a mixture of 1,2,4-triazole (8g), potassium carbonate (20g) and dimethylformamide (50ml) under a nitrogen atmosphere and the mixture heated at 70 ° overnight The cooled solution was filtered, the solid washed with xylene (50ml) and the combined filtrates in vacuo The last traces of dimethylformamide were removed by azeotroping with xylene (2 × 30 ml) The crude residue was partitioned between methylene chloride (200 ml) and water (100 ml) and the methylene chloride extract was washed with water and dried over MgSO4 Vacuum, the residue was flash chromatographed on silica (150g) using methylene chloride with 8% by volume methanol

Elution was used. Appropriate fractions (i.e., fractions 29-39 of 50 ml each) were combined to afford, after evaporation, 1.1 g of a mixture of diastereomeric pairs. The isomer pairs were separated by flash chromatography on silica (100 g) eluting with ethyl acetate / diethylamine / methanol (80: 20: 2 volumes). Fractions 13-16 (each 25 ml) were combined and concentrated to give the isomer pair 1 (114mg), mp 112-113 °, yield from ethyl acetate / hexane (mass spectrum m / E318 (M ^+);. Calculated for C ₁₄ Hi ₆ CIN ₆ OiIvI ⁺ = 318). Evaporation of fractions 31-49 (again 25 ml each) followed by crystallization from ethyl acetate / hexane afforded the isomer pair 2 (246 mg), mp 50-51 ° (mass spectrum m / e 318 (M ⁺ ); calculated for Ci ₄ H ₁₅ CIN ₆ CkM ⁺ = 318).

Isomer pair 1 NMR (CDCl ₃ ) δ = 1.25 (d, J = 7Hz, 3H, CH ₃ ), 3.76 (d, J = 13Hz, 1H, N-CH ₂ ), 4.32 (d , J = 13 Hz, 1H ₁ N-CH ₂ ), 4.92 (q, J = 7Hz, 1H ₇ N-CH [CH ₃ ]) 5.48 (s, -OH: exchange with D ₂ O) , 7.12 (m, 4H, C ₆ H _4), [7.55 (s, 1 H), 7.70 (s, 1 H), 7.92 (s, 1H), 8.30 (s , 1H) -triazole protons].

Isomer pair ₂ NMR (CDCl ₃ ) · δ = 1.53 (d, J = 7Hz, 3H, CH ₃ ),

9h3

4.56 (s, 2H, N-CH ₂ ), 4.72 (J = 7Hz, 1H, CH), 5.52 (s, OH: exchange with D ₂ O), 6.95 (m, 4H , C ₆ H ₄ ), [7.65 (s, 1 H), 7.78 (s, 2H) 7.88 (s, 1H) -triazole protons.n].

Example 2

1,3-Bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) butan-2-ol was prepared by a procedure similar to that of the previous example and incorporated into the separated two Dfermereomerenpaare, of course, suitable starting materials were used. Isomer pair 1 was characterized and found to be identical to the product of Example 2 of copending application AP C 07 D / 260 944.2. The isomer pair 2 had a mp of 123-125 ° and the following microanalysis:

Analysis for C ₁₄ H ₁₄ F ₂ N ₆ O,%

calc .: C52.5 H 4.4 N 26.2.

gef.:C52,55H4,5N26,1

The PDgo values (oral) for the compounds of the formula (I) against C. albicans in mice, obtained according to the test method described in the text, are as follows:

Product compound of Example PD ₅₀ (mg / kg)

1 (pair of diastereomers 1) 0.1

1 (pair of diastereomers 2) 0.3

2 (pair of diastereomers 2) 0.5

In activity tests on systemic aspergillosis in mice, mice are infected with a strain of Aspergillus flavus maintained at Pfizer by i.v. injection via the tail vein. Untreated (control) mice usually go. within 5 to 10 days since infection with A. flavus. Each test compound is administered to a group of infected mice at an oral dose of 20 mg / kg 1 h and 4 h after infection and then twice a day for the next four days. The increase in mean survival time (MUC) of the treated mice compared to that of a control group of mice infected with the same strain simultaneously is then determined.

The compounds of formula (I) have been shown to be unexpectedly active towards the important A. flavus strain, and the results given below compare a compound of Example 1 versus its analog with "-CH ₂ -" (see GBPS 2078719A) Compared to

ii I -C- Il OH I HI CH 3 I 1-CH ₀ -C - ² IR I -C-N in the chain. λ. N \ V =

Claims (1)

Invention claim ' 1. A process for the preparation of a compound of the formula OH H , I, or an O-ester, O-ether or a pharmaceutically or agriculturally acceptable salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, J, CF ₃ , C ₁ -C ₄ -Alkyl and C ₁ -C ₄ -alkoxy, or R 5-chloropyrid-2-yl, characterized in that a compound of the formula OH
X-CH 1 -C-CH-X (Υ)