CN1557808A - 3-Substituted piperazine triazole alcohol antifungal compounds and their salts - Google Patents

Abstract

The invention relates to the field of medical technology, and is a novel 3-substituted piperazine triazole alcohol antifungal compound and its salts. Its general chemical structure is as the right formula, wherein: X is hydrogen or methyl; M is Hydrogen, hydroxyl, ester group; Y is 2,4-difluoro; R represents: (1) heterocyclic formyl or acetyl, substituted heterocyclic formyl or acetyl; (2) heterocyclic methyl or substituted hetero Cyclomethyl; (3) heterocyclic methoxyphenyl or substituted heterocyclic methoxyphenyl; (4) 3', 4'-heterocyclic fused phenyl; (5) 3', 4'- Heterocyclic fused benzyloxyphenyl. Substituents refer to: a. aliphatic chains of 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, such as F, Cl, Br, I; c. Electron-withdrawing or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl Acyl, N,N-Dimethylcarbamoyl, N,N-Diethylcarbamoyl, Methoxyacyl, Ethoxyacyl, Amino, Formamido, Acetylamino, Hydroxyl, Methoxy, Ethoxy . The substituents can be at various positions of the heterocycle, and can be monosubstituted or polysubstituted. These compounds can form salts with various inorganic and organic acids. The 3-substituted piperazine triazole alcohol antifungal compound and its salts of the invention exhibit strong antifungal activity and can be used for the preparation of antifungal drugs.

Description

3-Substituted piperazine triazole alcohol antifungal compounds and their salts

Technical field

The invention relates to the technical field of medicine, and is a novel 3-substituted piperazine triazole antifungal compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4- Difluorophenyl)-3-substituted piperazinyl-2-propanol compounds and salts thereof.

Background technique

In the past three decades, due to the extensive use of broad-spectrum antibiotics in clinical practice, the increase in the number of patients with cancer radiotherapy, chemotherapy and organ transplantation, the widespread use of corticosteroids and immunosuppressants, and the prevalence of AIDS, the rate of deep fungal infection has increased by 40%. times. The latest statistics show that 60% of the direct cause of death among AIDS patients is deep fungal infection. Deep fungal infection is increasingly becoming a common and frequently-occurring disease, and has become one of the main causes of death in patients with cancer and immunodeficiency diseases. Therefore, there is an urgent need for new deep antifungal drugs with high efficiency, low toxicity and high selectivity in clinic. However, currently commonly used clinical antifungal drugs such as amphotericin B (Amphotericin B), ketoconazole (Ketoconazole), fluconazole (Fluconazole) and itraconazole (Itraconazole) have large toxic and side effects, narrow antibacterial spectrum, resistance Drug strains are increasing and other issues.

Contents of Invention

The present invention provides a novel triazole alcohol compound with high efficiency, low toxicity and broad spectrum, and its common medicinal salts such as hydrochloride, hydrobromide, methanesulfonate, acetate, oxalate, Maleate, fumarate, gluconate, tartrate, lactate or succinate.

The general structural formula of the compound of the present invention is as follows:

Wherein: X represents hydrogen or methyl, preferably methyl.

M is a hydroxyl or ester group;

The ester group here refers to a straight-chain or branched ester group with 1 to 4 carbon atoms, such as formate, acetate, propionate, isopropionate, preferably with 1 to 3 carbons Atomic ester groups, particularly preferably acetate groups;

Y represents various substituents on the aromatic ring, and the substitution position can be located in the ortho, meta, or para positions, and can be mono-substituted or multi-substituted. The substituent refers to:

a. Halogen, such as F, Cl, Br, I, preferably 2,4-difluoro or 2,4-dichloro;

b. An aliphatic chain with 1 to 4 carbon atoms, such as methyl, ethyl, trifluoromethyl, tert-butyl, etc., preferably substituted by trifluoromethyl;

Particularly preferred is 2,4-difluoro;

R stands for:

(1) Heterocyclic formyl or acetyl group, substituted heterocyclic formyl or acetyl group:

Heterocycle refers to common five-membered or six-membered heterocycles, such as furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, etc. A six-membered heterocycle is preferred, especially pyridine or pyrimidine. The substituents can be located at various positions of the heterocycle, and can be single or multiple substitutions. The substituents refer to:

a. Aliphatic chains with 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl, etc.;

b. Halogen, such as F, Cl, Br, I;

c. Electron-withdrawing groups or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy, etc.;

(2) Heterocyclic methyl or substituted heterocyclic methyl:

Heterocycle refers to common five-membered or six-membered heterocycles, such as furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, etc. A six-membered heterocycle is preferred, especially pyridine or pyrimidine. The substituents can be located at various positions of the heterocycle, and can be single or multiple substitutions. The substituents refer to:

a. Aliphatic chains with 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl, etc.;

b. Halogen, such as F, Cl, Br, I;

c. Electron-withdrawing groups or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy, etc.;

(3) Heterocyclic methoxyphenyl or substituted heterocyclic methoxyphenyl:

Heterocycle refers to common five-membered or six-membered heterocycles, such as furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, etc. A six-membered heterocycle is preferred, especially pyridine or pyrimidine. The substituents can be located at various positions of the heterocycle, and can be single or multiple substitutions. The substituents refer to:

a. Aliphatic chains with 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl, etc.;

b. Halogen, such as F, Cl, Br, I;

c. Electron-withdrawing groups or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy, etc.;

(4) 3', 4'-heterocyclic fused phenyl:

The heterocyclic ring at the 3,4-position of the phenyl group can be a five-membered ring or a six-membered ring; it can be an aliphatic heterocyclic ring or an aromatic heterocyclic ring, such as 1,3-dioxolane, lactone ring , lactam ring, pyrrole, imidazole, triazole, oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidine, etc. Preference is given to five-membered rings, particular preference to 1,3-dioxolane and imidazole. The heterocyclic substituents can be located at various positions of the heterocyclic ring, and can be monosubstituted or polysubstituted. Substituent means:

a. Aliphatic chains with 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl, etc.;

b. Halogen, such as F, Cl, Br, I;

c. Electron-withdrawing groups or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy, etc.;

(5) 3', 4'-heterocyclic fused benzyloxyphenyl:

The heterocyclic ring at the 3,4-position of the benzyl group can be a five-membered ring or a six-membered ring; it can be an aliphatic heterocyclic ring or an aromatic heterocyclic ring, such as 1,3-dioxolane, lactone ring , lactam ring, pyrrole, imidazole, triazole, oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidine, etc., preferably five-membered ring, especially preferably 1,3-dioxolane and imidazole, heterocyclic substitution The group can be located at each position of the heterocycle, and can be monosubstituted or multi-substituted, and the substituent refers to:

a. Aliphatic chains with 1-4 carbon atoms, such as methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl, etc.;

b. Halogen, such as F, Cl, Br, I;

c. Electron-withdrawing groups or electron-donating groups, such as nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, methoxyacyl, ethoxyacyl, amino, formamido, acetamido, hydroxyl, methoxy, ethoxy, etc.

Salts of the compounds of the present invention include hydrochloride, hydrobromide, methanesulfonate, acetate, oxalate, maleate, fumarate, gluconate, tartrate, lactate and Common medicinal salts such as succinate.

The preparation method of compound of the present invention is as follows:

1. Preparation of Intermediates

According to the different groups of the target compound, 1-(2-substituted phenyl-2,3-epoxypropyl)-1H-1,2,4-triazole is prepared from substituted benzene with different groups of Y Methanesulfonate or 1-(2-substituted phenyl-2,3-epoxybutyl)-1H-1,2,4-triazole methanesulfonate ring intermediate.

2. Preparation of Target Compounds

Intermediate 1-(2-substituted phenyl-2,3-epoxypropyl)-1H-1,2,4-triazole methanesulfonate and monosubstituted piperazine compounds with different R groups under basic conditions The following ring-opening reaction takes place to generate X as H and M as the compound of the present invention of hydroxyl; intermediate 1-(2-substituted phenyl-2,3-epoxybutyl)-1H-1,2,4-triazole Methanesulfonate and monosubstituted piperazine compounds with different R groups undergo ring-opening reactions under alkaline conditions to generate compounds of the present invention in which X is a methyl group and M is a hydroxyl group; Anhydride reaction will give the corresponding esters.

Taking Y as 2,4-difluoro group and X as H as an example, the preparation method is as follows:

1. The preparation of intermediate 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III) ( See Sun Qinggong and Liu Chaomei et al.: Journal of Second Military Medical University, 2001; 22(9): 871)

Using m-difluorobenzene as the starting material, under the catalysis of aluminum trichloride, a Friedel-Crafts reaction occurs with chloroacetyl chloride at a molar ratio of 1:1 in dichloromethane at 50-55°C. Stir the reaction for 8 hours to form 2-chloro-2', 4'-difluoroacetophenone (IV); (IV) react with triazole in toluene for 24 hours to form 2', 4'-difluoro-2-(1H -1,2,4-triazol-1-yl)acetophenone (V); nucleophilic addition of (V) to the carbonyl group at 60°C with the thio-ylid reagent trimethyloxythioiodide reaction to form an epoxide, which can be salted with methanesulfonic acid to obtain the intermediate 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2 , 4-Triazole methanesulfonate (III).

2. Preparation of target compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted piperazine-2-propanol

The ring-opening reaction between the intermediate epoxide (III) and the monosubstituted piperazine compound under basic conditions produces the piperazine-substituted triazole alcohol compound (I).

3. Preparation of salts

The preparation method of the 3-substituted piperazine triazole alcohol compound salts of the present invention is to react the 3-substituted piperazine triazole alcohol antifungal compound (I) prepared above with an equimolar acid for 1 to 2 hours, and the reaction ends Afterwards, the concentrated reaction solution was precipitated, and the corresponding salts were obtained by filtration.

Table 1 lists the structures, yields, melting points and molecular formulas of some preferred target compounds in the present invention.

The preparation method of the present invention will be further described in detail in conjunction with examples.

The chemical structure, yield, melting point ^{(a, b)} and molecular formula of the preferred compound in Table 1

Compound R group Molecular formula

No. (%) (℃)

1 2-Furoyl 84.4 123-5 C ₂₀ H ₂₁ F ₂ N ₅ O ₃

2 2-Thienoyl 79.9 105-7 C ₂₀ H ₂₁ F ₂ N ₅ O ₂ S

3 2-Pyridinecarbonyl 76.6 144-6 C ₂₁ H ₂₂ F ₂ N ₆ O ₂

4 3-Pyridinecarbonyl 83.2 132-3 C ₂₁ H ₂₂ F ₂ N ₆ O ₂

5 4-Pyridinecarbonyl 81.8 156-8 C ₂₁ H ₂₂ F ₂ N ₆ O ₂

6 6-quinolinecarbonyl 64.2 134-6 C ₂₅ H ₂₄ F ₂ N ₆ O ₂

7 5-NO ₂ -2-Furoyl 90.1 118-9 C ₂₀ H ₂₀ F ₂ N ₆ O ₅

8 5-Cl-2-thiophenoyl 59.9 107-9 C ₂₀ H ₂₀ ClF ₂ N ₅ O ₂ S

9 2-thiopheneacetyl 49.2 107-8 C ₂₁ H ₂₃ F ₂ N ₅ O ₂₈

10 2-Pyridineacetyl 90.5 154-6 C ₂₂ H ₂₄ F ₂ N ₆ O ₂

11 4-Pyridineacetyl 76.9 138-40 C ₂₂ H ₂₄ F ₂ N ₆ O ₂

12 1-(1,2,4-triazol-1-yl)acetyl 79.6 121-2 C ₁₉ H ₂₂ F ₂ N ₈ O ₂

13 1-imidazole acetyl 88.2 123-4 C ₂₀ H ₂₃ F ₂ N ₇ O ₂

14 4-(2-furanmethoxy)phenyl 48.5 96-8 C ₂₆ H ₂₇ F ₂ N ₅ O ₃

15 4-(5-NO ₂ -2-furanmethoxy)phenyl 55.6 115-7 C ₂₆ H ₂₆ F ₂ N ₆ O ₅

16 4-(2-Pyridinemethoxy)phenyl 52.2 142-4 C ₂₇ H ₂₈ F ₂ N ₆ O ₂

17 4-(3-Pyridinemethoxy)phenyl 62.5 90-2 C ₂₇ H ₂₈ F ₂ N ₆ O ₂

18 4-(4-Pyridinemethoxy)phenyl 56.5 122-4 C ₂₇ H ₂₈ F ₂ N ₆ O ₂

19 4-(2-pyrimidinemethoxy)phenyl 63.1 114-7 C ₂₆ H ₂₇ F ₂ N ₇ O ₂

20 4-(4-pyrimidinemethoxy)phenyl 67.1 123-4 C ₂₆ H ₂₇ F ₂ N ₇ O ₂

21 4-(4-CF ₃ -2-pyridinemethoxy)phenyl 80.1 117-8 C ₂₈ H ₂₇ F ₅ N ₆ O ₂

22 4-(5-CF ₃ -2-pyridinemethoxy)phenyl 59.2 125-8 C ₂₈ H ₂₇ F ₅ N ₆ O ₂

23 4-(6-CF ₃ -3-pyridinemethoxy)phenyl 69.7 121-3 C ₂₈ H ₂₇ F ₅ N ₆ O ₂

24 4-(2-CF ₃ -4-pyridinemethoxy)phenyl 80.1 166-8 C ₂₈ H ₂₇ F ₅ N ₆ O ₂

25 4-(4-F-2-pyridinemethoxy)phenyl 57.3 115-6 C ₂₇ H ₂₇ F ₃ N ₆ O ₂

26 4-(5-Cl-2-pyridinemethoxy)phenyl 60.3 109-10 C ₂₇ H ₂₇ ClF ₂ N ₆ O ₂

27 4-(3-CN-2-pyridinemethoxy)phenyl 64.1 111-3 C ₂₈ H ₂₇ F ₂ N ₇ O ₂

28 4-(5-Cl-3-pyridinemethoxy)phenyl 76.2 107-9 C ₂₇ H ₂₇ ClF ₂ N ₆ O ₂

29 4-(4-OCH ₃ -2-pyridinemethoxy)phenyl 67.2 93-5 C ₂₈ H ₃₀ F ₂ N ₆ O ₃

30 4-(4-quinolinemethoxy)phenyl 82.1 136-8 C ₃₁ H ₃₀ F ₂ N ₆ O ₂

31 4-(6-quinolinemethoxy)phenyl 79.9 141-3 C ₃₁ H ₃₀ F ₂ N ₆ O ₂

32 4-(5-isoxazolemethoxy)phenyl 84.8 132-4 C ₂₅ H ₃₀ F ₂ N ₆ O ₃

33 4-(Benzo[d]1,3-dioxolane-5-methoxy)benzene 67.8 145-7 C ₂₉ H ₂₉ F ₂ N ₅ O ₄

base

34 4-(Benzo[d]thiazole-5-methoxy)phenyl 74.7 152-4 C ₂₉ H ₂₈ F ₂ N ₆ O ₂ S

35 4-(Benzo[d]oxazole-5-methoxy)phenyl 71.8 163-5 C ₂₉ H ₂₈ F ₂ N ₆ O ₃

36 4-(1-isopropylbenzo[d]imidazole-5-methoxy)

Phenyl 58.3 138-9 C ₃₂ H ₃₅ F ₂ N ₇ O ₂

37 4-(1-Ethylbenzo[d]triazole-5-methoxy)

Phenyl 60.6 126-8 C ₃₀ H ₃₂ F ₂ N ₈ O ₂

(a). The difference between the measured values of C, H and N and the theoretically calculated values is less than 0.3%.

(b). The thermometer is not calibrated.

Pharmacological experiments show that the compound of the invention has strong antifungal activity, broad antibacterial spectrum and is effective against clinical fluconazole-resistant strains, so it can be used to prepare antifungal drugs.

Detailed ways

Example 1

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(2-furoyl)piperazine]-2- Preparation of Propanol (Compound 1 in Table 1)

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 1.08g (6mmol) of 2-mercaptopyridine, 2.07g (15mmol) of anhydrous potassium carbonate and 0.1g of phase transfer catalyst hexadecyltrimethylammonium bromide, 30ml of dimethylformamide, in an oil bath at 90-95°C The reaction was heated and stirred for 8 hours. Cool, add 50ml of water under stirring, extract with ethyl acetate (3×70ml), wash with water (30ml×3), dry over anhydrous Na ₂ SO ₄ , recover the solvent, recrystallize with absolute ethanol to obtain 1.76g of white solid, melting point 123～5°C, yield 84.4%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.24 (1H, s, triazole C ₃ -H), 7.82 (1H, s, triazole C ₅ -H), 6.77～8.30 (6H, m, Ar-H ), 5.10 (1H, s, OH), 4.49-4.58 (2H, AB system, triazole-CH ₂ ), 3.33-3.35 (4H, m, N(CH ₂ ) ₄ N), 3.04-3.08 (1H, d , J=13.6Hz, -N(CH ₂ ) ₄ N-CHa), 2.66-2.72(1H, d, J=13.6Hz, -N(CH ₂ ) ₄ N-CHb), 2.32-2.34(4H, m , N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3341, 3057, 2970, 2806, 1615, 1588, 1559, 1272, 1102, 1060

Example 2

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(2-(1,2,4-triazole- 1-yl) acetyl) piperazine] -2-propanol (compound 12 in table 1) preparation

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 2-(1,2,4-triazol-1-yl) acetylpiperazine 1.17g (6mmol), anhydrous potassium carbonate 2.07g (0.015mol) and phase transfer catalyst cetyltrimethylammonium bromide 0.1 g, 25ml of dimethylformamide, heated and stirred in an oil bath at 90-95°C for 8 hours. Cool, add 50ml of water under stirring, extract with ethyl acetate (60ml×3), combine the extracts, wash with water (25ml×3), dry over anhydrous Na ₂ SO ₄ , filter, and recover the solvent to obtain a crude product, which is subjected to Column chromatography, eluting with CHCl ₃ :C ₂ H ₅ OH=9:1, afforded 1.72 g of a light yellow solid with a melting point of 121-2°C and a yield of 79.6%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.12-8.15 (2H, m, triazole C ₃ -H), 7.75-7.78 (2H, m, triazole C ₅ -H), 6.75-7.58 (3H, m, Ar-H), 5.20 (1H, s, OH), 4.56-4.64 (2H, AB system, triazole-CH ₂ ), 3.60-3.68 (4H, m, N(CH ₂ ) ₄ N), 3.17- 3.20 (1H, d, J=13.2Hz, -N(CH ₂ ) ₄ N-CHa), 2.80-2.84 (1H, d, J=13.2Hz, -N(CH ₂ ) ₄ N-CHb), 2.60- 2.66 (4H, m, N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3234, 3077, 2975, 2891, 2806, 1612, 1564, 1273, 1249, 1060

Example 3

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(2-pyridinemethoxy)phenyl ) piperazine] the preparation of -2-propanol (compound 16 in table 1)

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 4-(4-(2-pyridylmethoxy)phenyl)piperazine 1.62g (6mmol), anhydrous potassium carbonate 2.07g (0.15mol) and phase transfer catalyst cetyltrimethylammonium bromide 0.1g , 25ml of dimethylformamide, heated and stirred in an oil bath at 90-95°C for 8 hours. Cool, add 50ml of water under stirring, extract with ethyl acetate (60ml×3), combine the extracts, wash with water (25ml×3), dry over anhydrous Na ₂ SO ₄ , filter, and recover the solvent to obtain a crude product, which is subjected to Column chromatography, eluting with CHCl ₃ :C ₂ H ₅ OH=9:1, afforded 1.32 g of a yellow solid with a melting point of 142-4°C and a yield of 52.2%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.29 (1H, s, triazole C ₃ -H), 7.75 (1H, s, triazole C ₅ -H), 6.80～8.56 (11H, m, Ar-H ), 5.62 (1H, s, OH), 5.08 (2H, s, -OCH ₂ -), 4.59 (2H, s, triazole-CH ₂ ), 2.90-2.94 (1H, d, J=13.6Hz, -N (CH ₂ )4N-CHa), 2.87-2.90 (4H, m, N(CH ₂ ) ₄ N), 2.71-2.75 (1H, d, J=13.6Hz, -N(CH ₂ ) ₄ N-CHb) , 2.50-2.56 (4H, m, N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3421, 3137, 2806, 2230, 2180, 1621, 1580, 1561, 1174, 1024

Example 4

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(3-pyridinemethoxy)phenyl ) piperazine] the preparation of -2-propanol (compound 17 in table 1)

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 4-(4-(3-pyridylmethoxy)phenyl)piperazine 1.62g (6mmol), anhydrous potassium carbonate 2.07g (0.15mol) and phase transfer catalyst cetyltrimethylammonium bromide 0.1g , 25ml of dimethylformamide, heated and stirred in an oil bath at 90-95°C for 8 hours. Cool, add 50ml of water under stirring, extract with ethyl acetate (60ml×3), combine the extracts, wash with water (25ml×3), dry over anhydrous Na ₂ SO ₄ , filter, and recover the solvent to obtain a crude product, which is subjected to column Chromatography, eluting with CHCl ₃ :C ₂ H ₅ OH=9:1, afforded 1.58 g of a yellow solid with a melting point of 90-2°C and a yield of 62.5%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.28 (1H, s, triazole C ₃ -H), 7.74 (1H, s, triazole C ₅ -H), 6.80～8.63 (11H, m, Ar-H ), 5.57 (1H, s, OH), 5.08 (2H, s, -OCH ₂ -), 4.60 (2H, s, triazole-CH ₂ ), 2.91-2.95 (1H, d, J=13.6Hz, -N (CH ₂ ) ₄ N-CHa), 2.87-2.90 (4H, m, N(CH ₂ ) ₄ N), 2.72-2.76 (1H, d, J=13.6Hz, -N(CH ₂ ) ₄ N-CHb ), 2.51-2.56 (4H, m, N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3432, 3154, 3118, 2941, 1617, 1610, 1551, 1301, 1271, 1015

Example 5

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(4-pyridinemethoxy)phenyl ) piperazine] the preparation of -2-propanol (compound 18 in table 1)

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 4-(4-(4-pyridylmethoxy)phenyl)piperazine 1.62g (6mmol), anhydrous potassium carbonate 2.07g (0.15mol) and phase transfer catalyst cetyltrimethylammonium bromide 0.1g , 25ml of dimethylformamide, heated and stirred in an oil bath at 90-95°C for 8 hours. Cool, add 50ml of water under stirring, extract with ethyl acetate (60ml×3), combine the extracts, wash with water (25ml×3), dry over anhydrous Na ₂ SO ₄ , filter, and recover the solvent to obtain a crude product, which is subjected to column Chromatography, eluting with CHCl ₃ :C ₂ H ₅ OH=9:1, afforded 1.43 g of a yellow solid with a melting point of 122-4°C and a yield of 56.5%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.28 (1H, s, triazole C ₃ -H), 7.75 (1H, s, triazole C ₅ -H), 6.80～8.56 (11H, m, Ar-H ), 5.62 (1H, s, OH), 5.08 (2H, s, -OCH ₂ -), 4.59 (2H, s, triazole-CH ₂ ), 2.89-2.93 (1H, d, J=13.6Hz, -N (CH ₂ ) ₄ N-CHa), 2.87-2.89 (4H, m, N(CH ₂ ) ₄ N), 2.71-2.75 (1H, d, J=13.6Hz, -N(CH ₂ ) ₄ N-CHb ), 2.50-2.57 (4H, m, N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3431, 3154, 3020, 2838, 1621, 1598, 1574, 1428, 1138, 1063

Example 6

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(benzo[d]1,3- Preparation of dioxolane-5-methoxy)phenylpiperazine)]-2-propanol (compound 33 in table 1)

Take 1.65 g (5 mmol) of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate (III), 4-(4-(benzo[d]1,3-dioxolane-5-methoxy)phenylpiperazine 1.87g (6mmol), anhydrous potassium carbonate 2.07g (0.15mol) and phase transfer catalyst Hexadecyltrimethylammonium bromide 0.1g, dimethylformamide 25ml, heat and stir in 90-95°C oil bath for 8 hours. Cool, add 50ml water under stirring, extract with ethyl acetate (60ml ×3), combined the extracts, washed with water (25ml×3), dried with anhydrous Na ₂ SO ₄ , filtered, and recovered the solvent to obtain the crude product, which was subjected to column chromatography, using CHCl ₃ : C ₂ H ₅ OH=9:1 After elution, 1.86 g of a white solid was obtained, with a melting point of 145-7° C. and a yield of 67.8%.

¹ H-NMR (DMSO-d ₆ ) δ, ppm: 8.13 (1H, s, triazole C ₃ -H), 7.79 (1H, s, triazole C ₅ -H), 6.77～7.61 (10H, m, Ar-H ), 5.94 (1H, s, -OCH ₂ O-), 5.19 (1H, s, OH), 4.89 (2H, s, -OCH ₂ -), 4.50-4.59 (2H, AB system, triazole-CH ₂ ) , 3.10-3.14 (1H, d, J=13.2Hz, -N(CH ₂ ) ₄ N-CHa), 2.94-2.97 (4H, m, N(CH ₂ ) ₄ N), 2.72-2.76 (1H, d , J=13.2Hz, -N(CH ₂ ) ₄ N-CHb), 2.51-2.53(4H, m, N(CH ₂ ) ₄ N)

IR (cm ^-1 , KBr): 3442, 3346, 3178, 2930, 1618, 1592, 1564, 1440, 1235, 1088

Example 7

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(3-pyridinemethoxy)phenyl ) piperazine] the preparation of -2-propanol (compound 18 in table 1) fumarate

Take 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-(3-pyridinemethoxy)benzene Base) piperazine]-propanol-2 (compound 18 in table 1) 2.53g (5mmol), fumaric acid 0.58g (5mmol), add 25ml methanol, stir and reflux for 1 hour, let cool, add 25ml dichloromethane, After standing, the solid was filtered out and recrystallized with absolute ethanol to obtain 2.73 g of white solid with a yield of 87.8%.

The remaining target compounds can repeat the operation steps of the above examples, and react with the key intermediate epoxide (III) under alkaline conditions with different monosubstituted piperazines to obtain various 3-substituted piperazine triazole alcohols compounds and their salts. All reagents used in the examples are commercially available analytically pure.

1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted piperazine-2-propanol compounds synthesized by the present invention and its Salts have antifungal effects, and the antibacterial test methods and results are as follows:

The standardized antifungal susceptibility test method recommended by the National Committee for Clinical Laboratory Standards (NCCLS) was used to test its antifungal activity in vitro, and the concentration at which the target compound inhibited 80% of the growth of the selected fungus was used as the judgment endpoint (MIC ₈₀ , reference: Antimicrob Agents Chemother 45(9):2420, 2001).

(1), materials and methods

1. Experimental fungal strains

The present invention selects two kinds of ATCC standard strains and six clinical strains. The ATCC standard strains are provided by Shanghai Changzheng Hospital's Culture Preservation Center, and the clinical strains are provided by Shanghai Changhai Hospital's Fungus Department and identified by morphology and biochemistry.

The 8 fungi selected included: 4 deep fungi, 1 superficial fungus, 2 subcutaneous fungi and Aspergillus fumigatus.

Deep fungi: Candida albicans (Candida albicans) ATCC76615 (Ca. for short)

    Cryptococcus neoformans (Cryptococcus neoformans) ATCC32609 (referred to as Cn.)

    Candida tropicalis (Ct. for short)

    Candida parapsilosis (Cp. for short)

Superficial fungi: Trichophyton rubrum (Tr.)

Subcutaneous fungus: Sporothrix schenckii (Ss. for short)

Fonsecaea pedrosoi (Fp. for short)

  Aspergillus fumigatus (Af. for short)

2. Culture medium

RPMI1640 culture solution: RMPI1640 (Gibco BRL) 10g, NaHCO ₃ 2.0g, morpholine propanesulfonic acid (MOPS) (Sigma) 34.5g (0.165M) was dissolved in 900ml of three-distilled water, 1N NaOH was added to adjust the pH to 7.0 ( 25°C), dilute to 1000ml, sterilize by filtration, and store at 4°C.

Sand Castle Dextrose Agar Medium (SDA): 10g of peptone, 40g of glucose, 18g of agar, add 900ml of triple distilled water to dissolve, add 50ml of 2mg/ml chloramphenicol aqueous solution, adjust the pH to 7.0, fix the solution to 1000ml, after autoclaving Store at 4°C.

YEPD culture solution: Yeast extract 10g, peptone 20g, glucose 20g, add 900ml triple distilled water to dissolve, add 2mg/ml chloramphenicol aqueous solution 50ml, dilute to 1000ml, store at 4°C after autoclaving.

3. Experimental method

Bacteria solution: Inoculate yeast into 1ml of YEPD culture solution, incubate at 35°C for 16 hours, adjust the concentration of the bacteria solution to 1×10 ³ ～5×10 ³ cells/ml with RPMI1640 culture solution; inoculate mold into SDA slant, and incubate at 35°C for one week , adjust the spore concentration to 1×10 ³ -5×10 ³ /ml with RPMI1640 culture medium.

Medicinal solution: the test drug and the control drugs fluconazole and ketoconazole were respectively made into 6.4g/L solutions with dimethyl sulfoxide, and diluted with RPMI1640 culture solution to 640mg/L before the experiment.

Antimicrobial susceptibility plate: take a sterile 96-well plate, add 100 μl of RPMI1640 culture solution to No. 1 well of each row as a blank control; add 100 μl of freshly prepared bacterial solution to each of No. 10 μl of the test compound solution; 10-fold dilutions in wells 2 to 11; well 12 containing no drug was used as a positive control.

Two, MIC value determination

After Candida, Cryptococcus neoformans and filamentous bacteria were cultured at 35°C for 24h, 72h and one week, respectively, the OD value of each well was measured at 630nm with an enzyme label analyzer. Compared with the positive control wells, the drug concentration in the lowest concentration wells whose OD value drops by more than 80% is MIC80 (concentration when fungal growth is inhibited by 80%).

When the MIC ₈₀ value of the drug exceeds the concentration range of the test, the following methods are used for statistics: when the MIC ₈₀ value is higher than the highest concentration of 64 mg/L, it is recorded as "> 64 mg/L"; the MIC ₈₀ value is the lowest concentration or below the lowest concentration When, no distinction is made, and they are all recorded as "≤0.125mg/L".

The above experiments were performed 2 to 3 times in parallel. When the MIC ₈₀ value can be accurately repeated or only differs by one concentration, it is accepted, and a higher concentration is used as the MIC ₈₀ value; when the MIC ₈₀ value differs by more than two concentrations, it is required to Experiment again until you meet the requirements. The results are shown in Table 2.

             Table 2 Antifungal activity of target compounds in vitro

MIC ₈₀ (μg/ml)

in FIG. 1

Compound Ca. Cn. Ct. Cp. Ss. Fp. Tr. Af.

serial number

1 ≤0.125 1 2 2 16 ＞64 ≤0.125 64 8

3 ≤0.125 2 ≤0.125 ≤0.125 >64 ≤0.125 2 4

5 0.125 1 2 2 16 ＞64 ≤0.125 64 8

12 ≤0.125 ≤0.125 ≤0.125 ≤0.125 16 ≤0.125 32 16

13 ≤0.125 0.25 0.5 16 16 ≤0.125 ＞64 32

16 ≤0.125 ≤0.125 ≤0.125 ≤0.125 ＞64 ≤0.125 4 64

17 ≤0.125 ≤0.125 ≤0.125 ≤0.125 ＞64 ≤0.125 16 64

18 ≤0.125 ≤0.125 ≤0.125 0.25 64 0.25 8 8

33 ≤0.125 1 ≤0.125 ≤0.125 >64 ≤0.125 4 8

Ketoconazole ≤0.125 0.5 ≤0.125 ≤0.125 4 ≤0.125 ≤0.125 8

Fluconazole 0.5 16 0.5 0.5 ＞64 2 8 ＞64

Above-mentioned experimental result shows that heterocyclic triazole alcohol compounds and salts thereof of the present invention have better antifungal activity, and most compounds are all stronger than fluconazole to the in vitro inhibitory activity of selected fungus, and are equivalent or higher than ketoconazole Excellent, indicating that the compounds of the present invention and their salts can be used to prepare medicines for treating fungal infections.

Claims (4)

1. A 3-substituted piperazine triazole alcohol antifungal compound, the general chemical structure of which is:

Where: X stands for hydrogen or methyl;   M represents a hydroxyl group or an ester group;   The ester group here refers to a straight-chain or branched-chain ester group with 1 to 4 carbon atoms, selected from formate,    Acetate, Propionate, Isopropionate;   Y represents various substituents on the aromatic ring, and the substitution position can be located in the ortho, meta, or para positions, which can be   Single or multiple substitutions are possible, and the substituents refer to: (1) Halogen, selected from F, Cl, Br, I; (2) An aliphatic chain with 1 to 4 carbon atoms selected from methyl, ethyl, trifluoromethyl, tert-butyl base; R stands for: (1) Heterocyclic formyl or acetyl group, substituted heterocyclic formyl or acetyl group: The heterocyclic ring refers to a five-membered or six-membered heterocyclic ring selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine. The substituents can be located at various positions of the heterocycle, and can be single-substituted or multi-substituted. The substituents refer to: a. an aliphatic chain of 1-4 carbon atoms selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, selected from F, Cl, Br, I; c. electron-withdrawing group or electron-donating group, selected from nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy; (2) Heterocyclic methyl or substituted heterocyclic methyl: Heterocycle refers to a five-membered or six-membered heterocycle selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, heterocycle The upper substituent can be located at each position of the heterocycle, and can be single-substituted or multi-substituted. The substituent refers to: a. an aliphatic chain of 1-4 carbon atoms selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, selected from F, Cl, Br, I; c. electron-withdrawing group or electron-donating group, selected from nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy; (3) Heterocyclic methoxyphenyl or substituted heterocyclic methoxyphenyl: Heterocycle refers to a five-membered or six-membered heterocycle selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, heterocycle The upper substituent can be located at each position of the heterocycle, and can be single-substituted or multi-substituted. The substituent refers to: a. an aliphatic chain of 1-4 carbon atoms selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, selected from F, Cl, Br, I; c. electron-withdrawing group or electron-donating group, selected from nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy; (4) 3', 4'-heterocyclic fused phenyl: The heterocyclic ring at the 3,4-position of the phenyl group can be a five-membered ring or a six-membered ring; it can be an aliphatic heterocyclic ring or an aromatic heterocyclic ring, selected from 1,3-dioxolane, lactone Ring, lactam ring, pyrrole, imidazole, triazole, oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidine, heterocyclic substituents can be located at various positions of the heterocyclic ring, and can be monosubstituted or polysubstituted Substitution, the substituent refers to: a. an aliphatic chain of 1-4 carbon atoms selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, selected from F, Cl, Br, I; c. electron-withdrawing group or electron-donating group, selected from nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, formylamino, acetamido, hydroxyl, methoxy, ethoxy; (5) 3', 4'-heterocyclic fused benzyloxyphenyl: The heterocyclic ring at the 3,4-position of the benzyl group can be a five-membered ring or a six-membered ring; it can be an aliphatic heterocyclic ring or an aromatic heterocyclic ring, selected from 1,3-dioxolane, lactone Ring, lactam ring, pyrrole, imidazole, triazole, oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidine, heterocyclic substituents can be located at various positions of the heterocyclic ring, and can be monosubstituted or polysubstituted Substitution, the substituent refers to: a. an aliphatic chain of 1-4 carbon atoms selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl; b. Halogen, selected from F, Cl, Br, I; c. electron-withdrawing group or electron-donating group, selected from nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyacyl, ethoxyacyl, amino, formamido, acetamido, hydroxyl, methoxy, ethoxy. 2. The 3-substituted piperazine triazole alcohol antifungal compound according to claim 1, wherein the M, X, Y and R groups are respectively: (1) M is hydroxyl, X is H, Y is 2,4-difluoro, R is furoyl; (2) M is hydroxyl, X is methyl, Y is 2,4-difluoro, R is 4-pyridineformyl; (3) M is hydroxyl, X is methyl, Y is 2,4-difluoro, R is 2-(1,2,4-triazol-1-yl)acetyl; (4) M is hydroxyl, X is H, Y is 2,4-difluoro, R is benzo[d]thiazol-5-yl; (5) M is hydroxyl, X is H, Y is 2,4-difluoro, R is 4-(2-pyridinemethoxy)phenyl; (6) M is hydroxyl, X is H, Y is 2,4-difluoro, R is 4-(3-pyridinemethoxy)phenyl; (7) M is hydroxyl, X is H, Y is 2,4-difluoro, R is 4-(4-pyridinemethoxy)phenyl; (8) M is hydroxyl, X is methyl, Y is 2,4-difluoro, R is 4-(2-pyridylmethoxy)phenyl; (9) M is hydroxyl, X is methyl, Y is 2,4-difluoro, and R is 4-(benzo[d]1,3-dioxolane-5-methoxy)phenyl. 3. The salts of 3-substituted piperazine triazole alcohol compounds according to claim 1 or 2, selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate, acetate, oxalic acid salt, maleate, fumarate, gluconate, tartrate, lactate or succinate. 4. The use of the 3-substituted piperazine triazole alcohol antifungal compounds or salts according to claim 1, 2 or 3 in the preparation of antifungal drugs.