CN103819464B - Thiochroman compounds, synthesis method thereof and application thereof in preparing antifungal medicines - Google Patents

Abstract

The invention relates to a thiochroman compound, which can be applied to the preparation of antifungal drugs and has a structural formula: Wherein Z is sulfur, sulfinyl or sulfonyl; Y is carbon or nitrogen; R5 and R8 are independently or simultaneously selected from hydrogen, fluorine, chlorine, bromine or iodine; R6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, C1 -C3 alkoxy or C1-C4 alkyl, amino, five-membered or six-membered nitrogen-containing heterocyclic ring; especially preferred: R7 is selected from fluorine or _{C1 -} C3 alkoxy, R5, R6, R8 Both are hydrogen. The compound has extensive antifungal physiological activity and can be used to prepare broad-spectrum, low-toxicity and high-efficiency antifungal drugs and plant fungicides for agriculture and gardening.

Description

Thiochroman compound and its synthesis method and the application of preparing antifungal drug

technical field

The invention relates to an antifungal thiochroman compound, a synthesis method of the compound and its application in the preparation of antifungal drugs.

Background technique

Diseases such as athlete's foot, ringworm, candidiasis, and cryptococcal meningitis are mostly caused by fungal infections. In recent years, due to the widespread use of broad-spectrum antibiotics, immunosuppressants and various hormonal drugs, combined with the application of radiotherapy and chemotherapy, organ transplantation and other treatment methods, as well as HIV infection and other reasons, the function of the human immune system has declined, and fungal infections The chances of infection have increased, leading to an increase in the morbidity and mortality of fungal diseases. In addition, problems such as drug resistance and narrow antibacterial spectrum in clinical treatment have also exacerbated the difficulty in the treatment of fungal infections. Therefore, it is urgent to develop new antifungal drugs with broad spectrum, high efficiency and low toxicity for clinical treatment.

Antifungal drugs are usually divided into polyenes, azoles, allylamines, and thioureas. Thichromanone is a sulfur-containing antifungal drug developed rapidly in recent years. Studies have shown that it is effective against Cryptococcus neoformans, yeast Several important pathogenic bacteria such as fungus, microsporothrix, mold and trichophyton have strong inhibitory activity. The chemical structural formula of thiochromanone is:

In order to develop high-efficiency and low-toxic antifungal drugs, the structural modification of thiochromone mainly focuses on the 1, 3, and 4 positions. Among them, the 1-position modification generates thiochromone 1,1-dioxide, and the 3-position modification includes β-aminoketone compounds, 3-benzyl-6-chlorothiochromanone and 3-benzyl-thio For chromanone, the 4-position modification is currently more heteroatom and amino group-containing modification. The antifungal activity of the thiochromone derivatives obtained through the above modifications is improved to varying degrees, or has higher activity against certain types of fungi. However, the antifungal drugs of thiochrome (man) ketones are far more than that. According to the structure-activity relationship of thiochrome (man) ketone compounds, the present invention further studies to obtain thiochrome ( full) ketones.

Contents of the invention

The object of the present invention is to provide a thiochroman antifungal compound, which has strong inhibitory activity against common pathogenic fungi and deep fungi, and has low toxicity, good stability, wide antifungal spectrum, and safety Good features. The invention also provides the preparation method of the thiochroman antifungal compound and its application in the preparation of medicine for treating systemic fungal infection.

A thiochroman compound, chemical structure such as formula (I):

In formula (I):

Z is selected from sulfur (S), sulfinyl or sulfonyl

Y is selected from carbon or nitrogen;

R ₆ is selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁ -C ₃ alkoxy or C ₁ -C ₄ alkyl;

R ₅ and R ₈ are independently selected from hydrogen, fluorine, chlorine, bromine or iodine;

R ₇ is selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁ -C ₃ alkoxy, amino, or selected from the following five-membered or six-membered nitrogen-containing heterocycles:

in:

W, V, M, and G are independently selected from hydrogen, C ₁ -C ₄ hydrocarbon groups, hydroxyl groups, C ₁ -C ₄ hydrocarbon oxy groups or amino groups, and one or more hydrogens in the amino group can be replaced by C ₁ -C ₄ Hydrocarbyl substituted;

L is selected from hydrogen, C ₁ -C ₄ hydrocarbyl, hydroxyl or C ₁ -C ₄ hydrocarbyloxy.

Among the thiochroman compounds of the formula (I), the preferred scheme is: Z is a sulfonyl group; Y is selected from carbon or nitrogen; R7 is selected from fluorine or a C ₁ -C ₃ alkoxy group; R5, R6, R8 Both are hydrogen.

Synthetic method of thiochromans compound of the present invention, following steps:

Using the compound of formula (II) as a raw material, in a polar solvent, under the action of a hydride reducing agent, react to obtain a solid compound of formula (Ia), that is, a product of formula (I) thichroman compounds whose Z is selected from sulfur; The polar solvent is selected from at least one of dimethyl sulfoxide, ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and water; the hydride reducing agent is selected from sodium borohydride, boron Potassium hydride, lithium borohydride, lithium aluminum hydride, aluminum isopropoxide or diborane or their derivatives, the reaction formula is as follows:

wherein Y is selected from carbon or nitrogen;

R ₆ is selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁ -C ₃ alkoxy or C ₁ -C ₄ alkyl;

R ₅ and R ₈ are independently selected from hydrogen, fluorine, chlorine, bromine or iodine;

R ₇ is selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁ -C ₃ alkoxy, amino, or selected from the following five-membered or six-membered nitrogen-containing heterocycles:

W, V, M, and G are independently selected from hydrogen, C ₁ -C ₄ hydrocarbon groups, hydroxyl groups, C ₁ -C ₄ hydrocarbon oxy groups or amino groups, and one or more hydrogens in the amino group can be replaced by C ₁ -C ₄ hydrocarbyl substituted.

React the obtained compound of formula (Ia) with acetic anhydride first to protect the hydroxyl group, then add 0.9-1.1 equivalent of an oxidizing agent, and undergo an oxidation reaction under the action of the oxidizing agent to obtain oxothiochroman compounds, and finally dissolve them in sodium hydroxide solution hydrolyzed to obtain the oxothiochroman compound of formula (Ib), which is the product of formula (I) thiochroman compound whose Z is selected from thionyl; the oxidizing agent is selected from manganese dioxide, hydrogen peroxide , peroxybenzoic acid, m-chloroperoxybenzoic acid, magnesium monoperoxyphthalate or peracetic acid; the reaction formula is as follows:

The compound of formula (Ia) obtained in step 1 is first reacted with acetic anhydride to protect the hydroxyl group, and then more than 2 equivalents of oxidant are added for oxidation reaction to obtain oxothiochroman compounds, which are finally hydrolyzed in sodium hydroxide solution to obtain formula ( Ic) compound, that is, the product of formula (I) thiochroman compound whose Z is selected from sulfonyl group; magnesium oxyphthalate or peracetic acid; the reaction formula is as follows:

The invention provides the application of the thiochroman compounds in the preparation of human medicine or animal medicine for treating fungal infection diseases.

In addition to the thiochroman compound as the active ingredient, the medicine also contains pharmaceutically acceptable carriers, adjuvants and/or diluents to form a composition.

The dosage form of the drug is a solution, cream, suppository, ointment or solution.

The present invention also provides the application of the thiochroman compounds as agricultural and horticultural fungicides.

The bactericide contains not only active ingredients such as thiochroman compounds, but also pharmaceutically acceptable carriers, adjuvants and/or diluents to form a composition.

The antifungal activity of the thiochroman compounds of the present invention was evaluated in vitro by measuring the minimum inhibitory concentration MIC (that is, the concentration at which the compound can inhibit the growth of test microorganisms). Tests have confirmed that the thiochroman compounds of the present invention have broad-spectrum antifungal activity, and have pharmacological activity in humans and animals (especially mammals), and can be mixed with common chemotherapy acceptable diluents or carriers, or with other Excipients, made into solutions, creams, suppositories, ointments, solutions and other dosage forms, in the form of drugs for local application. It can also be used in combination with other antibacterial agents, such as amphotericin B, nystatin, antitrichotomycin, penicillin or clindamycin, etc., which has obvious curative effect on fungal infection diseases. In addition to being used for the preparation of antifungal human or animal antifungal drugs, the thiochroman compounds of the present invention can also be used as plant fungicides for agriculture and gardening, for various plant pathogenic diseases such as rice blast, barley and wheat powder Mildew and powdery mildew of various host plants (such as cucumber, apple, grape), rust of wheat, crown rust of oats and rust of various other hosts, late blight of tomato and pathogenic rot of other host plants, etc. prevention is very effective.

Detailed ways

The above content of the present invention will be further described in detail below by way of examples. It should be noted that the scope of the present invention is not limited by the examples, but by the claims.

Example 1: Synthesis and preparation of 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman (Formula Ia1) The reaction formula is as follows:

Follow the steps to prepare:

Take 22.4mmol of 2-ethylthio-3-(1H-1,2,4-triazol-1-yl)thiochromone compound, dissolve it in 50mL of 50% ethanol; add 89.6mmol of sodium borohydride in batches The above solution was stirred overnight at room temperature, the solvent was distilled off under reduced pressure, the solid was extracted with 50 mL of ethyl acetate and 50 mL of water, the ethyl acetate layer was taken, washed twice with water (50 mL×2), and the organic layer was recovered and evaporated to dryness. The product of formula (Ia1) 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman was 19.3 mmol, and the yield was 86%.

¹ H NMR (CDCl ₃ ): 8.77(s,1H), 8.06(s,1H), 7.26-7.32(m,3H), 7.14(t,1H), 5.17(d,1H), 4.50(d,1H ),4.42-4.44(m,1H),3.30-3.34(m,1H),3.06-3.08(m,1H).

Example 2-Example 19: Preparation of thiochroman compounds of formula (Ia)

The compound of formula (II) is used as the raw material to prepare the compound of formula (Ia) (the target product is each compound of formula (Ia2) to formula (Ia19) in Table 1), and the reaction formula is as follows:

The preparation steps are as follows:

Take 22.4 mmol of the compound of formula (II) and dissolve it in a polar solvent, add 89.6 mmol of reducing agent into the solution in batches, stir overnight at room temperature, and process according to the method of Example 1 to obtain formula (Ia2) to formula (Ia19) Various sulfur chroman compounds.

In Examples 2 to 19, the selection of each group of the thiochromans of the product formula (Ia), the preparation reagents and the detection data are listed in Table 1.

Table 1

Example 20: Synthesis of 3-(1H-1,2,4-triazol-1-yl)-4-hydroxy-1-thiochroman oxide

Using 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman as raw material, the target product (Ib1) thiochroman compounds were prepared.

The preparation reaction formula is as follows:

The preparation steps are as follows:

Take the raw material 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman 19.3mmol, add it into 35mL acetic anhydride solvent, acetylation reaction occurs to protect the hydroxyl group, and distill under reduced pressure after the reaction Remove the acetic anhydride solvent. Add 30mL of saturated sodium bicarbonate solution and 30mL of ethyl acetate, separate the ethyl acetate layer; extract the water layer with 20mL of ethyl acetate and combine the organic layer, then add 3.4g of 30% concentration of hydrogen peroxide (20mmol ) undergoes an oxidation reaction. After the reaction, wash with 10 mL of saturated sodium sulfite solution and 30 mL of water, separate the organic layer and evaporate to dryness. Finally, a mixture of 20mL of 20% sodium hydroxide solution and 20mL of ethanol was added, heated and hydrolyzed at 50°C, evaporated to dryness after complete reaction, washed with 20mL of water and 20mL of ethyl acetate, and the organic layer was taken, evaporated to dryness to obtain the product Sulfone compound 3-(1H-1,2,4-triazol-1-yl)-4-hydroxy-1-thiochroman oxide (13.8mmol), yield 72%.

¹ H NMR (CDCl ₃ ): 8.71(s,1H), 8.03(s,1H), 7.51-7.55(m,3H), 7.38(t,1H), 5.19(s,1H), 4.55(d,1H ),4.18-4.22(m,1H),3.30-3.34(m,1H),3.09-3.13(m,1H).

Example 21-Example 38: Synthesis of sulfoxide-like thiochromans (Ib)

Using the thiochroman compound of the formula (Ia) as a raw material, prepare the thiochroman compound product of the general formula (Ib) (the target product is the formula Ib2 to formula Ib19 in Table 2, and the preparation steps are the same as in Example 20. The reaction formula is as follows:

The selection of each group of the thiochroman compounds of the formula (Ib) in Examples 21 to 38, as well as the preparation reagents and detection data are listed in Table 2.

Table 2

Example 39: Synthesis of 3-(1H-1,2,4-triazol-1-yl)-4-hydroxy-1,1-thiochroman (Formula Ic1)

Using 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman as raw material, the target product (Ic1) compound was prepared, and the reaction formula is as follows:

Add 3-(1H-1,2,4-triazol-1-yl)-4-hydroxythiochroman (19.3mmol) into 35mL of acetic anhydride solvent, acetylation reaction occurs to protect the hydroxyl group, after the reaction is completed, vacuum distillation Remove the acetic anhydride solvent. Add 30mL of saturated sodium bicarbonate solution and 30mL of ethyl acetate, separate the ethyl acetate layer, extract the aqueous layer with 20mL of ethyl acetate, combine the organic layer, and then add 13.6g of excess 30% hydrogen peroxide (80mmol ) undergoes an oxidation reaction. After the reaction, wash with 10 mL of saturated sodium sulfite solution and 30 mL of water, separate the organic layer and evaporate to dryness. Finally, add a mixture of 20mL of 20% sodium hydroxide solution and 20mL of ethanol, heat and hydrolyze at 50°C, evaporate the solvent to dryness after complete reaction, wash with 20mL of water and 20mL of ethyl acetate, take the organic layer, and evaporate to dryness to obtain sulfone compounds 3-(1H-1,2,4-triazol-1-yl)-4-hydroxy-1,1-sulfur dioxide chroman (14.1 mmol), yield 73%.

¹ H NMR (CDCl ₃ ): 8.73(s,1H), 8.09(s,1H), 7.81(d,1H), 7.68(d,1H), 7.51(t,1H), 7.35(t,1H), 5.19(s,1H),4.45(d,1H),4.19-4.24(m,1H),3.96-4.01(m,1H),3.79-3.84(m,1H).

Example 40-Example 57: Synthesis of sulfone thiochromans (Formula Ic)

Using the thiochromans of the formula (Ia) as raw materials, the same method as in Example 39 was used to prepare the thiochromans of the general formula (Ic) (the target products are formula Ic2 to formula Ic19 in Table 3). The reaction formula is as follows:

Table 3 lists the group selection, preparation reagents and detection data of the thiochroman compounds of formula (Ic) in Examples 40 to 57.

table 3

Example 58: In vitro antifungal activity test

1. Test strains

Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae Aspergillus, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verrucous, Trichophyton violaceum, Cryptococcus neoformans , Candida krusei, Epidermophyton flocculus, Trichophyton gypsum.

2. Reagents and materials

Test materials:

Modified Martin's medium, 96-well culture plate, DMSO

Control drug: fluconazole

3. Test method

(1) Preparation of antibacterial liquid

Dissolve the test drug in DMSO respectively to make a 25.6 g/L solution, and store it below -20°C for future use. Before the test, the test drug solution refrigerated at low temperature was taken out, melted in a 35°C incubator, diluted 10 times with RPMI1640, and set aside.

(2) Preparation of inoculum

Each tested Candida strain (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis) was replanted on the modified Martin's medium, and the suspension was made with 0.85% sterile saline. Count the spores with a hemocytometer and adjust the bacterial content so that the colony forming unit is 1×10 ⁶ to 5×10 ⁶ CFU/mL. When inoculating, dilute it 200 times with RPMI-1640 culture medium, then dilute it 10 times, adjust the CFU value to 0.5×10 ³ ~6.0×10 ³ CFU/mL, and set aside.

(3) Preparation of MIC plate

Under aseptic operation, 100 μL of RPMI-1640 culture solution was added to the No. 1 well of a sterilized 96-well polystyrene plate as a blank control. Add 190 μL of bacterial solution to the No. 2 well, and add 100 μL of prepared bacterial solution to the No. 3-12 wells. Then add 10 μL of the test drug solution to No. 2 well, and dilute the concentration of No. 2-11 wells according to 10 grades, so that the final concentrations of each well are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25mg/L, the No. 12 hole was not added with the test solution as a growth control. Each MIC plate was sealed and placed in a normal air incubator at 35°C, and incubated for 24 hours to judge the result.

(4) Result judgment

Measure the OD value of each well at 620nm with an enzyme label analyzer, and take the lowest concentration at which the OD value drops by more than 80% as the MIC value. When the MIC value is higher than 128mg/L, it is calculated as >128mg/L; when the MIC value is lower than 0.25mg/L, it is calculated as ≤0.25mg/L.

(5) Repeated observation and statistics

The above test needs to be repeated at least three times. When a single hole jump occurs in the MIC value, it is recorded as the maximum inhibitory bacterial concentration. When there are two or more hole jumps in the MIC value, the test is repeated.

4. Antifungal susceptibility test results

By preliminary MIC determination, it is found that the test compound has broad-spectrum antifungal activity, wherein Example 1, Example 4, Example 5, Example 9, Example 10, Example 11, Example 13, Example 14, Implementation Example 15, the thiochroman compounds of Example 20 to Example 57 have more significant antifungal activity, and the MIC values against the above tested strains are all less than 2 mg/L.

Claims (10)

1. a sulphur chroman compound, it is characterized in that chemical structure such as formula ( ):

Formula ( ) in:

Z be selected from sulphur (S), sulfinyl ( ) or alkylsulfonyl ( );

Y is selected from carbon or nitrogen;

R ₆be selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁-C ₃-oxyl or C ₁-C ₄alkyl;

R ₅, R ₈separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;

R ₇be selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁-C ₃-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:

；

Wherein:

W, V, M, G are separately selected from hydrogen, C ₁-C ₄alkyl, hydroxyl, C ₁-C ₄-oxyl or amino, the one or more hydrogen in described amino can by C ₁-C ₄alkyl replaced;

L is selected from hydrogen, C ₁-C ₄alkyl, hydroxyl or C ₁-C ₄-oxyl.

2. sulphur chroman compound according to claim 1, it is characterized in that described formula ( ) in sulphur chroman compound, Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R ₇be selected from fluorine or C ₁-C ₃-oxyl; R ₅, R ₆, R ₈be hydrogen.

3. a sulphur chroman compound synthetic method for claim 1, is characterized in that according to the following steps:

With formula II compound for raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula ( a) solid chemical compound, namely Z be selected from sulphur formula ( ) sulphur chroman compound product; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:

Wherein, Y is selected from carbon or nitrogen;

R ₆be selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁-C ₃-oxyl or C ₁-C ₄alkyl;

R ₅, R ₈separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;

R ₇be selected from fluorine, chlorine, bromine, iodine, hydrogen, C ₁-C ₃-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:

，

W, V, M, G are separately selected from hydrogen, C ₁-C ₄alkyl, hydroxyl, C ₁-C ₄-oxyl or amino, the one or more hydrogen in described amino can by C ₁-C ₄alkyl replaced.

4. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of gained ( a) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, oxidizing reaction occur, obtain oxo sulphur chroman compound, be finally hydrolyzed in sodium hydroxide solution such as formula ( b) oxo sulphur chroman compound, its be Z be selected from sulfinyl formula ( ) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:

。

5. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of step 1 gained ( a) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, be finally hydrolyzed in sodium hydroxide solution such as formula ( c) compound, be Z be selected from alkylsulfonyl formula ( ) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:

。

6. the application of sulphur chroman compound described in a claim 1 or 2 in people's medicine or medicine for animal of preparation treatment fungal infection disease.

7. application according to claim 6, is characterized in that except containing except activeconstituents sulphur chroman compound in described medicine, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, and composition composition.

8. application according to claim 7, is characterized in that the formulation of described medicine is solution, creme, suppository or ointment.

9. sulphur chroman compound described in a claim 1 or 2 is as application that is agriculture and horticultural bactericides.

10. application according to claim 9, is characterized in that except containing except activeconstituents sulphur chroman compound in described sterilant, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, and composition composition.