CN105061387A - Diaryl ether fused ring compounds, preparation methods and applications - Google Patents

Abstract

The invention discloses diaryl ether fused ring compounds, preparation methods and applications. The diaryl ether fused ring compounds are brand-new diaryl ether fused ring structural compounds with a structure represented in a formula I, and have better activity resisting to MTB (mycobacterium tuberculosis) with multi-drug resistance. At the cellular level, for part of embodiments, the inhibitory activity IC50 on MTB is smaller than 10 mu g/mL.

Description

Diaryl ether fused ring compounds, preparation method and use

technical field

The invention belongs to the field of medicine, in particular, the invention relates to the preparation and application of a diaryl ether condensed ring compound.

Background technique

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis infection. In the middle of the 20th century, with the emergence of a large number of anti-tuberculosis drugs, tuberculosis was effectively controlled. However, in recent years, due to reasons such as improper use of drugs, drug-resistant Mycobacterium tuberculosis has emerged, making the incidence and mortality of tuberculosis increase year by year. According to the report of WHO in 2008, the total drug resistance rate of tuberculosis in the world is 20.0%. Especially with the growth of population, the increase of travel and population movement around the world, the cases of drug-resistant tuberculosis are on the rise, with an increase of about 300,000 new cases every year. cases.

Although many drugs used in the treatment of tuberculosis in the early stage have good effects, in recent years, with the emergence of multidrug-resistant tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis ( XDR-TB) is particularly difficult to be cured, and its morbidity and mortality are increasing year by year. Therefore, the existing anti-tuberculosis drugs are difficult to meet the requirements of current tuberculosis treatment. Finding and discovering new preventive and therapeutic drugs that can resist multidrug-resistant tuberculosis is still an important research field in today's academic and industrial circles.

Contents of the invention

The purpose of this section is to outline some aspects of embodiments of the invention and briefly describe some preferred embodiments. Some simplifications or omissions may be made in this section, as well as in the abstract and titles of this application, to avoid obscuring the purpose of this section, the abstract and titles, and such simplifications or omissions should not be used to limit the scope of the invention.

In view of the above and/or existing problems in the preparation and application of diaryl ether fused ring compounds, the present invention is proposed.

Therefore, an object of the present invention is to provide a novel diaryl ether compound with a fused ring structure, which has better activity against multidrug-resistant Mycobacterium tuberculosis. At the cellular level, the inhibitory activity of some embodiments on MTB reaches IC50<10ug/mL. .

In order to solve the above-mentioned technical problems, the present invention provides the following technical scheme: a kind of diaryl ether condensed ring compound, its chemical structural formula is as shown in formula I below,

in,

R is selected from substituted C1-C6 alkyl, and the substituent is one of hydroxyl, amino, alkoxy, alkylamino, carboxyl, ester, amido or cyano;

R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, and adjacent R4 and R5 can form a ring system;

R1, R2, R3 are independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkoxy, carbonyl, cyano, sulfone, sulfoxide, sulfonyl, aryl;

Ar1, Ar2, and Ar3 are independently selected from 5-10 membered aromatic groups, heteroaromatic groups, or aromatic groups/heteroaryl groups and a saturated or partially unsaturated ring system;

m, n, t are each independently selected from an integer of 0-4, preferably 0, 1, 2.

As a preferred version of the diaryl ether fused ring compound of the present invention, wherein: the substituents are alkylamino-CH2(CH2)qNR4R5, alkylalkoxy-CH2(CH2)qOR6, More preferably -CH2CH2NMe2, -CH2CONMe2, -CH2CH2OMe, wherein q is an integer of 0-5.

As a preferred embodiment of the diaryl ether condensed ring compound of the present invention, wherein: said Ar1, Ar2 and Ar3 are independently selected from benzene ring, pyridine ring, naphthalene ring and quinoline ring.

Another object of the present invention is to provide a method for preparing diaryl ether fused ring compounds.

In order to solve the above technical problems, the present invention provides the following technical scheme: a method for preparing diaryl ether fused ring compounds, the chemical reaction formula of which is:

Among them, the first step: adding inorganic base powder to the substituted o-fluoroacetophenone, substituted o-halophenol and solvent mixture, heating to 80°C-180°C for 2-48 hours; the second step: using the transition metal catalyst In the presence of an intramolecular coupling reaction, the palladium catalyst, phosphorus ligand and base are mixed according to a certain ratio, and the reaction is heated in an appropriate solvent under the protection of an inert gas; the third step: in the presence of a palladium catalyst, the substituted bromobenzene Molecular coupling reaction occurs with the product of the second step, the palladium catalyst, phosphorus ligand and alkali are mixed according to a certain ratio, under the protection of an inert gas, the reaction is heated in an appropriate solvent; the fourth step: under alkaline conditions, the R anion and Ketone reaction generates formula (I) compound;

The solvent described in the above each step reaction is selected from the following group: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2 -Dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

The base includes inorganic bases and organic bases, such as sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, Sodium bicarbonate, or a combination thereof; or pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU ), lithium hexamethyldisilazyl, sodium hexamethyldisilazyl, LDA, lutidine, or a combination thereof;

The transition metal catalysts are tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), palladium acetate, palladium chloride, Dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphinepalladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-ortho Benzylphosphine) palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or a combination thereof; the ligand refers to: tri-tert-butylphosphine, tetrafluoro Tri-tert-butylphosphine borate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tri-o-phenylmethylphosphine, or combinations thereof.

Another object of the present invention is to provide a pharmaceutical composition.

In order to solve the above-mentioned technical problems, the present invention provides the following technical solutions: a pharmaceutical composition comprising, diaryl ether fused ring compounds, or pharmaceutically acceptable salts thereof, or enantiomers thereof, Diastereomers, tautomers, solvates, polymorphs or prodrugs; and, a pharmaceutically acceptable carrier.

The application of a diaryl ether fused ring compound in the preparation of a drug for preventing or treating tuberculosis, especially a drug for treating drug-resistant tuberculosis.

Beneficial effects of the present invention: the present invention prepares a class of compounds with a new diaryl ether fused ring structure having the structure shown in formula I, and finds that it has better activity against multidrug-resistant Mycobacterium tuberculosis. At the cellular level, the inhibitory activity of some embodiments on MTB reaches IC50<10ug/mL.

Detailed ways

In order to make the above objects, features and advantages of the present invention more comprehensible, the specific implementation of the present invention will be described in detail below in conjunction with specific examples.

In the following description, a lot of specific details are set forth in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described here, and those skilled in the art can do it without departing from the meaning of the present invention. By analogy, the present invention is therefore not limited to the specific examples disclosed below.

Second, "one embodiment" or "an embodiment" referred to herein refers to a specific feature, structure or characteristic that may be included in at least one implementation of the present invention. "In one embodiment" appearing in different places in this specification does not all refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, I will not repeat them here.

Below in conjunction with specific embodiment, further elaborate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods without specific conditions indicated in the following examples are generally in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Reaction principle of the present invention:

The general method is:

The first step: add a palladium catalyst such as PdCl2 (1 molar equivalent), a phosphorus ligand such as PPh3 (2-5 molar equivalents), and a base such as Cs2CO3 (5-15 molar equivalents) into a two-necked bottle, and inject an appropriate solvent such as After stirring tetrahydrofuran at room temperature for 10 minutes, inject a solution of substrate diaryl ether such as tetrahydrofuran (1 molar equivalent), raise the temperature to 80°C-150°C, and stir for 4-12 hours. After TLC detects that the reaction is complete, cool to room temperature and add Extract with water and an organic phase such as dichloromethane, combine the organic phases, dry, concentrate, column chromatography or recrystallization to obtain a light yellow solid with a yield of 80%-95%.

The second step: add palladium catalyst such as Pd2(dba)3 (0.05 molar equivalent), phosphorus ligand such as X-Phos (0.06 molar equivalent) and base such as NaOt-Bu (1.2-2.5 molar equivalent) in the two-necked flask, nitrogen Inject an appropriate solvent such as anhydrous dioxane under protection, stir at room temperature for 10 min, then inject an appropriate solution of the light yellow solid (1 molar equivalent) and aryl halide (1-2 molar equivalent) in the previous step, and heat to 80°C- React at 180°C. After the reaction is completed, cool to room temperature, add an appropriate organic phase such as ethyl acetate, filter to remove the insoluble palladium catalyst, add H O, extract, dry the organic layer, concentrate, column chromatography or recrystallization to obtain the target compound, the yield is greater than 80% %.

Step 3: Add N,N-dimethylacetamide or Grignard reagent (1 molar equivalent) into a two-necked flask, protect it with nitrogen, add anhydrous tetrahydrofuran, cool to -78°C, and add LDA (2mol/ l) solution, dropwise adding time exceeds 0.5h, continue stirring for 0.5h. Then a THF solution of the corresponding ketone (0.3 molar equivalent) was added dropwise. After the dropwise addition, the temperature was slowly raised to -20° C. and stirred overnight. After the reaction is complete, add saturated ammonium chloride solution, add ethyl acetate (30ml×3), extract, combine the organic layers, dry over MgSO4, concentrate, and perform column chromatography.

Dissolve the corresponding amide analogue (1 molar equivalent) in anhydrous THF, cool to 0°C, add borane tetrahydrofuran complex solution (5.0 molar equivalent) dropwise, react for 1h, slowly rise to 55°C, react for 1h, After the reaction was complete, add 1ml of methanol to quench, add ethyl acetate and water, extract, concentrate the organic layer, add methanol, heat up to 60°C, react for 2h, concentrate, and column chromatography to obtain the target product.

Adopt the first step of above-mentioned general preparation method to prepare successively the following intermediate compounds:

The following ketone compounds were prepared sequentially by adopting the second step of the above-mentioned general preparation method:

Adopt the third step of the above general preparation method to prepare the following target compounds sequentially:

Adopt literature method (J.Antimicrob.Chemother., 2005,56,968-974.) to carry out the inhibitory activity test of embodiment compound to multi-drug resistant Mycobacterium tuberculosis, the MIC of most embodiment compounds is all less than 100uM for Mycobacterium tuberculosis H37Ra, part Examples such as 7, 9, 17, 18, 19, 20, 21 etc. all have MICs for H37Ra less than 10uM, which is equivalent to the activity of Capreomycin. Therefore, the embodiment of the present invention provides a class of compounds with a new structure, which can better resist multidrug resistance to Mycobacterium tuberculosis.

It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation, although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (6)

1. A diaryl ether condensed ring compound is characterized in that: its chemical structural formula is as shown in formula I, in, R is selected from substituted C1-C6 alkyl, and the substituent is one of hydroxyl, amino, alkoxy, alkylamino, carboxyl, ester, amido or cyano; R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, and adjacent R4 and R5 can form a ring system; R1, R2, R3 are independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkoxy, carbonyl, cyano, sulfone, sulfoxide, sulfonyl, aryl; Ar1, Ar2, and Ar3 are independently selected from 5-10 membered aromatic groups, heteroaromatic groups, or aromatic groups/heteroaryl groups and a saturated or partially unsaturated ring system; m, n, t are each independently selected from an integer of 0-4, preferably 0, 1, 2. 2. the diaryl ether condensed ring compound as claimed in claim 1, is characterized in that: described substituting group is alkyl amino-CH2 (CH2) qNR4R5, alkyl alkoxyl group-CH2 (CH2) qOR6, More preferably -CH2CH2NMe2, -CH2CONMe2, -CH2CH2OMe, wherein q is an integer of 0-5. 3. The diaryl ether fused ring compound according to claim 1 or 2, characterized in that: said Ar1, Ar2 and Ar3 are independently selected from benzene ring, pyridine ring, naphthalene ring and quinoline ring. 4. A preparation method of the diaryl ether condensed ring compound as claimed in any one of claims 1 to 3, characterized in that: its chemical reaction formula is: Among them, the first step: adding inorganic base powder to the substituted o-fluoroacetophenone, substituted o-halophenol and solvent mixture, heating to 80°C-180°C for 2-48 hours; the second step: using the transition metal catalyst In the presence of an intramolecular coupling reaction, the palladium catalyst, phosphorus ligand and base are mixed according to a certain ratio, and the reaction is heated in an appropriate solvent under the protection of an inert gas; the third step: in the presence of a palladium catalyst, the substituted bromobenzene Molecular coupling reaction occurs with the product of the second step, the palladium catalyst, phosphorus ligand and alkali are mixed according to a certain ratio, under the protection of an inert gas, the reaction is heated in an appropriate solvent; the fourth step: under alkaline conditions, the R anion and Ketone reaction generates formula (I) compound; The solvent described in the above each step reaction is selected from the following group: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2 -Dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof. The base includes inorganic bases and organic bases, such as sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, Sodium bicarbonate, or a combination thereof; or pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU ), lithium hexamethyldisilazyl, sodium hexamethyldisilazyl, LDA, lutidine, or a combination thereof; The transition metal catalysts are tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), palladium acetate, palladium chloride, Dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphinepalladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-ortho Benzylphosphine) palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or a combination thereof; the ligand refers to: tri-tert-butylphosphine, tetrafluoro Tri-tert-butylphosphine borate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tri-o-phenylmethylphosphine, or combinations thereof. 5. A pharmaceutical composition, characterized in that: comprising, The diaryl ether fused ring compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, or tautomer forms, solvates, polymorphs or prodrugs; and, pharmaceutically acceptable carrier. 6. A use of the diaryl ether fused ring compound according to any one of claims 1 to 3 in the preparation of a drug for preventing or treating tuberculosis, especially a drug for treating drug-resistant tuberculosis.