CN110615800A

CN110615800A - Nitroimidazole compound and preparation method and application thereof

Info

Publication number: CN110615800A
Application number: CN201910983899.6A
Authority: CN
Inventors: 李丽丽
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-10-16
Filing date: 2019-10-16
Publication date: 2019-12-27

Abstract

The invention discloses a nitroimidazole compound, in particular to a compound shown in a formula (I), and also discloses a preparation method of the compound and application of the compound in preparing a medicament for treating diseases related to infection caused by tubercle bacillus.

Description

Nitroimidazole compound and preparation method and application thereof

Technical Field

The invention relates to a nitroimidazole compound, in particular to a compound shown in a formula (I), and also relates to a preparation method of the compound and application of the compound in preparing a medicament for treating diseases related to infection caused by tubercle bacillus.

Background

Tuberculosis (also known as TB) is a disease caused by infection of tubercle bacillus. According to the WHO estimation, the number of tuberculosis latent infection people in 2017 is about 17 hundred million worldwide, and the latent infection rate is 23 percent. The worldwide new tuberculosis patients are about 1000 million, the tuberculosis incidence rate is 133/10 million, wherein children patients less than 15 years old and HIV infected patients respectively account for 10 percent and 9 percent of the new tuberculosis patients; the number of new patients in 30 tuberculosis-burdened countries accounts for 87.2% of the world; new patients in india (27.4%), china (8.9%), indonesia (8.4%) and philippines (5.8%) make up about 50% of the world. The number of new patients with the estimated tuberculosis in China is 88.9 ten thousand, the estimated tuberculosis incidence rate is 63/10 ten thousand, and the estimated tuberculosis incidence rate is ranked 28 in 30 tuberculosis high-burden countries.

In 2017, tuberculosis is still one of the first 10 causes of death worldwide, the number of deaths of tuberculosis is estimated to be about 157 ten thousand globally, the mortality is 17/10 ten thousand, and the cause of death of tuberculosis changes from the 9 th to the 10 th. The number of tuberculosis deaths in China is 3.7 ten thousand, the tuberculosis mortality rate is 2.6/10 ten thousand, and the tuberculosis mortality rate ranks 29 th in 30 high-burden countries.

Delamanid was approved in europe for the treatment of multi-drug resistant mycobacterium tuberculosis on 21/11/2013. Delamanid has certain curative effect in the multi-drug resistant tuberculosis treatment, but has further excellent space in the aspects of administration frequency and cure rate.

Disclosure of Invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

R₁selected from H, halogen, OH, CN, NH₂、C_1-6Alkyl and C_1-6Alkoxy radical, said C_1-6Alkyl or C_1-6Alkoxy is optionally substituted with 1, 2 or 3R;

r is respectively and independently selected from F, Cl, Br, OH, CN and NH₂。

In some embodiments of the invention, R is as defined above₁Selected from the group consisting of H, F, Cl, Br, OH, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, said methyl, ethyl, isopropyl, cyclopropyl, methoxy or ethoxy being optionally substituted with 1, 2 or 3R.

In some embodiments of the invention, R is as defined above₁Selected from the group consisting of H, F, Cl, Br, OH, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy.

In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

the present invention also provides a process for the preparation of a compound of formula (I) as defined above, which comprises the steps of:

step 1: heating the reaction solution of the compound (I-1) and the compound (I-2) to 100 ℃ under the basic condition of triethylamine, and stirring for 3-5 hours to obtain a compound (I-3);

step 2: dissolving the compound (I-3) and the compound (I-4) in dichloromethane, and reacting under the condition of a condensing agent dicyclohexylcarbodiimide to obtain a compound shown in a formula (I);

wherein R is₁As defined above.

The invention also provides application of the compound in preparing a medicine for treating tuberculosis.

The invention also provides application of the pharmaceutical composition containing the compound shown in the formula (I) in preparing a medicine for treating tuberculosis.

In some embodiments of the present invention, the tuberculosis includes active tuberculosis, single-drug-resistant tuberculosis, multi-drug-resistant tuberculosis, and extensive multi-drug-resistant tuberculosis, wherein the tuberculosis includes pulmonary tuberculosis and extrapulmonary tuberculosis.

The invention also provides a pharmaceutical composition taking the compound shown in the formula (I) as an active ingredient.

In some embodiments of the present invention, the pharmaceutical composition is prepared into any pharmaceutically acceptable dosage form, preferably a dosage form selected from the group consisting of: tablet, capsule, granule, syrup, powder for injection, and injection.

Definitions and general terms

The examples of the invention are accompanied by a graphic representation of the structural formula and the chemical formula. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.

In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, deuterium, F, Cl, Br, OH, C_1-8Alkyl radical, C_1-8Alkoxy, and the like.

As used herein, the term "alkyl group contains from 1 to 6 carbon atoms, in other embodiments the alkyl group contains from 1 to 4 carbon atoms, and in other embodiments the alkyl group contains from 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) 2-methylpropyl or isobutyl (i-Bu, -CH)₂CH(CH₃)₂) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃)，Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)2), 1-butoxy (n-BuO, n-butoxy, -OCH₂CH₂CH₂CH₃) And so on.

In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently," and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, alginates, salts of alginic acid, salts of citric acid, malic acid, salts of lactic acid, lauryl sulfate, malic acid, malonic acid, salts of lactic acid, salts of, Picrate, picrate,Pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include alkali metals, alkaline earth metals, and the like. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

Detailed Description

The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. The materials and equipment used in the examples of the present invention are commercially available unless otherwise specified.

Synthetic schemes

step 2: dissolving the compound (I-3) and the compound (I-4) in dichloromethane, and reacting under the condition of a condensing agent dicyclohexylcarbodiimide to obtain the compound shown in the formula (I).

Example 1: synthesis of Compound 1

Step 1: preparation of Compound A-3

To a mixture of compound A-1(3.0g, 20.0mmol) and compound A-2(1.80g, 24.0mmol) was added triethylamine (0.6mL), and the mixture was stirred at 120 ℃. For 3 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to obtain compound A-3(2.53g, 13.1 mmol).

MS m/z：194.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ7.41(s,1H),6.73(d,J＝6.1Hz,3H),6,22(s,1H),6.01(m,2H),4.14(dd,J＝8.4,3.0,2H),3.13(dd,J＝7.8,4.2,2H).

Step 2: preparation of Compound 1

Compound A-3(2.53g, 13.1mmol) and compound A-4(3.49g, 16.4mmol) were dissolved in 5mL of dichloromethane at 0 deg.C, 4-dimethylaminopyridine (0.2g) was added, the mixture was stirred well, and dicyclohexylcarbodiimide (0.22g, 1.6mmol) was added in one portion under argon atmosphere. After stirring for half an hour, the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was filtered, the filtrate was washed with saturated aqueous ammonium bicarbonate (15mL), the organic layer was concentrated and purified by silica gel chromatography (30% EtOAc in hexane) to give compound 1(3.67g)

MS m/z：389.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.28(s,1H),7.19(m,2H),6.81(m,3H),4.88(dd,J＝8.1,3.0,1H),4.6(m,2H),4.49～4.40(m,2H),4.14(m,2H),1.89(s,3H).

Examples 2 to 9 preparation

Examples 2 to 6 differ from example 1 in the linker (A-1), and thus examples 2 to 6 were obtained by substituting the compound (A-1) in step 1 of example 1 accordingly. The substituted fragments are commercially available, and the results are shown in Table-1 below

Biological Activity test experiment

Experiment one: in vitro activity test of anti-tubercle bacillus

1. Experimental materials:

the strain is as follows: MTB Standard strain H37Rv (ATCC 27294)

Reagent: DMSO (QN 0748, Beijing Baiolai Boke technology Co., Ltd.)

Culture medium: 7H9 Medium (American BD Co.)

Cell culture plate: v-bottom 96 well plates (greiner, 651201), flat-bottom 96 well plates (greiner, 650201)

2. Experimental procedure

1) Dissolving the compound in DMSO, and diluting the compound to a concentration of 10mg/mL as a mother solution;

2) the above mother liquor was diluted in a V-bottom 96-well plate in a gradient of 2 times to give mother liquor having concentrations of 5mg/mL, 2.5mg/mL, 0.625mg/mL, 0.3125mg/mL, 0.156mg/mL, 0.078mg/mL, 0.039mg/mL, 0.002mg/mL and 0.001mg/mL in that order.

3) Adding 2 μ L of the mother liquor obtained in the step 2) into a flat-bottom 96-well plate (no mother liquor is added in the wells of 1A, 1H, 12A and 12H), and adding 98 μ L of 7H9 culture medium into all the wells of the plate;

4) selecting a mycobacterium tuberculosis H37Rv strain, inoculating the mycobacterium tuberculosis H37Rv strain into a 7H9 culture medium of 0.05 Tween80 and 10% ADC, and culturing for 2-3 weeks at 37 ℃;

5) adjusting the absorbance of the bacterial liquid in the step 4) to be about OD550 to 0.4 by using a Mach turbidimetry method;

6) diluting the bacterial liquid obtained in the step 5) by 1000 times;

7) adding 100 mu L of diluted bacteria liquid into a flat-bottom 96-well plate respectively, and arranging 1 row of control wells without the bacteria liquid in the plate;

8) placing the flat-bottom 96-well plate in the step 8) into an incubator to be incubated under the conditions of 37 ℃ and 80% humidity;

9) after 7 days, 20. mu.L of a mixture of 10 × Alamar Blue and 5% Tween 8050. mu.L was added to the culture wells and the control wells, and after further incubation at 37 ℃ for 24 hours, observation was made, and if the color changed from Blue to pink, the above-mentioned amount of the mixture of Alamar Blue and Tween80 was added to the wells of each test drug, the color of each well was recorded after further incubation at 37 ℃ for 24 hours, and 590nm fluorescence value was measured using a microplate reader, and the minimum final drug concentration was calculated.

Table 1: MIC value of the compound of the invention to Mycobacterium tuberculosis H37Rv

Compound numbering	MIC(μg/mL)
		Delamanid	0.0215
Compound 1	0.00371
		Compound 2	0.00316
Compound 3	0.00402
		Compound 4	0.00227
Compound 5	0.00298
		Compound 6	0.00173

And (4) conclusion: the compound of the invention has very good inhibitory activity to tubercle bacillus H37Rv, the compound 6 has the strongest activity which is 12 times of that of a reference substance Delamanid, and the activity is higher than that of the reference substance by one order of magnitude. Compound 3 was the least active, 5-fold more active than the control.

Experiment 2: in vivo pharmacokinetic experiments

The experimental method comprises the following steps: the compound of the invention is prepared into 0.5 percent of carboxymethyl cellulose and 0.5 percent of Tween80 to prepare 2.5mg/mL suspension, and the suspension is gastric lavage to male mice (3 mice in each group, 22-23 g each). Blood samples were collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing, respectively. Various pharmacokinetic data were calculated for each compound using the winnonlin5.2.1 software. The results are shown in Table 2.

TABLE 2 pharmacokinetic test results

Compound numbering	T_1/2(h)	AUC_0-24(mg·h/L)	C_max(μg/mL)	Pulmonary drug concentration (μ g/mL, 1h)
					Delamanid	6.10	5.53	0.435	0.157
Compound 4	10.2	9.47	0.582	1.16
					Compound 6	9.79	9.06	0.615	1.32

And (4) conclusion: the compound 4 and the compound 6 of the invention have a plurality of pharmacokinetic parameters superior to those of the positive compound Delamanid, wherein the half-life prolongation shows the potential of reducing the administration frequency later; the exposure (AUC) of compound 4 and compound 6 was approximately 2-fold that of Delamanid of the positive compound, showing better pharmacokinetic properties; the lung drug concentration of the compound 4 is more than 7 times of that of the positive compound Delamanid, and the lung drug concentration of the compound 6 is more than 8 times of that of the positive compound Delamanid, so that the compound is obviously superior to a reference compound, and is very favorable for treating lung diseases.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is₁Selected from H, F, Cl, Br, OH. CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, said methyl, ethyl, isopropyl, cyclopropyl, methoxy or ethoxy being optionally substituted with 1, 2 or 3R.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R is₁Selected from the group consisting of H, F, Cl, Br, OH, CN, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from:

5. a process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises the steps of:

wherein R is₁As defined in claims 1 to 3.

6. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of tuberculosis.

7. Use of a pharmaceutical composition comprising a compound of formula (I) in the manufacture of a medicament for the treatment of tuberculosis.

8. Use according to claim 6 or 7, characterized in that the tuberculosis comprises active tuberculosis, single-drug resistant tuberculosis, multi-drug resistant tuberculosis and extensively multi-drug resistant tuberculosis, wherein the tuberculosis comprises pulmonary tuberculosis, extrapulmonary tuberculosis.

9. A pharmaceutical composition comprising a compound of formula (I) as an active ingredient.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is prepared in any pharmaceutically acceptable dosage form, preferably in a dosage form selected from the group consisting of: tablet, capsule, granule, syrup, powder for injection, and injection.