WO2019029613A1 - Deuterated quinoline compound, preparation therefor and use thereof - Google Patents

Abstract

A deuterated quinoline compound, specifically a compound represented by formula (I), a stereochemical isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating tuberculosis.

Description

Deuterated quinoline compound and preparation and use thereof Technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a deuterated quinoline compound, its preparation and use.

Background technique

Tuberculosis is a chronic infectious disease caused by infection with Mycobacterium tuberculosis. In global infectious disease statistics, tuberculosis is the second leading cause of infectious diseases after AIDS. Despite the large number of anti-tuberculosis drugs currently in clinical use, first-line anti-tuberculosis drugs have been used for decades with isoniazid, rifampicin, pyrazinamide and ethambutol. The long-term use of these drugs, the tubercle bacilli in patients showed significant drug resistance.

The patent application published as WO2004011436A1 discloses diarylquinoline derivatives of the formulae Ia and Ib which have better antituberculosis activity.

On this basis, a new type of anti-tuberculosis drug has been developed, named TMC-207, whose structure is shown in the following formula, which was approved for marketing in 2012. However, the drug has serious side effects including QT prolongation leading to severe arrhythmia and risk of death.

Deuterated drugs refer to the replacement of some of the hydrogen atoms in a drug molecule with hydrazine. Since strontium is close in shape and volume to hydrogen in the drug molecule, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction, and its half-life is prolonged.

Due to the complex metabolic process of biological systems, the pharmacokinetic properties of drugs in vivo are affected by many factors, and also show corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show great contingency and unpredictability. Deuteration at some sites may not extend the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406.), degrading its pharmacokinetic properties; On the other hand, hydrogen at certain positions on the drug molecule is not easily deuterated due to steric hindrance and the like. Therefore, the deuteration of the drug is not arbitrary, and the site of degeneration is unpredictable.

The present inventors hope that by deuteration of the TMC-207 compound, a class of deuterated drugs which are resistant to tuberculosis and tuberculosis, have good pharmacokinetic properties, and reduce toxic side effects.

Summary of the invention

It is an object of the present invention to provide a quinoline derivative which is biologically active against tuberculosis.

A quinoline derivative of the formula (I) or a stereochemical isomer, solvate or pharmaceutically acceptable salt thereof:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, hydrazine, C ₁ -C _{a 10} alkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ heterocycloalkyl group, a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ heterocyclic aryl group; wherein the alkyl group, naphthenic group The hydrogen in the group, heterocycloalkyl, aryl, heteroaryl group may be further substituted by one or more deuterium atoms;

A is a phenyl group substituted with phenyl or fluorene, the structure of which is represented by formula (II), and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ on the benzene ring are each independently taken from H and D;

B is a naphthyl or an anthracene-substituted naphthyl group, the structure of which is represented by the formula (III), and R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ are each independently taken from H and D;

And the quinoline derivative contains at least one D atom.

Further, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, hydrazine and C ₁ ～ C ₅ alkyl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ heterocycloalkyl, C ₆ -C ₈ aryl, C ₆ -C ₈ heteroaryl; wherein alkyl, ring The hydrogen in the alkyl, heterocycloalkyl, aryl, heteroaryl group may be further substituted with one or more deuterium atoms.

Further, R ¹ , R ² and R ³ are each independently selected from the group consisting of H, D, CH ₃ and CD ₃ ; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , R ^{12 is} each independently selected from the group consisting of hydrogen, deuterium, C ₁ -C ₃ alkyl, wherein the hydrogen in the alkyl group may be further substituted with one or more deuterium atoms.

Further, R ¹ , R ² and R ³ are each independently selected from the group consisting of H, D, CH ₃ , CD ₃ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^{12 is} independently selected from hydrogen or hydrazine.

Further, R ¹ and R ^{2 are} all CD ₃ , R ^{3 is} selected from CH ₃ or CD ₃ , R ^{8 is} selected from H or D, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ^{12 is} all hydrogen.

Further, all of R ¹ , R ² and R ³ are CD ₃ , R ^{8 is} selected from H or D, and R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} all hydrogen. .

Further, the stereochemical isomer is (1R, 2S).

Further, the pharmaceutically acceptable salt is a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate. , succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate; preferably fumarate.

Further, the quinoline derivative structure is

The present invention also provides the use of the above quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of tuberculosis.

A pharmaceutical composition which is prepared by using the above quinoline derivative or a stereochemical isomer, a solvate thereof or a pharmaceutically acceptable salt as an active ingredient, together with a pharmaceutically acceptable adjuvant .

In the present invention, "treatment" also includes relapse prevention or phase prevention, as well as treatment of acute or chronic signs, symptoms and/or dysfunction. Treatment can be symptomatic treatment, such as inhibition of symptoms. It can be achieved in the short term, adjusted in the medium term, or it can be said to be long-term treatment, for example in maintenance therapy.

The term "prevention" includes delaying and/or preventing the onset of a condition, disease or condition and/or its associated symptoms; preventing the subject from contracting the condition, disease or condition; or reducing the risk of the subject being infected with the condition, disease or condition. .

As used herein, "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.

In the present invention, the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season. An ammonium salt such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing a compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. An acid salt, an oxalate salt, a malate salt, a succinate salt, a fumarate salt, a maleate salt, a tartrate salt or a trifluoroacetate salt.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C _a - C _b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C ₁ -C ₆ )alkyl means an alkyl group containing from 1 to 6 carbon atoms.

The C ₁ -C ₅ alkyl group means an alkyl group of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , that is, a linear or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group. , ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and the like.

Similarly, "C _a - C _b heterocycloalkyl" refers to all hetero atom-containing cycloalkyl groups having from a to b carbon atoms.

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

Detailed ways

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

The reagents and test equipment used in the present invention are conventional commercially available reagents and equipment, unless otherwise noted.

Example 1. Synthesis of (1R,2S)-1-(6-bromo-2-trideutereromethoxyquinolin-3-yl)-4-(di(tris-methyl)amino)-2- (na-1-yl)-1-phenylbutan-2-ol (3)

The first step: synthesis of 3-benzyl-6-bromo-2-tridemethoxy methoxyquinoline (3-2)

3-Benzyl-6-bromo-2-chloroquinoline (3-1) was purchased from Tianjin Glades Rand Pharmaceutical Co., Ltd. 6.64 g (20 mmol, 1.0 eq) of 3-benzyl-6-bromo-2-chloroquinoline, 4.6 g (80 mmol, 4.0 eq) of sodium methoxide hydride was added to 70 mL of acetonitrile, and the mixture was stirred and refluxed for 12 hr. The reaction was monitored by TLC. After the disappearance of the material, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The solvent was evaporated to ethyl acetate (50 mL), and washed with water (3×30 mL). The oily liquid was allowed to stand at room temperature to form a white solid 6.6 g, yield: 98%. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.07 (s, 1H), 7.97 (s, 1H), 7.73-7.68 (m, 2H), 7.32-7.19 (m, 5H), 4.00 (s, 2H ESI-MS (m/z): 331.2 [M+H] ⁺ .

Step 2: Synthesis of 3-(bis(tris-methyl)amino)-1-(na-1-yl)propan-1-one (3-3)

1.70 g (10 mmol, 1.0 eq) of 1-acetylnaphthalene, 0.39 g (13 mmol, 1.3 eq) of paraformaldehyde and 1.14 g (13 mmol, 1.3 eq) of deuterated dimethylamine hydrochloride were sequentially added to 25 mL of ethanol solution. 0.1 mL of hydrochloric acid was added, and the reaction solution was heated under reflux and stirred overnight. It was naturally cooled to room temperature, and the solvent was evaporated under reduced pressure. Water was dissolved in 30 mL of water and extracted with ethyl acetate (2×20 mL) to remove the unreacted starting material 1-acetylnaphthalene. The organic phase was combined with ethyl acetate (3×30 mL). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 - 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 8.08-8.06 (m, 1H), 8.02-7.99 (m, 1H), 7.63 -7.58 (m, 3H), 3.25-3.22 (t, J = 6.8 Hz, 2H), 2.69-2.65 (t, J = 6.8 Hz, 2H), ESI-MS (m/z): 234.2 [M+ H] ⁺ .

Step 3: Synthesis of (1R,2S)-1-(6-bromo-2-trideuteromethoxyquinolin-3-yl)-4-(di(tris-methyl)amino)-2- (na-1-yl)-1-phenylbutan-2-ol (3)

Under nitrogen protection, 15 mL of anhydrous tetrahydrofuran was added to the three-necked flask, and the temperature was lowered to -65 ° C or lower with a dry ice/acetone bath. LDA (2N, 15 mL, 30 mmol, 2.0 eq) was added to the reaction system, and 3-benzyl-6 was added. -Bromo-2-trideuterine methoxyquinoline (3-2) 4.9 g (15 mmol, 1.0 eq) in 50 mL of tetrahydrofuran solution. After the addition, the temperature was raised to -40 ± 5 ° C, and the reaction was stirred for 1 hour. Displayed in dark black. Re-cooling to -65 ° C or less, add 3-deuterated dimethylamino-1-(naphthalen-5-yl)acetone (3-3) 3.8 g (16.5 mmol, 1.1 eq) in 40 mL of tetrahydrofuran solution, after the addition is maintained The system was stirred at -65 ° C for 30 minutes with stirring. The saturated ammonium chloride solution was added dropwise to the reaction system to quench the reaction, the outer bath was removed, and the temperature was naturally raised to room temperature. The organic phase was extracted with ethyl acetate (3×100 mL), evaporated, evaporated, evaporated, evaporated. The chiral column (IC-3) was fractionated, and the fraction of the forward column retention time of 2.873 minutes was collected to obtain 370 mg of the target compound D9-betaquinoline A1 in a yield of 4.4%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.73 -7.59 (m, 5H), 7.49 (t, J = 6.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.11 (s, 2H), 6.89-6.87 (m, 3H), 5.89 ( s, 1H), 2.51 (s, 1H), 2.04-1.97 (m, 3H), ESI-MS (m/z): 564.2 [M+H] ⁺ .

Example 2 Synthesis of (1R,2S)-1-(6-bromo-2-trideutereromethoxyquinolin-3-yl)-4-(bis(tris-methyl)amino)-1- Indole-2-(n-yl)-1-phenylbutan-2-ol (1)

First step: synthesis of 6-bromo-3-(phenyl(dimercaptomethyl))-2-tridemethoxy quinolate (1-1)

2.53 g of metal sodium (11 mmol, 1.1 eq) was added to 20 mL of deuterated methanol solution, and stirred at 0-10 ° C for 30 minutes to prepare a deuterated methanol solution of sodium methoxide, followed by the addition of compound 3-1 (3). -benzyl-6-bromo-2-chloroquinoline) 3.33 g (10 mmol, 1.0 eq), heated to reflux and stirred for 12 h. The reaction was monitored by TLC. After the disappearance of the material, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The solvent was evaporated to ethyl acetate (50 mL), and washed with water (3×30 mL). The oily liquid was slowly placed at room temperature to form a white solid 3.28 g, yield: 99.1%. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.07 (s, 1H), 7.97 (s, 1H), 7.73-7.68 (m, 2H), 7.32-7.19 (m, 5H); LCMS (ESI, m /z): C ₁₇ H ₉ D ₅ BrNO [M+H]+333.1.

The second step: synthesis of (1R, 2S)-1-(6-bromo-2-trideuteromethoxyquinolin-3-yl)-4-(di(tris-methyl)amino)-1- Indole-2-(n-yl)-1-phenylbutan-2-ol (1)

Using the method similar to the method of Example 1, the compound 1-1 was used as a starting material to prepare the target compound 1.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ1.91-1.95 (m, 1H), 1.99-2.10 (m, 2H), 2.51 (d, J = 14.1Hz, 1H), 6.87-6.89 (m, 3H), 7.10-7.15 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 8.5 Hz, 1H), 7.61 (t, J = 8.5 Hz, 1H), 7.63 - 7.67 (m , 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H) ), 8.60 (d, J = 8.5 Hz, 1H), 8.89 (s, 1H);

LCMS (ESI, m / z) : C 32 H 21 D 10 BrN 2 O 2 [M + H] +565.2.

Example 3 Synthesis of 1-(6-bromo-2-trideutereromethoxyquinolin-3-yl)-4-(tris-methylamino)-2-(naphthalen-1-yl)-1- Phenyl-2-butanol (4)

First step: Preparation of tert-butyltridecylmethyl [3-(naphthalen-1-yl)-3-oxopropyl]carbamate (4-1):

1-acetylnaphthalene 8.5 g (50.0 mmol, 1.0 eq), paraformaldehyde 1.5 g (50.0 mmol, 1.0 eq) and deuterated methylamine hydrochloride 7.05 g (100.0 mmol, 2.0 eq) were sequentially added to 15 mL of ethanol. To the solution, 0.86 g (5.0 mmol, 0.1 eq) of p-toluenesulfonic acid was added, and the mixture was stirred and stirred under reflux overnight. The mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. The above solid, methylene chloride (50 mL) was added to the reaction mixture, and the mixture was stirred and evaporated. The reaction mixture was washed with water (25 mL), EtOAc (EtOAc) 4.8 g, yield: 30.3%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.95 - 7.84 (m, 2H), 7.64 - 7.45 (m, 3H), 3.70 (t, J = 6.9 Hz, 2H), 3.32 (s, 2H), 1.44 (s, 9H). ESI-MS (m/z): 217.4 [M+H-Boc] ⁺ .

Step 2: Preparation of 1-(6-bromo-2-trideutereromethoxyquinolin-3-yl)-4-(tris-methylamino)-2-(naphthalen-1-yl)-1- Phenyl-2-butanol (4)

Under nitrogen protection, add 7 mL of dry tetrahydrofuran to a three-necked flask, cool to -65 °C with a dry ice/acetone bath, add 13.6 mL (27.3 mmol, 2.0 eq) of LDA (2N) to the reaction system, and slowly add 3- Benzyl-6-bromo-2-deuteromethoxyquinoline 4.5 g (13.6 mmol, 1.0 eq) in 5 mL of tetrahydrofuran solution, after the addition, the temperature was raised to -40 ± 5 ° C, the reaction was stirred for 1 hour, the color showed It is dark black. Re-cooling to below -65 ° C, adding tert-butyl deuterated methyl [3-(naphthalen-1-yl)-3-oxopropyl]carbamate 4.3 g (13.6 mmol, 1.0 eq) in 5 mL of tetrahydrofuran After the solution is added, the system is kept under stirring at -65 ° C for 30 minutes. The saturated ammonium chloride solution was added dropwise to quench the reaction in the reaction system. The organic layer was extracted with EtOAc (EtOAc)EtOAc.

The oil was dissolved in DCM (50 mL). The reaction mixture was extracted with a saturated aqueous solution of sodium carbonate (50 mL), and then evaporated and evaporated and evaporated. Purification by column chromatography, eluting with PE/EA = 1 / 1 to afford 162 mg of white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.54 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 6.3 Hz) , 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.60 - 7.48 (m, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.10 (dd, J = 6.4, 2.8 Hz, 2H), 6.85 - 6.75 (m, 3H), 5.81 (s, 1H), 2.61 (d, J = 13.3 Hz, 1H), 2.43 (d, J = 12.0 Hz, 1H), 2.10 - 1.86 (m, 2H). ESI-MS (m/z): 546.8 [M+H] ⁺ .

Example 4 Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(bis(tris-methyl)amino)-1-indol-2-(N--1- Base)-1-phenylbutan-2-ol (7)

First step: Preparation of 3-deuterobenzyl-6-bromo-2-methoxyquinoline (7-1)

3-benzyl-6-bromo-2-methoxyquinoline 938 mg (2.85 mmol, 1.0 eq), potassium tert-butoxide 800 mg (7.30 mmol, 2.5 eq) was added to a 25 mL sealed tube containing 10 mL of deuterated methanol. The mixture was heated to 80 ° C, stirred overnight, and the reaction was monitored by TLC. After the material disappeared, the mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and ethyl acetate (30 mL) was added to extract, washed with water (3×20 mL) The mixture was dried, filtered and concentrated to give a colorless oily liquid, which was allowed to stand at room temperature to form a white solid 923 mg, yield: 98%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.74 (d, J = 2.0Hz, 1H), 7.69 (d, J = 9.2Hz, 1H), 7.60 (dd, J = 2.0,9.2Hz, 1H), 7.49 (s, 1H), 7.32 (m, 2H), 7.26-7.22 (m, 3H), 4.08 (s, 3H); ESI-MS (m/z): 330.2 [M+H] ⁺ .

Step 2: Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(bis(tris-methyl)amino)-1-indol-2-(N--1- Base)-1-phenylbutan-2-ol (7)

Using Compound 7-1 as a starting material, Compound 7 (38 mg yield: 3.4%) was obtained in a procedure similar to Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.88 (t, J = 6.6 Hz) , 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.64 (td, J = 7.7, 5.7 Hz, 3H), 7.52 - 7.46 (m, 1H), 7.30 (t, J = 7.7 Hz, 1H) , 7.12 (d, J = 3.2 Hz, 2H), 6.91 - 6.85 (m, 3H), 4.21 (s, 3H), 2.58 (s, 1H), 2.13 (s, 2H), 1.96 (s, 1H). MS (ESI+) m/z: 562.3 [M+H] ⁺ .

Other compounds of the invention can be prepared in a similar manner.

The advantageous effects of the present invention will be described below by way of test examples.

Test Example 1. Liver microsome metabolic stability test of the compound of the present invention

(1) Preparing a mother solution: high purity water, phosphate buffer (100 mM), MgCl ₂ solution (5 mM);

(2) adding reduced coenzyme II (NADPH) and liver microsomes to the incubation experiment;

(3) adding a positive control Verapamil to the control test, adding the test compound to the test, the final concentration of the test compound is 2 μM;

(4) Samples were taken from the reaction solution at time points of 0, 15, 30, 45 and 60 minutes, and then centrifuged after treatment. The supernatant was diluted with high purity water and analyzed by LC-MS/MS;

(5) Data analysis: The peak area was determined from the extracted ion chromatogram. The slope value k is determined by a linear regression of the remaining percentage of the parent drug versus the natural log of the incubation time curve.

The in vitro half-life (t ₁ / ₂ in vitro) is determined by the slope value: in vitro t _1/2 =-(0.693/k)

The in vitro internal clearance (in vitro CL _int , in μL/min/mg) was converted from the in vitro half-life t _1/2 (minutes) using the following equation (average of repeated measures):

Enlarged intrinsic clearance (Scale up CL _int in mL/min/kg) is converted from in vitro t _1/2 (minutes) by using the following formula (average of repeated measurements):

The experimental results of metabolic stability of canine, monkey and human liver microsomes are shown in Table 1:

Table 1, Experimental results of metabolic stability of canine, monkey and human liver microsomes

As shown in the above table, the compounds prepared in Example 1 and Example 2 have longer half-lives in liver microsomes of dogs, monkeys and humans than the half-life of bedaquinoline, showing the metabolic stability of the deuterated compounds of the present invention. Both are better than the non-deuterated compound bedaquinoline, indicating that the compounds of the present invention have better pharmacokinetics, have better safety and effectiveness.

Test Example 2, Rat Pharmacokinetics of the Compound of the Invention

1) Experimental materials and instruments:

LC-20AD high performance liquid chromatography system, purchased from SHIMADZU (Shimadzu), Japan

API4000 Triple Quadrupole Mass Spectrometer, purchased from Applied Biosystem, USA

PhenixWinnolin Pharmacokinetics Software (Version 6.3), purchased from Certara, USA

High speed refrigerated centrifuge from Thermo Fisher Scientific

Analytical balance, purchased from Sartorius, SECURA225D-1CN

SD rat, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

N,N-dimethylacetamide (DMA) (Sigma)

2) Experimental methods and results

Weigh accurately the appropriate amount of drug (equivalent to the original drug 25mg/kg), use DMA / HP-β-CD / water as a solvent, ultrasonic, vortex and mix. 0.2 ml of the final solution was prepared and stored at -20 ° C for concentration determination. Healthy adult male SD rats (180-250g), fasted overnight (free drinking water), administered intragastrically; before administration and after administration 0.5,1,2,4,6,8,12, After 24 hours, 0.1 ml of blood was collected from the posterior venous plexus, and the plasma was separated by centrifugation at 4 ° C for 5 min, and stored at -20 ° C for testing. The concentration of the test compound in the plasma was then determined by LC/MS/MS.

Table 2. Rat pharmacokinetic parameters of the compounds of the invention

It can be seen from Table 2 that the exposure amount (AUC) of the compound of the present invention is significantly higher than that of the betadaquinoline, showing better pharmacokinetics. It is expected that the dose can be reduced clinically and become a safer and more patient-resistant anti-tuberculosis drug.

In summary, the deuterated quinoline compound provided by the present invention has better metabolic stability and pharmacokinetics and can be used for preparing a safer and more effective drug for treating tuberculosis. The application prospect is excellent.

Claims (11)

1. A quinoline derivative of the formula (I) or a stereochemical isomer, solvate or pharmaceutically acceptable salt thereof:

   

   Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, hydrazine, C ₁ -C _{a 10} alkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₁₀ heterocycloalkyl group, a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ heterocyclic aryl group; wherein the alkyl group, naphthenic group The hydrogen in the group, heterocycloalkyl, aryl, heteroaryl group may be further substituted by one or more deuterium atoms;

   A is a phenyl group substituted with phenyl or fluorene, the structure of which is represented by formula (II), and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ on the benzene ring are each independently taken from H and D;

   B is a naphthyl or an anthracene-substituted naphthyl group, the structure of which is represented by the formula (III), and R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ are each independently taken from H and D;

   

   And the quinoline derivative contains at least one D atom.
2. The quinoline derivative or a stereochemical isomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^6. R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, hydrazine, C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ a heterocycloalkyl group, a C ₆ -C ₈ aryl group, a C ₆ -C ₈ heterocyclic aryl group; wherein the hydrogen in the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group can be further The ground is replaced by one or more deuterium atoms.
3. The quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof according to claim 2, wherein R ¹ , R ² and R ³ are each independently selected from H and D. And CH ₃ , CD ₃ ; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, hydrazine, C ₁ -C ₃ alkyl, The hydrogen in the alkyl group described therein may be further substituted by one or more deuterium atoms.
4. The quinoline derivative according to claim 3 or a stereochemical isomer, solvate or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² and R ³ are each independently selected from H and D. And CH ₃ and CD ₃ ; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from hydrogen or hydrazine.
5. The quinoline derivative according to claim 4 or a stereochemical isomer, solvate or pharmaceutically acceptable salt thereof, wherein R ¹ and R ^{2 are} all CD ₃ and R ^{3 is} selected from CH _{3 .} Or CD ₃ , R ^{8 is} selected from H or D, and R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} all hydrogen.
6. The quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof according to claim 5, wherein all of R ¹ , R ² and R ³ are CD ₃ .
7. The quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the stereochemical isomer is (1R, 2S).
8. The quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride or a sulfate. , citrate, besylate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, rich A horse salt, a maleate salt, a tartrate salt or a trifluoroacetate salt; preferably a fumarate salt.
9. The quinoline derivative or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound has a structure of

   
10. Use of the quinoline derivative according to any one of claims 1 to 9, or a stereochemically isomeric, solvate or pharmaceutically acceptable salt thereof for the preparation of a medicament against TB and antituberculosis.
11. A pharmaceutical composition comprising the quinoline derivative according to any one of claims 1 to 9, or a stereochemical isomer, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Formulations prepared with pharmaceutically acceptable excipients.