WO2013039428A2

WO2013039428A2 - Quinoline derivatives, in particular 5,6,7-substituted 1-(2-chloroquinolin-3-yl)- 4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ols, method for producing same and use of said compounds

Info

Publication number: WO2013039428A2
Application number: PCT/RU2012/000725
Authority: WO
Inventors: Анна Борисовна НАЗАРЕНКО; Владимир Егорович ФЕДОРОВ; Вадим Егоревич ИЛЬИН; Антон Владимирович ОМЕЛЬКОВ; Евсей Александрович РУЧКО
Original assignee: Закрытое Акционерное Общество "Фарм-Синтез"
Priority date: 2011-09-12
Filing date: 2012-09-04
Publication date: 2013-03-21
Also published as: WO2013039428A3; RU2011137490A; RU2486175C2

Abstract

The present invention relates to novel quinoline derivatives, such as substituted 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1- phenylbutan-2-ols, to a method for producing same, and also to the use thereof as antimycobacterial agents, in particular to 5,6,7-substituted 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1- phenylbutan-2-ols of general formula (I), where R1 is Н or methoxy, R2 is Н, methoxy or -O-(CH2)n-O-, R3 is Н, methoxy or -O-(CH2)n-O-, n=1-2, and also to the pharmaceutically acceptable salts thereof with acids which exhibit activity in relation to mycobacteria. The invention also relates to a method for producing compounds of formula (I), which consists in interacting corresponding arylquinolines with an aromatic ketone and using said compounds as an active principle in the creation of anti-tubercular medicinal preparations.

Description

Derivatives of quinoline, in particular 5,6,7-substituted 1- (2-chloroquinolin-3-yl) - 4-dimethyl ino-2- (naphthalen-1-yl) -1-phenylbutan-2-ol, the method for their preparation and application of compounds

Description of the invention

The invention relates to biologically active substances, in particular to derivatives of substituted quinolines having cytostatic and cytotoxic activity against mycobacteria, namely, substituted derivatives of 1 - (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalene-1 -yl) - 1 - phenylbutan-2-tins of the general formula (I), to the method for their preparation, and also to their use as antimycobacterial agents, in particular, substances of drugs (agents) for the treatment of tuberculosis and other infectious diseases mycobacterial th nature.

According to the WHO, every year more than 8-9 million people fall ill with tuberculosis, the causative agent of which is the bacterial bacillus Micobacterium Tuberculosis. Moreover, mortality from resistant and non-resistant forms varies from 20 to 30% (2-3 million people). The current approaches to the treatment of this disease are based on combination therapy with a number of drugs, such as ethambutol, isoniazid, rifampicin, pyrazinamide, cycloserine, etc. Taking into account the growing worldwide incidence of resistant forms of tuberculosis, as well as the relatively high toxicity of the above drugs and their sufficiently long intake, the search for new chemicals with high antimycobacterial activity, is an urgent task of modern mennoy medicine and pharmacology.

Recently, a number of derivatives of the diarylquinoline series of the general formula (II) have been synthesized and tested for activity against mycobacteria [WO 2004/011436, 02/05/2004, WO 2008068270, 06/12/2008, WO 2006/125769, 11/30/2006], whose structure is related to quinine used since the beginning of the 17th century for the treatment of infectious diseases:

(AND)

where Ri is H, halogen, haloalkyl, cyano, hydroxy, aryl, hetaryl, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, aryl alkyl;

R ₂ is H, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono and dialkylamino;

R ₃ is hydrogen, halogen, alkyl;

R4 is naphthyl, halonaphthyl, phenyl, haloaryl, arylalkyl, pyridinyl, alkyl, thienyl;

R ₅ , R is alkyl, H, benzyl, imidazolyl, hetaryl, alkylthio, pyrimidyl. Quinoline derivatives of the general formula are known from RU 2404971, 27.1.

(III)

(III) where Ri means halogen, R ₂ means halogen, R ₃ means hydroxy, R ″, R ₅ means Ci-C3-alkyl, R6 means aryl, R ₇ means aryl, n = 1 or 2, and their pharmaceutically acceptable salts with acids having activity against mycobacteria.

In these patents, a method for producing these derivatives is described, which consists in the interaction of 2-arylmethylquinolines and the corresponding acetophenones and acetylnaphthalenes under the action of metalating agents, in particular lithium diisopropylamide.

Compounds of general formula (III), starting from patent N ° 2404971, 11/27/2010, can be obtained from intermediates (VI) and (IV) using a metalating reagent, for example, lithium disopropylamide, in particular obtained in situ from butyl lithium and disopropylamine in a suitable solvent, preferably an ether type, such as, for example, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl tert-butyl ether and mixtures thereof, as well as mixtures with other solvents or cosolvents (Scheme 1). All radicals have definitions as in formula (III). The reaction can be easily carried out in the temperature range from -70 to + 20 ° C, preferably from -70 to -20 ° C.

Scheme 1

The mixture of diastereomers formed during the reaction can be separated using known methods, such as chromatography or crystallization of diastereomeric salts.

The presence of a chlorine atom in the R ₂ position, all other things being equal, does not critically affect the cytostatic activity of the compounds obtained with respect to mycobacteria, while their chemical synthesis is simplified by one stage, which affects the practical yield of the target products.

At the same time, the presence of two halide substituents in the quinoline nucleus is the reason for the low solubility of the corresponding arylquinolines in a number of solvents used in organometallic chemistry (such as THF, diethyl ether), which results in poor reproducibility of the conditions of the lithiation process when scaling the reaction, accompanied by typically low yields of final compounds.

The objective of the present invention is the introduction of arylquinoline into the quinoline core, instead of a halogen atom, of electron-donating substituents in order to increase the solubility of intermediates of the general formula (VI) in THF at temperatures below -50 ° C, and also to obtain new compounds of the formula (I) with improved and reproducible practical solution, as well as with improved antibacterial activity.

So, the technical task of the invention is to obtain new compounds - derivatives of quinoline [General formula (I)] with reproducible practical yield, with increased antibacterial activity, as well as their pharmaceutically acceptable salts with acids. The technical result is achieved by obtaining substituted derivatives of 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalene-1-yl) - 1-phenylbutan-2-ol having antimycobacterial activity, namely, such quinoline derivatives, as 5,6,7-protected 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-ol of general formula (I)

where Ri is H, methoxy;

R ₂ means H, methoxy, -0- (CH ₂ ) _p -0-;

R ₃ means H, methoxy, -0- (CH ₂ ) _p -0-;

n = 1-2, as well as their pharmaceutically acceptable salts with acids.

The invention also relates to a method for producing said new substituted derivatives of I - (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-tins having antimycobacterial activity, by reacting substituted 2-arylmethylquinolines, for example, of general formula (VI):

(VI) and 2- (H, 1) -dimethylaminoethyl-1-naphthylketone (IV):

(IV) in an organic solvent medium under the action of metalizing agents in the form of organic metal amides at temperatures in the range from -70 to + 20 ° C for 1-3 hours. Organic metal amides, such as lithium diisopropylamide, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidide, etc., can be used as metalating agents in the method for producing said substituted quinolines of the general formula (I) according to the invention.

Pharmaceutically acceptable salts with acids of the indicated substituted quinoline derivatives of general formula (I) are characterized in that they contain therapeutically active non-toxic salt forms formed by the compounds of formula (I) with acids. These salts with acids can be obtained treating the free base materials represented by the formula (I) with suitable inorganic and organic acids.

Such acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid , tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid lot.

It was found that the compounds of the invention have antimycobacterial activity, and therefore can be used to treat infectious diseases caused by Mycobacterium tuberculosis, in particular, they can be used as a biologically active component (active principle) in the preparation of drugs (drugs) for treatment of tuberculosis, that is, to obtain anti-TB drugs.

General description of the synthesis

The compounds of the invention of formula (I) can be prepared from an intermediate of formula (VI) and an intermediate of formula (IV) using a metalating reagent such as lithium diethylamide, in particular obtained from in situ from n-butyl lithium and diethylamine in a suitable solvent, such like THF, diethyl ether, diisopropyl ether, methyl tert-butyl ether and their mixtures, as well as in mixtures with other solvents and cosolvents (Scheme 2). All radicals have definitions as in formula (I). The reaction is carried out in the temperature range from -70 to + 20 ° C, preferably at -70 ° C for 1-3 hours.

Scheme 2

The resulting mixture of diastereomers (1-1 + 1-2) can be separated using known methods such as chromatography or crystallization of diastereomeric salts.

The starting compounds and intermediates of formulas (VI) and (IV) are compounds that are either commercially available or can be obtained by conventional methods known in the literature [D. Mature, et al., Med. Chem., 2005, 48, 2134-2153].

For example, intermediates of formula (I) may be prepared according to Scheme 3:

Scheme 3 where Ri is H, methoxy;

R.2 is H, methoxy, -0- (CH2) _p -0-;

R ₃ means H, methoxy, -0- (CH ₂ ) _p -0-;

n = 1-2

The synthesis according to the presented scheme includes step (a), in which the substituted arylamine is reacted with 3-phenylpropionic acid in the presence of a suitable catalyst (strong Lewis acid) and an inert solvent such as benzene or toluene. The process is carried out in the temperature range from 20 to 110 ° C, preferably by boiling the reaction mass.

In the next step (b), the addition product obtained in step (a) is reacted with phosphorus oxychloride (POC1 ₃ ) in the presence of Ν, Ν-dimethylformamide (Vilsmeier-Haack formylation followed by cyclization). The reaction can be carried out in the temperature range from 20 to 80 ° C, preferably at 75 ° C.

The products of reactions (a) and (b) can be isolated individually and purified by extraction, crystallization or chromatography. The products of reaction (I), existing as diastereomers, can be purified by chiral preparative high performance liquid chromatography.

The following examples illustrate the invention without limiting it.

A. Preparation of Intermediates (General Method)

Example 1

Obtaining an intermediate compound (Vb).

(Vb) To a mixture of 123 g (1 mol) of 4-methoxyaniline and 150 g (1 mol) of 3-phenylpropanoic acid, 200 ml of benzene, 7.01 g (0.05 mol) of boron trifluoride ether or 5 g (0.08 mol) of boric acid are added and boil with stirring for 5 hours. The resulting product is cooled, filtered, washed with toluene, distilled alcohol and water. Dried to constant weight. The practical yield of intermediate (Vb) is 240 g (92.5%).

Example 2

Obtaining compound (VIb)

(SH)

To a mixture of 84 g (1.15 mol) of dimethylformamide and 160 g (0.627 mol) of intermediate (Vb) cooled to 10 ° C in 600 ml of chloroform, 300 ml (480 g, 3.13 mol) of phosphorus oxychloride are added dropwise, after which the resulting solution is boiled during the night. After cooling to room temperature, the reaction mass was then poured into a mixture of water and ice, the organic layer was washed with an aqueous solution of Na ₂ C0 ₃ , distilled water, dried over MgS0 ₄ , filtered and the solvent was distilled off in vacuo. The residue is crystallized from methanol. The practical yield of intermediate (VIb) is 95 g (53%).

Example 3

Obtaining compound (IV)

(Iv)

A mixture of 340 g (2 mol) of 1-acetylnaphthalene, 56 g (1.86 mol) of paraform and 200 g (2.07 mol) of dimethylamine hydrochloride in 700 ml of dichloroethane is boiled for 1.5 hours, cooled to room temperature, the precipitate is filtered off, and the precipitate is filtered off with water. ammonia and diethyl ether. Promshayut organic layer with water, dried over MgS0 _4, filtered and the solvent was distilled off to dryness. The yield of intermediate (IV) is 335 g (79%).

B. Preparation of Compounds of the Invention

Example 4. 1 - (6-methoxy-2-chloro-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl-yl) - 1 - phenyl-butan-2-ol (lb).

(Ib)

50 g (0.68 mol) of lithium diethylamide are added to a solution of 190 g (0.83 mol) of intermediate naphthyl ketone (IV) in 2 L of absolute THF under argon flow and cooled to -30 ° C. The mixture is stirred for 1 hour, cooled to -70 ° C and 129 g (0.45 mol) of intermediate arylquinoline (VIb) are added dropwise in 500 ml of THF. The mixture was stirred for 30 minutes, then heated to 20 ° C, after which 120 ml of glacial acetic acid was added. Warmed to room temperature, the reaction mass is evaporated to dryness, dissolved in chloroform, washed several times with water. The organic layer was dried over MgS0 ₄ and the solvent was distilled off. The desired products (1-1 b and 1-2b) in the form of separate diastereoisomeric pairs are isolated using preparative chiral high performance liquid chromatography. The practical yield of a mixture of diastereomeric pairs (I-lb + I-2b) in a 1: 1 ratio was 134.5 g (85.5%).

The resulting compounds in the form of diastereomeric pairs were separated into individual enantiomers. In this case, the Arabic designation "1" connection characterizes the diastereomeric pair with the minimum retention time on the chromatographic system (RRSS configuration of the diastereomeric center), while the designation "2" characterizes the diastereomeric pair with the RSSR configuration, and, accordingly, the maximum retention time.

Derivatives (I-la + I-lb, as well as 1-1с-е + 1-2с-е) were obtained by a method similar to that described for (I-lb + I-2b). The practical yields of the synthesized substances, as well as their mass spectral characteristics, are given in the following Table. one :

1-1 ae + 1-2a-e

Table 1

Compound Ri R ₂ R ₃ [M + H] ^{+ *} Yield,% ^**

1a HHH 454 61.1 lb H OCH ₃ H 484 85.5

Ic OCH ₃ OCH ₃ OCH ₃ 544 39.5

Id H -0-CH ₂ -0- -O-CH ₂ -O- 498 29.5

Ie H OCHS OCH 514 84.4 ^* The main peak in the electrospray mass spectrum (ESI-MS) with a positive ionization mode.

^** Practical yield of a mixture of diastereomeric pairs

Description of the method for determining the antibacterial activity of the obtained compounds

Antimycobacterial action given in Table. 1 compounds were studied by the growth dynamics of M. tuberculosis H37Rv strain in Middlebrook 7H9 enriched liquid medium in the presence of various concentrations (0.312 μg / ml, 0.625 μg / ml, 1.25 μg / ml, 2.5 μg / ml, 5 μg / ml , 10 μg / ml, 20 μg / ml, 40 μg / ml) compared with the growth of these strains on a medium containing no compounds and a medium containing a first-line preparation of rifampicin in the same concentrations.

Mycobacterial suspension was seeded in an amount of 10 ⁵ CFU / ml. Each of the concentrations, including control tubes without compound and tubes with rifampicin, was examined in triplicates.

Mycobacterium culture growth was detected using a Bactec MGIT 960 automated crop growth accounting system (Becton Dickenson, USA) in special MGIT tubes containing a bound fluorophore under a semipermeable membrane at the bottom of the tube. Mycobacterial culture growth was detected every hour using Epicenter software (Becton Dickenson, USA). The dynamics of the division of mycobacterial cells was expressed in relative fluorescence units (OEF).

The experiment lasted 42 days, according to the Becton Dickinson protocol. After that, all grown cultures were subjected to species specificity control (belonging to Mycobacterium tuberculosis).

The bacteriostatic activity of the compound was evaluated:

1) by delaying the onset of culture growth compared with the control without drugs

2) by the duration of the active division phase. The results of the study of the above compounds on antimycobacterial activity, expressed in unit M1Cuo, are shown in Table 2:

Table 2.

Compound MIC loo, μg / ml ^*

On "> 40

1-2a 10

l ib 20

I-2b 5

I-lc> 25

I-2c> 25

I-ld> 25

I-2d 5

I-le> 25

I-2e> 25

^{* the} concentration of the compound at which there is a complete loss of growth of M. tuberculosis culture for 42 days.

each compound was tested as a diastereomeric pair and was not separated into individual enantiomers.

Using the compound (I-2b, “R20Me”) as an example, the growth dynamics of the M. tuberculosis H37Rv strain upon exposure to various concentrations is shown (Fig. 1).

Determination of bactericidal activity against MBT compounds (Ia-b) in vitro in the automated system Bactec M GIT 960

To test bactericidal activity, tubes were selected containing the test compounds (Ia-b) and rifampicin at concentrations at which no growth of the sensitive laboratory strain M. tuberculosis H37Rv was observed throughout the entire experiment to determine the bacteriostatic activity. Accordingly, the study included compounds (I-lb) (20 μg / ml and 40 μg / ml), (1-2a) (10 μg / ml, 20 μg / ml and 40 μg / ml) and (1-2b ) (5 μg / ml, 10 μg / ml, 20 μg / ml and 40 μg / ml). The culture of the Office was seeded as a control; cultured without the drug, and the MBT culture exposed with rifampicin at concentrations of 0.625 μg / ml, 1, 25 μg / ml, 2.5 μg / ml, 5 μg / ml, 10 μg / ml, 20 μg / ml and 40 μg / ml, on which growth of culture was not recorded. The compound (1-1 a), which did not lead to a suppression of the growth of the MBT culture at any of the tested concentrations, was not used to determine the bactericidal activity.

To wash the precipitate from the preparation present in the medium, the tubes were centrifuged at 3000 rpm for 15 minutes at room temperature, after which the supernatant was removed. In each tube, 7 ml of sterile saline was added to the pellet and the pellet was resuspended. Then the tubes with the contents were centrifuged at 3000 rpm for 15 minutes and the supernatant was again removed. The washing procedure with sterile saline was repeated 2 times. The precipitate thus washed from the preparations (the entire volume of mycobacteria) from each tube was inoculated into tubes with fresh Middlebrook 7Н9 medium enriched with growth additives (Becton Dickinson). The presence of bactericidal activity of compounds (1-2a), (1-1b) and (1-2b) was assessed by the absence of growth of the culture washed from preparations during 42 days of incubation.

The results are shown in Table 3 and in Fig. 2. Figure 2 shows the growth curve of the M. tuberculosis H37Rv strain in fresh medium after exposure with the compound “R20Me” (I-2b) at a concentration of 5, 10, 20 and 40 μg / ml.

Table 3.

The beginning of the growth of culture

Concentration

Compound incubation 42 days (days)

(mcg / ml)

Mean CO

H37R.V without the drug 3.33 0.07

0.625 8.50 0.09

1.25 no growth

Rifampicin 2.5 No growth

5 no growth

10 no growth 20 no growth

40 no growth

20 12.63 1.15

I-lb

40 17.42 0.97

10 14.13 1.18 l-2a 20 13.92 1.11

40 18.63 1.26

5 12.67 1.47

10 no growth

l-2b

20 no growth

40 no growth

From the results shown in Table 2 and Table 3, it can be seen that compounds (1-2b) and (1-2d) showed a fairly high anti-tuberculosis activity against the mycobacterium H37Rv strain, comparable (of the same order) with that of rifampicin (1 μg / ml ), while the substance (1-2b) also showed bactericidal activity (10 μg / ml, Fig. 2). The results obtained are the basis for further testing of the isolated substances on infected animals with their subsequent use as the active principle of new and promising anti-TB drugs. The high practical yield of the compound (1-2b) allows us to conclude that the production of such a substance at high tonnage loads is profitable.

Claims

Claim

1. Quinoline derivatives, in particular 5,6,7-substituted 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-ol of the general formula ( I):

I where Ri means H, methoxy, R ₂ means H, methoxy, -0- (CH ₂ ) _n -0-, R ₃ means H, methoxy, -0- (CH ₂ ) _n -0-, n = 1- 2, or their pharmaceutically acceptable salts with acids having antimycobacterial activity.

2. A method for producing compounds of formula (I) according to claim 1 by reacting substituted 2-arylmethylquinolines and arylketones under the influence of metalating agents.

3. The method according to claim 2, characterized in that lithium diethylamide is used as the metallizing agent.

4. The use of compounds according to claim 1 for the treatment of infectious diseases of mycobacterial nature, in particular tuberculosis.