RU2530493C1 - Quinoline derivatives, particularly 6,7-substituted 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ols, method for production thereof and use of compounds to treat infectious mycobacterial dieseases, particularly tuberculosis - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol of general formula I

or their pharmaceutically acceptable salts with acids, where R₁ denotes H, R₂+R₃ denotes -O-(CH₂)_n-O-, where n=1-2, which forms additional dioxane and 1,3-dioxolane rings. The invention also relates to a method of producing a compound of formula I and to use of the compound of formula I in treating infectious mycobacterial diseases.

EFFECT: obtaining novel compounds with useful biological activity.

4 cl, 2 tbl, 3 ex

Description

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 a 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 of mycobacterial pr Herods.

According to the WHO, more than 8-9 million people fall ill with tuberculosis each year, caused by 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], the structure of which is related to quinine used since the beginning of the 17th century for the treatment of infectious diseases

where R ₁ -H, halogen, haloalkyl, cyano-, hydroxy-, aryl, hetaryl, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, arylalkyl;

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

R ₃ is hydrogen, halogen, alkyl;

R ₄ is naphthyl, halonaphthyl, phenyl, haloaryl, arylalkyl, pyridinyl, alkyl, thienyl;

R ₅ , R ₆ is alkyl, H, benzyl, imidazolyl, hetaryl, alkylthio, pyrimidyl.

Derivatives of quinoline of the general formula (III) are known from RU 2404971, 11/27/2010

where R ₁ means halogen, R ₂ means halogen, R ₃ means hydroxy, R ₄ , R ₅ means C ₁ -C ₃ -alkyl, R ₆ means aryl, R ₇ means aryl, n = 1 or 2, and also 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 No. 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 a solvent, preferably an ether type, such as 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.

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), resulting in poor reproducibility of the conditions of the lithiation process during reaction scaling, accompanied, as a rule, low yields of final compounds.

The objective of the present invention is the introduction of an arylquinoline into the quinoline core instead of a halogen atom, 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 an increased reproducible practical yield , 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, which is expressed in expanding the arsenal of drugs for the treatment of tuberculosis and other infectious diseases of mycobacterial nature.

The technical result is achieved by obtaining substituted derivatives of 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-tins 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 R ₁ means H,

R ₂ + R ₃ means —O— (CH ₂ ) _n —O—, where n = 1-2, which forms

additional dioxane and 1,3-dioxolane cycles, as well as their formally acceptable acid salts.

Specific examples of the general formula (I) are the compounds below:

The invention also relates to a method for producing said new substituted derivatives of 1- (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)

where R ₁ -R ₃ mean the above values;

and 2- (N, N) -dimethylaminoethyl-1-naphthylketone (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 acid salts can be obtained by 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 ota.

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.

The resulting mixture of diastereomers (I-1 + I-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.Mabire, et al., Med. Chem., 2005, 48, 2134-2153].

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

where R ₁ means H,

R ₂ + R ₃ means —O— (CH ₂ ) _n —O—, where n = 1-2, which forms additional dioxane and 1,3-dioxolane rings.

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 (POCl ₃ ) in the presence of N, N-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 (Va).

To a mixture of 123 g (0.9 mol) of 3,4- (methylenedioxy) aniline and 135 g (0.9 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 and boiled 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 (Va) is 224 g (92.5%).

Example 1 '

Preparation of Compound (VIa)

To a mixture of 79 g (1.08 mol) of dimethylformamide and 160 g (0.59 mol) of intermediate (Va) cooled to 10 ° C. in 600 ml of chloroform, 274 ml (451.6 g, 2.95 mol) are added dropwise. phosphorus oxychloride, after which the resulting solution is boiled overnight. After cooling to room temperature, the reaction mass was then poured into a mixture of ice-water, the organic layer was washed with an aqueous solution of Na ₂ CO ₃ , distilled water, dried over MgSO ₄ , filtered and the solvent was distilled off in vacuo. The residue is crystallized from methanol. The practical yield of intermediate (VIa) is 93 g (53%).

Example 2

Obtaining compound (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 formed is filtered off, treat it with aqueous ammonia and diethyl ether. The organic layer was washed with water, dried over MgSO 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 3. 1- (6,7- (methylenedioxy) -2-chloro-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl-yl) -1-phenyl-butan-2-ol (I -1a + I-2a).

51.3 g (0.65 mol) of lithium diethylamide are added to a solution of 180 g (0.79 mol) of intermediate naphthyl ketone (IV) in 2 L of absolute THF under argon flow, cooled to -30 ° C. The mixture is stirred for 1 hour, cooled to -70 ° C and 129 g (0.43 mol) of intermediate arylquinoline (VIa) are added dropwise in 500 ml of THF. The mixture was incubated 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 MgSO ₄ , and the solvent was distilled off. The target products (I-1a and I-2a) in the form of separate diastereoisomeric pairs are isolated using preparative high performance liquid chromatography. The practical yield of a mixture of acetates of diastereomeric pairs (I-1a + I-2a) in a 1: 1 ratio was 74.2 g (29.5%).

The resulting compounds in the form of diastereomeric pairs were separated into individual enantiomers. In this case, the Arabic designation “1” of the compound 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.

Compounds (I-1b + I-2b) were obtained by the same procedure as described for (I-1a + I-2a). The practical yields of the synthesized substances, as well as their mass spectral characteristics, are given in the following table 1:

Table 1 Compound R ₁ R ₂ + R ₃ [M + H] ^{+ *} Yield,% ^** I-1a I-2a N -O-CH ₂ -O- 526 29.5 I-1b + I-2b N -O- (CH ₂ ) ₂ -O- 540 35.7 * 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

The antimycobacterial effect of the compounds shown in Table 1 was 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 rifampicin preparation 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) to delay the onset of growth of culture 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 MIC ₁₀₀ , are shown in table 2:

table 2 Compound MIC ₁₀₀ , μg / ml ^* I-1a ^** > 25 I-2a 5 I-1b > 20 I-2b 10 * the concentration of the compound at which there is a complete loss of growth of the culture of M. tuberculosis within 42 days. ** Each compound was tested as a diastereomeric pair and was not separated into individual enantiomers.

From the results shown in Table 2, it can be seen that compounds (I-2a) and (I-2b) showed a rather high anti-tuberculosis activity against the mycobacterium H37Rv strain, comparable (of the same order) with that of rifampicin (1 μg / ml). 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.

Claims (4)

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

where R ₁ means H,
R ₂ + R ₃ means -O- (CH ₂ ) _n -O-, where n = 1-2, which forms additional dioxane and 1,3-dioxolane rings, 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-chloro-3-alkarylquinolines and arylketones under the action 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.