RU2457208C2 - 1H-PYRROLO[3,4-b]QUINOLINE-3,9(2H,4H)-DIONES EXHIBITING ANTI-TUBERCULOSIS ACTIVITY AND METHOD FOR PREPARING THEM - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives of general formula 1

wherein R¹=Alk, Ar; R²=H, Alk, halogen; R³=H, Alk, halogen; R⁴=H, Alk, halogen; R⁵=H, Alk, halogen; R⁶=CH₂Ar, R⁷=Ar,

Also, the invention refers to a method for preparing them.

EFFECT: there are prepared new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives possessing anti-tuberculosis activity.

3 cl, 1 tbl, 9 ex

Description

The invention relates to the field of organic chemistry, to derivatives of 4-quinolones, namely to previously unknown 1H-pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione of the general formula 1, which may find application in medicine as anti-tuberculosis drugs, as well as to a method for their preparation.

where R ¹ = C _1-12 alkyl, - (CH ₂ ) _n C _3-7 cycloalkyl, - (CH ₂ ) _n aryl, - (CH ₂ ) _n heteryl, where n = 0-6;

R ² = H, Alk, OAlk, halogen; R ³ = H, Alk, OAlk, halogen; R ⁴ = H, Alk, OAlk, halogen; R ⁵ = H, Alk, OAlk, halogen; R ⁶ = H, Alk, OAlk, halogen; R ⁷ = H, Alk, OAlk, halogen; R ⁸ = H, Alk, OAlk, halogen; R ⁹ = H, Alk, OAlk, halogen; R ² + R ³ , or R ³ + R ⁴ , or R ⁴ + R ⁵ , or R ⁵ + NH, or R ⁶ + R ⁷ , or R ⁷ + R ⁸ , or R ⁸ + R ⁹ = H, cycloalkyl , aryl, heteryl, which may also have substituents H, Alk, OAlk, halogen, Ar, Het;

The closest structural analogues of the claimed compounds are 1H-pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione 2, which have a pyrrole moiety annelated with the 4-quinolone system with the claimed compounds.

From literature sources, the following methods for producing compounds 2 are known.

Method 1

Winderfeldt oxidation of 2-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-1-ones [C. Tratrat, S. Giorgi-Renault, H.-P. Husson. Synlett (1998), 1071-1072], obtained in three stages from 2- (1H-indol-3-yl) -1-ethanamine according to the scheme

The yield of target products 70%.

Method 2:

Cyclization of Conrad-Limpach ethyl 4-anilino-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylates when heated in biphenyl oxide in the temperature range 245-250 ° C for half an hour in a nitrogen atmosphere [Madhav, R. ; Dufresne, Richard F .; Southwick, Philip L. Journal of Heterocyclic Chemistry (1973), 10 (2), 225-8].

The yields of compounds 3 are 57-99%.

All of the above analogues 2 contain common with the claimed compounds 1 tricyclic condensed system - pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione fragment. The differences of the analogues from the claimed compounds 1 are that in the analogues there are no substituents in position 1, in the aromatic ring of the condensed system, and there is no R ¹⁰ + R ¹¹ fragment, which is a quinazoline fragment.

A significant drawback of the above methods is their limitedness: the claimed 1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dions of general formula 1 cannot be obtained by any of the methods described in the literature.

The aim of this invention is to develop a method for producing new compounds that can be used in preparative organic chemistry, as well as in medicine as drugs with biological activity and, in particular, anti-tuberculosis properties.

Our proposed method for producing 1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione 1 consists in the reaction of the starting 1,4-dihydro-4-oxo-2-quinolinecarboxylates with substituted benzylamines and their analogues (Scheme 1), substituted by o-aminobenzylamines (Scheme 2) and their closest analogues. The reaction can be carried out in conventional organic solvents (dioxane, THF, alcohols, etc.). An excess of amine and an increase in temperature favor an increase in yield. The end time of the reaction is determined using physicochemical methods (for example, thin-layer chromatography).

Scheme 1:

Scheme 2:

The advantages of the proposed method compared to methods for producing analogues are the one-stage method and ease of execution (in comparison with method 1); the absence of the need to create special conditions for carrying out the reaction, for example, an inert atmosphere (in comparison with method 2) or high temperatures (method 2), and, in addition, a sufficiently short reaction time, high yields. You can use a wide range of solvents (in comparison with methods 1, 2). The structures obtained by this method may contain a wide range of various combinations of substituents.

The inventive 1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione 1 is a colorless or light yellow crystalline substance with high melting points, soluble in 1,4-dioxane, DMF, DMSO, it is difficult soluble in alcohols, chloroform, acetonitrile, insoluble in alkanes, water, hardly soluble in alcohols, chloroform. The structure of compounds 1 was confirmed by general physicochemical methods.

1H-Pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione 1 are potential biologically active substances, since the structure contains a 4-quinolone fragment. 4-Quinolones are successfully used in medical practice as antibacterial drugs with a wide spectrum of action [Mashkovsky M.D. Medicines, M .: New Wave, 2006; D.S.Hooper and E.Rubinstein (eds.), Quinolone Antimicrobial Agents, 3 ^rd ed, ASM Press, Washington 2003]. The pyrrolone fragment present in the molecule is also included in the structure of drugs currently used in medicine, namely isaphenin (as a laxative), metisazon (inhibits the reproduction of smallpox viruses), oxodoline (diuretic) [Mashkovsky M. D. Medicines, M .: New Wave, 2006].

Acute toxicity was determined for 1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione. It was found that these compounds have low toxicity (LD ₅₀ > 1000 mg / kg).

The antituberculous activity of the synthesized compounds was determined under conditions of active growth of microorganisms (MABA test - Microplate Almar blue assay) [L. Collins, S. G. Franzblau. Antimicrobial agents and chemotherapy (1997), 41 (5), 1004-1009]. The percentage of inhibition of growth of mycobacterium tuberculosis was determined for a substance concentration of 100 μmol / L. Rifampicin was used as a control.

M. tuberculosis H ₃₇ Rv (ATCC 27294; American Type Culture Collection, Rockville, Md.) Was grown to the late logarithmic phase on Middlebrook 7H9 medium supplemented with 0.2% vol. Glycerol, 0.05% Tween 80, 10% OADC (oleic acid, albumin, dextrose, catalase). The culture was centrifuged for 15 minutes at 4 ° C (3150 rpm), washed twice and suspended in a solution of saline in phosphate buffer. Suspensions were filtered through a filter with a pore size of 8 μm to remove clots and aliquots were frozen at - 80 ° C. The number of colonies formed was counted on 7H11 agar.

Solutions of the compounds were prepared by sequentially diluting twice in Middlebrook 7H12 medium in a volume of 100 μl in a black 96-well plate with a transparent bottom (BD Biosciences, Franklin Lanks, NJ). 100 μl of M. tuberculosis H ₃₇ Rv, (number of colonies formed 2 · 10 ⁴ ) was added to each well.

As the zero control, we used solutions prepared according to this scheme without adding the test substance or control preparation. The plates were incubated at 37 ° C. On the seventh day of incubation, 12.5 μl of 20% Tween 80 and 20 μl of Almar Blue were added to each well. After further incubation at 37 ° C for 16-24 hours, fluorescence was measured for each cell at λ = 590 nm (λ _exc 530 nm).

The research results are presented in the table.

Tuberculosis activity of 1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione 1

No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ Inhibition of M. tuberculosis growth at a concentration of 100 μmol / L,% 1a Ph NHCH ₂ Ph CH ₂ Ph H H H 55 1b ^* Ph NHCH ₂ Ph CH ₂ Ph H H Me 31 1c Ph NHCH ₂ Ph CH ₂ Ph Br H H 95 1g Ph NHCH ₂ Ph CH ₂ Ph F H H 59 1d Ph

H H H 86 1st Ph

H H Me 80 1g Ph

Br H H 93 rifampicin one hundred * the compound was tested at a concentration of 50 μmol / l

As can be seen from the table, the percentage of growth inhibition of M. tuberculosis H ₃₇ Rv by compounds 1 is close to that for rifampicin.

Thus, the claimed compounds 1 can find application in preparative organic synthesis and in medicine as drugs with anti-tuberculosis activity in combination with low toxicity.

The following examples illustrate the inventive method of obtaining and physico-chemical characteristics of the claimed compounds.

Example 1:

2-benzyl-1- (benzylamino) -1-phenyl-1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione (1a)

5.4 mmol of benzylamine was added to 1.8 mmol of methyl 3-benzoyl-4-oxo-1,4-dihydro-2-quinoline carboxylate dissolved in 50 ml of dioxane. It was refluxed for 4 hours. The mother liquor was evaporated by half, the precipitate formed was filtered off and recrystallized from acetonitrile. Yield 83% mp. 230-232 ° C (with decomp.). IR spectrum, cm ^-1 : 3292 (NH), 1702 (C (3) = O), 1645 pl., 1626 (C (9) = O), 1594 (C = C). ¹ H NMR spectrum, ppm: 3.05-3.09 (m, 1H, NH CH ₂ ); 3.22-3.27 (m, 1H, NH CH _2); 3.41 (t, 1H, N (1 ') H); 4.18 (d, 1H, NCH ₂ , ² J = 15.2); 4.67 (d, 1H, NCH ₂ , ² J = 15.2); 7.11-7.25 (m, 13H, Ar); 7.37 (dd, 1H, H (7), ³ J = 8.0, ⁴ J = 0.8); 7.50-7.53 (m, 2H, H (2 '), H (6'); 7.72 (dd, 1H, H (6), ³ J = 7.6, ³ J = 8.2, ⁴ J = 1.6) ; 7.86 (d, 1H, H (5), ³ J = 8.0); 8.08 (d.d, 1H, H (8), ³ J = 8.0, ⁴ J = 1.2); 12.85 (s, 1H, N ( 4) H). Found,%: C 78.86; H 5.20; N 8.81. C ₃₁ H ₂₅ N ₃ O _2. Calculated,%: C 78.96; H 5.34; N 8.91.

Example 2:

2-benzyl-1- (benzylamino) -5-methyl-1-phenyl-1H-pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione (1b)

Prepared analogously to 1a from 2.2 mmol of methyl-3-benzoyl-8-methyl-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 6.6 mmol of benzylamine. Recrystallized from dioxane. Yield 86%, mp. 236-237 ° C (decomp.). IR spectrum, cm ^-1 : 3300 (NH), 1700 (C (3) = O), 1636 (C (9) = O), 1590 (C = C). ¹ H NMR spectrum, ppm: 2.66 (s, 3H, Me); 3.06-3.25 (m, 3H, NH CH ₂ , N (1 ') H); 4.17 (d, 1H, NCH ₂ , ² J = 15.3); 4.63 (d, 1H, NCH ₂ , ² J = 15.3); 7.09-7.29 (m, 13H, Ar); 7.47-7.55 (m, 3H, Ar); 7.97 (d, 1H, H (8), ³ J = 8.1); 11.08 (s, 1H, N (4) H). Found,%: C 79.20; H 5.63; N, 8.60. C ₃₂ H ₂₇ N ₃ O ₂ . Calculated,%: C 79.15; H 5.60; N, 8.65.

Example 3:

2-benzyl-1- (benzylamino) -7-bromo-1-phenyl-1H-pyrrolo [3,4-b] quinolium-3,9 (2H, 4H) -dione (1c)

Prepared analogously to 1a from 1.8 mmol of methyl-3-benzoyl-6-bromo-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 5.4 mmol of benzylamine. Recrystallized from dioxane. Yield 96%, mp. 236-238 ° C (decomp.). IR spectrum, cm ^-1 : 3300 (NH), 1704 (C (3) = O), 1636, 1626 (C (9) = O), 1586 (C = C). ¹ H NMR, ppm .: 3.05-3.12 (m, 2H, NH CH _2); 3.40 (t, 1H, N (2) H); 4.19 (d, 1H, NCH ₂ , ² J = 15.3); 4.65 (d, 1H, NCH ₂ , ² J = 15.3); 7.11-7.23 (m, 13H, ArH); 7.48-7.51 (m, 2H, ArH); 7.79-7.51 (m, 2H, ArH); 8.14 (d, 1H, 8-H, ⁴ J = 2.8); 13.01 (s, 1H, N (4) H). Found,%: C 67.72; H 4.39; Br 14.56; N, 7.40. C ₃₁ H ₂₄ BrN ₃ O ₂ . Calculated,%: C 67.64; H 4.39; Br 14.52; N, 7.63.

Example 4:

2-benzyl-1- (benzylamino) -1-phenyl-7-fluoro-1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione (1g)

Prepared analogously to 1a from 2.0 mmol of methyl-3-benzoyl-6-fluoro-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 6.6 mmol of benzylamine. Recrystallized from dioxane. Yield 89%, mp. 233-234 ° C (decomp.). IR spectrum, cm ^-1 : 3288 (NH), 1704 (C (3) = O), 1644 (C (9) = O), 1598 (C = C). ¹ H NMR, ppm .: 3.05-3.12 (m, 2H, NH CH _2); 3.39 (t, 1H, N (2) H); 4.18 (d, 1H, NCH ₂ , ² J = 15.3); 4.64 (d, 1H, NCH ₂ , ² J = 15.0); 7.09-7.23 (m, 12H, Ar); 7.48-7.51 (m, 2H, ArH); 7.59-7.72 (m, 2H, ArH); 7.91 (dd, 1H, H (8), ³ J = 9.0, ⁴ J = 4.8); 13.00 (s, 1H, N (4) H). Found,%: C 75.99; H 4.90; N, 8.52. C ₃₁ H ₂₄ FN ₃ O ₂ . Calculated,%: C 76.06; H 4.94; N, 8.58.

Example 5:

13a-phenyl-5,8,13,13a-tetrahydroquino [3 ', 2': 3,4] pyrrolo [2,1-b] quinazolin-6,14-dione (1e)

3.1 mmol of o-aminobenzylamine was added to 3.1 mmol of methyl 3-benzoyl-4-oxo-1,4-dihydro-2-quinoline carboxylate dissolved in 50 ml of dioxane. Refluxed for 2 hours and 30 minutes. The mother liquor was evaporated halfway, the precipitate was filtered off, recrystallized from dioxane. Yield 88%, mp. > 315 ° C. IR spectrum, cm ^-1 : 3320, 3312 (NH), 1704 (C (6) = O), 1640, 1630 (C (14) = O, 1596 (C = C). ¹ H NMR spectrum, m. d: 3.94 (d, 1H, C (8) H, J = 16.8), 5.06 (d, 1H, C (8) H, J = 17.1), 6.62 (t, 1H), 6.96-7.04 (m, 2H, Ar), 7.23-7.31 (m, 3H, Ar); 7.36-7.45 (m, 4H, Ar); 7.73 (dd, 1H, H (2), ³ J = 6.9, ⁴ J = 1.5) , 7.84 (d, 1H, H (4), ³ J = 8.1); 8.10 (d.d, 1H, H (1), ³ J = 8.4, ⁴ J = 1.2); 13.02 (s, 1H, N ( 5) H). Found,%: C 75.98; H 4.21; N 10.81. C ₂₄ H ₁₇ N ₃ O _2. Calculated,%: C 75.96; H 4.52; N 11.07.

Example 6:

4-methyl-13a-phenyl-5,8,13,13a-tetrahydroquino [3 ', 2': 3,4] pyrrolo [2,1-b] quinazolin-6,14-dione (1e)

Prepared analogously to 1a from 1.6 mmol of methyl-3-benzoyl-8-methyl-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 1.6 mmol of o-aminobenzylamine. Recrystallized from dioxane. Yield 90%, mp. 305-306 ° C (decomp.). IR spectrum, cm ^-1 : 3300 (NH), 1704 (C (6) = O), 1634 (C (14) = 0, 1578 (C = C). ¹ NMR spectrum, ppm: 2.66 (s, 3H, Me); 3.95 (d, 1H, C ⁸ H, J = 16.8), 5.09 (d, 1H, C ⁸ H, J = 17.2), 6.64 (dd, 1H, H (12) , ³ J = 7.6, ⁴ J = 1.2), 6.98-7.06 (m, 2H, Ar), 7.22-7.34 (m, 4H, Ar), 7.42-7.46 (m, 3H, Ar); 7.59 (d, 1H , H (3), ³ J = 6.4); 8.00 (d, 1H, H (1), ³ J = 7.2); 11.75 (s, 1H, N (5) H). Found,%: С 76.26; Н 4.77; N 10.54. C ₂₅ H ₁₉ N ₃ O _2. Calculated,%: C 76.32; H 4.87; N 10.68.

Example 7

2-bromo-13a-phenyl-5,8,13,13a-tetrahydroquino [3 ', 2': 3,4] pyrrolo (2,1-b] quinazolin-6,14-dione (1g)

Prepared analogously to 1a from 1.2 mmol of methyl-3-benzoyl-6-bromo-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 1.2 mmol of o-aminobenzylamine. Recrystallized from dioxane. Yield 80%, mp. > 300 ° C (with decomp.). IR spectrum, cm ^-1 : 3336 (NH), 1708, 1640 (C (6) = O), 1635, 1624 (C (14) = O), 1588 (C = C). ¹ H NMR spectrum, ppm: 3.95 (d, 1H, C (8) H, J = 16.8), 5.08 (d, 1H, C (8) H, J = 17.2), 6.64 (dd d, 1H, H (12), ³ J = 7.4, ³ J = 7.2, ⁴ J = 1.0); 6.98-7.06 (m, 2H, Ar); 7.25-7.32 (m, 3H, Ar); 7.45-7.48 (m, 3H, Ar); 7.81 (d, 1H, H (4), ³ J = 8.8); 7.91 (dd, 1H, H (3), ³ J = 8.8, ⁴ J = 2.4); 8.18 (d, 1H, H (l), ⁴ J = 2.4); 13.25 (s, 1H, N (5) H). Found,%: C 62.95; H 3.54; Br 17.40; N 9.15. C ₂₄ H ₁₆ BrN ₃ O ₂ . Calculated,%: C 62.90; H 3.52; Br 17.43; N 9.17.

Example 8:

4-methyl-2-chloro-13a-phenyl-5,8,13,13a-tetrahydrochino [3 ', 2': 3,4] pyrrolo [2,1-b] quinazolin-6,14-dione (1h)

Prepared analogously to 1a from 1.4 mmol of methyl-3-benzoyl-8-methyl-6-chloro-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 1.4 mmol of o-aminobenzylamine. Recrystallized from dioxane. Yield 95%, mp. > 300 ° C (with decomp.). IR spectrum, cm ^-1 : 3300 (NH), 1704 (C (6) = O), 1634 (C (14) = O, 1578 (C = C). ¹ NMR spectrum, ppm; 2.66 (s, 3H, CH ₃ ), 3.95 (d, 1H, C ⁸ H, J = 16.9), 5.08 (d, 1H, C ⁸ H, J = 17.2); 6.64 (dd, 1H, H (12), ³ J = 7.4, ³ J = 7.2, ⁴ J = 1.2); 6.98-7.05 (m, 2H, Ar); 7.22-7.32 (m, 3H, Ar); 7.41-7.43 (m, 3H, Ar); 7.76 (d, 1H, H (3), ³ J = 1.2); 7.07 (dd, 1H, H (1), ⁴ J = 2.0); 13.03 (s, 1H, N (5) H ). Found,%: C 70.25; H 4.20; N 8.30; Cl 8.34. C ₂₅ H ₁₈ ClN ₃ O _2. Calculated,%: C 70.18; H 4.24; Cl 8.29; N 9.82.

Example 9:

2-benzyl-1- (benzylamino) -7-bromo-1-tert-butyl-1H-pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione (1i)

Prepared analogously to 1a from 1.4 mmol of methyl 6-bromo-3-tert-butyl-4-oxo-1,4-dihydro-2-quinolinecarboxylate and 5.6 mmol of benzylamine. Recrystallized from ethanol. Yield 50%, mp. 228-230 ° C (decomp.). IR spectrum, cm ^-1 : 3088 (NH), 1700 (C (3) = O), 1636, 1626 (C (9) = O), 1598 (C = C). ¹ H NMR spectrum, ppm: 0.97 (s, 9H, 3Me); 3.10-3.28 (m, 3H, NHCH ₂ ); 4.62-4.72 (m, 2H, NCH ₂ ); 7.20-7.40 (m, 10H, ArH); 7.80 (d, 1H, 6-H, ³ J = 9.2); 7.89 (dd, 1H, 6-H, ³ J = 8.8, ⁴ J = 2.4); 8.28 (d, 1H, 8-H, ⁴ J = 2.4); 12.99 (s, 1H, N (4) H). Found,%: C 67.72; H 4.39; Br 14.56; N, 7.40. C ₃₁ H ₂₄ BrN ₃ O ₂ . Calculated,%: C 67.64; H 4.39; Br 14.52; N, 7.63.

Claims (3)

1.1H-Pyrrolo [3,4-b] quinolin-3,9 (2H, 4H) -dione of the general formula 1

where R ¹ is Alk, Ar; R ² is H, Alk, halogen; R ³ is H, Alk, halogen; R ⁴ is H, Alk, halogen; R ⁵ is H, Alk, halogen; R ⁶ - CH ₂ Ar,

. 2. The method of obtaining 1H-pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione of the General formula 1

where R ¹ is Alk, Ar; R ² is H, Alk, halogen; R ³ is H, Alk, halogen; R ⁴ is H, Alk, halogen; R ⁵ is H, Alk, halogen; R ⁶ is CH ₂ Ar, R ⁷ is Ar,

,
characterized in that the starting 1,4-dihydro-4-oxo-2-quinoline carboxylates interact with substituted benzylamines and their analogs (with substituted o-aminobenzylamines and their analogs) when heated in ordinary organic solvents (dioxane, THF, alcohols, etc. .) for 2-6 hours (control by thin layer chromatography). 3. 1H-pyrrolo [3,4-b] quinoline-3,9 (2H, 4H) -dione of the general formula 1 having anti-tuberculosis activity.