PL165363B1 - Method for the preparation of new 6H-Indolo [2,3-b] quinoline derivatives - Google Patents

Abstract

A method for the preparation of the new 6Hindolo [2,3-b] quinoline derivatives of the general formula 1, in which R 1 - R 9 are the same or different and represent a hydrogen atom, a primary, secondary or tertiary alkyl or alkoxy group with a carbon number of 1 - 4, trifluoromethyl, hydroxyl, nitro, amino or halogen, and R10 is a carbon number 1-6 primary, secondary or tertiary alkyl group or a substituted or unsubstituted aminoalkyl group RiiRi2N (CH2) n-, where R11 and R12 are the same or different and represent a hydrogen atom or an alkyl group of 1-4 carbon atoms, n = 1-6, optionally in the form of pharmaceutically acceptable salts, characterized in that the 6H-indolo [2,3-b] quinoline derivative of the formula Is alkylated with a compound of formula Rk) X, where R10 is as defined above and X is a halogen atom or an addition salt thereof, and the optionally obtained compound is converted into a pharmaceutically acceptable salt.

Description

The subject of the invention is a process for the preparation of novel 6H-indolo [2,3-b] quinoline derivatives.

The new 6H-ikZolo [2,3-b] quinoline derivatives have the general formula 1 where R1-R9 are the same or different and represent a hydrogen atom, a primary, secondary or tertiary alkyl or alkoxy group with a carbon number of 1- 4, trifluoromethyl, hydroxyl, nitro, amino or halogen, and Rio is a carbon number 1-6 primary, secondary or tertiary alkyl group or a substituted or unsubstituted avinoalkyl group RnR.2N (CH2) n-, where Rn and R12 are the same or different and represent a hydrogen atom or an alkyl group of 1-4 carbon atoms, and n = 1-6. Also within the scope of the invention is a process for the preparation of pharmaceutically acceptable salts of the compounds of Formula 1.

These new compounds of the nature of DNA intercalators and inhibitors of topoieoweraky II show strong cytostatic, baeteriostatic, anti-gray, and immunosuppressive properties (biological data are presented in the table).

The new animals exhibit good digestibility and are therefore much more advantageous than the previously known 5H-icdolo [2,3-b] quinolics having cytostatic, bacteriostatic and anti-gray effects.

Weoree 1 compounds, optionally in the form of pharmaceutically acceptable salts, can be used as anti-cancer drugs and / or anti-gray and / or bacteriostatic and / or nasosuppressive drugs.

The process for the preparation of the new 6H-ikZolo [2,3-b] ehinoline derivatives of the formula 1, in which R 1 -R 10 have the meaning given above, consists in that the 6H-ikZolo [2,3-b] ehinoline derivative of the formula Is alkylated with a compound of formula RioX, where R10 is as defined above and X is halogen, optionally in the form of an addition salt.

The obtained compound is converted, if necessary, into a pharmaceutically acceptable salt by known methods.

The alkylation reaction is carried out in an alkaline medium, e.g. in the presence of metal hydrides, alkoxides, amides, bases and alkali metal salts.

The preparations may also contain suitable preserving, stabilizing, wetting, flavoring, coloring, flavoring, etc. agents.

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As already mentioned the 6H-indole [2,3-b] quinoline derivatives of the general formula I, in which R 1 - R 10 are as defined above, are potent DNA intercalators and inhibitors of topolysomerase II (enzyme involved in DNA synthesis). The effect of this is cytostatic, fungistic and bacteriostatic activity of the discussed group of compounds.

The biological data obtained in in vitro studies for compounds selected from the group of compounds of formula 1 are presented in the table, comparing them with the data obtained for known compounds, namely 5,1l-dimethyl-5H-indolo [2,3-b] quinoline (5H -IC) and the cytostatic alkaloid Ellipticin.

Table

^L .p. Formula 1 (R1, R3-R8 = H, R9 = CH3) MIC (µM / ml) ID50 Staphylococcus aureus Candida albicans Trichophyton mentagroph. (µM / ml) KB 1. R2 = H, R10 = 3-dimethylaminopropyl 1x 10-1 2x10-2 5x10-2 1x10- ² 2. R2 = H, R10 = 2-dimethylaminoethyl 2x10-2 4x10'2 X 5x10'2 3. R2 = CH3, R10 = 3-dimethylaminopropyl 2x10-2 2x10-2 X 1x10-2 4. R2 = F, R10 = 3-dimethylaminopropyl 2x10'2 2x10-2 X 1x10'2 5. 5H-IC 2.5x10-1 2x10-2 2.5x10'- 1x10 ' ³ 6. Ellipticine x X X 1x10-2

MIC - the lowest concentration that inhibits the growth of microorganisms;

ID50 - the concentration that inhibits the growth of neoplastic cells in 50%; KB - human nasopharyngeal carcinoma cells;

x - not tested.

In in vitro tests, the compounds according to the invention show a stronger bacteriostatic (Staph. Aureus) and fungistatic (Trichophyton mentagr.) Activity than the standard 5H-IC. Their cytostatic effect, on the other hand, is weaker than that of 5H-IC, although comparable with another known reference compound - Ellipticin.

A very significant advantage of the new compounds over the standard 5H-IC is their excellent bioavailability. In in vivo bioavailability studies in mice, these compounds are absorbed from the peritoneal cavity up to 60 minutes after injection, while 5H-IC is not completely resorbed up to 96 hours after addition.

The maximum tolerated dose, i.e. the dose at which no toxic symptoms are observed, is up to about 75.0 mg / kg body weight (mice).

LD50 dose = 78 mg / kg (mice).

The following examples illustrate the invention without limiting its scope.

Example 1 11-Methyl-6H-indolo [2,3-b] quinoline (2.32 g 0.01 mol) was added to a solution of sodium ethoxide (0.75 g, 0.011 mol) in abs. Ethanol. (20 ml) then the ethanol was evaporated in vacuo and the residue was dissolved in dry DMF (50 ml). A solution of CH3J (1.56 g, 0.011 mol) in dry DMF (5 ml) was added dropwise to the resulting solution while cooling with water (temperature below 20 ° C) and the mixture was heated on a boiling water bath for 1 hour. After distilling off the solvent in vacuo, the residue was purified on a short column of silica gel (100-200 mesh), eluting with 10: 1 hexane-acetone and collecting the first fraction. After recrystallization from hexane-benzene mixture, 6,11-dimethyl-6H-indolo [2,3-b] quinoline (Formula 1, R9 = Ri1 = CH3) was obtained as cream crystals, m.p. 138-139 ° C, yield 2.00 g ( 81%).

MS (-70 eV, m / e): 246 (100%), 231 (14%).

Analysis: for C17H14N2 (246.3).

Calculated: 82.90% C, 5.73% H, 11.37% N.

Found: 82.61% C, 5.54% H, 11.09% N.

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Example II. From 1 l-methyl-6H-indolo [2,3-b] quinoline (2.32 g, 0.01 mol) and hexyl bromide (1.80 g, 0.011 mol), 6-hexyl-11-methyl-6Hiindolo [was prepared by proceeding as in Example 1). 2,3ib] quinolline (Formula 1, R9 = CH3, Rio = CeHn) as yellow crystals, mp 91-92 ° C (from hexane), yield 2.60 g (82%).

MS (-70 eV, m / e): 316 (43%), 287 (13%), 259 (12%), 246 (88%), 232 (100%).

Analysis: for C22H24N2 (316.4).

Calculated: 83.50% C, 7.64% H, 8.85% N.

Found: 83.33% C, 7.57% H, 9.12% N.

Example III. A 50 mL three-neck flask equipped with a thermometer and magnetic stirrer and filled with argon was filled with 80% NaH (0.33 g, 0.011 mol), washed with dry hexane and then dried on an oil pump. Dry DMF (25 ml) and 1 l-methyl-6H-indole [2,3] bcehmoUn (2.32 g 1.0) were charged to the flask and the suspension was stirred at 100-120 ° C for 30 minutes. After the mixture was cooled below 20 ° C, a solution of isopentyl bromide (1.65 g, 0.011 mol) in DMF (5 ml) was added dropwise and the mixture was heated on a boiling water bath for 30 minutes. The solvent was then distilled off in vacuo, the residue was diluted with water and extracted with CHCl 2. The extract was washed with water (3 times), dried with MgSO 4, the solvent was distilled off and the residue was purified on a silica gel column (hexane-acetone 10: 1). 6-isopentyl-1-methyl-6Hindolo [2,3-b] quinoline (formula 1, R9 = CH3, Rio = isopentyl) was obtained as orange crystals, m.p. 110-111 ° C (from hexane), yield 2.70 g ( 89%).

MS (-70 eV, m / e): 302 (29%), 287 (3%), 259 (4%), 246 (100%).

Analysis: for C21H22N2 (302.4).

Calculated: 83.40% C, 7.33% H, 9.26% N.

Found: 83.27% C, 7.25% H, 9.31% N.

Example IV. 6H-indolo [2.3lb] quinoline (2.18g, 0.01 mol) was alkylated with chloride

3-dimethylaminopropyl (1.33 g, 0.011 mol) as in Example 3. 6L (3-dimethylaminopropyl) -6H-indole, 3-btahinoline (formula 1, R10 = 3-dimethylaminopropyl) was obtained as orange crystals, mp 76-78 ° C (from hexane), yield 2.40 g (79%).

MS (-70 eV, m / e): 303 (27%), 245 (20%), 232 (100%).

Analysis: for C20H21N3 (303.4).

Calculated: 79.17% C, 6.98% H, 13.85% N.

Found: 79.32% C, 6.89% H, 13.54% N.

Example 5 A mixture of 1 l-methyl-6H-indolo [2,3] ^ εΚΐηοΗιτφ (4.6 g 1 0.02 mota, 1 dimethylaminoethyl chloride hydrochloride (3.6 g, 0.025 mol), powdered KOH (10 g), tetrabutyl ammonium bromide (1 g) and DMSO (100 ml) was stirred vigorously at 110 ° C for 2 hours After cooling, the mixture was filtered through Celite (washed with Celite with a portion of DMSO), DMSO was distilled off in vacuo, the residue was diluted with water and extracted with chloroform. The extract was washed 4 times with water, dried with MgSO4. and the solvent was distilled off, and the residue was recrystallized from hexane to give 1l-methyl-6- [2] dimethylaminoethyl) 16H-indolo [2.3lb] cholinoline (Formula 1, R9 = CH3, R10 = 2-dimethylaminoethyl) as orange crystals at a temperature of mp 97-98 ° C, yield 5.8 g (96%).

MS (-70 eV, m / e): 303 (4%), 245 (8%), 232 (72%), 58 (100%).

Analysis: for C20H21N3 (303.4).

Calculated: 79.17% C, 6.98% H, 13.85% N.

Found: 79.36% C, 6.97% H, 13.89% N.

Example VI. A mixture of 1 l-methyl-6H-indolo [2,3] b] quinoline (4.6 g, 0.02 moles, 1 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 0.022 mol), tetrabutylammonium bromide (1 g), toluene (20 ml) and 50% NaOH (20 ml) was stirred vigorously at reflux for 2 hours After cooling, the mixture was diluted with water (80 ml) and toluene (30 ml) and stirred for 5 minutes, then the toluene layer was separated and washed with water (4 x 50 ml). The post-reaction and wash layers were re-extracted with toluene (50 ml), then the combined extracts were dried (anh. MgSO4), toluene was distilled off,

165 363 and the residue was crystallized from hexane. 1 l-methyl-6- (3-dimethylaminopropyl) 6H-indolo [2,3) b] quinoline (formula 1, R.9 = CH3, Ro = 3-dimethylaminopropyl) was obtained as orange crystals, m.p. 76) 78 ° C, yield 6.0g (95%).

MS (-70 eV, m / e): 317 (22%), 302 (2%), 259 (22%), 246 (100%).

Analysis: for C21H23N3 (317.4).

Calculated: 79.46% C, 7.30% H, 13.24% N.

Found: 79.45% C, 7.30% H, 13.47% N.

1l) methyl) 6) (3) dimethylaminopropyl)) 6H) indolo [2,3) b] quinoline oxalate - water (1/1). The obtained compound (3.17 g, 0.01 mol) was dissolved in acetone (50 ml), added to a solution of oxalic acid (1.0 g, 0.011 mol) in acetone (20 ml) and the mixture was heated to reflux for 30 minutes. The solvent was decanted, acetone (50 ml) was added again and the precipitate of oxalate was filtered off. After recrystallization from methanol, yellow crystals are obtained, m.p. 204) 206 ° C (decomposition), yield 4.0 g (94%).

Analysis: for C23H27N3O5 (425.48).

Calculated: 64.93% C, 6.40% H, 9.88% N.

Found: 65.39% C, 6.79% H, 9.56% N.

Example VII. Alkylating 1) -methyl-6H-indolo [2,3-tilhinol (4.6 g, 0.02 mol with diethylaminoethyl chloride 2) hydrochloride (3.8 g, 0.022 mol) as in Example 6 gave a dark oil which was chromatographed on silica gel column in hexanacetone 3: 1 system. 6) (2) diethylaminoethyl) -1 l) methyl) 6H) indolo [2,3) b] quinoline (formula 1, R9 = CH3, Rio = 2) diethylaminoethyl) was obtained in the form of yellow crystals with a melting point of 4345 ° C, yield 5.9 g (89%).

MS (-70 eV, m / e): 331 (2%), 259 (3%), 245 (10%), 232 (39%), 86 (100%).

Analysis: for C22H25N3 (331.5).

Calculated: 79.72% C, 7.60% H, 12.68% N.

Found: 80.02% C, 7.71% H, 12.73% N.

Example VIII. Alkylating 2,11) dimethyl) 6H) indolo [2,3) b] quinoline (4.9 g, 0.02 mol) with 3) dimethylaminopropyl chloride hydrochloride (3.4 g, 0.022 mol) as in Example 6, 2.11) dimethyl was obtained) 6) (3) dimethylaminopropyl)) 6H) indolo [2,3) b] quinoline (Formula 1, R2 = R9 = CH3, Rio = 3) dimethylaminopropyl) as dark yellow crystals, m.p. 107) 109 ° C (from hexane ), yield 6.3 g (95%).

MS (-70 eV, m / e): 331 (17%), 316 (1%), 273 (22%), 260 (100%).

Analysis: for C22H25N3 (331.5).

Calculated: 79.72% C, 7.60% H, 12.68% N.

Found: 79.62% C, 7.64% H, 12.67% N.

Example IX. Alkylating 9-methoxy-1l-methyl) 6H-indolo [2,3) b] quinoline (5.2 g, 0.02 mol) with 3) dimethylaminopropyl chloride hydrochloride (3.4 g, 0.022 mol) as in Example 6 gave 9-methoxy-II - methyl-6) (3-dimethylaminopropyl) -6H) indolo [2,3) b] quinoline (formula 1, R7 = OCH3, R9 = CH3, Ri0 = 3) dimethylaminopropyl) as orange crystals, m.p. 90-91 ° C (from hexane), yield 6.7 g (96%).

MS (-70 eV, m / e): 347 (28%), 289 (27%), 276 (100%).

Analysis: for C22H25N3O (347.5).

Calculated: 76.05% C, 7.25% H, 12.09% N.

Found: 75.95% C, 7.28% H, 11.88% N.

Example X. Alkylating 2-fluoro-1,1-methyl) 6H) indolo [2,3) b] quinoline (5.0 g, 0.02 mol) with 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 0.022 mol) as in Example 6, gave 2 -fluoro-1l-methyl) 6- (3-dimethylaminopropyl)) 6H) indolo [2,3-b] quinoline (Formula 1, R2 = F, R9 = CH3, Rio = 3) dimethylaminopropyl) as yellow crystals with a temperature of mp 140-141 ° C (from hexane), yield 6.4 g (96%).

MS (-70 eV, m / e): 335 (20%), 278 (23%), 264 (100%).

Analysis: for C21H22N3F (335.4).

Calculated: 75.20% C, 6.61% H, 12.53% N.

Found: 74.92% C, 6.72% H, 12.44% N.

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Example XI. Alkylating 1-methyl-9-nitro-6H-indolo [2,3-b] quinoline (5.5 g, 0.02 mol) with 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 0.022 mol) as in Example 6, there was obtained 6> (^^ dimiety / k ^^ nin ^ (: ^ p ^ i ^ c ^ p ^ ylc ^) - 9-nitro-6H-ir ^^ olc ^ [2,3-b] quinoline (in ^ 2 (1) R7 = NO2, R9 = CH3, Rk) = 3-dimethylaminkpropyl) as yellow crystals, m.p. 141-142 ° C (from hexane) yield 1.5 g (21%).

MS (-70 eV, m / e): 362 (3%), 332 (2%), 318 (45%), 58 (100%). Analysis: for C21H22N4O2 (362.4).

Calculated: 69.59% C, 6.12% H, 15.46% N.

Found: 69.54% C, 6.21% H, 15.08% N.

The pharmaceutical was prepared in the form of a solution with the following composition: compound of Example 4 - 10 parts by weight, methylcellulose, water

- 1 part by weight.

- 89 parts by weight.

pattern 1

pattern 2

Publishing Department of the UP RP. Circulation of 90 copies

Price: PLN 10,000

Claims (1)

Patent claim A method for the preparation of new 6H-indolo [2,3-b] quinoline derivatives of the general formula I, in which R1 - R9 are the same or different and represent a hydrogen atom, a primary, secondary or tertiary alkyl or alkoxy group of carbon atoms 1-4, trifluoromethyl, hydroxy, nitro, amino or halogen, and R10 is a carbon number 1-6 primary, secondary or tertiary alkyl group or a substituted or unsubstituted aminoalkyl group RnRi2N (CH2) n-, where R11 and R12 are the same or different and represent a hydrogen atom or an alkyl group of 1-4 carbon atoms, n = 1-6, optionally in the form of pharmaceutically acceptable salts, characterized in that the 6H-indolo [2,3-b] quinoline derivative of Formula 2, wherein R 1 - R 9 are as defined above, is adkylated with compound k of Formula RioX, where R 10 is as defined above and X is halogen or an addition salt thereof, and optionally the resulting compound is converted into a pharmaceutically acceptable salt.