The method of obtaining polycyclic biocidal compounds or their salts

 

(57) Abstract:

The inventive product - polycyclic biocidal compounds of General f-ly Ar CH2Other, where Ar is 2-benzo/b/oil /2,1-d/ thiophene-5-yl; 2-benzo/b/ oil/2,3-d/furan-6-yl; 2-benzo-/b/oil/1,2-d/furan-5-yl; 2-(7-methyl-7H-benzo/c/carbazole-10-yl)methyl; 2-/benzo/b/oil/2,1-d/furan-5-yl; R-C(CH3) (CH2OH)2or their salts. Reagent 1: compound f-ly Ar CHNR, where R, Ar is as defined above; Reagent 2: the restorer. table 2.

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= - H3or their salts, which can be used as anticancer agents.

Known (1-nitro-9-[(3-dimethylaminopropyl)-amino]-acridine) containing 2-amino-2-methyl-1,3-propandiol and Tris(oxymethyl)-methylaminopropyl with antitumor action.

However, among heteroalicyclic aromatic alkanols derived anticancer drugs nicheskij aromatic alkanols derivatives, with antitumor activity with less toxicity for warm-blooded.

This goal is achieved by a method of obtaining compounds of General formula I by the reduction of compounds of General formula

(II) ArCHNR, where Ar and R above.

P R I m e R 1. 2-[Benzo/b/oil/2,1-d/thiophene-5-ylmethyl/-amino]-2-methyl-1,3-propertiesmetaltheme.

In a round bottom flask equipped with a magnetic stir bar, a refrigerator, a thermometer, a trap Dean-stark tube for nitrogen and a bubbler, download 4.94 g of benzo/b/oil/2,1-d/thiophene-5-carbaldehyde (18,83 mmol), 1.98 g of 2-amino-2-methyl-1,3-propane diol (18,83 mmol), 0.1 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene. The mixture is stirred at the boiling temperature with removal of water for 2.5 hours, or until no longer water, which is extracted with 3 portions of 500 ml of ethyl acetate. An ethyl acetate extracts are collected. A large part of the toluene is then removed by distillation. The mixture is then cooled in a bath with ice and diluted with 200 ml of absolute ethanol, and then further cooling. In the reaction mixture in one portion add 0,712 g of solid Na borohydride (18,83 mmole). Next, bath with ice is removed, the reaction mixture is at what Laney acid in a rotary evaporator to remove the solvent. The crude solid product is subjected to shaking in 300 ml of 1 N. hydrochloric acid, filtered off, washed with hydrochloric acid, subjected to vacuum filtration to a moist condition and washed with 300 ml of diethyl ether. Then the material is dissolved in 200 ml of methanol, filtered the solution and alkalinized 1 l of 1 n solution of hydrate of sodium oxide. The washing liquid with the solid white material combine, filtered, washed with 3 portions of 500 ml of saturated sodium chloride solution, dried over 25 g of potassium carbonate, filtered and concentrated in a rotary evaporator to obtain a white solid product. This latter dissolved in a mixture of 200 ml of absolute ethanol with 3 ml of methansulfonate, the solution is filtered and diluted to a volume of 4 liters of a mixture of diethyl ether and hexane in a ratio of 1: 1. This material is recrystallized three times from ethanol-hexane in the ratio of 1:3, resulting in a gain 2-/benzo/b/oil/2,1-d/thiophene-5-yl-methyl/-amino-2-me-til-1,3 - propertiesmetaltheme with so pl. 221-222aboutWith that put an exact analysis for determining the structure of carbon, hydrogen, nitrogen and sulphur.

P R I m m e R 2. 2[/benzo/b/oil/2,3-d/furan-6-ylmethyl-amino]-2-Mattara described in example 1, from benzo/b/oil/2,3-d/furan-6-carbaldehyde and 2-amino-2-methyl-1,3-propane diol get 2-[/benzo/b/- oil/2,3-d/furan-6-ylmethyl/-amino] -2-methyl-1,3 - propertiesmetaltheme. 0,4 H2About including square 187-190aboutWith (a mixture of ethanol-diethyl ether), which is subjected to the exact analysis for determining the structure of the elements carbon, hydrogen, nitrogen and sulphur.

P R I m e R 3. 2-[Benzo/b/oil/1,2-d/furan-5-ylmethyl/-amino]-2-methyl-1,3 - propertiesmetaltheme.

Using the procedure of restorative amination described in example 1, benzo/b/oil/1,2-d/-furan-5-carbaldehyde and 2-amino-2-methyl-1,3-propane diol get 2-[/benzo/b/oil/1,2-d/furan-5-ylmethyl/-amino]-2-me - til-1,3 - propertiesmetaltheme with melting point 215-217aboutWith (a mixture of ethanol-diethyl ether), which is subjected to the exact analysis for determining the structure of the elements carbon, hydrogen, nitrogen and sulphur.

P R I m e R 4. 0,3-hydrate-2-methyl-2-[(/7-methyl-7H-benzo/with/carbazole-10-yl/-methyl)-amino]- 1,3-propeciageneric.

The specified connection get in the way similar to described in example 1 from 7-methyl-7H-benzo/c/carbazole-10-carbaldehyde and 2-amino-2-methyl - 1,3-propane diol; its so pl. is 229-230aboutWith (razloga is 0; H Is 6.61; N 7,18; Cl Remaining 9.08.

C22H15N2O2Cl.0,3 H2O

Found,%: C 67,61; H 6,53; N 7,17; Cl 9,05.

This structure was consistent with the NMR spectrogram.

P R I m e R 5. 2-[benzo/b/oil/2,1-d/furan-5-ylmethyl/-aminomethyl]-1,3-propandiol.

According to methods similar to described in example 1 using benzo/b/oil/2,1-d/- furan-5 - carboxaldehyde and 2-amino-2-methyl-1,3-propane diol got mentioned in the title compound in the form of methane - sulphonate salt so pl. 216-218aboutWith (a mixture of ethanol with diethyl ether in the ratio 1:1).

Calculated, %: C 60,23; H To 5.93; N 3,19; S 7,31.

C22H25NO6S.

Found,%: C 60,22; H To 5.93; N 3,18; S 7,30.

These NMR spectrum was consistent with this structure.

Test lymphoid leukemia R/0.

For this test as experimental animals used mice DM2-F1 single-sex weighing 20 3 g / day 0 animals as the control group and the group that was exposed to treatment, intraperitoneal injection was administered a suspension of 106living tumor cells R/0. During each test was evaluated by several dosages, which cover also has Polzovali in the form of drugs or physiological solution, which contained 0.05% product Turen-80, or in distilled water that contained 5% dextrose, and these drugs were injected intraperitoneally on the 1st, 5th and 9th days in relation to implantation of tumor cells. Dosage was calculated in mg/kg based on the mass of each individual animal; recorded the day of death of each animal was calculated averages for each group of animals, as well as the magnitude of the ratio of the average life expectancy of the animal groups treated (T) and control groups (). The criterion of activity of the compounds was determined by the formula T/Sh 120%. The results of the tests with R/0 are given in table.1 and 2.

Compounds according to the invention result in a significantly larger number of 30-day survivors of individuals than the reference compound.

Another advantage of the compounds I is their lower toxicity.

The method of obtaining polycyclic biocidal compounds of General formula

Ar CH2OTHER,

where Ar is 2-benzo(b)oil(2,1-d)thiophene-5-yl, 2-benzo(b)oil(2,3-d)furan-6-yl, 2-benzo(b)oil(1,2 - d)furan-5-yl, 2-[7-methyl - 7H - benzo(c)carbazole - 10 - yl]methyl, 2- [benzo(b)oil(2,1 - d]furan - 5 - yl;< / BR>
R- - H3< / BR>
or their salts, different tyuleniy.

 

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