SU1001855A3 - Process for preparing 2-substituted-1h-phenanthro(9,10-d)imidazo or their salts - Google Patents

Description

(5) METHOD FOR OBTAINING 2-SUBSTITUTED-1NFENANTRO C9,10-ZYMIDAZOLES OR THEIR SALTS

This invention relates to new, 2-substituted-1H-phenanthro (9, 1-d) imidazol-1m. general formula

(0) „- L1

R

where n 0-2;

  X and y are independently selected from the group consisting of H, F or OCH, or their salts with acids, if n 0 or their salts with metals, if n 1-2, which have anti-inflammatory properties.

A known method for the preparation of alkyl mercaptoimidvzols consists in the alkylation of mercaptoimidazoles with valuable pharmaceutical

properties The purpose of the invention is the synthesis of new compounds with anti-inflammatory properties.

The goal is achieved 5 in that the compound of the formula

ten

15

where X and y have the indicated values, are alkylated with tetrafluoroethylene to release the desired product in free form or. in the form of salt, or in the case when

20 p 1-2, the resulting compound is subjected to oxidation with m-chloroperbenzoic acid with the selection of the target product in free form or in the form of a salt. 310 EXAMPLE 1, 1H-phenanthro 9, 10-d imidazol-2-thiol. 10 g of imidazole is suspended in 100 ml of sulfanol / tetramethylene sulfone; and add 3 g of powdered sulfur. The half-reaction mixture is under nitrogen at 200–205 0 with thorough mixing for 8 hours. After the reaction mixture is cooled, it is diluted with 500 ml of ice-cooled water. The separated dark brown mass is collected by filtration, carefully washed with water and dried in a vacuum oven at 100 ° C for 10 hours. The crude product is purified by chromatography on a column using basic aluminum (degree according to Belum O and dimethyl form as a MID eluent. The purified product is triturated with boiling acetonitrile, mp above 375 C. Example 2. 2-C1,1,2,2 tetrafluoroethyl; -thio -1H-phenanthine 9.10 dJ Imidazole 6 g of the abovementioned thiimiidazole (Example 1) suspended in 100 ml of dimethylformamide and 3.5 ml of diisopropylamine added. 4.8 g of tetrafluoroethylene is metered into the pressure vessel of stainless steel, evacuated several times with nitrogen purge and at the end. The mixture is heated in a closed system to 50 ° C for 8 hours. The reaction mixture is cooled and poured into 1000 ml of water. collected by filtration, washed thoroughly with water and dried.The product recrystallized from benzene, melted at 230-231 ° C. Found: C 58.01, H 3.03; N 7.89; F 21.54; S 9.5 IT .5. Calculated: C 58.37; H 2.87; N 7.99; F 21.69; S9, i5. Example 3. 2-t (l J, 2,2-tetrafopretyl) sylphenyl 3-1H-phenanto 5. 10-3-imidazole. To a suspension of 2-C1,1,2,2-tetraftopoethyl) -thioZ-1H-phenan-tpo-9, Yul-fl 1 imidazole (3.5 g, 0.01 mol) in 75 ml of chloroform is gradually added a solution of chloro-hydroxybenzoic acid ( 86, 4.47 g; 0.022 mol) in chloroform (50 ml) and the mixture heated under reflux for 24 hours. The cooled reaction mixture is diluted with a large amount of 54 chloroform, washed with saturated sodium bicarbonate solution and water, then dried with anhydrous magnesium sulfate . Filtration of the chloroform solution by evaporation gives the residue, after recrystallization from benzene, to give a product (2.8 g), which melts at 25i-256 ° C. PRI me R 4. 6,9-dimethoxy-1Nphenanthro 9, -10-b imidazole. A solution of 5-bisC-methoxyphenyl imidazole in absolute ethanol alcohol (3.5 g, 0.0125 mol, in 800 ml of absolute ethanol alcohol, mg of iodine as a catalyst is subjected to photolysis using a Gavovi 50-watt lamp and Zicor filter e for 6 hours. The combined photolysates of six photocyclizations are combined and recrystallized from ethanol. 5.1 g of product is obtained as the first fraction, which melts at 231–23 C. Additional product is obtained by isolation on a column chromatography Found: C 73, t; H 5.38; N 9, EA; C, -, H, 4NiO ,, Computed but%: C 73.36; H 5.07; N 10.07. Example 5; 6,9-dimethoxy-2- (trifluoromethylthio) -1H-phenanthroC9, 10 h3 J-imidazole. A. 6.9- dimethoxy-1- (1-ethoxyethyl) - 1H-phenanthro1 9,10- | -imidazole Suspension of 6.9-Aimethoxy-1H-phenanto 9, 10- (33-imidazole (8, g) in toluene (200 ml) is treated with ethyl vinyl ether (15 ml), then with di-, chloroacetic acid (3.9 g). The mixture is slightly heated under reflux for 1 hour. A solution is formed after 30 minutes. The reaction mixture is cooled, diluted with 200 ml of toluene, 100 ml of sodium hydroxide are added and stirred overnight. The organic phase is separated, washed several times with water and dried with anhydrous potassium carbonate. The inorganic salts are filtered off and the crude product is tested by thin layer chromatography using 50 h of tetrahydrofur and 50 parts of toluene. The product is purified by chromatography on a column using basic aluminum and tetrahydrofuran and toluene (50:50). The infrared spectrum of the purified sample does not show the ether group. b. B, 9-dimethoxy-2- (trifluorometh 1L thio) -TH-phenanthrome, Yu-a-imidazole, To a solution of 10.5 g (0.03 mol) 6.9 dimethoxy-1- (l-ethoxyethyl) - 1H-phenanthro | 19, .10-YZimidazole and A, 6 g {Q, Q mol) M, S, M, Zetramethyl-ethylene diamine in 150 ml of ether at 778 ° C, add 25 ml (0.035 mol) of solution 1 , 4-M butyl lithium in hexane. The reaction mixture is stirred for another 15 minutes at -7 ° C, then a solution of 7.0 g (.0.035 mol) of bistrifluoromethyldisulfY-D (toxic) in 25 m of ether is added dropwise. The mixture was stirred at -78 1h, then PO aqueous saturated sodium bicarbonate was added dropwise. The mixture is stirred overnight at room temperature, the pot is diluted with an additional amount of saturated aqueous sodium bicarbonate piw and extracted with ether. The ether extracts are dried and concentrated to give 13.5 g of a yellow oil. This oil is dissolved in 150 ml of ethano. And 30 ml of 1N is added. hydrochloric acid. The mixture is stirred for 1 hour, then diluted with water, and the precipitated solid material is collected, washed with water, then with hexane, and then dried in air to obtain a crude brown product. The crude product is purified by chromatography on 300 g of silica gel, eluted with a mixture of toluene and ethyl acetate (5-10% ethyl acetate) to give, after recrystallization from ethanol / water, 5 g of product, mp. 201-202, (polymorphic species, mp. 160). ; The IR spectrum, proton, fluorine, NMR spectrum correspond to the desired structure. Mass spectrum. Calculated: 378.06 Found: 378 ,. Found: C 56.86; H 3-, b1; N 7.28. Calculated: C 57, Z. N 7.0. Example 6. 6,9-Dimethoxy-2, (triFluoromethylsulfonyl) -1H-phenanthro 9 10- | Zimidazole. T-chloroperbenzoic acid (2.5 g) is added to a solution of 1.9 g of trifluoromethyl thiocompound (Example 5) in 100 ml of methylene chloride and the mixture is heated under reflux for 2 hours. The reaction mixture gets a very dark purple color. The excess oxidant is removed by addition of methyl sulfide Cl. The acidic components are removed by extraction with a dilute sodium bicarbonate solution and the organic phase is washed with water. The crude product is isolated by evaporation of the solvent; purification was carried out using silica gel column mathematics using toluene (80) and ethyl acetate (20); recrystallized from toluene, so pl. 228-231 0. Example 7-6.9 DIFF-2- (1, 1,2,2-tetrafluoroethyl) thioE-1H-phenanthro-19, 10-midazole., A. 6,9-Difluoro-1H-phenanthro L9, lO-cQ imidazole. . The compound is obtained by photocyclization, carried out according to example k. The recrystallized phenanthrene compound melts at 32-325 ° C. b. 6.9-Difluoro-1H-phenanthro | 1 9,10-imidazol-2-thiol,. This compound is prepared according to the method described in the example; the product does not melt below 390 C. in. 6.9-Difluoro-2-C1,1,2,2-tetrafluoroethyl tirD-1H-phenanthro-19,10-41 imidazole. The reaction with tetrafluoroethylene is carried out according to example 2; the pure product melts at 238-2-1. Found: C 52.93; H 2.23; N 7.03. , F6S: Calculated,%: C, 52.85; H 2.23; N 7.03. Example 6,9-Difluoro-2 t 1, 2,2-tetrafluoroethyl) sulf {ynyl -1H-phenanthro t 9, and idazole. The tetrafluoroethyl derivative (7) is oxidized using chloroperbene. zoic acid (conditions described in example 3). The clean product melts at 258 ° C. The following compounds are prepared according to the methods mentioned above and illustrated in the previous examples (see Table 1 and 2).

(O)

Kg

Anti-arthritis agents according to the invention are used in the treatment of arthritis in any way that ensures contact of the active principle with the active zone of action in the mammalian body. Agents can be administered in any manner and manner that is suitable when using pharmaceutical

drugs, either as individual therapeutic agents, or in combination with several therapeutic agents. They can be administered in pure form, however, as a rule, they are administered with a pharmaceutical carrier selected on the basis of the known method of administration and accepted pharmaceutical practice. The dosage administered varies depending on the pharmacodynamic characteristics of each agent, in particular, their mode of administration and composition, age, health and weight of the recipient, the nature and extent of symptoms, the type of concurrent treatment, frequency of administration and the desired effect. Typically, the daily dose of active ingredient is about 0.0 100 mg / kg body weight. Usually, 0 mg / kg per day, preferably 0.01-25 mg / kg per day in partial doses 2-4 times per day or as a slow-acting preparation are sufficient to achieve the desired effect. Standard doses (formulations) suitable for intravenous D / 1) contain about 100 mg to about 10 g of the active ingredient per unit, pharmaceuticals - 0.5 to 95 by weight, calculated on the total weight of the composition. The active ingredient may be administered orally in solid form, for example in. capsules, tablets and powders, in liquid form, for example, in the form of elixir, syrups and suspensions, as well as parenteral using sterile liquid unit doses. Gelatin capsules contain the active ingredient and powdered carriers, for example, lactose, sucrose, mannitol starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar dispersers can be used to make compressed tablets. Both tablets and capsules can be obtained as substances that contribute to the continuous relief of pain over a defined period. Compressed tablets may be coated with a layer of sugar or another film in order to eliminate unpleasant taste or to protect tablets from atmospheric effects, as well as to have an internal coating to achieve selective disintegration to the gastrointestinal tract. Liquid unit doses may contain coloring and flavoring agents for oral administration to facilitate the administration to the patient. Water, suitable oil, hydrochloric acid, dextrose (I, glucose) and sugar solutions and glycol as propylene glycol or polyethylene. glycols are suitable carriers for ferric solutions. Solutions for parenteral administration preferably contain an active-water soluble salt, appropriate stabilizers, buffers. Antioxidants, such as sodium bisulfite or ascorbic acid, in pure form or in mixture with each other, are appropriate stabilizers. Citric acid with its salts, as well as the sodium salt of ethylenediaminetetraacetic acid are also used. In addition, parenteral 1e solutions may contain preservative agents, for example, benzalkonium chloride, methyl or propyl paraben and lorbutanol. Suitable unit doses for administering the compounds of the present invention. Capsules J A large amount of .capsules are obtained by filling 50 mg of powdered active principle, 110 mg of lactose, 32 mg of talc and 8 mg of magnesium stearate into solid capsules made of hard gelatin. Capsules A mixture of active ingredient with soybean oil is pumped through a volumetric pump into gelatin, to form soft gelatin capsules containing 50 mg of active ingredient each. The capsules are washed in petroleum ether and dried. Tablets A large number of tablets are prepared in the usual way, reaching the formulation of doses of each at 50 mg of the active principle, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of corn starch and 98, 8 mg of lactose. Special coatings may be applied in order to improve taste or enhance absorption. Injectable Preparations A parenteral composition suitable for injection is prepared by stirring 1.5% by weight of the active principle in 10% by volume of propylene glycol and water. The solution is sterilized by filtration. Suspension For oral administration, an aqueous suspension is prepared so that each 5 ml contains 10 ml of finely dispersed active principle, -500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution; 5 mg of sodium saccharin and 1.0.025 ml vanilla tincture. Injectables; A parenteral composition suitable for injection is prepared by dissolving 1 by weight of the active principle in an injection with sodium chloride and adjusting the pH of the solution to 6-7. The solution is sterilized by filtration. In order to distribute the anti-inflammatory activity of the proposed compounds and compare the latter with standard Medicines, a test using a standard type of arthritis is used, the results of which give indications regarding efficacy in humans. The standard type of arthritis is arthritis, viz Control (arthritis) The treated group average paw volume, ml average paw volume, ml

Control (arthritic) Control (non-arthritic) average paw volume, ml average paw volume, ml Corresponding dose regressive reduction lines (in% | applied to semi-log paper according to visual observation; decrease in ED5o compared to conpoimer 2 3

7

X 100% reduction compared with control over average paw volume.

25 28. 0, $ (1.6 baths by the introduction of a special agent in rats. Male River Charles Lewis rats (weighing 130-150 g each) were subcutaneously injected into the foot area of the right hind paw of 0.1 ml auxiliary agent (grown in Difco nutrient medium) , destroyed by heat, the libfilr microorganism MusoBacterlum ButyrJcum, weighed in mineral oil, 5 mg / ml.) 20 n "affected by arthritis with a control animal inject mineral oil. Experimental animals are kept for 2 weeks to develop arthritis. After treatment Untreated left hind paw volume agent treated animals are selected and distributed into groups of UO rats of the same stage of the disease. Untreated control animals are divided into two groups of 10 samples each. Rats are orally administered a compound or a mixture of 1% polyvinyl alcohol, 5% gum arabic; 0.5% methylparaben in the amount of 10 ml / kg in the first and the next 6 days. A day after the last dose was administered, the volume of the paws (untreated rear left paw) was measured using a differential volume meter 70101. The control (volume) was determined by checking , Data d l of some of the proposed compounds are given in table 3 in comparison with the known anti-inflammatory drugs. Table4a3

15

100185516

Continued table. 3

Claims (1)

Claim The method of obtaining 2-substituted-1H-phenantro | ~ 9 "10-s | ] imidazoles of the general formula 20 i VY / ^ (o.) _N -Pi 25 to Where η = about - 2; ; V CF ^ CE ^ H, x and y independently FRIEND from friend selected from the group thirty current from H, F or OCH ^,  or them salts with acids if η = or them salts with metals, if n = 1- about t l and feigning that compound of the formula 4®, where Y ”have the indicated meanings, is subjected to alkylation with tetrafluoroethylene to isolate the desired product in free form or in the form of a salt, or in the case where n = 1-2, the resulting compound is oxidized with m-chloroperbenzoic acid, with evolution the target product in free form or in the form of salt.