HU181871B - Process for manufacturing 4,5-diaryl-2-nitro-imidazole derivatives having antiinflammatory activity and pharmaceutical preparations containing such compounds - Google Patents

Description

The present invention relates to novel 4,5-diaryl-2-nitroimidazole derivatives having anti-inflammatory activity and to pharmaceutical compositions containing them.

Certain 4,5-diaryl-2-substituted-imidazole derivatives having anti-inflammatory activity have already been disclosed in U.S. Patent 3,707,475.

U.S. Patent 3,505,350 discloses 4-alkyl-5-aryl-1-substituted-2-thiimidazole derivatives having anti-inflammatory activity, and 4-alkyl-2 having anti-inflammatory activity in U.S. Patent 3,651,080. alkyl-thio-5-aryl-1-substituted imidazole derivatives are disclosed.

Zauer, K., et al., Chem. Bert., 106, 1638 (1973), discloses 4,5-bis (4-methoxyphenyl) -2-methylthiimidazole and

4,5-bis (4-chlorophenyl) -2-methylthiimidazole, however, no mention is made of their utility.

Numerous other articles, such as Current Sci. India, 17, 184-185 (1948) and Acta Chem. Acad. Sci. Hung. 79 (2) 197-212 (1973)] discloses 2- (substituted thio) -4,5-diphenylimidazole derivatives having a methyl, propyl, allyl or acetonyl substituent.

There is a constant need for safe and effective anti-inflammatory agents in medicine. Symptoms of inflammation as a cycle include181871 shakes such as redness, fever, swelling and pain. In its various forms, arthritis, or arthritis, is the most common chronic and severe disorder of inflammation. The left _five ese inflammation occurs in case you injuries and infections, such as antiinflammatory drugs are often used also to treat them. Most commercially available anti-inflammatory drugs have limited utility due to their limited toxicity and ₁₀ adverse side effects. Many of them cause gastric irritation or other side effects such as changes in blood cells or the central nervous system. On the one hand, adrenocorticoid steroids cause gastric irritation,

IS, on the other hand, suppresses normal adrenal funk

It is an object of the present invention to provide novel compounds for the treatment of arthritis which have an anti-inflammatory activity and have minimal side effects, that is, can be used to treat arthritis with better results than currently available drugs.

Thus, we have discovered that the novel imidazole derivatives of formula (I) have the formula

R; and R ₂ independently represent 2-thienyl, 3-pyridyl, phenyl or (IV) with the proviso that at least one of them is (IV),

-1181871 also in the latter Vj represents a fluorine or chlorine atom or an alkoxy group containing 1 to 4 carbon atoms and Y _{2 represents a} hydrogen, fluorine or chlorine atom,

R ₃ is hydrogen or phenylcarbonyl, -CH (R ₅ ) OR ₆ , -C (O) OR ₇ or -C (O) R ₇ , and in the latter three R _{5 is} hydrogen or methyl, R _{6 is} Alkyl or benzyl group containing 3 carbon atoms, alkyl or benzyl group containing 1 to 4 carbon atoms, R ₇ having anti-inflammatory activity, and some of these compounds also exhibit analgesic activity. This latter adjunctive property is highly desirable in the treatment of arthritis or related conditions, however, analgesic compounds may also be used for "mere" analgesia.

Preferred compounds of formula I are those wherein one of R 1 and R ₂ is one of formula IV and the other is phenyl. Even more preferred are the compounds of formula I wherein R ₁ and R ₂ both contain a group of formula IV. Further preferred compounds are those compounds of formula (IV) wherein Y; is fluoro or chloro or methoxy and is particularly preferably in the para position while Y ₂ is hydrogen. Particularly preferred are compounds of formula I wherein R _{3 is} hydrogen.

Particularly preferred compounds are those wherein R _{3 is} hydrogen, while R 1 and R ₂ are both 4-fluorophenyl or 4-methoxyphenyl.

The compounds of formula (I) according to the invention are prepared by first reacting a 4,5-disubstituted imidazole derivative of formula (II) wherein R 1 and R ₂ are as defined above with a protecting group such as benzyl chloromethyl. ether, 2-chloro-tetrahydrofuran, dihydropyran, benzenesulfonyl chloride or ethyl vinyl ether (Scheme A). The compounds (III) of the formula 4,5-disubstituted-1 - (substituted with a protective group) -inüdazol derivative - wherein R, and _R2 are as defined above, and A represents the protecting group Pr - then a strong base such as n-butyl lithium, followed by dinitrogen tetroxide or other suitable nitrating agent such as acetyl nitrate or an alkyl nitrate. By appropriate selection of the protecting group and the processing conditions, a compound of formula (I) wherein R ₃ is hydrogen may be directly isolated (see Scheme B).

Alternatively, compounds of formula (I) wherein R ₃ is other than hydrogen are prepared by reacting a compound of formula (I) wherein R ₃ is hydrogen with a compound of formula (R ₃ -X) wherein R ₃ represents R equal ₃ report, but other than hydrogen and X is a leaving group - directly alkylated or acylated, optionally in the presence of a base such as potassium carbonate, pyridine, triethylamine, potassium tert-butoxide or 2 methyl lithium in the presence of ( Scheme C). The reaction may be carried out using the reagents themselves as a solvent or in the presence of an inert solvent such as dimethylformamide, ethylene glycol monomethyl ester, tetrahydrofuran, pyridine or methylene chloride. The reaction temperature may range from -78 ° C to the reflux temperature of the solvent or reagent used (when excess is used as a solvent). Examples of compounds of formula R ₃ -X include aralkoxymethyl halides (e.g., benzyloxymethyl chloride), acfoxymethyl halides (e.g., chloromethyl pivalate), dihydropyran, 2-chloro-tetrahydrofuran, alkyl chloroformates (e.g. ethyl chloroformates), alkanoic anhydrides and alkanoyl halides (e.g. acetic anhydride); aroyl halides (e.g. benzoyl chloride).

The 4,5-disubstituted imidazole derivatives of formula (II) are commercially available or are known in the art, for example, from Bredereck, H. et al., Bér., 86, 88 (1953) and ibid, 92, 338 (1959). ) may be prepared by methods described in the literature.

The invention is further illustrated by the following embodiments.

Example 1

4,5-bis (4-Fluorophenyl) -2-nitroimidazole

A mixture of 124 g (0.484 mole) of 4,5-bis (4-fluorophenyl) imidazole, 84 g (1.0 mole) of dihydropyran and 20 g of boron trifluoride diethyl ether complex in 1 liter of ethyl acetate was refluxed. using a boil over a weekend. Thin layer chromatography (ethyl acetate as the eluent) indicated that no starting material was detected. Thus, 20 g (nearly 0.24 mol) of dihydropyran and 5 g of boron trifluoride-diethyl ether complex are added to the reaction mixture, which is refluxed overnight. The reaction mixture was then diluted with 1 L of diethyl ether and washed 3 times with 1 L of 10% sodium bicarbonate solution. The organic phase is then dried and evaporated in a rotary evaporator. The resulting residue was recrystallized from methylcyclohexane (to remove some insoluble starting material by filtration) to give 140.2 g (85%) of 4,5-bis (4-fluorophenyl) -1- (m.p. 149-152 ° C) as a white solid. - (2-tetrahydropyranyl) -imidazole was obtained. The F-NMR test showed a purity of about 95%. A small amount is chromatographed to isolate the pure product, m.p. 158-159 ° C.

IR spectrum: 3.25 μ (= CH), 3.38, 3.49 μ (saturated CH), 6.22, 6.28, 6.41, 6.60, 6.69 μ QC-CC and / or -C = N), 8.20µ (CF), and 9µ region (COC). 1 H-NMR: m (1.4-2.1 δ, 6H), m (3.4 δ, 1H), m (4.0 δ, 1H), m (4.7 δ, 1H), m ( 6.6-7.5 δ, 8H) and s (7.8 δ, 1H). F NMR: two multiplets (112.4 and

116.5 δ, each decomposed into singlet).

-2181871

17.0 g (50 mmol) of 4,5-bis (4-fluorophenyl) -1- (2-tetrahydropyranyl) -imidazole, 6.4 g (55 mmol) of Ν, Ν, Ν ', Ν'-tetramethylene 35 ml (55 mmol) of a 1.6 M solution of butyl lithium in diethyl ether are added dropwise to a stirred mixture of dimethyl ether and 200 ml of diethyl ether, and 7.9 g (15 ml) are added dropwise after stirring for 15 minutes. A solution of N2O (86 mmol) in diethyl ether (50 mL) was added. The reaction mixture was allowed to warm to room temperature and partitioned between 5% aqueous sodium bicarbonate and diethyl ether. The ethereal phase was separated, dried and evaporated to give 21.7 g of an amber oil.

The oil was then refluxed in a mixture of ethanol (125 mL) and aqueous hydrochloric acid (10 mL) for a few minutes, and the reaction mixture was concentrated in vacuo. Chromatography of the residue and recrystallization from toluene gave 6.1 g of the title compound, m.p. 245-246 ° C.

Infrared, H-NMR and F-NMR spectra confirm the expected structure.

Analysis results for C ₁₅ H ₉ F ₂ N ₃ O ₂ ;

Calculated: C, 59.81; H, 3.01;

N = 13.95%;

Found: C, 60.21; H, 3.03;

N, 13.55%.

calculated: 325, 1062, found: 325, 1030.

Example 2

4,5-bis (4-Methoxyphenyl) -2-nitroimidazole

As described in Example 1, first paragraph, 4,5-bis (4-methoxyphenyl) imidazole was obtained in 50% yield as a white precipitate of 4,5-bis (4-methoxy) m.p. 123-125 ° C. -phenyl) -1- (2-tetrahydropyranyl) -imidazole.

IR spectrum: 3.26 µ (= CH), 3.40, 3.53 µ (saturated CH), 6.17, 6.32, 6.58, 6.68 µ (CC = CC ^ and / or 3C = N), 8.03 μ (aryl-O>, 9.60 and 9.72 μ (COC). 1 H-NMR: m (1.3-2.1 δ, 6H), two singlets (3 , 75-3.85 δ, 6H), m (3.2-4.2 δ, 2H), triplet (4.85 δ, 1H), two Δ ₂ B ₂ quartets (6.7-7.6 δ, 8H) and s (7.85 δ, 1H).

Analysis results for C ₂₂ H ₂₄ N ₂ O ₃

r John: ) date: C = 72.51% N, 7.69%; H = 6.64%, found: C = 72.32% N, 7.37%. H = 6.35%, 1. described in Example 14.5 g of 4.5-

-his (4-methoxyphenyl) -1- (2-tetrahydropyranyl) imidazole can be converted to the title compound. Chromatography gives an analytically pure sample, m.p. 174 ° C (dec.).

The IR and NMR spectra were consistent with the expected structure.

Mass spectrum for C ₁₇ H ₅ N ₃ O ₄ :

Example 3

To a mixture of 4 <4-Fluorophenyl) -5- (2-thienyl) -2-nitro-imineazole (100 g, 0.65 mol) in 4-fluorophenylacetic acid and 260.0 g of thiophene heated to 40 ° C Trifluoroacetic anhydride (150.0 g, 0.71 mole) was added dropwise and the reaction mixture was refluxed, cooled and poured onto ice. After drying over carbonate and evaporating to give 150.5 g of an oil, crystallization from methanol gives 94.1 g of 2- (4-fluorophenyl) -1- (2-thienyl) ethanone, m.p. 60-61 ° C. C.

Calcd for C ₉ H _f2 FOS formula:

Calculated: C, 65.45; H, 4.09;

found; C = 65.45%, H = 4.06%.

To a solution of 2- (4-fluorophenyl) -1- (2-thienyl) ethanone (94.1 g, 0.43 mol) in diethyl ether (700 mL) was added dropwise bromine (65.0 g, 0.41 mol). A solution of methylene chloride (140 mL) was stirred at room temperature under stirring and the solvent was evaporated in vacuo to give 125.0 g of 2-bromo-2- (4-fluorophenyl) -1- (2-thienyl) ethanone.

A mixture of the thus obtained 2-bromo-2- (4-fluorophenyl) -1- (2-thienyl) ethanone and 465 ml of formamide was refluxed for 2 hours and then allowed to cool to room temperature.

73.3 g of 4- (4-fluorophenyl) -5- (2-thienyl) imidazole, m.p. 182-189 ° C, are isolated. Recrystallization from nitromethane gives an analytically pure sample, m.p. 200-202 ° C.

1 H-NMR: m (6.9-7.7 δ, 7H) and s (7.8 δ, JH). Analysis results for C ₁₃ H ₉ N-FS:

Calculated: C, 63.93; H, 3.69;

N, 11.48%;

Found: C, 63.43; H, 3.82;

N, 11.56%.

In the same manner as in the first paragraph of Example 1, 3 5.0 g of 4- (4-fluorophenyl) -5- (2-thienyl) imidazole 5 6.6 g of 4- (4-fluorophenyl) -5 - ( 2-thienyl) -1- (2-tetrahydropyranyl) imidazole. Chromatography on neutral alumina (Woelm activity: Grade I) with chloroform as eluent afforded 30.0 g of pure material which was a mixture of two isomers.

1 H-NMR: m (1.4-2.1 δ, 6H), m (3.3 6, 1H), m (4.0 δ, 1H), m (4.8 δ, 1H), m ( 6.7-7.7 δ, 7H) and 2s (7.9 δ, 1H).

In the same manner as in Example 1, 30.0 g of 4- (5 '- (4-fluorophenyl) -5 (4) - (2-thienyl) -1 <2-tetrahydropyr

-3181871 nyl-imidazole can be converted to the title compound. Purification is accomplished by dissolving the crude product in 0.2 M aqueous potassium hydroxide solution, filtering the resulting solution and then acidifying it with acetic acid to precipitate an analytically pure sample, m.p. 177.5-179 ° C.

The IR and NMR spectra are consistent with the expected structure.

MS for C ₃ H ₈ FN ₃ O ₂ S Calcd:

Calculated: 289;

found: 289.

Analysis results based on the above formula:

Calculated: C, 53.98; H, 2.77;

N = 14.53%;

Found: C, 54.5; H, 2.84;

N, 14.4%.

Example 4

4- (4- (ethoxyphenyl) -5- (4-fluorophenyl) -2-nitroimidazole

24.4 g (86.5 mmol) of 4- (4-ethoxyphenyl) -5- (4-fluorophenylindioxole), 12.5 g (0.173 mol) of ethyl vinyl ether and

A mixture of dichloroacetic acid (11.2 g, 86.8 mmol) in toluene (175 mL) was heated at reflux for a few hours, then cooled to room temperature and stirred with 20% aqueous sodium hydroxide (85 mL) overnight. The toluene layer was separated and washed several times with water, dried over anhydrous potassium carbonate and concentrated to give 21.6 g of 4- (5X4-ethoxyphenyl) -5 (4) - (4-fluorophenyl) -1 as an oil. - (1-Ethoxyethyl) imidazole was obtained. The oil was purified by chromatography on neutral alumina (Woelm activity: Grade I), eluting with chloroform, to give 18.0 g of pure material. 1 H-NMR: m (1.0-1.8 δ, 9H), q (3.2δ, 2H), q (4.1 δ, 2H), q 5.1 δ, 1H), m = (6 , 7-7.7 δ, 8H) and s (7.8 δ, 1H).

In the same manner as in Example 1, 8.5 g of 4- (5) - (4-ethoxyphenyl) -5- (4X4-fluorophenyl) -1- (1-ethoxyethyl) imidazole was converted to the title compound. The IR and NMR spectra are consistent with the expected structure. Chromatography on Silica-AR with chloroform as eluent followed by recrystallization from 1-chlorobutane gave an analytically pure sample, m.p. 176 ° C (dec.).

MS for C ₁₇ H ₁₄ N ₃ FO ₃ Calcd:

Calculated: 327;

found: 327.

Analysis results based on the above formula:

Calculated: C, 62.39; H, 4.28;

N = 12.84%;

Found: C, 62.4; H, 4.33;

N, 12.6%.

Example 5

4- (3,4-Dichlorophenyl) -5-phenyl-2-nitroimidazole

Under a nitrogen atmosphere, 14.5 g (50 mmol) of 4- (3,4-dichlorophenyl) -5-phenylimidazole, 10 mL (100 mmol) of ethyl vinyl ether and 4.2 mL (50 mmol) of dichloroacetic acid in 100 mL The toluene mixture was refluxed for 1 hour, and after cooling, the reaction mixture was treated with 50 ml of 20% aqueous sodium hydroxide solution. The resulting mixture was then stirred overnight and allowed to stand at room temperature for two days. The organic phase is then washed with water, dried over anhydrous potassium carbonate and evaporated in a rotary evaporator to give 4- (5X3,4-dichlorophenyl) -5- (4-phenyl-1- (1-ethoxyethyl) imidazole as an oil).

1 H-NMR: 1.13 (t, J = 7Hz, 3H), 1.63 (d, J = 6Hz, 3H), 3.3 (2q, J = 7Hz, 2H), 5.13 (q, J = 6 Hz, 1H), 7.28-7.8 (m, 8H) and 7.91 δ (s, 1H).

In a nitrogen atmosphere, 50 mmol of 4 (5) - (3,4-dichlorophenyl) -5- (4Xenyl-1- (1-ethoxyethyl) imidazole and

To a solution of 7.5 ml (55 mmol) of Ν, Ν, Ν ', Ν'-tetramethylethylenediamine in 200 ml of tetrahydrofuran and cooled to -78 ° C was added dropwise 41 ml (65 mmol) of 1.6M n- butyl lithium solution and, after stirring for 15 minutes, a solution of 7 ml (110 mmol) of dinitrogen tetroxide in 25 ml of diethyl ether are also added dropwise. The reaction mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. The dark reaction mixture was poured into saturated aqueous sodium bicarbonate (300 mL) and the aqueous mixture was extracted with diethyl ether. The extract was washed with brine, dried and divided into two portions (3: 1 by volume). The major portion was evaporated in a rotary evaporator and the resulting residue was redissolved in 125 mL of ethanol, 30 mL of n hydrochloric acid was added to the ethanolic solution and the resulting mixture was refluxed for 10 minutes. The mixture was cooled to room temperature and diluted with water (35 mL). The precipitated crystals are filtered off, washed with 0.1 N potassium hydroxide solution and recrystallized from methylene chloride to give 1.2 g of the title compound, m.p. 248-249 ° C.

The IR &lt; 1 &gt; H-NMR spectrum was consistent with the expected structure. In its mass spectrum, the value corresponding to M ⁺ is 333.

Analysis results based on the formula Ci _S H ₉ N ₃ O ₂ Cl ₂ :

Calculated: C, 53.91; H, 2.71;

N, 12.58%;

Found: C, 53.86; H, 2.54;

N, 12.67%.

Example 6

4- (4-Fluorophenyl) -5- (3-pyridyl) -2-nitroimidazole

With stirring at room temperature, a solution of 0.9 mol sodium ethylate in 250 ml ethanol

A mixture of 82.0 g (0.6 mol) of methyl nicotinate and 81.0 g (0.6 mol) of 4-fluorobenzyl cyanide was added dropwise, and the reaction mixture was refluxed overnight and then cooled. and pour it into ice water. The aqueous mixture was washed with diethyl ether and then acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with water. A mixture of the precipitate in 350 ml of 48% hydrobromic acid was heated at reflux overnight, allowed to cool to room temperature and the precipitated crystals were filtered off. The crystals were then suspended in water and basified with concentrated ammonium hydroxide. The reaction mixture was extracted with diethyl ether and the extract was dried over anhydrous potassium carbonate and concentrated to give (4-fluorobenzyl) (3-pyridyl) ketone (77.9 g) as colorless crystals, mp 64-65 ° C. . IR spectrum: 6.0 m (2X = O). 1 H-NMR (4.3 δ, 2H), m (6.9-7.6 δ, 5H), d / t (8.2 δ, 1H), d / d (8.8 δ, 1H ) and d (9.3 δ, 1H).

To a solution of (4-fluorobenzyl) (3-pyridyl) ketone (15.0 g, 69.8 mmol) in acetic acid (120 mL) was added dropwise a solution of bromine (12.3 g, 76.9 mmol) in acetic acid (120 mL) at room temperature. while stirring overnight, 18.4 g of a-bromo- (4-fluorobenzyl) - (3-pyridyl) ketone hydrobromide were isolated by filtration.

A mixture of the latter compound in formamide (150 mL) was refluxed under nitrogen for 2 hours, then allowed to cool to room temperature and poured into water. The aqueous mixture was made basic with sodium carbonate and extracted with diethyl ether. The extract was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous potassium carbonate and evaporated,

7.5 g of 4- (4-fluorophenyl) -5- (3-pyridyl) imidazole are obtained. The product was chromatographed on neutral alumina (Woelm activity: Grade I) using ethyl acetate / tetrahydrofuran as eluent and crystallized from diethyl ether to give 2.2 g of pure product, m.p. 154-156 ° C. .

1 H-NMR: m (6.8-7.58δ, 5H), s (7.6 δ, 1H), d / t (7.8 δ, 1H), d / d (8.4 δ, 1H) and d (8.7 δ, 1H). Analysis results for C ₁₄ H ₁₉ FN ₃ :

Calculated: C, 70.29; H, 4.18;

N, 17.57%;

Found: C, 70.3; H, 4.43;

N, 18.0%.

Alternatively, a solution of 28.8 g of α-bromo (4-fluorobenzyl) (3-pyridyl) ketone hydrobromide and 40.0 g of potassium acetate in 50 ml of acetic anhydride was stirred at room temperature overnight and then poured into water. The aqueous mixture was extracted with diethyl ether and the extract was washed first with water, then with 10% aqueous sodium bicarbonate solution, dried over anhydrous potassium carbonate and evaporated. A solution of the resulting residue in 250 ml of 1 N aqueous hydrochloric acid was refluxed for 30 minutes, then cooled and made basic with solid sodium carbonate. The reaction mixture was extracted with diethyl ether and the extract was dried over anhydrous potassium carbonate and evaporated to give 16.5 g of α-hydroxy (4-fluorobenzyl) (3-pyridyl) ketone.

An amount of 16.5 g of the latter compound is then reacted with 12.5 g of ammonium thiocyanate in 1 propanol, and the reaction mixture is refluxed. Yield: 11.3 g of 4- (4-fluorophenyl) -5- (3-pyridyl) -1H-2-thiimidazole, m.p. 335-338 ° C.

8.2 g of the latter compound are added in small portions to 30 ml of 35% nitric acid solution at room temperature, and the resulting mixture is stirred overnight, diluted with water and made basic with sodium carbonate. The reaction mixture was extracted with ethyl acetate and the extract was dried over potassium carbonate to give 4- (4-fluorophenyl) -5- (3-pyridyl) imidazole (5.3 g).

Then, as described in the first paragraph of Example 4, 1.5 g of 4- (4-fluorophenyl) -5- (3-pyridyl) imidazole was then treated with 4 (5) - (4-fluorophenyl) -5 (4). ) - (3-pyridyl) -1- (1-ethoxyethyl) imidazole. Chromatography on neutral alumina (Woelm activity: grade I) with tetrahydrofuran as the eluent affords the pure product.

1 H NMR (1.2 δ, 3H), d (1.6 δ, 3H), m (3.0-3.4 δ, 2H), q (5.1 δ, 1H), m ( 6.8-7.5 δ, 5H), t (7.7 δ, 1H), d / d (8.4 δ, 1H), s (7.8 δ, 1H) and d (8.7 δ) , 1H).

In the same manner as in Example 1, 1.0 g of 4 (5) - (4-fluorophenyl) -5 (4) - (3-pyridyl) -1- (1-ethoxyethyl) imidazole was converted to the title compound. Rf = 0.19 for TLC on silica gel G with 90:10 ethyl acetate: methanol.

Example 7 1-Benzoyl-4,5-bis (4-methoxyphenyl) -2-nitroimidazole

In a nitrogen atmosphere at 0 ° C, 3 g (9.2 mmol)

To a solution of 4,5-bis (4-methoxyphenyl) -2-nitroimidazole and 3.9 mL (27.6 mmol) of triethylamine in 30 mL of tetrahydrofuran is added dropwise 1.2 mL (10.1 mmol) benzoic chloride in 5 ml of tetrahydrofuran was added and the reaction mixture was stirred at 0 ° C for 8 hours and then allowed to stand overnight in a refrigerator. The reaction mixture was diluted with diethyl ether (30 mL) and filtered. The filtrate was evaporated in a rotary evaporator and the residue chromatographed on Florisil. Recrystallization from methylcyclohexane gave 1.89 g of the title compound, m.p. 161-163 ° C.

IR: 1745 cm ^-1 . 1 H-NMR: 3.73 (s, 3H), 3.75 (s, 3H) and 6.67-7.83 δ (m, 13H). Mass Spectrum M ^{@ +} : 429.

Analysis results for C ₂₄ H ₁₉ N ₃ O _S :

H, 4.46; C, 67.12; H, 4.46;

N = 9.7%;

Found: C, 67.2; H, 4.40;

N, 9.5%.

Example 8 l-ethoxycarbonyl-4,5-bis (4-methoxyphenyl) -2-nitroimidazole ¹⁰

To a solution of 1.5 g (4.6 mmol) of 4,5-bis (4-methoxyphenyl) -2-nitroimidazole in 25 ml of pyridine at 0 ° C is added dropwise 1.5 ml (156 mmol) of chloroformic acid ethyl ester was added and the reaction was allowed to stand at 0 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 3N hydrochloric acid, three times with saturated sodium bicarbonate solution and once with brine, dried and concentrated in a rotary evaporator. The residue was chromatographed on Florisil (487 mg) to give the title compound as an oil.

IR: 1795 ^cm-first 1 H-NMR: 1.21 (t, 25 J = 7Hz, 3H), 3.7 (s, 3H), 3.8 (s, 3H), 4.3 (q,

J = 7 Hz, 2H) and 6.6-7.76 δ (2 AB quartet, J = 8 Hz, 8H). Mass Spectra M ⁺ 397.

Example 9 1-Acetyl-4,5-bis (4-methoxyphenyl) -2-nitroimidazole

To a solution of 3.0 g (9.22 mmol) of 4,5-bis (4-methoxyphenyl) -2-nitroimidazole and 7 mL (51 mmol) of triethylamine in 30 mL of tetrahydrofuran under nitrogen atmosphere at 0 ° C add drop by drop

1.3 ml (18.4 mmol) of acetyl chloride in 5 ml of allowed tetrahydro- ⁴⁰ furan was added and the mixture was stored at 0 ° C • for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with n hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried ( ⁴⁵⁾ and concentrated in a rotary evaporator. Crystallization from diethyl ether yields about 600 mg of starting material. The mother liquor was subjected to high performance liquid chromatography followed by crystallization from diethyl ether to give the title compound, mp 146-151 ° C. H NMR showed purity greater than 95%.

1 H-NMR: 2.41 (s, 3H), 3.8 (s, 3H) and 6.73-7.56 δ, (2 AB quartets, J = 9 Hz, 8H).

Example 10 1- (1-Ethoxyethyl) -4,5-bis (4-methoxyphenyl) -2-nitroimidazole

In a nitrogen atmosphere, 1 g (3.08 mmol) of 4,5-bis (4-methoxyphenyl) -2-nitroimidazole, Imi (6.16 mmol) of ethyl vinyl ether and 0.3 mL (3.08 mmol) of dichloroacetic acid (10 mmol) in toluene (10 ml) was refluxed for 1 hour, cooled, ethyl vinyl ether (2 ml) was added and refluxing continued overnight. The reaction mixture was cooled, stirred with 5 ml of 20% sodium hydroxide solution for 24 hours, then the organic phase was separated, washed with water and brine, dried over anhydrous potassium carbonate and evaporated in a rotary evaporator. The residue was chromatographed on Florisil to give 178 mg of the title compound as an oil.

1 H-NMR: 1.08 (t, J = 7H ₂ , 3H), 1.65 (d, J = 6H ₂ , 3H), 3.4 (q, J = 7H, 2H), 3.73 (s, 3H), 3.86 (s, 3H),

5.9 (q, J = 6H _2, 1H) and δ 6.6 to 7.36 (two AB-quartet, 8H). Mass Spectrum: 352 (M-OC ₂ H ₅ ), 325 (MC ₂ H ₃ OC ₂ H ₅ ).

The anti-inflammatory and analgesic compounds of the present invention may be administered to the body for the treatment or alleviation of arthritis and / or pain by any means which provides a suitable relationship between the mammal and the active ingredient. The compounds of formula (I) obtained by the process of the present invention can be used in any of the customary formulations used in pharmaceutical preparation. These formulations may contain one or more active ingredients. In some cases, the compounds of formula (I) may be administered alone, but will generally be administered in conjunction with customary carriers and / or excipients selected according to the route of administration and pharmaceutical practice.

The dose administered to the body will, of course, depend on known factors such as the pharmacodynamic properties of the active ingredient; the route and route of administration; the age, health, weight, nature and degree of symptoms of the treated subject; the nature of the other treatment being administered at the same time; the frequency of treatment and the desired therapeutic effect. Typically, the daily dose of the active ingredient will range from about 0.1 mg to about 100 mg per kilogram body weight; it is desirable to administer from 0.1 to 50 mg, preferably from 1 to 25 mg, of active ingredient per kilogram of body weight per day, divided into 2 to 4 times daily or in a delayed-release formulation.

Dosage forms for internal administration contain from about 1 mg to about 500 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5% to about 95% by weight of the total composition.

The active compounds may be administered orally in the form of solid pharmaceutical preparations (e.g. capsules, tablets and powders) or liquid pharmaceutical preparations (e.g. elixirs, syrups or suspensions) or may also be administered parenterally in the form of sterile liquids.

Among the solid pharmaceutical compositions, gelatin capsules contain the active ingredient, as well as powdered carriers and excipients such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate or stearic acid. Similar excipients may also be used to make compressed tablets. Both pills and

-613 capsules can be formulated as sustained release products that release the active ingredient over a period of several hours. Compressed tablets may be coated with sugar or other protective layer to mask the unfavorable taste or to protect the tablet from the atmosphere, or may be coated with a coating that permits selective disintegration in the gastrointestinal tract.

Liquid pharmaceutical preparations for oral administration may contain coloring and flavoring agents.

Suitable carriers for parenteral solutions include water, suitable oils, sodium chloride solution, aqueous dextrose solution (glucose solution) and the like, and glycols such as propylene glycol or polyethylene glycols. Solutions for parenteral administration preferably contain the active ingredient in the form of a water-soluble salt. They also contain suitable stabilizing agents and, if necessary, buffering agents. Suitable stabilizing agents include antioxidants such as sodium bisulfite, sodium sulfite, and ascorbic acid, alone or in combination. In addition, citric acid and its salts as well as the sodium salt of ethylenediaminetetraacetic acid can be used. Solutions for parenteral administration may also contain preservatives such as benzalkonium chloride, methyl and propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described by Martin, E.W. in Remington's Pharmaceutical Sciences as a reference work in this field.

The following are some formulations for the preparation of useful pharmaceutical compositions.

capsules

A large number of capsules are prepared by filling each of two conventional hard gelatin capsules with 50 mg of powdered active ingredient, 175 mg of lactose, 24 mg of talc and 6 mg of magnesium stearate.

capsules

A mixture of the active ingredient is prepared with soybean oil and the resulting mixture is injected into a gelatin by means of a forced-pump to produce soft gelatin capsules, each containing 50 mg of the active ingredient. The capsules are finally washed with petroleum ether and dried.

tablets

A large number of tablets are prepared in a conventional manner such that a unit dose contains 50 mg of active ingredient, 6 mg of magnesium stearate, 70 mg of microcrystalline cellulose, 11 mg of corn starch and 275 mg of lactose. The tablets may be coated with a suitable coating to increase digestibility or delay release of the active ingredient.

Solution for injection

An injectable parenteral preparation is prepared by dissolving 1.5% by weight of the active ingredient in 10% by volume of propylene glycol in water and sterilizing the resulting solution by filtration. Suspension

An aqueous suspension for oral administration is prepared by administering 10 mg of finely powdered active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP) and 0.025 ml per 5 ml. contain vanilla.

Solution for injection

An injectable parenteral preparation is prepared by dissolving 1% by weight of the active ingredient in sodium chloride solution for injection (US Pharmacopoeial quality), adjusting the pH of the resulting solution to between 6 and 7, and finally sterilizing the solution by filtration.

For the purpose of comparing the anti-inflammatory activity of the compounds of formula (I) with known compounds, an experimental method which has a good correlation with human efficacy in arthritis is used. The aim of the experimental method was to investigate the effect of adjuvant-induced arthritis in rats. Federation Proceedings, Volume 32, Number 2 (1973), states that "Minerals of Mycobacterium tuberculosis" polyadthritis in rats by intradermal injection of a suspension of oil (adjuvant) can be widely used to test drugs that are believed to be useful in the treatment of rheumatoid arthritis. '

Thus, the experiments are performed as follows. Male rats weighing 130-150 g, Charles River Lewis, were injected subcutaneously with 0.1 m adjuvant (lyophilized in Difco apparatus, lyophilized at 5 mg / ml in mineral oil). Twenty non-arthritic control animals were injected with only mineral oil. Animals are kept for two weeks so that arthritis can develop. The volume of the non-injected left hind paw is determined, and the animals injected with the adjuvant are examined and divided into groups of 10 according to their condition of nearly equal severity. Non-arthritic control animals were divided into two groups of 10. The rats are dosed orally with a solution of the active ingredient or 1% polyvinyl alcohol in the same day and for six consecutive days at a dose of 10 ml / kg body weight and 5% gum arabic (U.S. Pat.

-7181871 Pharmacopoeia quality) and contains 0.5% methyl paraben. One day after the last dose, the paw volumes are measured using a Ugo Basile Model 7101 Differential Volumeter.

arthritic control mean paw - volume (ml) arthritic control _ average paw volume (ml) = mean paw volume (ml) of the group treated relative to tooth

- 100 = Non-arthritic control mean paw volume (ml) Control mean pawThe dose response curves from percentage reductions on semi-logarithmic paper are visualized and the ED ₅₀ is determined. For some compounds of formula I and known comparators, the values obtained are shown in Table II. Table.

II. spreadsheet

Example number ED ₅₀ (mg / kg)

1 0.6 (1.3) 2 2.5 indomethacin 0.3 phenylbutazone 10 ibuprofen 100 Aspirin 305

To investigate the analgesic effect of the compounds of formula I, the phenylquinone uptake assay modified by Siegmund et al., Proc. Soc Exp Bioi. Med., 95, 729 (1975)], as this assay is well correlated with human efficacy. Using 5-20 animals per double-blinded experimental method, white female mice, fasted for 17-21 hours, were orally suspended in 1% methylcellulose solution and 24 minutes later in 0.2 ml of 0.01% aqueous solution per mouse. a solution of phenyl p-benzoquinone is injected intraperitoneally. After 30 minutes of oral administration of the test compound, mice are observed for 10 minutes for the characteristic jerky or trembling syndrome, which is characterized by phenyl p-benzoquinone pain. Thompson, WR moving average method [Bact. Rev., 11, 115-145 (1947)], then calculates 8 effective analgesic doses, i.e., ED _SO , for 50% of the mice, but also peak times for many compounds. The results obtained are shown in Table III. Table.

III. spreadsheet

The number of the example _ED50 ⁺ 1 59 (30) 2 <130

+ mg / kg unit at 0.5 hour

Claims (2)

Patent claims: A process for the preparation of imidazole derivatives of the formula (I): R 1 and R ₂ are independently 2-thienyl, 3-pyridyl, 25 is phenyl or IV, provided that at least one is IV, Y 1 is fluoro or chloro, or C 1-4 alkoxy 30 and Y _{2 is} hydrogen, means fluorine or chlorine, R ₃ represents a hydrogen atom or a phenyl group, -CH (R _{s) OR6,} -C (O) _OR7 or -C (0) _R7 cso35 port, which latter three groups, R ₅ is hydrogen or methyl, R ₆ alkyl or benzyl, _R7 is an alkyl group having 1-3 carbon atoms or benzyl group having 1-4 carbon atoms for the preparation of 40, wherein (III) compound of general formula - wherein R and _R2 are as defined above, and Pr represents a protecting group - nitrate, protecting group 45 is removed and, if desired, a resulting compound of the formula R ₃ is hydrogen, (I) a (R ₃ X) a compound of formula - wherein the same R ₃ is R ₃ report, but other than hydrogen, and X represents a leaving group X - alkylating or acylating. A process for the preparation of a pharmaceutical composition, characterized in that it is as claimed in claim 1 A process for the preparation of an imidazole derivative represented by the general formula (I) obtained by the method of (55) R 1 and R ₂ are each independently 2-thienyl, 3-pyridyl, phenyl or IV, with the proviso that at least one of them is of formula IV, and in the latter, Y 1 is fluoro; or a chlorine atom or an alkoxy group containing 1 to 4 carbon atoms and Y _{2 a} hydrogen, fluorine or chlorine atom 65 mean, -817 lg R ₃ represents a hydrogen atom or a phenyl group, -CH (R) OR _6, -C (O) _OR7 or -C (O) _R7 group, the three latter groups, and R _s is hydrogen, _R6 1-3 alkyl or benzyl, _R7 is an alkyl or alkyl benzyl group having from 1 to 4 carbon atoms containing 5 represents - carrier * and / or in admixture with excipients are made into a pharmaceutical preparation conventionally used in the pharmaceutical industry. Figure 2 page Responsible for publishing: Economics and Law Publishing Company $ 84,4453 - Zrínyi Nyomda, Budapest -9181871 International classification: C 07 D 233/91, 401/04, 405/04, 409/04 The reaction scheme