CH638791A5 - METHOD FOR PRODUCING SPECIFIC IMIDAZOLE DERIVATIVES AND USE THEREOF. - Google Patents

Description

The invention relates to a method for producing special imidazole derivatives and to the use thereof.

In US-PS 3707 475 anti-inflammatory 4,5-diaryl-2-substituted imidazoles are described.

U.S. Patent 3,505,350 describes anti-inflammatory 4-alkyl-5-aryl-1-substituted 2-mercapto-imidazoles.

In Chem. Ber. 106 (1973) 1638, 4,5-bis (4-methoxyphenyl) -2-methylthioimidazole and 4,5-bis (4-chlorophenyl) -2-methylthioimidazole are described, but no information is given on the uses of these compounds.

In a number of publications, e.g. Current Be. India 17 (1948) 184-85 and Acta Chem. Acad. Be. Hung. 79 (2) (1973) 197-212 describes 2- (substituted-thio) -4,5-diphenyl-imidazoles with substituents such as methyl, propyl, allyl and acetonyl.

There is an ongoing need for safe and effective anti-inflammatory agents; inflammation is a disease process characterized by redness, fever, swelling and pain. Arthritis in its various forms is the most prevalent, chronic, and severe inflammatory disease. Traumatic injuries and infections are also associated with inflammation, and anti-inflammatory drugs are often used to treat them. The benefits of most commercially available anti-inflammatory agents are limited by toxicity and adverse side effects. Many of these agents cause gastric irritation and other effects, e.g. Changes in blood cells and the central nervous system. Adrenocortical steroids cause gastric irritation and suppression of normal kidney function.

The publication "Primer on the Rhematic Diseases" in Journal of the American Medicai Association, volume 224, no. 5 (supplement), 1973, states that "immunological reactions seem to play a greater role in the persistent duration of rheumatoid inflammation . » Commonly used non-steroidal anti-inflammatory agents such as Aspirin, indomethacin, phenylbutazone and ibuprofen have no effect on these immunological reactions, but only relieve the symptoms of the inflammatory reaction. These drugs do not stop the progressive and ultimately destructive processes of rheumatoid arthritis. Immunosuppressive drugs, e.g. Cyclophosphamide, are effective for the treatment of rheumatoid arthritis, but too toxic for widespread use.

The imidazole derivatives obtained in the process according to the invention are those of the formula (I)

20th

25th

S (0) "- Ri

(HD

with the same characterizations for R1; R2 and R3. Said use according to the invention is characterized in the preceding claim 9.

The exception in claim 1, according to which, when Yx 30 and Y2 are hydrogen, Rt cannot be vinyl, is based on the prior publication according to Russian Patent No. 480 073, which is a process for the preparation of compounds of the formula

35

40

S-CH = CH,

teaches with R H or vinyl.

It has been shown that the vinyl thio derivatives mentioned are only weakly active if both aromatic groups are Ph 4-methoxyphenyl. Due to considerations regarding the relationship between structure and activity, the exceptions mentioned are postulated.

Compounds in which Rx is a group of the formula -CF2CF2H are preferred on the basis of their activity.

Also preferred are compounds in which R2 and R3 are independent for

55

where Yt is H, Cl or F.

Also preferred are compounds in which n has the value 1 or 2.

More preferred are compounds in which Rj is -CF2CF2H and R2 and R3 are independently

65

638791

where Yj is H, Cl or F and n d'en is 0, 1 or 2.

Particularly preferred because of the ease of synthesis are compounds in which Rj for -CF2CF2H,

R2 and R3 are independently where Yx is H, Cl or F, and n is 0 or 2.

The following compounds are particularly preferred: 4,5-diphenyl-2- (l, l, 2,2-tetrafluoroethylthio) imidazole

(from the process according to claim 1) and 4,5-bis- (4-f luorphenyl) -2- (i, 1,2,2-tetrafluoroethylsulfonyl) imidazole,

4 (or 5) - (4-fuorphenyl) -5 (or 4) -phenyl-2- (l, l, 2,2-tetra-

fluoroethylsulfonyl) imidazole, 4,5-bis (4-chlorophenyl) -2- (l, l, 2,2-tetrafluoroethylsulfonyl) imidazole,

4 (or 5) - (4-chlorophenyl) -5 (or 4) -phenyl-2- (l, l, 2,2-tetra-

fluoroethylsulfonyl) imidazole,

4,5-diphenyl-2- (1,1,2,2-tetraf Iuoräthylsulfonyl) imidazole, 4,5-bis (4-methoxyphenyl) -2- (trifluoromethylsulfonyl) imidazole and

4 (or 5) -phenyl-5 (or 4) - (3,4-dichlorophenyl) -2- (l, 1,2,2-

-tetrafluoroethylsulfonyD-imidazole.

(from the use according to the invention according to claim 9).

In addition to the anti-inflammatory and immuno-regulating properties, the compounds obtainable according to the invention show analgesic effects in experiments. This additional property is desirable in the treatment of arthritis and similar diseases. However, these compounds can also be used solely for pain relief.

The following compounds are preferred for their analgesic activity:

s <° VRi

10th

Ri is an alkyl group optionally substituted by at least one halogen atom,

Yj and Y2, which are the same or different, are hydrogen, IS2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chlorine or 4-chlorine,

n is the number 0, 1 or 2.

Within this group, those compounds 20 are preferred in which

Rj is a polyhaloalkyl group with one or two carbon atoms,

Y1 and Y2) which are the same or different, are hydrogen, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chlorine or 25 4-chlorine, at least one of the radicals Yx and Y2 being 4-methoxy or 4 Are ethoxy, and n is the number 0, 1 or 2.

The following compounds are particularly preferred because of their analgesic activity: 4,5-bis (4-methoxphenyl) -2- (l, l, 2-trifluoroethylsulfonyl) imidazole;

4,5-bis (4-methoxyphenyl) -2- (l, 1,2,2-tetrafluoroethylsulfonyl) imidazole;

35 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthio) imidazole; 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfinyl) imidazole;

4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfonyl) imide azole and '

40 4,5-bis (4-methoxyphenyl) -2- (trifluoromethylsulfonyl) imidazole. If R2 and R3 are different, the following two structures are tautomers:

S (°) nRi s (0) -r, n 1

Pharmaceutically acceptable salts of compounds in which n has the value 1 or 2 are the salts with certain metals such as sodium, potassium and calcium. Pharmaceutically acceptable salts of compounds in which n has the value 0 include pharmaceutically acceptable acid addition salts, preferably those formed with mineral acids, in particular those formed with hydrochloric acid, nitric acid or sulfuric acid. The 60 acids preferably have a pKa that is not greater than 2.5. The salts can be prepared by methods known per se for the preparation of salts.

Preferred embodiments of the invention are explained in more detail below with the aid of examples. All An-6S in "parts" and "percent" are - unless otherwise stated - weights.

The examples relate to the preparation of the compounds mentioned in each case.

5

638791

example 1

4,5-diphenyl-2- (2,2,2-trifluoroethylthio) imidazole

A mixture of 71.9 g (0.285 mol) of 4,5-diphenyl-2-mercaptoimidazole, 80.3 g (0.285 mol) of 2,2,2-trifluoroethyl trichloromethanesulfonate, 28.8 g (0.285 mol) of triethylamine and 700 ml of toluene is heated under nitrogen on a reflux condenser for 4 hours. After cooling to room temperature, 13.4 g of 4,5-diphenyl-2-mercaptoimidazole are isolated by filtration. The filtrate is washed twice with water and the product crystallizes by cooling the organic phase. 46.2 g (49%) of the desired compound are obtained as almost colorless crystals with a melting point of 185.5 to 187 ° C.

Elemental analysis for: C17HJ3F3N2S

calculated: C 61.06 H 3.92 N 8.38 found: C 61.28 H 3.97 N 8.49

4,5-Diphenyl-2- (2,2,2-trifluoroethylsulfinyl) imidazole To a mixture cooled in an ice bath of 13.9 g (0.0416 mol) of 4,5-diphenyl-2- (2,2,2 -trifhioräthylthio) -imidazole and 75 ml of chloroform are added dropwise 8.4 g (0.042 mol) of 86.4% m-chloroperbenzoic acid in 85 ml of chloroform. The mixture is stirred overnight and then washed with saturated sodium bicarbonate, dried over magnesium sulfate and freed from the solvent to give 12.3 g of crude product. By recrystallization from toluene, 10.1 g (69%) of the desired compound are obtained in the form of colorless prisms with a melting point of 198 ° C. (dec.).

Elemental analysis for: C17H13F3N2OS

calculated: C 58.28 H 3.74 V P 00 found: C 58.27 H 3.76 'I 8.10

4,5-Diphenyl-2- (2,2,2-trifluoroethylsulfonyl) imidazole To a mixture of 15.7 g (0.0470 mol) cooled in an ice bath of 4,5-diphenyl-2- (2,2,2 trifluoroethylthio) imid-azole and 100 ml of chloroform are added dropwise 19.0 'g (0.0952 mol) of 86.4% m-chloroperbenzoic acid in 200 ml of chloroform. The mixture is stirred for 4 days at room temperature, whereupon tetrahydrofurate! added and the mixture washed with saturated sodium 'onate, dried with magnesium sulfate and freed from solvent, 16.9 g of crude product being obtained. After two recrystallizations from AcetoneUril, 8.8 g (51%) of the desired compound are obtained in the form of colorless needles with a melting point of 228 ° C. (dec.).

Elemental analysis for: C17H13F3N202S

calculated: C 55.73 H 3.58 N 7.65 F 15.56 found: C 56.18 H 3.94 N 7.45 F 15.44 56.06 3.95 7.52

Example 2

4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthioj - imidazole

A mixture of 31.2 g (0.100 mol) of 2-mercapto-4,5-bis - (4-methoxyphenyl) imidazole, 31.0 g (0.110 mol) of 2,2,2-tri-fluoroethyltrichloromethanesulfonate, 11, 1 g (0.110 mol) of triethylamine and 300 ml of toluene are heated under reflux condenser for 6 hours under nitrogen. The mixture is cooled, washed three times with water, dried over magnesium sulfate and concentrated to give 43.4 g of crude product which is chromatographed on a column containing 0.454 kg of silica gel, eluting with chloroform. The residue from the larger fraction is recrystallized from methyl-cyclohexane, 21.5 g (55%) of the desired compound being almost colorless crystals of

Melting point 119-120 ° C can be obtained. A polymorphic form has a melting point of 150-151 ° C. Elemental analysis for: Ci9H17F3N202S:

calculated: C 57.86 H 4.34 N 7.10 5 found: C 57.96 H 4.01 N 7.09

4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfinyl) imidazole

Using 4,5-bis (4-methoxyphenyl) -2-10 - (2,2,2-trifluoroethylthio) imidazole instead of the 4,5-diphenyl-2- (2,2,2-trifluoroethylthio used in Example 1 ) -imidazole is obtained as the product 4,5-bis (4-methoxyphenyl) -2 - (2,2,2-trifluoroethylsulfinyl) imidazole. By recrystallization of the crude product from aqueous ethanol, the pure product of melting point 193.5 ° C. (dec.) Is obtained in a yield of 83%.

Elemental analysis for: c19h17f3n2o3s calculated: C 55.60 H 4.18 N 6.83 found: C 55.52 H 3.80 N 6.77

20th

4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfonyl) imidazole

To a mixture of 6.0 g (0.015 mol) of 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethyl-25 thio) imidazole and 75 ml of chloroform, cooled in an ice bath 1, dropwise 6 , 1 g (0.031 mol) of 86.4% m-chloroperbenzoic acid in 75 ml of chloroform. The mixture is stirred at room temperature overnight and washed with saturated sodium bicarbonate, dried with magnesium sulfate and concentrated to give 7.1 g of crude product. By recrystallization from 1-chlorobutane, the desired pure compound is obtained in the form of colorless needles with a melting point of 173-174 ° C.

Elemental analysis for: C19H17F3N204S 35 calculated: C 53.51 H 4.02 N 6.57 found: C 53.47 H 4.06 N 6.55 63.81 3.69 6.59

40 Example 3

4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) imidazole

A mixture of 32.1 g (0.100 mol) of 4,5-bis (4-chlorophenyl) -2-mercaptoimidazole, 28.1 g (0.100 mol) of 2,2,2-tri-45 fluoroethyl trichloromethanesulfonate, 5.9 g (0.109 mol) of sodium methoxide and 300 ml of ethanol are refluxed for 3 hours. The reaction mixture is poured into water and the solid is filtered off, washed with water and dried. This solid (43.9 g) is then stirred in 400 ml of ethyl acetate for 50 nights. The mixture is filtered and the filtrate is freed from the solvent, whereby 21.7 g of a residue are obtained. This residue is recrystallized from toluene, giving 15.1 g (37%) of the desired pure compound in the form of colorless crystals with a melting point of 212-213 ° C. Elemental analysis for: C17HnCl2F3N2S

calculated: C 50.63 H 2.75 N 6.95 found: C 50.87 H 3.05 N 6.69

60 4,5-bis (4-chlorophenyl) -2 ~ (2,2,2-trifluoroethylsulfinyl) imidazole Using 4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) imidazole instead of 4,5-diphenyl-2- (2,2,2-trifluoroethylthio) imidazole, which was used in the experiment described in Example 1, is used as product 4,5-bis-65 (4-chlorophenyl) - Obtained 2- (2,2,2-trifluoroethylsulfinyl) imidazole. By recrystallization of the crude product from acetonitrile, the pure product of melting point 214 ° C. (dec.) Is obtained in a yield of 77%.

638791

6

Elemental Analysis - "tir: C17HnCl2F3N2OS

calcd: C 48, 70 H 2.64 N 6.68 found: C 48.97 H 2.89 N 6.47

4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoro'ethylsulfonyl) imidazole

To a mixture cooled in an ice bath of 5.3 g (0.013 mol) of 4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) imidazole and 50 ml of chloroform are added dropwise 5.3 g (0.027 mol) 86.4% m-chloroperbenzoic acid in 60 ml of chloroform. The mixture is stirred at room temperature overnight, refluxed for 15 minutes and cooled. The solid is isolated and washed with cold chloroform. The solid is then dissolved in a mixture of ether and tetrahydrofuran and the solution obtained is washed with saturated sodium bicarbonate. The organic phase is dried with magnesium sulfate and freed from the solvent, giving 5.8 g of a colorless solid residue which is recrystallized from 125 ml of nitromethane. 4.1 g (72%) of the desired pure compound are obtained in the form of colorless needles with a melting point of 241 ° C. (decomp.). Elemental analysis for: C37H21Cl2FsN302S

calculated: C 46.91 H 2.55 N 6.44 found. C 47.29 H 2.58 N 6.58 47.29 2.58 6.58

Example 4

2-ethylthio-4,5-bis (4-methoxyphenyl) imidazole

6.5 g (0.12 mol) of sodium methoxide are added all at once to a suspension of 31.2 g (0.100 mol) of 2-mercapto-4,5-bis (4-methoxyphenyl) imidazole in 200 ml of methanol; the mixture is stirred for 15 minutes. A solution of 17.1 g (0.11 mol) of iodoethane in 50 ml of methanol is added dropwise, after which the mixture is refluxed for 4.5 hours. The mixture is stirred at room temperature overnight and then poured into water. The solid which precipitates is isolated, washed with water and dried, giving 33.0 g of crude product. By recrystallization from aqueous ethanol 28.8 g (85%) of the desired pure compound of melting point 108-109 ° C are obtained. Elemental analysis for: Ci9H20N, O2S

calculated: C 67.03 H 5.92 N 8.23 found: C 66.96 H 6.10 N 7.85

Example 5

2-allylthio-4,5-bis (4-methoxyphenyl) imidazole

A mixture of 31.2 g (0.100 mol) of 2-mercapto-4,5-bis (4-methoxyphenyl) imidazole, 13.1 g (0.108 mol) of allyl bromide, 20.2 g (0.200 mol) of triethylamine and 500 ml Chloroform is refluxed overnight. After adding 4.8 g (0.040 mol) of allyl bromide, the mixture is heated under a reflux condenser for a further 2 hours. Two further portions of 4.8 g allyl bromide each are added, and in each case the mixture is then heated for 2 hours on a reflux condenser. The clear solution is cooled, washed three times with water, dried over magnesium sulfate and concentrated. The residue is triturated with ether and the solid is isolated, giving 31.5 g of crude product. By recrystallization from aqueous ethanol, 26.7 g (76%) of the desired pure compound of melting point 167 to 167.5 ° C are obtained.

Elemental analysis for: C2oH2qN202S

calculated: C 68.16 H 5.72 N 7.95 found: C 67.22 H 5.87 N 7.81

4, S-bis (4-methoxyphenyl) -2- (methylthiomethylthio) imidazole By using chloromethyl methyl sulfide instead of allyl bromide, which was used in the experiment described above, the desired product of 5 melting point 171-172 ° C is obtained.

Elemental analysis for: C19H20NaO2S2

calculated: C 61.26 H 5.41 N 7.52 found: C 61.32 H 5.57 N 7.32

10th

2-ethylsulfinyl-4,5-bis (4-methoxyphenyl) imidazole To a solution cooled in an ice bath of 10.2 g (0.0300 mol) of 2-ethylthio-4,5-bis (4-methoxyphenyl) imidazole in 200 ml of dichloromethane is added dropwise a solution of 15 6.0 g (0.030 mol) of 86.4% m-chloroperbenzoic acid in 100 ml of dichloromethane '. The reaction mixture is stirred overnight at room temperature and then washed three times with 75 ml of saturated sodium bicarbonate. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The oil which remains as a residue is triturated with ether and the solid formed is isolated and recrystallized from 500 ml of 1-chlorobutane, 7.5 g (70%) of the desired pure compound having a melting point of 161-162 ° C. 25 being obtained.

Elemental analysis for: C19H2oN203S

calculated: C 64.02 H 5.66 N 7.86 found: C 63.98 H 5.59 N 7.97

2-ethylsulfonyl-4,5-bis (4-methoxyphenyl) imidazole When using 12.0 g (0.060 mol) of 86.4% m-chloroperbenzoic acid instead of the 6.0 g of this acid used above, after recrystallization from 125 ml 35 1-chlorobutane 6.0 g (54%) of the desired compound of melting point 136-137 ° C.

Elemental analysis for: C19H20N2O4S

calculated: C 61.27 H 5.41 N 7.52 found: C 61.47 H 5.47 N 7.35

40

4,5-bis (4-methoxyphenyl) -2-methylthioimidazole If iodomethane is used instead of the iodoethane used in Example 4, the product is 4,5-bis (4-methoxyphenyl) -2-methylthioimidazole with a melting point of 157 to 45 158 , 5 ° C.

Elemental analysis for: Ci8H18N202S

calculated: C 66.23 H 5.56 N 8.58 found: C 65.84 H 5.53 N 8.46

30th

Example 6

2-A cetonylthio-4,5-bis (5-methoxyphenyl) imidazole

55 10.2 are added dropwise to a stirred mixture of 31.2 g (0.100 mol) of 2-mercapto-4,5-bis (4-methoxyphenyl) imidazole, 11.0 g (0.11 mol) of triethylamine and 500 ml of chloroform g (0.11 mol) of chloroacetone added to 50 ml of chloroform. The mixture is heated at reflux condenser 60 overnight, whereupon the reaction mixture is washed three times with water, dried over magnesium sulfate and concentrated to give 32.0 g of crude product. Chromatography (silica gel, chloroform) gives 27.0 g (73%) of the desired pure compound of melting point 65-115.5 ° C.

Elemental analysis for: C20H20N2O3S

calculated: C 65.20 H 5.47 N 7.60 found: C 65.14 H 5.42 N 7.36

7

638791

Example 7 (see Example 5)

4,5-bis (4-methoxyphenyl) -2- (methylthiomethylsulfinyl) imidazole and 4,5-bis (4-methoxyphenyl) -2- (methylsulfinylmethylthio) imidazole

To a solution of 7.4 g (0.020 mol) of 4,5, bis (4-methoxyphenyl) -2- (methylthiomethyl-thio) imidazole in 100 ml of dichloromethane, cooled in an ice bath, is added a solution of 4.0 g (0.020 Mol) 86.4% m-chloroperbenzoic acid in 100 ml dichloromethane. The mixture is stirred at room temperature overnight and the reaction mixture is washed three times with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue (7.5 g) is chromatographed on silica gel, which is eluted with a mixture of toluene and ethyl acetate.

The first pure compound eluted from the column is 4,5-bis (4-methoxyphenyl) -2- (methylthiomethylsulfinyl) imidazole, melting point 142.5 to 143.5 ° C. Elemental analysis for: Ci9H20N2O3S2

calculated: C 58.74 H 5.19 N 7.21 found: C 59.00 H 5.13 N 6.93 By further elution of the column, pure 4,5-bis (4-methoxyphenyl) -2- ( methylsulfinylmethylthio) imidazole of melting point 84.5 to 86.5 ° C.

Elemental analysis for: C19H20N2O3S2

calculated. Found C 58.74 H 5.19 N 7.21: C 58.85 H 5.36 N 6.94

Example 8

4,5-diphenyl-2- (l, l, 2,2-tetrafluoro'dthylthio) imidazole

In a stainless steel tube, 5.0 g (0.020 mol) of 4,5-diphenyl-2-mercaptoimidazole and 50 ml of dimethylformamide containing 0.5 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol are placed . The tube is purged several times with dry nitrogen, after which 2.2 g (0.022 mol) of tetrafluoroethylene are added. The tube is moved for 7 hours. The reaction mixture is poured into water and the solid is isolated and washed with water to give 5.7 g of crude product. Column chromatography (silica gel, chloroform) gives 3.5 g of the desired pure compound with a melting point of 212-213 ° C.

Elemental analysis for: C17H12F4N2S

calculated: C 57.95 H 3.43 N 7.95 found: C 57.71 H 3.70 N 7.89

Example 9

4,5-bis (4-methoxyphenyl) -2-vinylthioimidazole

15.0 g (0.05 mol) of 4,5-bis (4-methoxyphenyl) -2-mercaptoimidazole, 0.75 g of copper (II) chloride and 100 ml of dimethylformamide are placed in a stainless steel tube. The tube is cooled, evacuated and then pressurized with 1.3 g acetylene. It is shaken at 150 ° C for 8 hours, cooled and blown off. The contents are diluted with 500 ml of water and 25 ml of concentrated ammonium hydroxide are added. The aqueous mixture is extracted with ether (4 X 300 ml). The combined ether extracts are washed with water (3 × 300 ml) and then dried and concentrated on a rotary evaporator. The residue is chromatographed on a column containing 600 g of silica gel (SilicAR CC-7). The product is eluted with chloroform (cut 6-8, 11 each), 2.9 g of crystals being obtained after concentration. By recrystallization from 1-chlorobutane / hexane, 2.8 g of pure product with a melting point of 114 to 115 ° C. are obtained.

Elemental analysis for: C19H18N202S

calculated: C 67.43 H 5.36 N 8.28 found: C 67.17 H 5.40 N 8.42

5 Example 10

4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole sodium salt

A mixture of 5.0 g (0.0119 mol) of 4,5-bis (4-fluorophenionyl) -2- (l, l, 2,2-tetrafluoroethylsulfonyl) imidazole, 0.6 g (0.0111 mol ) Sodium methoxide and 300 ml ether is stirred overnight at room temperature. The solid is isolated and washed with ether, giving 2.1 g of the desired compound having a melting point of 290 to 292 ° C. 15 Elemental analysis for: 6N202SNa calculated: C 46.16 H 2.05 N 6.33 found: C 45.98 H 2.19 N 6.07

Example 11

20th

4, S-Diphenyl ~ 2- (l, l, 2,2-tetrafluoroethylsulfonyl) imidazole - sodium salt

In the manner described in Example 10 using 4,5-diphenyl-2- (l, l, 2,2-tetrafluoroethyl-23 sulfonyl) imidazole as the starting material, the sodium salt of 4,5-diphenyl-2- ( 1, l, 2,2-tehrafluoroethylsulfonyl) imidazole of melting point 296-302 ° C (dec.) obtained.

Using the corresponding starting materials, the compounds mentioned in Table I can be prepared by the process described in Example 4. Typical solvents that can be used are methanol, ethanol and toluene.

Using the corresponding starting materials, the compounds mentioned in Table II can be prepared according to the procedure described in Example 8. Typical catalysts that can be used are diisopropylamine and benzyltrimethylammonium hydroxide.

Using the appropriate starting materials, materials can be prepared according to the procedure described in Example 5. the compounds listed in Table III are prepared.

Further compounds which can be prepared by the processes described in the examples are listed in Table IV.

Example 12

A) 4,5-Diphenyl-l- (2-tetrahydropyranyl) imidazole

50

A mixture of 27 g (0.122 mol) of 4,5-diphenylimide-azole, 21 g (0.25 mol) of dihydropyran, 250 ml of ethyl acetate and 4.0 g of BFj. EtaO was refluxed for 5 days. The almost clear solution was diluted with ether and filtered to remove 0.6 g of insoluble starting material. The ether filtrate was washed several times with 10% NaHCO 3, then dried and evaporated. Thin layer chromatography indicated that starting material was still present, so the crude product was chromatographed on 21b Silic 60 AR CC-7 and eluted with toluene containing 20-40% ethyl acetate. In this way, 30.3 g (81.7%) of pure product with a melting point of 170 to 171 ° C. were obtained.

IR 3.21 = CH; 3.40, 3.49 | A saturated CH; 6.25, 6.64, 65 6.73 [i, aromatic C = C and / or C = N; strong 9-10 | x, C-O-C; 12.98 and 14.38 p, monosubstituted aromatic. H-NMR: mult (1.6-2.3 8, 6H); mult. (~ 3.4, 4.0, 4.8 5 each ~ 1H); mult + singlet (7.0 - 7.6 + 7.4 8, 10H); S (7.8 8 IH).

638791

8th

Mass spectrum for: C2 „H20N, O calculated: 304.1574 found: 304.1559 Analysis for: C20H20N2O

calculated: C 78.92 H 6.62 N 9.20

found: C 78.57 H 6.89 N 9.07

B) 4,5-Diphenyl-2-trifluoromethylthioimidazole Under nitrogen and in a glass vessel dried with a heat gun, a solution of 0.9 g (3 mmol) of 4,5-diphenyl-l- (2-tetrahydropyranyl) was imid-azole in 15 ml tetrahydrofuran and 15 ml ether cooled to -78 ° C. The cold solution was added dropwise to a solution of 2.5 ml (4 mmol) of 1.6 molar n-butyllithium in hexane in 10 ml ether. The solution was stirred at -78 ° C and then 0.55 g (4 mmol) of trifluoromethanesulfenyl chloride (toxic) was added as a gas. The mixture was stirred at -78 ° C for 2 hours and then at room temperature overnight. The mixture was poured into water and extracted with ether (pH of the aqueous layer approximately 4). The aqueous layer was neutralized with bicarbonate and then extracted with more ether. The combined ether extracts were dried and concentrated. The crude residue was chromatographed on 50 g of Silic AR CC-7 and eluted with 98% toluene / 2% ethyl acetate to give 0.45 g (47%) of product. Recrystallization from toluene gave 0.3 g (31%) of a white solid with a melting point of 254-256 ° C.

IR: broad 3-4 ji, NH; 3.28 n, = CH; 6.24, 6.34, 6.42, 6.71 Ii, aromatic C = C and / or C = N; strong 8.5-9 \ i, C-F; 13.09, 14.34 \ i monosubstituted aromatic. H NMR: mult (7.1-7.7 8, 10H); broad (13 8, IH) F NMR: S (42.46 5). Mass spectrum: molecular ion C16H11F3N2S:

found: 320.0609 Analysis for: C1GHnF3N, S

calculated: C 59.99 H 3.46 N 8.75 found: C 60.20 H 3.57 N 8.52

Example 13

4,5-diphenyl-2-trifluoromethylsulfonylimidazole

A mixture of 0.48 g (1.5 mmol) of 4,5-diphenyl-2-trifluoromethylthioimidazole and 0.72 g (3.6 mmol) of 85% m-chloroperoxybenzoic acid in 30 ml of methylene chloride were stirred at room temperature overnight and then when thin layer chromatography indicated incomplete oxidation, another day was stirred at reflux. Thin layer chromatography still indicated incomplete oxidation, so the methylene chloride was removed by rotary evaporation and replaced with 30 ml of chloroform, and the mixture was refluxed for 6 hours. The chloroform was evaporated and the residue triturated with approximately 20 ml ether. The ether-insoluble solid (approximately 0.3 g) was combined with approximately 0.1 g of solid obtained from the ether filtrate by washing with 10% sodium sulfite, 10% sodium bicarbonate, drying and concentration. Recrystallization from toluene gave 0.37 g (70%) of a white product, melting point 292 to 293.5 ° C (sublimed above 250 ° C).

IR: 3-4 [X, NH; 6.33, 6.44, 6.72 ji, aromatic C = C and / or C = N; 7.23, 8.32 jt; -S02-; 8.97 \ x, C-F; 13.05, 14.30 fx, monosubstituted aromatic. H-NMR: mult (7.1-7.7, 8.10H). F NMR: S (78.25 8); small singletts were also observed at 42.43 8 (approximately 2%, sulfide) and at 72.69 8 (approximately 3%, sulfoxide).

Analysis for: OmHuF3N202S

calculated: C 54.54 H 3.15 N 7.95

found: C 55.13 H 2.94 N 8.06 54.98 2.95 8.05

5

The compound of the example had an adjuvant arthritis ED50 of 0.03 mg / kg in the rat.

In various tests to determine the anti-inflammatory and immunoregional activity, the 10 compounds according to the invention showed unique properties. The biological profiles of these compounds are different from those of the non-steroidal anti-inflammatory drugs and immunosuppressive drugs. These unique properties open up a new way of treating rheumatoid arthritis and can also be beneficial in the treatment of other diseases in which altered immune states occur.

The antiarthritic agents which contain the compounds obtained according to the invention can be administered for the treatment of this disease by all means with which the active ingredient is brought into contact with its place of action in the body of a mammal. They can be administered as a single therapeutic agent or in a combination of therapeutic agents in all of the usual ways available for use in connection with drugs. They can be administered alone, but administration is generally with a pharmaceutical carrier chosen based on the chosen route of administration and standard pharmaceutical practice.

The dose administered is of course different depending on known factors such as the pharmacodynamic properties of the respective agent and the mode of administration and route of administration, age, health status and weight of the recipient, type and severity of symptoms, type of simultaneous treatment, frequency of Treatment and desired effect. The daily dose of the active ingredient can usually be about 0.001 to 40 mg / kg body weight. Usually the desired results are obtained with 40 0.005 to 20, preferably 0.01 to 4 mg / lcg per day, given in divided doses two to four times a day, or in a form with a delayed release of the active ingredient.

Dosage forms suitable for internal administration (preparations * contain about 0.1 to 500 mg of active ingredient per unit. In these pharmaceutical preparations, the active ingredient is usually present in an amount of about 0.5 to 95% by weight on the total weight of the preparation.

50

In order to determine and compare the anti-inflammatory and immunoregulative effects of compounds of this series and of standard medications, a series of tests was carried out on the basis of a standard 5S standard model which is in good agreement with the effectiveness in humans. The model is adjuvant arthritis in rats. In Federation Proceedings, Volume 32, No. 2, 1973 "Models Used for the Study and Therapy of Rheumatoid 60 Arthritis" Symposium of the American Society for Pharmacology and Experimental Therapeutics states: "The intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) in rat-induced polyarthritis is widely used for 6S in the selection of drugs of potential benefit in rheumatoid arthritis. »

Established adjuvant arthritis in rats.

9

638791

This test is primarily used to determine the anti-inflammatory effect.

Male Charles River-Lewis rats (130-150 g) receive 0.1 ml of adjuvant (Difco heat-killed freeze-dried Mycobacterium butyricum suspended in mineral oil 5 mg / ml) by subcutaneous injection in the plantar region of the right hind paw. 20 control animals without arthritis only the mineral oil is injected. The animals are kept for 2 weeks so that the arthritis can develop. The volume of the paw (left hind paw that was not injected) is measured and the rats injected with the adjuvant are sorted and divided into treatment groups of 10 animals each with the same severity of the disease. The control animals without arthritis are divided into two groups of 10 animals each. The rats are given oral doses of the compound or PVA gum arabic (polyvinyl alcohol 1%, gum arabic U.S.P. 5%, methyl paraben 0.5%) (10 ml / kg) with the drinking water that day and for the following 6 days. One day after the last dose, the volume of the paws (left hind paw, which was not injected) is measured with a volume differential measuring device "Ugo Basile Model 7101".

Average paw volume Average paw - the arthritic volume - volume (ml) of the same animals (ml) treated group

X 100 =

Average paw volume Average paw (ml) of the arthritic - volume (ml) of the control animals non-arthritic

Comparison animals percentage reduction based on the average paw volume of the comparison animals.

Dose-regression lines of percent volume reduction are drawn on semi-log paper with visual adjustment, and the ED50, i.e. the dose that causes a 50% reduction in volume based on the paw volume of the control animals is determined by eye measurement.

Not established adjuvant arthritis in rats.

This is an attempt primarily to determine the effects of the compounds on the immunological reactions taking place in the induction process and to prevent the development of arthritis.

Male Charles River Lewis rats (130-150 g) received 0.1 ml of adjuvant (Difco heat-killed, freeze-dried Mycobacterium butyricum as a suspension in mineral oil, 5 mg / ml) by subcutaneous injection into the plantar region of the right hind paw. 40 control animals Mineral oil is injected only, mineral groups are injected, and groups of 20 rats are given oral single daily doses of the compound (in PVA gum arabic vehicle, 10 ml / kg) or only the vehicle with drinking water, starting immediately after the injection in A total of 14 doses are administered The volume of the paw that was not injected (left hind paw) is measured 24 hours after the last dose with a volume differential meter "Ugo Basile Model 7101". The EO50, ie the dose that is 50 % volume reduction based on the control animals is determined in the manner described above.

To further evaluate the immunoregulative properties of these compounds, two additional experiments, described below, were carried out. With the help of the hemolytic plaque determination according to Jerne, the effect of the compounds on special antibody-forming cells (lymphocytes B) is determined.

The relative proportion of lymphocytes B and lymphocytes T (which are involved in cell-mediated immunity 5) is determined by fluorescent staining of the antibodies.

Modified hemolytic plaque determination methods on spleen cells according to Jerne.

A modification of the method described by N.K. Jerne and A.A. Nordin io [Science, 140 (1963) 450] was used in these studies. Rats (Charles River Lewis) with adjuvant-induced arthritis (and non-arthritic control animals) received the PVA gum arabic vehicle (polyvinyl alcohol 15%, gum arabic 5%, methyl paraben 0.5% in water) or the compounds orally once a day in the vehicle from day 14 (after injection of the adjuvant) to day 20. The animals were sensitized intravenously with red sheep blood cells (SRBC) (0.2 ml of a 10% suspension = 2 to 3 X 106 cells) on day 17 20 . The SRBC (Micobiological Associates) were washed three times in 0.9% sodium chloride solution before injection. On day 21, the rats were anesthetized intraperitoneally with 1% sodium pentobarbital, after which the spleen was removed. Each spleen was placed on a stainless steel sieve suspended over a plastic beaker in an ice bath and gently macerated with the plunger of a glass syringe. The cells were washed through the sieve using a Pasteur pipette, with approximately 10 ml of Eagle's Minimal Essential Medium (MEM) 30 being applied during the maceration process until only fiber material remained on the sieve. Large particles were allowed to sit for about 5 minutes and about 5 ml of the supernatant was transferred to a plastic tube. Dilutions of 1:10 and 1:20 were made in cold MEM. 35 Plating: 2 ml 0.7% agarose (1.4%, diluted 1: 2 with 2X Eagles MEM) and 0.2 ml of a 10% SRBC suspension were preheated in a water bath kept at 45 ° C. 20 X spleen cell dilution was added, mixed gently and poured into a supporting layer of 40 2 ml 1.4% agarose in a plastic petri dish of 60 X 15 mm. The plates were incubated for 1.5 hours at 37 ° C in a humidified incubator. After the addition of 1.5 ml guinea pig complement (diluted 1:10 with MEM), incubation was continued for another hour. 45 The hemolysis zones (plaques) per plate were counted against a diffuse light source without enlargement. Assuming that each plaque was caused by hemolysin formed by a single spleen cell, the number of plaque forming cells (50 PFC) per million spleen cells was calculated for each dilution. Statistical calculations (mean, standard error and "t" ~ test) included the PFC / million count for each dilution of each spleen.

Immunofluorescent antibody staining of B cells in 55 of the rat spleen.

method

Rats (Charles Rivel Lewis strain) were used to determine the percentage of B cells in the process of developing adjuvant arthritis. The rats received the PVA gum arabic vehicle (polyvinyl alcohol 1%, gum arabic 5%, methyl paraben 0.5% in water) or the drug in the vehicle orally once a day. Treatment started on day -3 before administration of the adjuvant. On day 0, the rats received 0.1 ml (5 mg / ml) of Mycobacterium butyricum (Difco-dried, heat-killed) by subcutaneous injection into the left hind paw in mineral oil. Treatment with the medicinal

10th

638791

ment continued until day 7. The spleen was removed on day 8 after administration of the adjuvant.

Spleen cell suspensions were prepared by maceration of the spleen on a stainless steel sieve in the RPMI 1640 medium. Large particles were allowed to settle and the supernatant was transferred to pure tubes and centrifuged for 10 minutes at 800 rpm using the IEC centrifuge (International Centrifuge Model K, size 2). The cell sediment (cell button) was resuspended in 0.83% NH1C1 (adjusted to pH 7.0 with NaOH) for lysis of the red cells (about 1 part of compressed cells to 3 parts of NH1Cl). These suspensions were kept in ice for 5 to 7 minutes and then centrifuged at 800 rpm for 10 minutes. The cells were washed twice in phosphate-buffered Dulbecco saline (PBS) and finally suspended in Dulbecco-PBS. The final cell concentration was so high that a drop of the cell suspension on a microscope slide covered with a coverslip gave 10 to 15 cells for each high power field1. Based on experience, the size of the cell sediment was assessed by adding 8 to 10 ml of Dulbecco-PBS per spleen to this final cell suspension

For immunofluorescence staining, 0.2 ml of cell suspension was mixed with 0.2 ml of a 1: 4 dilution of rabbit anti-rat IgG (Miles-Yeda Laboratories) conjugated with fluorescein isothiocyanate. The cells were incubated at 2 to 4 ° C for one hour, centrifuged at 800 rpm for 10 minutes, washed twice in 2 ml of Dulbecco-PBS and resuspended in 0.2 ml of Dulbecco-PBS. A drop of the cell suspension was placed on a microscope slide, covered with a coverslip and examined with the optical microscope and fluorescence microscope. A total of 200 to 300 cells were counted for each spleen suspension. The number of fluorescent lymphocytes or B cells was expressed as a percentage.

The data relating to the effects of some compounds from this series in the experiments described above are given in Tables V, VI and VII.

As the values in Table V show, the compounds according to the invention had the same effect in the treatment of established arthritis in rats (anti-inflammatory effect) and in the prevention of the development of arthritis in rats (non-established arthritis). The usual anti-inflammatory drugs, e.g. Indo-methacin and phenylbutazone were less effective in preventing the development of arthritis in rats than in treating inflammation in established arthritis. An immunosuppressive drug, cyclophosphamide, was more effective in preventing the development of rat arthritis than in treating established rat arthritis. The compounds of this series showed unique properties in these tests.

Rats with adjuvant-induced arthritis have greatly altered immunological systems, such as the increased number of; Show plaque-forming (antibody-forming) cells (PFC) in spleen cell suspensions (hemolytic plaque determination, Table VI). By treating arthritic rats with the compounds according to the invention, the number of plaque-forming cells was reduced to normal. Treatment with indomethacin had no effect on the number of plaque-forming cells, while treatment with cyclophosphamide reduced the number of plaque-forming cells far below normal. The compounds according to the invention showed unique activity in this test.

Spleen cell suspensions from rats with adjuvant-induced arthritis have a higher proportion of B-lymphocytes than cells from normal rats

(Antibody-producing lymphocytes) as T-lymphocytes (mediators of cell immunity) (Table VII). The proportion of B lymphocytes was reduced to the normal value by treating the arthritic rats with compounds according to the invention. Treatment with indomethacin had no effect on the lymphocyte population while! treatment with cyclophosphamide reduces the proportion of B lymphocytes below the normal value.

10 (3) Phenylquinone curvature test

A standard method for determining and comparing the analgesic activity of compounds that offers a good comparison with the activity in humans is the standard phenylquinone curvature test, mo-15 differentiated from Siegmund et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). A test compound suspended in 1% methyl cellulose was orally given to female white mice, 5 to 20 animals per double-blind test, who had starved for 17 to 21 hours. Aqueous (0.01% phenyl-p-benzo-20 quinone) phenylquinone was injected intraperitoneally 24 hours later using 0.20 ml per mouse. Starting at 30 minutes after oral. Administration of the test compound was observed in the mice for 10 minutes for a characteristic stretching or curvature syndrome 25, which indicates the pain caused by phenylquinone. The effective analgesic dose for 50% of the mice (ED50) was determined using the motion average method of Thompson, W.R., Bact. Rev. 11, 115-145 (1947); in addition, the time of main action was determined for many of these compounds. The data obtained are shown in the following list:

11

638791

R

n

ED50 *

Main working time (min.)

CHF2

2nd

1.5

cf3

2nd

0.045

240

CH2CF3

1

0.86

60

CH2CF3

0

1.2

240

CH CF-

2nd

0.58

60

CF2CH2F

2nd

0.25

160

CF2CHF2

1

0.8

CF2CHF2

2nd

0.11

120

CF2CHBrF

2nd

2.8

* Units are mg / kg

; l ys (o) n-R

X

Y

R

n ed50 *

Main action time (min.)

4-ch ^ o

2-cl cf2chf2

2nd

0.56

60

4-ch30

H

cf2chf2

2nd

0.33

240

4-c2h50

H

cf2chf2

2nd

0.95

120

H

H

cf2chf2

2nd

0.48

120

* Units are mg / kg

Tables I to V below summarize compounds prepared according to the invention, stating their effect on the arthritis caused by adjuvant in rats.

The preparation of some of the listed compounds is illustrated in the preceding examples.

638791 12

TABLE I 4,5-diaryl-2- (substituted-thio) imidazoles

No.

X

Y

R

Melting point, ° .C

Adjuvant arthritis

* ed50 *) 2

1

4-CH30

4-CH30

ch3

156-157 °

4.4

2nd

4-C1

4-Cl ch3

241-242 °

3.0

3rd

4-CH30

4-CH30

CH3CH2CH2

152-153 °

9.0

4th

4-f

4-F

ch3

222-223.5 °

3.5

5

4-CH30

4-CH30

chf2

170.5-172 °

1.8

6

H

H

chf2

227-228 °

21st

7

4-cl

4-Cl chf2

222-223 °

0.35

8th

4-F

4-F

chf2

192.5-194 °

0.42

9

4-cl

4-F

ch3

222-223 °

3.8

10th

4-CF3

H

ch3

176-177 °

20th

11

4-f

4-cf3

ch3

196-197 °

17th

12

4-c1

4-cf3

CH3

214-215 °

3.6

13

3.4-0ch20

3.4-0ch20

ch3

201-202 °

20th

14

4-CH30

4-CH30

CF3CH2

150-151 ° 3

20th

15

4-cl

4-cl

CF3CH2

212-213 °

5.0

16

4-ch30

4-CH30

CH3CH2

108-1090 "

4.7

17th

4-ch3

4-CH30

ch2 = chch2

167-167.5 °

22

18th

4-CH30

4-ch30

ch3coch2

115-117.5 °

9.4

19th

4-CH30

4-ch30

ch3soch2

84.5-86.5 °

52

1 This biological system has been described above

2 units in mg / kg

3 A polymorphic form had a melting point of 119-120 ° C

4 A polymorphic form had a melting point of 146 ° C

13

TABLE II

638791

4,5-diaryl-2- (polyhaloalkylthio) imidazoles

CF2ÇFH

Adjuvant

^ Arthritis

Melting, * 2

No. X Y R point, ° C vtu50%;

20th

4-CH30

4-CH30

F

134-136 °

4.2

21st

4-cl

4-cl

F

222.5-223.5 °

0.3

22

4-F

4-F

F

220-221.5 °

0.075

23

H

H

Cl

187-188 °

3.9

24th

4-cl

4-F

F

206.5-207.5 °

0.18

25th

4-CH3

4-CH3

F

204-205 °

18th

26

4-CH30

H

F

175-175.5 °

20th

27th

4-cl

H

F

205-206 °

0.3

28

3,4-0CH20

3,4-0CH20

F

204-205.5 °

10th

29

4-CF3

H

F

202-204 °

4.5

30th

4-F

4-CF3

F

182.5-183.5 °

1.5

31

4-F

H

F

196-197.5 °

0.2

32

3-C1

3-cl

F

208-209 °

1.2

33

4-CH30

4-CH30

Br

151-153 °

10th

34

H

H

Br

184-186 °

11

35

4- (CH3) 2N

H

F

189-192.5

2.5

36

H

H

F

218-219.5

0.75

1 This biological system has been described above

2 units in mg / kg

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

14

TABLE III

4,5-diaryl-2- (alkylsulfinyl) imidazoles and 4,5-diaryl-2- (alkylsulfonyl) imidazoles

Adjuvant Enamel Arthritis x

y r

n point, C

(ed

) 2

50%

h h

cf3ch2

1

198 ° (dec.)

48

h h

cf3ch2

2nd

226.5 ° (dec

.)

12

4-CH30

4-CH30

cf3ch2

1

193.5 ° (dec.

)

10th

4-CH30

4-CH30

CF3CH2

2nd

173.5-174.5 °

3.8

4-cl

4-Cl cf3ch2

1

214 ° (dec.)

3.0

.u l

O M

4-Cl cf3ch2

2nd

241 ° (dec.)

4.5

4-CH30

4-CH30

ch3ch2

1

161-162 °

10th

4-CH30

4-CH30

ch3ch2

2nd

136-137 °

5.2

4-CH30

4-CH30

CH2 = CHCH2

1

118-119 ° (dec.)

11

4-CH30

4-CH30

CH2 = CHCH2

2nd

162-163 °

11

4-CH30

4-CH30

CH3

1

167-168.5 °

6.2

4-CH30

4-CH30

CH 7

2nd

142-143 °

6.4

4-cl

4-Cl cf3ch2

1

214 ° (dec.)

3.0

4-cl

4-Cl ch3

1

202 ° (dec.)

2.3

H

H

HCF2CF2

2nd

239-240 °

0.13

4-ch30

4-ch30

ch3ch2ch2

1

143-144.5 °

13

4-CH30

4-CH30

ch3 (ch2) 2

2nd

152-153 °

9

4-ch30

4-ch30

(CH,) CH j 2

2nd

175-176 °

30th

4-ch30

4-ch30

HCF2CF2

2nd

156-157 °

1.1

4-ch30

4-ch30

HCF2CF2

1

162.5-163.5 °

2.4

No

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

15

TABLE III (continued)

638791

Adjuvant

X

Y

n

Melting point, ° c

Arthritis fED50%) 2

H

H

hcf2cf2

1

181-182 °

0.18

4-cl

4-Cl ch3

2nd

255-256 °

2.0

4-cl

4-Cl hcf2cf2

1

198 ° (dec.

) 0.2

4-cl

4-Cl hcf2cf2

2nd

235-236.5 °

0.2

4-f

4-f cf3ch2

2nd

247 ° (dec.

) 3.5

4-F

4-F

HCF2CF2

2nd

241.5-242 °

0.025

4-f

4-F

CH3

2nd

239-240 °

4.5

h h

C1FCHCF2

2nd

213-214 °

0.25

4-CH30

4-CH30

CHF2

2nd

186-187 °

0.5

H

H

CHF2

2nd

265 °

0.35

H

H

HC12CF2

2nd

223-223.5 °

1.5

4-cl

4-Cl chf2

2nd

244-245 °

0.35

4-F

4-F

chf2

2nd

246.5-247 °

0.1

4-cl

4-F

CH3

2nd

226-227 °

2.8

4-cl

4-F

HCF2CF2

2nd

212-213 °

0.09

4-CH3

4-CH3

HCF2CF2

2nd

225-226 °

0.35

4-CH30

H

HCF2CF2

2nd

169-170 °

1.1

2-C1

4-ch30

HCF2CF2

2nd

176-177 °

7.2

3-CH30

3-ch30

HCF2CF2

2nd

155.5-156.5

6 4.0

4-Cl h

CH3

2nd

169-170 °

30th

4-cl

H

HCF2CF2

2nd

206-207.5 °

0.065

4-F

4-CF3

CH3

2nd

189-190 °

3.7

4-cl

4-CF3

C »3

2nd

224-225 °

2.2

4-CF3

H

HCF2CF2

2nd

188-189 °

2.4

4-cl

4-CF3

HCF2CF2

2nd

208-209 °

1.8

638791 16

TABLE III (continued)

No.

X

Y

R

n

Melting point, ° C

Ad juvans arthri t is

<ecw2

82

2-C1

2-C1

HCF2CF2

2nd

183-184 °

0.8

83

4-F

H

HCF2CF2

2nd

228-229 °

0.027

84

3-C1

3-C1

HCF2CF2

2nd

208-209 °

0.16

85

4-cl

4-Cl chf2

1

203-206

0.19

86

4-CH30

4-CH30

BrFCHCFj

2nd

187-188 °

2.4

87

4-CH3

H

HCF2CF2

2nd

202-203 °

0.6

88

3,4-0CH20

3,4-0CH20

hcf2cf2

2nd

212-214 °

1.0

89

4-CH30

4-CH30

ch3sch2

1

142.5-143.5

28

90

4-CH30

4-ch30

CI ^ COCH

1

138-140 °

56

91

4-CH30

4-CH30

ch3s02ch2

2nd

202-203 °

54

92

4-CH30

4-CH30

CH3COCH2

2nd

134-135 °

18th

93

H

H

CF3

2nd

292-293.5 °

0.03

94

4-F

4-F

cf3

2nd

264-265 °

0.015

1 This biological system has been described above

2 units in mg / kg

No.

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

17th

TABLE IV Compound of Formula

638791

(0) nR

x y R

3-f h

hcf2cf2

2nd

3-c1

h hcf2cf2

1

2-c1

2-Cl hcf2cf2

2nd

4-n-c4h9

4-n-C4H9

hcf2cf2

2nd

4-c2h5 °

4-c2h50

hcf2cf2

0

4-nh2

4-nh2

hcf2cf2

0

4-n (ch.)

3 2

4-n (ch,)

3 2

hcf2cf2

0

4-nhcoch3

4-nhcoch3

hcf2cf2

2nd

4-n02

h hcf2cf2

2nd

4-ch3s

4-ch3s hcf2cf2

0

4-ch3s02

4-ch3s02

hcf2cf2

2nd

3,4-Cl2

h hcf2cf2

2nd

4-ch30

4-CH30

c1ch2cf2

0

4-t-C4H90

4-t-C4H90

hcf2cf2

2nd

4-f

4-f h2cfcf2

2nd

18th

638791

TABLE V Rat Adjuvant Arthritis

Compound No. EDno% ^ mg / kg

Outbreak of unbroken arthritic arthritis

36

1.5

2.3

21st

0.2

0.06

62

0.03

0.03

78

0.1

Phenylbutazone

10th

35

Indomethacin

0.3

3rd

Cyclophosphamide

10th

1.5

TABLE VI

Determination of haemolytic plaques in spleen cell suspensions of arthritic, non-arthritic and 5 drug-treated arthritic rats

Connection no.

1

Oral

Daily dose, mg / kg

Average of plaque-forming cells per million spleen cells (N = 20)

36

1.5

197

15

320

21st

0.1

788

1.0

488

62

0.03

499

0.03

439

i arthritic

Comparative bulls *

-

863

Non-arthritic

Comparison animals *

-

323

; Indomethacin **

1.0

720

Cyclophosphamide

5.0

25th

* Averages from three experiments. 3Q ** values averaged from two experiments.

TABLE VII

Proportion of B-lymphocytes in spleen cell suspensions of arthritic, non-arthritic and drug-treated rats, determined by fluorescent antibody staining

Compound No. Oral Average

Daily dose, of the B cells,% 40 mg / kg

36 1.5 37

15 33

0.2 39

2.0 38

0.03 40

0.3 43

0.1 48

1.0 42

- 57

- 42 20 53

0.5 57

5 25

* Average values from 7 attempts.

45 21

62

so 78

Arthritic vegan bulls *

55 non-arthritic veggies *

Phenylbutazone

Indomethacin

60

Cyclophosphamide v

Claims (4)

638791 Is 1 or 2, R2 and R3, in which Y1 and Y * are the same or different, hydrogen, hydroxyl, methoxy, ethoxy, acetoxy, an alkyl group having 1 to 4 carbon atoms, chlorine, fluorine, trifluoromethyl-10, Amino, dimethylamino, or together form a dioxymethylene group, where and Y2 is not hydrogen if Rx is an alkyl group having 1 to 4 carbon atoms, a fluoroalkyl group having 3 or 4 carbon atoms in which the fluorine atom is in 3 or 4 Position 15 is allyl or acetonyl and where Yi and Y, not p-Cl or p-OCH3 if Rx is the methyl group, is prepared. 4. The method according to claim 1, characterized in that a compound of formula I, wherein Rt 20 1.1.2.2-tetrafluoroethyl or trifluoromethyl means is produced. 5. The method according to claim 1, characterized in that a compound of formula I, wherein R2 and R3 independently of one another the group 25th wherein Yt and Y2, which are the same or different, are hydrogen, hydroxy, alkoxy having 1 to 4 carbon atoms, acetoxy, alkyl having 1 to 4 carbon atoms, chlorine, fluorine, trifluoromethyl, amino, dimethylamino, nitro, acetylamino, methylmercapto, methylsulfonyl or together form a dioxymethylene bridge, where Rj ^ is not the vinyl group when Yt and Ya are hydrogen and Yj and Y2 are not hydrogen when Rj is an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 3 or 4 carbon atoms the halogen is in the 3- or 4-position, the allyl or acetonyl group and where Y1 and Y2 are not p-Cl or p-OCH3 when Rx is the methyl group, characterized in that a compound of the formula II 30th where Yj is hydrogen, chlorine or fluorine. 6. The method according to claim 3, characterized in that a compound of formula I, wherein Rj is the • 35 1.1.2.2-tetrafluoroethyl group and R2 and R3 independently of one another the group 40 (ii) wherein R2 and R3 have the meanings given above, and P is hydrogen or a protective group for the = NH group, is reacted with a corresponding compound containing the radical -Rt, whereupon the protective group P is optionally split off. 2. The method according to claim 1, characterized in that a compound of formula II with a compound of formula RtHal, wherein Rx has the meaning given in claim 1 and shark is a halogen atom, preferably iodine, especially with 2,2,2-trifluoroethyl tri chloromethanesulfonate or with a fluorinated olefin, preferably with tetrafluoroethylene. 2nd PATENT CLAIMS 1. Process for the preparation of imidazole derivatives of the formula I s-r, (I) wherein Ri is an alkyl radical with 1 to 4 carbon atoms, optionally substituted with at least one halogen atom, the allyl, vinyl or acetonyl group or the group -CH2S (0) mCH3, where m 0, are the same or different, the group 3rd 638791 m-chloroperbenzoic acid, sodium metaperiodate, hydrogen peroxide or potassium permanganate is oxidized. 11. Use according to claim 9, characterized in that 4,5-bis- (4-fluorophenyl) -2- (l, l, 2,2-tetrafluoroethylsulfonylimidazole, 3. The method according to claim 1, characterized in that a compound of formula I, wherein Ri is an optionally substituted by at least one halogen atom alkyl group having 1 to 4 carbon atoms, the allyl or acetonyl group or the group -CH2S (0) mCH3, wherein m Is 0, 1 or 2, R2 and R3, which are the same or different, the group in which Yt is hydrogen, chlorine or fluorine is prepared. 7. The method according to claim 1, characterized in that 4,5-diphenyl-2- (l, l, 2,2-tetrafluoroethylthio) - imidazole is prepared. 8. According to the method according to claim 1 Herge-50 imidazole derivatives of the formula (I). 9. Use of the imidazole derivatives of the formula (I) prepared by the process according to claim 1 for the preparation of imidazole derivatives of the formula (III) 55 60 S (0 »n-Rl (in) wherein Rj, R2 and R3 have the meanings given in patent claim 1 and a denotes 1 or 2, characterized in that a compound of the formula (I) is oxidized to the compound of the formula (III). 10. Use according to claim 9, characterized in that a compound of formula (I) with 4 (or 5) - (4-fluorophenyl) -5- (or 4) phenyl-2- (1,1,2,2-tetra- fluoroethylsulfonyl) imidazole, 4,5-bis (4-chlorophenyl) -2- (l, l, 2,2-tetrafluoroethylsulfonyl) imidazole, (4or 5) - (4-chlorophenyl) -5 (or 4) -phenyl-2- (l, l, 2,2-tetra- fluorethylsulfonyl) imidazole, 4,5-diphenyl-2-trifluoromethylsulfonylimidazole or 4,5-diphenyl-2- (l, l, 2,2-tetrafluoroethylsulfonyl) imidazole is obtained. (I). io Rt, R2 and R3 are defined in the preceding claim 1, in which claim the process according to the invention for the preparation of the compounds of the formula (I) is also characterized. According to the invention, the compounds 15 of the formula (I) are used for the preparation of compounds of the formula (III):