DE2226298B2 - 3-Arylaminocarbonyl-4-hydroxybenzo square bracket on square bracket to thiacyclohex (3) en-1,1-dioxide, process for their preparation and pharmaceuticals containing them - Google Patents

Description

in which R ^{1 represents} a phenyl or naphthyl radical which can optionally be substituted by a halogen atom or an NC, O ₂ N or F ₃ C group, and R ^{2 is} a hydrogen or halogen atom or an NC, O ₂ Means N- or F ₃ C-ReSt.

2. 3-Pheny laminocarbony 1-4-hydroxy-benzo- [b] thiacyclohex (3) -ene-1,1 -dioxide.

3. Process for the preparation of 3-arylaminocarbonyl - 4 - hydroxy - benzo [b] thiacyclohex (3) ene 1,1-dioxides according to one of claims 1 and 2, characterized in that a connection the general formula

in which the radical R ^{2 has} the meaning given, reacts with a base and the anion obtained is reacted in a manner known per se with an aryl isocyanate of the formula R ¹ NCO in which the radical R ^{1 has} the meaning given, in particular with phenyl isocyanate.

4. Medicament, characterized by a content of a compound according to claim 1 or 2.

NC, O ₂ N or F ₃ C group can be substituted, and R _{2 is} a hydrogen or halogen atom or an NC, O ₂ N or F ₃ C-RfSt, as well as a process for their preparation and these Medicines containing compounds.

The compounds according to the invention are anti-inflammatory substances. if they, for example, test animals such as rats, orally or intraperitoneally in a dose of 10 to 200 mg /

ίο kg, they can be given by injection an irritant, e.g. B. from carrageenin, in the paws caused swelling (of the paws) decrease

permit.

The compounds according to the invention are indicated for the relief of inflammations which occur, for example, in mammals, such as cats, dogs or monkeys, as a result of arthritis. Typically, a dose of 10 to 200 mg two or three times a day is indicated to treat such inflammation. The dosage regimen can be varied in a manner known in the art, depending on the age, weight, sex and species of the mammal to be treated.
The compounds according to the invention can be used for their use by combining them with customary pharmaceutical diluents, such as lactose or mannitol, and shaping the resulting mixtures in a conventional manner known in the pharmaceutical field in administration forms customary for oral ingestion, e.g. B. tablets, are transferred. Furthermore, they can be transferred into injection solutions suitable for intramuscular administration using sterile carriers, such as water. In the administration forms mentioned, the respective active ingredient is present in an amount of about 10 to 200 mg per dose unit.

When carrying out the method according to the invention for the preparation of the 3-arylaminocarbonyl-4-hydroxy-benzoCbJthiacyclohexPJen -1,1 -dioxides, a first step is given by IWJ Still and coworkers in the journal "JOC", 33, p. 2730 (1968), described thiochroman-4-one-1,1-dioxide of the formula II, in which the radical R ^{2 has} the meaning given, reacted with a base such as sodium hydride, whereupon the anion obtained in this way with an aryl isocyanate of the formula R ¹ NCO, in which the radical R ^{1 has} the meaning given is converted into a 3-arylaminocarbonyl-4-hydroxy-benzo [b] thiacyclohex (3) -en-1,1-dioxide of the formula given.

The invention relates to 3-arylaminocarbonyl-4-hydroxybenzo [b] thiacyclohex (3) ene -1,1 -dioxide of the general formula

HO

1.NaH

2. R ¹ NCO

Uli)

“R

CNHR ¹

(D

The connections according to the invention can also by aminolysis of the corresponding 3-alkoxycarbonyl-4-hydroxy-benzo [b] thiacyclohex (3) ene-1,1-dioxide can be obtained.

in which R ^{1 represents} a phenyl or naphthyl radical, the following examples are intended to illustrate the invention in more detail

which may optionally be exemplified by a halogen atom or a.

example 1

3 - Phecylaminocarbonyl - 4 - hydroxy - benzo [b] thiacyclohex (3) en-1,1-dioxide the formula

HO

A. 3 - (2 '- chloro) - phenylinocarbonyl-4-b-hydroxybenzo [b] thiacyclohex (3) en-1,1-dioxide the formula

A slurry of 0.088 moles of sodium hydride (3.7 g of a 57% mineral oil dispersion) in 50 ml of tetrahydrofuran was at room temperature within 30 minutes of a solution of 7.8 g (0.04 mol) thiochroman-4-one-1,1-dioxide in 100 ml Tetrahydrofuran added. The mixture obtained was then admixed with 10 g of phenyl isocyanate and stirred at room temperature for 1 hour. After adding excess sodium hydride by carefully adding Was destroyed by methanol, the resulting mixture was poured into ice water and washed with Ether extracted. The formed aqueous layer was acidified and extracted with dichloromethane. Of the residue obtained after evaporation of the solvent was slurried with hot methanol. The solids insoluble in the hot metal oil were separated and removed from ethyl acetate recrystallized, whereby 3 g of the desired end product with a melting point of 205 to 208 C. (Decomp.) Were obtained.

An elemental analysis of the compound

C ₁₆ H ₁₃ NO ₄ S

resulted in the following values:

Calculated ... C 60.94, H 4.16, N 4.44, S 10.17;
Found .... C 61.13, H 4.18, N 4.70, S 9.87.

Example 2

Preparation of 3-arylaminocarbonyl-4-hydroxybenzo [b] thiacyclohex (3) enes -1,1-dioxides by aminolysis of corresponding S-alkoxycarbonyl- ^ hydroxybenz [b] thiacyclohex (3) en-1,1 -dioxide:

General procedure

A mixture of 9.4 g (0.04 mol) of 3-methoxycarbonyl-4-hydroxy-6-chlorobenzothiacyclohex (3) en- 1,1-dioxide, 0.06 mole of an appropriately substituted one aromatic amine and 250 ml of xylene were 16 hours in a Soxhlet apparatus, whose The hood was filled with 20 g of a molecular sieve sold under the name Linde Type 4A Heated to reflux temperature. After the reaction mixture had cooled to room temperature, the crystalline precipitate formed was isolated and described in the case of the individual examples Way cleaned.

Cl

10 Using 7.7 g of o-chloroaniline were obtained 9.9 g of a crude product having a melting point 149-152 ° C. On recrystallization once from benzene and the other time from isopropanol, 5.6 g of said compound with a melting point of 167 to 169.5 ° C. were obtained.
An elemental analysis of the compound

C ₁₆ H ₁₂ ClNO ₄ S
resulted in the following values:

Calculated ... C 54.94, H 3.46, Ci 9.17, N 4.00,

S 10.14;
found .... C 55.14, H 3.63, Cl 8.98, N 4.04,

S 10.13.

B. 3 - (T - Trifluoromethyl) - phenylaminocarbonyl-4-hydroxy-benzo [b] thiacyclohex (3) ene 1,1-dioxide of the formula

CF ₃

When using 9.7 g of o-trifluoromethylaniline in the general process, no separation of the crude product from the reaction mixture could be observed on cooling. For this reason, the crude product was extracted with a 1N sodium hydroxide solution, whereupon the alkaline solution was carefully neutralized with dilute hydrochloric acid. The precipitate formed in this way was separated off and recrystallized once from methanol and the other time from isopropanol, 6.7 g of the compound mentioned having a melting point of 174 to 177 ° C. being obtained.
An elemental analysis of the compound

C ₁₇ H ₁₂ F., NO ₄ S.
resulted in the following values:

Calculated ... C 53.26, H 3.16, F 14.87, N 3.65,

S 8.36;
found .... C 53.24, H 3.10, F 14.84, N 3.62,

S 8.59.

C. 3 - Phenylaminocarbonyl - 4 - hydroxy - 6 - chlorobenzo [b] thiacyclohex (3) ene 1,1-dioxide the formula

HO
Cl I CNH-

A mixture of 11.5 grams (0.04 moles) of 3-methoxycarbony 1 - 4 - hydroxy - 6 - chloro - benzo [b] thiacyclohex (3) en-

1,1-Dioxide, 5.6 g (0.06 mol) of aniline and 250 ml of xylene were heated to reflux for 4.5 hours in a Soxhlet apparatus, the hood of which contained 20 g of a Linde 4A molecular sieve. After cooling of the reaction mixture to room temperature, the crystalline precipitate obtained was separated off and recrystallized from acetic acid, 9.8 g of the desired product having a melting point of 235 to 238 ° C. (decomp.) being obtained.
An elemental analysis of the compound

C ₁₆ H ₁₂ ClNO ₄ S
resulted in the following values:

Calculated ... C 54.94, H 3.46, Cl 10.13, N 4.00,

S 9.17;
found .... C 54.87, H 3.55, Cl 10.42, N 3.76,

S 9.16.

The compounds of Example 1 and Examples 2A to 2C were used against the known anti-inflammatory Substance »acetylsalicylic acid« according to two known test methods for detection and for Evaluation of anti-inflammatory activity tested. One of these test methods was the anti-inflammatory activity of the test substances with regard to those caused by carrageenin Rat paw edema tested (Test No. 1). The second test method was the anti-inflammatory Activity of the test substances tested with regard to polyarthritis caused by an adjuvant (Test No. 2). In Test No. 1, as the following table shows, the compounds of Example 1 were and of Examples 2A and 2C more active than acetylsalicylic acid, as does the compound of Example 2B active like acetylsalicylic acid. In test # 2, all of the compounds according to the invention were stronger active as acetylsalicylic acid.

Tabel

Anti-inflammatory properties of S-arylaminocarbonyl- ^ hydroxy-benzojTjjthiacyclohexiSJen-1,1-dioxides according to the invention compared to acetylsalicylic acid

link With carrageenin Rat paw Through a. left Polyarthritis (therapeutic Treatment) right according to induced 1 Hind paw Hind paw example edema Adjuvant induced dose left percentage 33 Hind paw 5 *) dose Inhibition (prophylactic treatment) 14 *) right (mg / kg) 2 *) (1 to 20 days) 14 *) Hind paw 1.56 - 6 *) -2 *) (mg kg) -22 *) dose 3.12 - 8th*) 1 10 -43 *) 26 *) 13th 6.25 -17 *) 25th -48 *) (mg / kg) 23 *) 6 *) 50 -58 *) 1.56 4 *) 100 -33 *) 6.25 31 2A 6.25 -40 *) 25.0 26 *) 15th 25.0 -48 *) 10 *) 100.0 -19 6.25 19 *) 1*) 2 B 6.25 -47 *) 25.0 11 *) 18th -6 *) 25.0 -40 *) 10 *) 11 *) 1.56 -13 *) 100.0 -31 *) 6.25 6.25 -25 *) 2C 6.25 -42 *) 25.0 21 10 *) 13th 12.5 -54 *) 23 6 *) 12th 25.0 -52 *) 1.56 6 *) 4 *) 25th 3 7 *) 100.0 -38 *) 6.25 50 S. 6 *) Acetylsali 50 -62 *) 25.0 19th 100 1*) cyclic acid 200 -57 *) 19th 200 -14 *) 400 25th 3 *) 100 400

*) Significant deviation from the blind test.

Claims (1)

Patent claims: 1. 3-Arylaminocarbonyl-4-hydroxy-benzo [b] -thiacyclohex (3) ene -1,1-dioxide of the general formula HO Il C - NH - R ¹