DE2226298C3 - 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 may 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-phenylaminocarbonyl-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

30th

35

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, N or F ₃ C group can be substituted, and R _{2 is} a hydrogen or halogen atom or an NC, O ₁ N or F ₃ C ReSt, and a process for their preparation and these Medicines containing compounds.

The compounds according to the invention are anti-inflammatory substances. When they, for example, test animals such as rats, orally or intraperitoneally in a dose of 10 to 200 mg / kg are administered, they can be administered by injection of an irritant, e.g. B. of carrageenin, in the paws caused swelling (of the paws) decrease

leave. .

The compounds according to the invention are for the relief of inflammation, for example in Mammals, such as cats, dogs, or monkeys, as a result of arthritis. Usually it is used for treatment For such inflammation a dose of 10 to 200 mg two or three times a day is indicated. the Dosage prescription can depend on the conventional manner known in the relevant art Age, weight, sex and the type of mammal being treated can be varied.

The compounds according to the invention can be used 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, z. B. tablets, are transferred. They can also be used with sterile vehicles, such as water, be transferred into injection solutions suitable for intramuscular administration. In the mentioned The respective active ingredient is in an amount of about 10 to 200 mg per dosage forms Dose unit before.

When carrying out the method according to the invention for the production of the 3-arylaminocarbonyl-4-hydroxy-benzo [b] thiacyclohex (3) en-1, 1 -dioxides, a first step is given by IWJ Still and colleagues in the journal “JOC”, 33 , P. 2730 (1968), described thiochroman-4-one-l, l-dioxide of the formula II, wherein the radical R ^{2 has} the meaning given, reacted with a base such as sodium hydride, whereupon the anion obtained in this way with a 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) -ene-1,1-dioxide of the given formula I .

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

C-NH-R ¹

QH Il

CNHR ¹

(D

The compounds according to the invention can also be obtained 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 - phenylamino carbonyl - 4 - hydroxy - benzo [b] thiacyclohex (3) en-l, l-dioxide the formula

HO

A slurry of 0.088 mol of sodium hydride (3.7 g of a 57% strength Minf.ral oil dispersion) in 50 ml of tetrahydrofuran was at room temperature within 30 minutes of a solution of 7.8 g (0.04 mol) of thiochroman-4-one-1.1 -dioxide added in 100 ml of tetrahydrofuran. The mixture obtained was then admixed with 10 g of phenyl isocyanate and stirred at room temperature for 1 hour. After excess sodium hydride was destroyed by carefully adding methanol, the resulting mixture was poured into ice water and extracted with ether. The formed aqueous layer was acidified and extracted with dichloromethane. The residue obtained after evaporation of the solvent was slurried with hot methanol. The insoluble in the hot Metahnol solids were collected and recrystallized from ethyl acetate to give 3 g of the desired final product having a melting point 205-208 ⁰ C (dec.) 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-hydroxy benzo [b] thiacyclohex (3) ene -1,1-dioxides by Ami nolysis of the corresponding 3-alkoxycarbonyl-4-hydroxy benz [b] thiacyclohex (3) en-1,1 -dioxide:

General procedure

A. 3 - (2 '- chloro) - phenylaminocarbonyl-4-hydroxybenzo [b] thiacyclohex (3) ene-i, l-dioxide the formula

HO Il

CNH-

-

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.

IO When using 7.7 g of o-chloroaniline were 9.9 g of a crude product having a melting point 149-152 ° C obtained. 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 connection

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

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

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

S 10.13.

3. 3 - (T - trifluoromethyl) - phenylaminocarbonyl-4-hydroxy-benzo [b] thiacyclohex (3) ene-Kl -dioxid of the formula

HO

35

CF ₃

When using 9.7 g of o-trifluoromethylaniline In the context of the general process, no separation of the crude product from the reaction mixture could be observed on cooling. From the- its base was the crude product with a 1N sodium hydroxide solution extracted, whereupon the alkaline solution was carefully washed with dilute hydrochloric acid was neutralized. The sediment formed in this way was separated off and once from methanol

and recrystallized the other time from isopropanol to obtain 6.7 g of the aforesaid compound having a melting point of 174 to 177 ° C.
An elemental analysis of the compound

C ₁₇ H ₁₂ F ₃ 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 - Phenylamino carbonyl - 4 - hydroxy - 6 - chlorobenzo [b] thiacyclohex (3) ene 1,1-dioxide the formula

ho I!

Cl I CNH

A mixture of 11.5 g (0.04 mol) 3-methoxycarbonyl - 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 temperature for 4.5 hours in a Soxhlet apparatus whose hood contained 20 g of a Linde 4A molecular sieve. After cooling the reaction mixture to room temperature the crystalline precipitate was separated and recrystallized from acetic acid to give 9.8 g of the desired product having a melting point of 235 to 23S ⁰ C (dec.) 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, 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.

table

Anti-inflammatory properties of S-arylaminocarbonyl ^ hydroxy-benzo ^ thiacyclohexi'SJen-1,1-dioxides according to the invention compared to acetylsalicylic acid

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.

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