DE1620190C - 4- (2-Carbo-alpha-glyceryloxyphenylamino) -8-chloroquinoline, its salts and a process for their preparation - Google Patents

Description

and its salts with therapeutically acceptable inorganic or organic acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that a 4- (2'-carbalkoxyphenylamino) -8-chloroquinoline is used in a manner known per se reacts in the presence of an alkaline transesterification catalyst with glycerol acetonide, the acetonide obtained des 4 - (2 '- Carbo - α - glyceryloxyphenylamino) -8-chloroquinoline hydrolyzed under acidic conditions and then optionally the resulting 4- (2'-carboa-glyceryloxyphenylamino) -8 -chlorquinoline converted into a salt with a therapeutically acceptable inorganic or organic acid.

The invention relates to 4- (2'-carbo-a-glyceryloxyphenylamino) -8-chloroquinoline the formula

COO - CH, - CHOH-CH ₇ OH

[1959], 412) observed the fact that the intraperitoneal injection of acetic acid in the mouse causes characteristic, repetitive stretching and twisting movements that last more than 6 hours can last; The analgesics prevent or suppress this syndrome, which is why it is embodied a diffuse abdominal pain can be seen.

An aqueous acetic acid solution (6% q) is used,

ίο which is mixed with 10% gum arabic. The dose that triggers the syndrome under these conditions is 0.01 ccm / g, that is 60 mg / kg acetic acid. The analgesics are administered by the buccal route V ₂ hours before the intraperitoneal injection of acetic acid, the mice being fasted from the day preceding the experiment. One or more groups consisting of five animals are used for each dose and for the control experiments (which are always carried out in a mandatory manner). The stretching movements are observed and counted in each mouse, then added up within a group of five animals, the observation period being 15 minutes and beginning immediately after the acetic acid injection.

The investigated products are given as an aqueous suspension by the oral route in different Doses administered. The table below summarizes the results obtained.

a) 4- (2'-Carbo-a-glyceryloxyphenylamino) -

8-chloroquinoline

Doses administered

40

45

its salts with therapeutically acceptable inorganic or organic acids and a process for their manufacture.

The 4- (2'-carbo-a-glyceryloxy- ⁱ phenylamino) -8-chloroquinoline according to the invention has a remarkable anti-inflammatory and an intense and uniform analgesic activity. In addition, it has in comparison to certain 7-chloroquinolines, such as 7-chloro-4- (3'-diethylaminomethyl-4-hydroxyphenylamino) -quinoline and 7-chloro-4- (4'-diethylamino-l-methylbutylamino) - quinoline, the advantage of showing neither kidney nor eye toxicity.

4 - (2 '- Carbo - α - glyceryloxyphenylamino) - 8 - chloroquinoline was compared with the 4- [2' - (ß- dimethylaminoethoxycarbonyl) -phenylamino] -7 known from the German Auslegeschrift 1 173 899 with regard to its analgesic activity and its toxicity -chlorquinoline compared.

65 1. Analgesic activity

The test used is based on that of R. Koster and co-workers (Fed. Proa, 18 10 mg / kg

20 mg / kg

50 mg / kg

100 mg / kg

percentage
the stretching

in comparison
to the control animals

80
75
36
37

percentage
of contraception

20th
25th
64
68

• b) 4- [2 '- (/ S-Dimethylaminoethoxycarbonyl) -phenylamino] -7-chloroquinoline

Doses administered percentage
the stretching
in comparison
to the control animals percentage
of contraception 5 _sec 0 mg / kg
100 mg / kg
200 mg / kg 50
31
12th 50
69
88

On the basis of these results it can be stated that the active dose, which reduces the number of stretching by 50% (DA ₅₀ ), is 35 mg / kg for the compound according to the invention, whereas the DA ₅₀ for the known substance is only 50 mg / kg is achieved.

2. Acute toxicity

Their determination was carried out on mice from the Rockland strain weighing 18 to 22 g. the Products in aqueous solution or suspension were administered orally in increasing doses.

The animals were kept under observation for one week. Under these conditions, the lethal dose (DL ₅ Q) of 4- (2'-Carbo-a-glyceryloxyphenylamino) -8-chloroquinoline is above 4 g / kg, whereas it is in the case of the known compound 4- [2 '- (/ 9 -Dimethylaminoethoxycarbonyl) -phenylamino] -7-chloroquinoline is 1.50 g / kg.

The process for the preparation of the new quinoline derivatives is that one is known per se Way a 4- (2'-carbalkoxyphenylamino) -8-chloroquinoline in the presence of an alkaline transesterification catalyst reacts with glycerol acetonide, the acetonide obtained of 4- (2'-carbo-a-glyceryloxyphenylamino) -8-chloroquinoline hydrolyzed under acidic conditions and, if necessary, the resulting 4- (2'-carboa-glyceryloxyphenylaminoJ-S-chloroquinoline with a therapeutically acceptable inorganic or organic Acid converted into a salt.

The alkaline transesterification catalyst is e.g. B. an alkali metal such as sodium, or the amide one Alkali metal such as sodium amide.

The hydrolysis of the acetonide of 4- (2'-carbo-λ a-glyceryloxyphenylaminoJ-S-chloroquinoline becomes advantageous with the aid of a strong mineral acid such as hydrochloric acid.

The following example illustrates the invention.

example

Level a

Acetonide of 4- (2'-Carbo-cc-glyceryloxyphenylamino) -8-chloroquinoline

43 ecm of glycerol acetonide become 30 ecm anhydrous Toluene added, the mixture in a stick substance atmosphere at a temperature of 120 to Heated to 125 ° C. and the water-toluene azeotrope is distilled off; finally the toluene is then in vacuo deducted.

After cooling to a temperature of 70 ⁰ C 130 mg sodium amide are introduced, and the mixture is heated IV2 hours to about 90 ⁰ C.

The temperature is then reduced to 60 ° C., then 10.4 g of 4- (2'-carbomethoxyphenylamino) -8-chloroquinoline are obtained introduced, and it is heated to about 80 ° C in a vacuum for 5 hours.

It is cooled, the solution is poured into a mixture of water and methylene chloride (10: 1), stirred and decanted.

The aqueous phase is extracted with methylene chloride, the extracts are washed with water, dried and distilled to dryness.

The residue is triturated in petroleum ether, filtered, filtered off with suction and dried; it will be 12.5 g of the acetonide of 4- (2'-carbo-a-glyceryloxyphenylamino) -8-chloroquinoline obtained, which melts at 115 ° C after recrystallization from ethanol.

The product is insoluble in water and ether, it is soluble in acetone, benzene, chloroform and in the heat in ethanol and isopropyl ether.

Analysis: Ca ₂ H ₂₁ O ₄ N ₂ Cl = 412.86.

Calculated. C 63.99, H 5.13, N 6.78, Cl 8.59%; found .., C 64.1, H 5.1, N 7.1, Cl 8.6%.

: As far as is known, this compound is not described in the literature.

Level B.

4- (2'-Carbo-a-glyceryloxyphenylamino) -
- 8-chloroquinoline

The acetonide of 4- (2'-carbo- a - glyceryloxyphenylamino) - 8 - chloroquinoline (13 g) obtained in stage A is taken up in 30 ecm hot water ^ then 6 ecm of a concentrated aqueous hydrochloric acid solution are added and 15 minutes at 95 ° C heated.

It is cooled, suction filtered and washed with water; the crystallized chlorohydrate is obtained in this way des 4- (2'-Carbo-7a-glyceryloxyphenylamino) -8-chloroquinoline.

As far as is known, this product is not described in the literature.

To obtain the free base, the hydrochloride in dimethylformamide, which is heated to 6O ⁰ C is dissolved, after filtration, water and a few cubic centimeters of triethylamine are added and it is cooled 1 hour.

It is filtered off with suction, washed with water and dried in vacuo; 13 g of 4- (2'-carbo-α - glyceryloxyphenylamino) - 8 - chloroquinoline, which is recrystallized from tetrahydrofuran; F. 184 to 185 ° C.

The product is obtained in the form of needles which are insoluble in water, ether and benzene; it's in acetone and ethanol very slightly soluble.

Analysis: Ci ₉ H ₁₇ ClN ₂ O ₄ = 372.8.

Calculated. C 61.21, H 4.59, Cl 9.51, N 7.52%; Found ... C 61.1, H 4.7, Cl 9.2, N 7.8%.

As far as is known, this compound is not described in the literature.

4- (2'-Carbo-a-glyceryloxyphenylamino) -8-chloroquinoline hydrochloride

A suspension of 5 g of 4 - (2 '- carbo - α - glyceryloxyphenylamino) - 8 - chloroquinoline in 50 ecm of methanol is heated under reflux, and 8 ecm of methanol containing 6.65% hydrochloric acid is added. The chlorine hydrate crystallizes on cooling. It is isolated by suction and drying in vacuo; F. 208 to 209 ⁰ C.

The 4- (2'-carbomethoxyphenylamino) -8-chloroquinoline required as a starting material is produced in the following way: 15 g of 4,8-dichloroquinoline, produced after D. S. Tarbe 11, Journ. At the. Chem. Soc, 68, 1277 (1946), are introduced into 75 ecm of 2N hydrochloric acid. 11.5 g of anthranilic acid methyl ester are added and the mixture is refluxed for 3 hours with stirring heated.

It is then cooled to ice bath temperature for 1 hour, filtered off with suction and washed with water; man thus receives the chlorohydrate of 4- (2'-carbomethoxyphenylamino) -8-chloroquinoline.

In order to obtain the free base, the hydrochloride is dissolved in 200 ecm of ethanol, there are 50 ecm concentrated ammonia is added until the reaction is clearly alkaline, and it is brought to ice bath temperature chilled. The precipitate formed is filtered off with suction, washed with ether and dried. After Recrystallization from ethanol gives 13 g of 4- (2'-carbomethoxyphenylaminoJ-S-chloroquinoline receive; M.p. 183 to 184 ° C.

Claims (1)

Patent claims: 1. 4 - (T - Carbo - α - glyceryloxyphenylamino) -. 8-chloroquinoline of the formula NH COO-CH ₇ -CHOH-CH ₉ Oh Cl