FR652M - New drug, containing as active compound an indole derivative or a salt thereof. - Google Patents

Description

French Republic

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

P.y. No. 838.483 International Classification:

N ° 652 M A 61 k - C 07 d

New drug, containing as active compound an indole derivative or one of its salts.

Company known as: A / S DUMEX (DUMEX LTD.) Residing in Denmark.

Requested on September 13, 1960, at 4:20 p.m., in Paris.

Issued by decree of July 3, 1961.

{Official Bulletin of Industrial Property [5.S.M.], No. 24 of 1961.)

(. Patent application filed in Denmark on September 14, 1959, under number 3.265, in the name of Company known as: A / S Meco-Dumex.)

The new medicament contains as active compound a hitherto unknown derivative of indole, of the attached formula 1 or a salt thereof; in this formula R1 represents a hydrogen, a halogen, a lower alkyl or alkoxyl group, or a nitro group, R2 and R3, which may be the same or different, represent hydrogens, halogens, lower alkyl or alkoxyl groups, groups acyl groups, benzyl groups, phenyl groups, or substituted phenyl groups, the possible substituents of which are halogens, lower alkyl or alkoxyl groups, hydroxyl groups or nitro groups, and X is an amino alkyl group substituted on nitrogen, the alkyl group of which is straight or branched and has from 1 to 5 carbon atoms and of which one or both substituents are either alkyl or cycloalkyl groups, or form together, with the atom d nitrogen, a saturated heterocyclic ring, such as a pyrrolidine, a piperidine, a morpholine, a piperazine or an N-alkyl or N-cycloalkyl pipe-razine, or X itself is such a no saturated heterocyclic yau, linked by one of the carbon atoms to the nitrogen atom of the indole group.

Animal testing has shown that the two compounds possess a series of interesting pharmacodynamic properties, mainly including analgesic properties which, in size, are close to those of the morphine group, but whose effect appears to have a different mechanism. Thus, a series of the compounds were compared with codeine and their analgesic effect was shown to be of the same order of magnitude, but the present compounds do not have the disadvantages of codeine, in particular its effect of hindering breathing. .

Furthermore, the compounds have an effect of decreasing the vitality of cats and a reducing effect of motility on small rodents, without having a hypnotic effect, even at large doses. In addition, the present compounds give catatonia just like chlorpromazine. Administered with hexobarbital, they prolong the effect of this barbiturate. The present compounds also have an antipyretic effect. These characters can be summarized by saying that the present compounds have many points of resemblance to chlorpromazine but additionally possess analgesic effect.

In clinical trials, the compounds have been found to be effective in the treatment of rheumatic pain, including arthritis.

The present compounds can be prepared by reacting a compound of the appended formula 2, where R1, R2 and R3 are defined as above, and Z represents hydrogen or a metal atom, with a reactive ester of an alcohol of the formula XOH , where X is defined as above, followed by isolating the resulting indole derivative, optionally in the form of a salt.

As reactive esters of this type, esters of strong organic or inorganic acids, such as sulphonic or halo-hydric acids, are preferably used.

For therapeutic applications, the present compounds are generally used in the form of their addition salts with pharmaceutically acceptable acids, in particular the hydrochlorides of the compounds.

In animal tests, the analgesic effect of a series of the present compounds was determined by comparison with that of codeine and also, for suitably chosen examples, acute toxicity.

The analgesic effect was tested on mice according to a method described by R. Singh Grewal

41347

Price of the booklet: 2 NF

[652 M] -

in the Brit, J, Pharmacol. 7, 433 (1952), which involves passing an electric current for about 1/25 of a second between two electrodes placed in contact with the tails of mice at intervals of one second. The experiments were carried out by first determining, for the untreated mice, the number of current pulses given before the mice start to cry, then by administering the compound whose analgesic effect is to be determined, and finally by determining again the number of electrical pulses that make mice scream. If this number has increased, compared to the number corresponding to the untreated mice, the substance administered is considered to have an analgesic effect proportional to the increase in the number.

The method was here modified by classifying the animals according to their sensitivity to electrical impulses before the test, so that in each test animals which had about the same sensitivity were used.

The tests were carried out by making the determinations fifteen minutes after the intraperitoneal injection of the compounds to be tested, and by carrying out comparative tests with equal doses of codeine phosphate. The following table gives the results of the analgesic effect taking the effect of codeine phosphate as the unit.

read 1

Compound

Number

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15.

16.

17.

Names

1 - (1 '-methyl-2-dimethylamino ethyl) -2 -methyl- 3 -phenyl-indole (Base)

l- (1'-Methyl-2'-dimethykminoethyl) -2-phenylindole (Base)

l- (1'-methyl-2'-dimethylammoethyl) -2-pherLyl-3-methyl-indole (Base)

1- (1'-Methyl-2'-dimethyllaimnoethyl) -2-p-cMorophenyl-indole (HCl).

1- (1'-methyl-2'-dimeth.ylammoethyl) -2-methyl-3-phenyl-6-cHoro-iiidole. . . .

l- (3'-dimethykminopropyl) -2-methyl-3-plienyl-6-cHoro-indole (HBr)

1- (1'-Methyl-2'-dimethylaminaethyl) -2-methyl-3-benzyl-indole (Tartrate) ....

l- (l '~ methyl-2'-dimethykminoethyl) -2-aceto-indole (HCl)

l- (1'-methyl-2'-dimethykminoethyl) -2 - ethyl-3-phenyl-mdole (Citrate) ......

1— (1'-methyl-2'-dimethykminoethyl) -3-phenyl-indole (HCl)

1- (2'-methyl-2'-dimethylaminoethyl) -3-plienyl-indole (HQ)

1- ^ 1'-methyl-2'-dimethylamirtoethyl) -2-chloro-3-phenyl-mdole (HQ)

1- (2'-dimethylsmmoethyl) -2-methyl-3-plienyl-indole (HQ)

l- (3'-Dimethykminopropyl) -2 ~ methyl-3-phenyl-indole (HQ)

1- (l '- methyl-2-dimethylsrmnoethyl) -2-met} iyl-3-phenyl-mdoIe (HCl)

N- (2-diethyiaimnoethyl) —2.3-diphenyl-indole (Base)

1- (2'- Diethylamino ethyl) -2 -methyl-3 -phenyl-indole (Base)

Analgesic effect (codeine = 1)

0.5-0.7 0.3 0.24 0.18 0.45 0.34 0.18 0.28 0.23 0.76 0.52 0.45 0.56 0.28 0.44 0 , 14 0.23

It is seen that the analgesic effect of many compounds is almost equal to that of codeine.

In addition, the acute toxicity of a number of the compounds in Table 1 was determined for intraperitoneal and intravenous administration in mice.The acute toxicity is the LD 50 dose in mg / kg of animal body weight, which kills 50 % of animals subjected to the experiment. The results of these determinations are given in Table 2 below, the numbers of the compounds corresponding to the numbers in Table 1.

(See table 2, column opposite)

For comparison, the acute toxicity of codeine is 150 mg / kg for intraperitoneal administration, and 75 mg / kg for intravenous injection.

In clinical trials, it was found that patients with arthritis, lumbago, or

Table 2

Toxicity

composed xi

Intraperitoneal administration

Intravenous administration

mg / kg mg / kg

1

110

31

5

400

60

6

100 DLso 150

55

7

100

45

8

-

78

-

60

100 DLso 150

40

about 150

55

13

-

58

75 DLso 100

63

15

150 LD50 200

70

other rheumatic pains were relieved by taking daily doses of 1 to 6 tablets, each containing 25 mg of 1 - (1'-methyl - 2'-dimethylaminoethyl) - 3 - phenyi-in-dole hydrochloride.

The following examples will illustrate the preparation of the new drug.

Example 1. - The raw material is 3-phenyl-indole which can be prepared as follows:

12.4 g of phenylacetaldehyde and 10.8 g of phenylhydrazine are mixed cold, the mixture is left to stand for one hour, then it is heated in a steam bath for half an hour. 100 cm3 of ethanol and 25 g of zinc chloride are then added and the mixture is heated under reflux for one hour.

After cooling, the complex formed with the zinc chloride which has precipitated is removed by suction.

The complex is boiled with 3% hydrochloric acid, from which it precipitates 3-phenyl-indole, melting point: 86-88 °. It is recrystallized from ligroin.

19.3 g of phenyl-indole are dissolved in 100 cm3 of dry toluene, 5 g of powdered sodium amide are added and the mixture is heated to boiling with stirring. After boiling for half an hour, 14 g of the compound C1CHCH2N (CH3) 2 dissolved in 1 are added dropwise over half an hour.

CH3

25 cm3 of toluene. The mixture is then heated at reflux for two hours, with stirring, then filtered hot. The filtrate is stirred once with 200 cm3 and twice with 100 cm3 of 3% hydrochloric acid. The hydrochloric acid solution was stirred with ether to remove toluene, then the solution was made strongly basic with 25% sodium hydroxide solution. The liberated base was stirred with a total of 500 cm3 of ether and the ethereal solution was dried over potassium carbonate. After filtration, the ether is distilled off, then the residue under vacuum (boiling point 198-200 ° under 0.01 mm of mercury). The base is a viscous yellow-brown oil, which is very easy to convert into the hydrochloride by precipitation with HCl in isopropanol. By coupling, a mixture of 1- (1'-methyl-2'-dimethyla-mino-ethyl) -3-phenyl-indole, HCl of melting point 229.9-231.6 ° and l - (2'-methyl-2'-dimethylamino-ethyl) -3-phenyl-mdole, HCl mp 184.1-186.6 °. The two compounds can be separated by fractional crystallization and the yield is found to be 75% and 25% respectively for the two compounds.

The following compounds are prepared in a corresponding manner:

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1- (1'-Methyl-2 '"dimethylaminoethyl) -2-methyl-3 -phenyl-indole, as the free base which boils at 170-172 ° under 0.05 mm Hg;

1- (1'-methyl-2'-dimethyl-diaminoethyl) -2-phenyl-in-dole, as the free base of bp 165-168 ° under 0.05 mm Hg;

1- (1'-methyl-2'-dimethylaminoethyl) -2-phenyl-3 -methyl-indole, as the free base of boiling point 168-170 ° under 0.05 mm Hg;

1- (3'-dimethylaminopropyl) -2-methyl-3-phenyl - 6-chloro-indole, in the form of the hydrobromide, melting point 163.9-167.7 °;

1- (1'-methyl-2'-diethylaminoethyl) -2-methyl - 3 -phenyl-indole, as the hydrochloride, which decomposes on heating;

1- (1'-Methyl-2'-dimethylaminoethyl) -3-phenyl-7 -ehloro-indole, as the hydrochloride, which melts at 184-186 °;

1- (1'-Methyl-2'-dimethylaminoethyl) -3-phenyl-5 -methoxy-indole, as the hydrochloride, which melts at 194.6-195-7 °;

1- (1'-Methyl-2'-dimethylaminoethyl) -3-phenyl - 7 -methoxy-indole, as the hydrochloride, which melts at 193-193.5 °;

1 - (2'-dimethyiaminoethyl) - 3 -phenyl-indole, as the hydrochloride, which melts at 204.0-204.9 °;

1- (1'-Methyl-2'- [4 "-methyl-1" -piperazinyl] - ethyl) -3-phenyl-indole, as the maleate, which melts at 147.3-152.6 °;

1- (1'-methyl-2'-dimethylaminoethyl) -3-m-chloro -phenyl-indole, as the hydrochloride, which melts at 200.4-202.0 °;

1- (1'-methyl-2'-dimethylaminoethyl) -3-phenyl - 7 -ethoxy-indole, as the hydrochloride, which melts at 210.1-212.6 °, and l- (2'-diethylaminoethyl) -2-methyl-3-phenyl-indole, as the free base, which boils at 175-177 ° under 0.05 mm Hg.

Example 2. - The starting material is 2-chloro-3-phenyl-indole which can be prepared as follows:

19.3 g of 3-phenyl-indole are dissolved in 100 cm3 of chloroform and 15 g of sulfuryl chloride in 50 cm3 of chloroform are added dropwise, with stirring and cooling. Excess sulfuryl chloride is removed by stirring with water and sodium carbonate solution. The chloroform phase is dried over sodium sulfate and the chloroform is distilled off. The residue is vacuum distilled (boiling point 218-220 ° under 0.01 mm of mercury). 2-chloro-3-phenyl-indole is obtained with a yield of 75%. 22.7 g of 2-chloro-3-phenyl-indole in dry toluene are treated with sodium amide, as described in Example 1. In this way, 1 - (l 'methyl - 2'-dimethylaminoethyl) -2-chloro-3-phenyl-indole (boiling point 205-207 ° under

Claims (41)

[652 M] - 4 - 0.01 mm Hg) as a viscous yellow-brown oil. The hydrochloride has a melting point of 200.5-201.6 °. Example 3. The starting material is obtained from 14.4 g of m-chlorophenyl-hydrazine and 13.5 g of phenyl-acetone, treated as described in Example 1, which makes it possible to obtain the 2-methyl-3-phenyl-6-chloro-indole (boiling point 212-214 ° under 0.01 mm Hg). By then treating the latter as described in Example 1, 1- (1'-methyl-2'-dimethyliaminoethyl) -2-methyl-3-phenyl-6-cHoro-indole, HBr of melting point 223.0-226.5 °. Example 4. 2.2 g of lithium in 100 cm3 of anhydrous ether are cooled to -10 ° and 15.3 cm3 of n-butyl bromide dissolved in 50 cm3 of anhydrous ether are added dropwise. This operation and the following are carried out under a nitrogen atmosphere. Slowly added, with stirring, 19.3 g of 3-phenyl-indole dissolved in 800 cm3 of anhydrous ether to the reagent - butyl lithium. The temperature is maintained below 15 ° by means of an ice bath. While continuing to stir, 15 g of the ester of methylsulfonic acid and of dimethylaminoisopropanol dissolved in 100 cm3 of anhydrous ether are finally added. After the addition, stirring is continued for a further hour. Then carefully add 500 cm3 of water. After filtration, the ethereal phase is stirred with two more times 250 cm3 of water. Finally, the ether is stirred once with 200 cm3 and twice with 200 cm3 of 3% hydrochloric acid. The acid extract is then treated as described in Example 1 to obtain the same final product. Example 5. As described in Example 1 or in Example 4, the compounds listed below having the melting points indicated, the numbers corresponding to those of Table 1, are prepared. j maldehyde, the reaction product is then evaporated in vacuo and the residue dissolved in ethanol. A slight excess of a solution of tartaric acid in ethyl alcohol is added with heating and stirring, from which it crystallizes the sparingly soluble tartrate of melting point 143.0-143.6 °. In an analogous manner, the following compounds are prepared: 1.3-bis-dimethylaminoethyl-indole, in the form of the free base, and 1-Dimethyl-amino-ethylindolyi-3-acetic acid ethyl ester, as the hydrochloride, which melts at 156.1-157.2 °. Example 7. To prepare 1000 tablets, each containing 25 mg of active compounds, the following operations are carried out: 25 g of 1- (1'-methyl-2'-dimethylaminoethyl) -3-phenyl-indole hydrochloride are mixed with 100 g of potato starch and 37 g of lactose. The mixture is moistened with a solution of 2 g of gelatin in 50 cm3 of water, then it is granulated and dried. The granules are mixed with 1 g of magnesium stearate and 15 g of talc and put into tablet form. (Formula 1) Compound n " Fusion point 4 258 ° -259 ° 86.1 ° - 88.3 ° 218.7 ° -220.8 ° 145.9 ° -149.1 ° 227.7 ° -229.9 ° 209.7 ° -212.6 ° 263, l ° - 264.5 ° 7 8 9 13 14 17 Example 6 - Using a Mannich reaction, 1-dimethylami-nomethyl-3-phenyl-indole tartrate is obtained as follows: 3-phenyl- is heated under reflux for three to four hours. indole, dimethylamine and for- ■ AV W-f-5 (Formula 2) -R3 VAn /! Z ABSTRACT -R2 New medicament containing as active substance an indole derivative of the appended formula 1 or one of its salts, formula in which R1 represents a hydrogen, a halogen, a lower alkyl or alkoxylic group, or a nitro group, R2 and R3 , which may be the same or different, represent hydrogens, halogens, lower alkyl or alkoxylic groups, acyl groups, benzyl groups, phenyl groups or substituted phenyl groups, the possible substituents being halogens, alkyl groups or lower alkoxylic groups, hydroxyl groups or nitro groups, and X being an aminoalkyl group substituted on nitrogen, the alkyl groups of which are straight or branched and have from 1 to 5 carbon atoms, and whose one or both substituents are, either alkyl or cycloalkyl groups, or form - 5 - [652 M] with the nitrogen atom a saturated heterocyclic ring, or else X itself forms such a heterocy- such as a pyrrolidine, piperidine, morpholine, saturated clique ring, linked by one of the carbon atoms to piperazine, or N-alkyl or N-cycloalkyl piperazine, the nitrogen atom of the indole group. Company known as: A / S DUMEX (DUMEX LTD.) Vicarious : i. Casanova (Young Armengaitd Cabinet) For the sale of fascicles, contact the Imprimerie Nationale, 27, rue de la Convention, Paris (15 ').