FI57100C - PROCEDURE FOR THE FRAMEWORK OF THIOALKYLAMINE N- (3-THIOPHENYLPROPYL) -N- (3,3-DIPHENYLPROPYL) AMIN JAEMTE DESS SALTER MED PHARMACOLOGICAL EQUIPMENT - Google Patents

Description

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Patant- och ragietaratyralsan '' Ameiun utkgd oeh uti ^ krifun pubifcmd 29.02.80 (32) (33) (31) ^ «« T etuellwu * —Btglrd priori »· * 15.07.71

Italia-Italien (lT) 3 ^ 76 A / 71 (71) ALFA pharmaceutical spa, Via Ragazzi del '99 n. 5 »U0133 Bologna, Italy- 'Italien (lT) (72) Pietro Bianchini, Modena, Eupremio Vitale, Bologna , Guido Guerra,

Bologna, Giustino Censoni, Bologna, Italy-Italy (1T) (7 ^) Forssen & Salomaa Oy (5k) Method for the preparation of a new thioalkylamine, N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine and its salts having pharmacological properties - Förfarande för framställning av en ny thio-alkylamine, N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) Amine residue in the form of pharmacological agents

The present invention relates to a process for the preparation of a new thioalkylamine of the formula O-CH-CH2-CH2-NH-CH2-CH2-CH2-S-Γ 7 (I) 'o and its salts. The novel thioalkylamine of the invention has valuable pharmacological properties.

The compound of the present invention represented by the above formula (I) has been shown to be remarkably active in the treatment of three common experimentally induced types of gastric ulcers, has weak spasmolytic activity and is useful in human medicine.

Pharmaceutically acceptable salts of the compound of formula (1) above include salts formed with acids that do not increase the intrinsic toxicity of the present compound. These acids can be both inorganic and organic. Among the inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, pyrophosphoric acid, sulfuric acid and nitric acid can be used.

Among the organic acids which are pharmaceutically acceptable, for example, acetic acid, formic acid, propionic acid, tartaric acid, malic acid and citric acid can be used.

The compound of formula (I) above is prepared according to the present invention by condensing the formula

O

CH - CH2 - CH2 - NH2 (II)

O

amine of formula x - ch2 - ch2 - ch2 - S - ^ ^ (III) or by condensing an amine of formula h2n - ch2 - ch2 - ch2 - S ^ (IV) with a halogenated compound of formula 3 57100

O

CH - CH- - CH - X (V)

O

wherein X in the formulas represents one of the following halogens: chlorine, bromine and iodine. According to another method of the present invention, a compound of formula (I) may be prepared by condensing an amine of formula (II) with a carbonyl compound of formula 0 = c - CH 2 - CH 2 - S - (VI) and reducing the condensation product to compound (I). ). Alternatively, the compound may be prepared by condensing an amine of formula (IV) of formula Q.

CH - CH- - CH- - C = O (VII) • with a carbonyl compound.

The condensation of compounds (II) and (III) and compounds (IV) and (V) is carried out a) by adding an amine of formula (II) to a halogen compound of formula (III) at a temperature of 30-100 ° C for 3-6 hours, preferably in solution and in an inert atmosphere, or b) adding an amine of formula (IV) to a halogen compound of formula (V) at a temperature of 30 to 100 ° C for 3 to 6 hours, preferably in solution and under an inert atmosphere.

Both reactions a) and b) can be carried out in the presence of an acid scavenger which scavenges the hydrohalic acid formed.

4 57100

After carrying out the reaction, the reaction mixture is kept at 30 to 100 ° C for 3 to 6 hours, then allowed to stand at room temperature for about 12 hours.

After separation of the precipitate, the compound of the invention is obtained as a free base from the filtrate by conventional methods such as concentrating to a small volume, dissolving the residue in chloroform, treating with acid, washing with water and basifying with ammonium hydroxide.

The crude product is usually obtained as a thick oil which solidifies on addition of organic solvents; the crude product can be purified by crystallization.

As already mentioned, the above condensation reaction is preferably carried out in solvents such as aliphatic alcohols, aliphatic or aromatic ethers, aliphatic or aromatic hydrocarbons, e.g.

When hydrohalic acid is formed in the condensation reaction, suitable basic substances for its removal include, for example, collidine, pyridine, N, N-dimethylaniline, N, N-diethylaniline, triethylamine and quinoline.

Pharmaceutically acceptable salts of a compound of formula (I) may be obtained by converting a base into a salt in a solvent in which the free base is soluble by reaction with an equivalent amount of acid or by gradually dissolving the free base in an acid solution.

The invention is illustrated by the following examples:

Example 1 120 g of hot 3-thiophenyl-1-bromopropane were slowly added under a nitrogen atmosphere to a solution of 110 g of 3,3-diphenylpropylamine in isopropanol and 150 ml of triethylamine. The mixture was then refluxed for 5 hours and allowed to stand at room temperature for 12 hours.

The precipitated triethylamine hydrobromide was filtered off, and the filtrate was concentrated. The oily residue was dissolved in chloroform, and then the solution was saturated with hydrogen chloride gas and then washed several times with warm water. The solution was dried over anhydrous sodium sulfate, then the solvent was evaporated.

the oily residue became solid upon addition of a 1: 1 (v / v) mixture of isopropanol and ether, after which the product was crystallized from isopropanol.

5 57100

50 N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine with a melting point of 115-116 ° C were obtained.

Analysis: C% H% N%

Calculated from the formula ^ 24 ^ 28 ^ Cl S 72.42 7.09 3.51 Found 72.73 7.25 3.63

Example 2

A solution of 3.5 g of 3-thiophenylpropylamine (prepared according to CA 52 16131 d) and 6 ml of triethylamine in 20 ml of benzene is heated to about 50 ° C, 5.3 g of 3,3- (bis-phenyl) are added. ) -1-bromopropane (prepared according to CA 69 86494 y) is refluxed for 12 hours and then allowed to stand for 8 hours.

The triethylamine hydrobromide is removed by filtration, the clear filtrate is evaporated in vacuo and the residual oil is dissolved in 12 ml of chloroform and saturated with hydrogen chloride gas.

The organic solution is washed with water, dried and evaporated to dryness in vacuo. The residual oil is crystallized from 40 ml of ethyl acetate. The solid product is filtered off, washed with ethyl ether and dried in vacuo.

3.9 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 46.5%).

Example 3 10.6 g of 3,3-diphenylpropylamine and 9.9 g of 3-thiophenylpropionaldehyde (prepared according to C.A. 59 8635 e) are boiled under reflux in 25 ml of benzene for 30 minutes.

The solvent is removed by distillation in vacuo and the residual oil is treated with 25 ml of methanol and 3 ml of water.

0.75 g of sodium borohydride are gradually added to the resulting emulsion, followed by boiling under reflux for 30 minutes.

The solvent is removed by distillation in vacuo and the residual oil is dissolved in 28,500 ml of 28 ml of chloroform and the resulting solution is saturated with hydrogen chloride gas.

The solution is washed with water, dried and concentrated in vacuo. The residual oil is crystallized from 80 ml of ethyl acetate and the solid product is filtered off, washed with ethyl ether and dried in vacuo.

4.5 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 22.5%).

Example 4 3.5 g of 3-thiophenylpropylamine (prepared according to CA 52 16131 d) and 5.2 g of 3,3-bis- (phenyl) propionic acid aldehyde (prepared according to CA 72 43154 g) are boiled under reflux in 10 ml of benzene for 30 minutes. I drive. The solvent is distilled off in vacuo and the residual oil is treated with 10 ml of methanol and 1 ml of water. 0.40 g of sodium borohydride are gradually added to the resulting emulsion, followed by refluxing for 30 minutes. The solvent is distilled off, and the residual oil is dissolved in 12 ml of chloroform, and the solution is saturated with hydrogen chloride gas.

The solution is washed with water, dried and evaporated to dryness in vacuo.

The residual oil is crystallized from 20 ml of ethyl acetate. The solid product is filtered off, washed with ethyl ether and dried in vacuo.

4.8 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 57.5%).

The following toxicity studies have been performed on the compound prepared above: 1 - Acute toxicity in mice and rats 2 - Subacute toxicity in rats (28 days) 3 - Chronic toxicity in rats (13 weeks) 4 - Chronic toxicity in rats and guinea pigs (26 weeks) 5 - 57100 7 1 - Acute toxicity in mice and rats

The table below shows the DL 2 values of the substance after a single administration intravenously, intraperitoneally, subcutaneously and orally.

METHOD OF ADMINISTRATION (°) DL50 (mg / Kg) “SEX MOUSE (Swiss) SEX RAT (Wistar) i.v. M 17.15 F 19.70 (16.59-17.76) (19.16-20.25) i.p. M 39.40 F 59.72 (24.38-63.54) (38.52-92.57) s.c. M> 1000 F> 1000 p.o. M> 1000 F> 1000 (°) Weil & Thomson method (confidence interval P * 0.05) 2 - Subacute toxicity test in rat Duration: 28 days

Animal: Wistar rats (Morini), both sexes Dose: 50 mg / kg s.c.

200 "p.c.

catered; - appearance - mortality - food consumption - change in body weight - urine analysis - hematology - blood chemistry - liver chemistry 57100 8 - pathological macro study and organ weights - histology

Score:

No significant changes were observed at either the hot dose tested compared to control animals.

3 - Extended toxicity test on rats Shelf life: 13 weeks

Animals: Wistar rats (Morini), both sexes Dose: 150 mg / kg p.o.

Same experiments as for subacute toxicity.

In any case, there were no significant changes compared to the control animals.

4 - Extended toxicity test on rat and guinea pig Duration: 26 weeks

Animals: Wistar rats (Morini), both sexes Doses: 25 - 75 - 150 mg / kg p.o. rat 500 mg p.o. the guinea pig

Same experiments as for subacute toxicity.

In any case, there were no significant changes compared to the control animals.

5 - Teratology in rats and rabbits Fetal toxicity in rats:

The compound was administered orally at a dose of 100 mg / kg for 28 days. The following parameters were taken into account in both experiments: 9 57100 - number of attached embryos and their distribution in the uterus - number of reabsorbings - number of fetuses removed - number of dead fetuses - deviation, type and number of malformations - weight of fetuses - alkali and staining with Alizarin S) "- femur lengths and distributions into different categories

The administration of the compound as a drug did not change the parameters in any way, considering all the factors.

To investigate the pharmacodynamic properties of the compound prepared above, the following experiments have been performed: 1 - In vitro experiments a) antispastic activity b) receptor blocking effect 2 - antiulcer activity _ - stress wound - Shay wound - Reserpine wound - Prednisolone wound - Histamine wound - Serotonin wound - Indomethacin wound - glucose wound 3 - Analgesic and anesthetic activity 4 - Other pharmacological activities 10 571 00 1 - In vitro tests (a) Antispastic activity:

It has been tested on parts of isolated organs of rats and guinea pigs with different concentrations of histamine (H), acetylcholine (Ach.), Serotonin (5 HT), bradykinin (BK), BaCl 2 and oxytocin (OXIT).

The following table shows the inhibitions in% and the relevant ED, ^: EXPERIMENTS ΙΟ-4 10 "5 10" 6 ED ^ g

Ach. 68.0 84.0 22.0 2 x 10 "5 H 71.5 36.9 28.3 4 x 10" 5

BaCl2 76.7 22.5 13.0 3 x ΙΟ-5 BK 69.0 17.0 - 3 x 10-5 5 HT inhibition depends on contact time OXIT contractions increase b) Receptor blocking effect:

The duration of compound-induced receptor blockade is determined by measuring the duration of antiserotonin action in vitro.

2 - Anti-gastric ulcer activity This activity, evaluated by experiment using a different mechanism of action, is shown in the following table: 11 571 00

EXPERIENCE Dose ADMINISTRATION INHIBITION

mg / kg TAPA%

Stress ulcer 5 os 51 10 "58 20" 63

Shay wound 10 s.c. 45 20 "" 50 _ Reserpine Wound 20 S.c. 48

Prednisolone Wound 10 i.m. 75

Histamine wound 50 os 63 ^ 100 "92 10 s.c. 82 20" "92

Serotonin wound 10 s.c. 75 50 os 72.5

Indomethacin wound 25 os 60 50 "73 125" 76 250 "88

Glucose wound 50 os 64 3 - Analgesic and anesthetic activity

Analgesic activity has been evaluated in the following experiments: - chemical contractions - rat tail surgery

In both experiments, the product proved ineffective.

Anesthetic activity has been evaluated in the following experiments: - loss of corneal contact reflex in rabbits - infiltration anesthesia in guinea pigs

Claims (3)

12 571 00 In the first experiment, the compound of Example 1 proved to be more effective than the reference drug lidocaine (1%) at the same concentration. In another experiment, the activity of the compound of Example 1 proved to be the same as that of lidocaine (0.1%). 4. Other Pharmaceutical Activities - Dextran Edema Subcutaneously administered at 10 mg / kg and orally at 50 mg / kg, the compound inhibits edema in the rat pocket by approximately 50%. - Intestinal peristalsis No changes in motility and intestinal transport. A process for the preparation of N- (3-thiophenylpropyl) -N- (3.3) of the formula O-CH-CH2-CH-NH-CH2-CH2-CH-S-x> (I) O u having pharmacological properties -diphenylpropyl) amine and its pharmaceutically acceptable salts, characterized in that the amine of the formula 13 571 00 O CH - CH2 - CH2 - NH2 (II) O is condensed by the formula x - ch2 - ch2 - ch2 - S - ^ ^ (III) or condensing an amine of formula h2n-ch2-ch2-ch2-S-^ (IV) CH-CH0-CH. - X; o. wherein X is one of the following halogens, chlorine, bromine or iodine, and the condensation is carried out at a temperature of 30 to 100 ° C and preferably in a solvent or condensed in a solvent of the formula O CH - CH 2 - CH 2 - NH 2 (II) O 1. 14 An amine of formula 571 00 with a carbonyl compound of formula H yt O = C - CH2 - CH2 - S - ft (VI) or an amine of formula (IV) h2n - ch2 - ch2 - ch2 - S - ^ (IV) is condensed, CH - CH. - CH. - with a carbonyl compound according to C = O (VII) O, and then the condensation product is reduced, wherein when the condensation is carried out in a solvent, the solvent is e.g. an aliphatic alcohol, an aromatic or aliphatic ether or an aliphatic hydrocarbon, e.g. methanol, ethanol, propanol or ethylene glycol, ethylene glycol monoalkyl ether, ethylene glycol dialkyl ether, anisole, ligroin, benzene or toluene, and in the case where a hydrohalic acid is formed in the reaction, a basic substance capable of binding N, a quinine, -dimethylaniline, N, N-diethylaniline, triethylamine or collidine. 15 57100 A compound for the preparation of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) -amine with the formula O CH - CH- - CH - NH - CH - CH - CH - S - ) The pharmacologically acceptable and pharmaceutically acceptable excipients, which may be used, are those of the formula Q CH - CH_ - CH. - NH- (II) ÖL LL condenser with halogen formulation of formula x - ch2 - ch2 - ch2 - S - ^ ^ (III) or Amine with formula h2n - ch2 - ch2 - ch2 - S - ^ ^ (IV) condenser in which halogenated compounds of formula ch2 - ch2 - X (V) ό