CS246338B1 - From benz (c,d) indole derived cyclic amidines and their hydrochlorides - Google Patents

Description

The present invention relates to benzylic (c, d) indole-derived cyclic solvents of the formula I

wherein either R ¹ is a hydrogen atom and then R 1 represents a (CH ₂ ) _n R ³ radical, wherein n is 1 to 3 and R ³ is isopropyl, phenyl, diethylamino or 4-morpholines, or wherein the entire NRfR ² radical represents 4-methyl-1-piperazinyl, and their hydrochlorides.

The compounds of formula I are novel and in particular in the form of their hydrochlorides have some neurotrophic and cardiovascular effects which make them useful in pharmacotherapy. Brief data on the results of pharmacological tests with the compounds of the invention are given. All were tested as hydrochlorides.

Isobutylaminobenz-2 (c, d) indole (I, ^R1 = H, n = 1, R ³ = isopropyl). Acute toxicity in mice, LD ₅₀ = 12 mg / kg _i.v. , At doses greater than 2 mg / kg iv, it has a central stimulating effect in mice, manifested by increased locomotor activity. In the form of an aqueous solution, it has a local anesthetic effect on the cornea of the rabbit eye, which is close to that of cocaine. At an iv dose of 2 mg / kg, it induces miosis in the mouse eye, suggesting a parasympathomimetic effect. At a dose of 1 mg / kg iv, it causes mild and short-term decreases in blood pressure in normotensive rats. In isolated rat duodenum in vitro it shows a spasmolytic effect on barium chloride contractions of about the same intensity as papaverine. A dose of 2 mg / kg iv leads to a slight decrease in body temperature in rats (hypothermal effect).

2- (benzylamino) benzo (c, d) indole (I, R ¹ - Η = n = 1, R ³ = phenyl). Acute toxicity in mice, LD _5n = 500 mg / kg orally. At an oral dose of 100 mg / kg, the duration of thiopental sleep in mice increases to 200% of the control value. At the same dose, it has an antiarrhythmic effect in mice that protects against ventricular fibrillation induced by chloroform inhalation.

2- (2-Diethylammoethylamino) benz (c, d) indole ( ¹ , R ¹ - Η, n = 2, R ³ - diethylamino). LD ₅₀ e = s 30 mg / kg i, v. Dose 3 mg / kg

248338

v. causes mild and short-term decreases in blood pressure in rats. It has a papaverine-like spasmolytic effect on isolated rat duodenum.

2- (2-Morpholinoethylamino) benz (c, d) Inidol (I, R ¹ = Η, n = 2, R ³ 4-morpholinyl). LD ₅₀ o = 50 mg / kg iv At doses of 5 mg / kg iv, it causes mild and short-term decreases in blood pressure in rats. At an intravenous dose of 10 mg / kg, it has an antiarrhythmic effect in mice that protects against ventricular fibrillation induced by chloroform inhalation.

2- (3-morpholin olinopropylamino) benz (c, d) indole (I, R ^J Η n = 3, R ³ = 4-morpholinyl). LD ₅₀ = 42.4 mg / kg iv At 4 mg / kg iv, it causes mild and short-term decreases in blood pressure in rats. At a dose of 8.5 mg / kg iv, it has a similar antiarrhythmic effect in mice to the previous agents.

2- (4-Methylpiperazino) benz (c, d) indole (I, NR ³ R ² = 4-methyl-1-piperazinyl). LD ₅₀ - = 40 mg / kg iv At intravenous doses of 8 mg / kg, it induces miosis in the mouse eye (parasympathomimetic effect), moderately and shortly decreases blood pressure in rats and shows peripheral vasodilatory effect in guinea pigs (increased ear temperature due to increased blood flow) . At the same dose, it slightly potentiates thiopental sleep in mice.

Of these, antiarrhythmic (against heart rhythm disorders), spasmolytic (against smooth muscle spasms, particularly the gastrointestinal system) and mild sedative effects, indicated by potentiation of thiopental, are practically applicable.

The compounds of the formula I according to the invention are amenable to the reactions of the known naphthostyril of the formula II (Dokunichin, N. S., Pletneva, I. D., Ob. Ob. Chim. 23, 798, 1953; U.S. Pat.

628 964)

with primary or secondary amines of the general formula HNR ^J R ² , in which R ¹ and R ² or all of NR ⁴ R ^{2 are the} same as in formula I. These reactions are made possible by the presence of titanium tetrachloride and carried out in suitable boiling solvents, preferably benzene. or in a mixture of benzene and tetrahydrofuran. The resulting products of formula (I) are basic in nature and usually already well crystallize as bases so that they can be isolated in this form. The bases of formula I provide crystalline hydrochlorides which are suitable for carrying out pharmacological tests and for preparing dosage forms by neutralizing with hydrogen chloride in ethanol or in a mixture of ethanol and ether. The identity of all substances according to the invention was assured by analyzes and spectra. The preparation of the compounds of formula I and their hydrochlorides is described in the following examples, which are intended to illustrate the possibilities of the invention, but the invention is not limited thereto.

Example 1

2- (Isobutylammo) benz (c, d) indole (I, R ¹ == H, n = 1, R ³ - isopropylj

To a solution of 8.45 g of naphthostyril (II) in 150 ml of tetrahydrofuran was added 20 g of isobutylamine and then a solution of 8.6 g of titanium tetrachloride in 30 ml of benzene was added dropwise with stirring over 5 minutes. The resulting mixture was refluxed for 16 h. After cooling, the reaction is quenched by addition of 10 ml of water and after standing for 30 min, the precipitate formed is filtered off and washed with 20 ml of tetrahydrofuran. The filtrate is evaporated under reduced pressure, the oily residue is dissolved in 100 ml of chloroform and the solution is washed with dilute aqueous ammonia and water. After drying over sodium sulfate, the chloroform is evaporated and the crystalline inhomogeneous residue (containing a small amount of starting naphthostyril) is dissolved in 250 ml of ether and shaken with excess dilute hydrochloric acid to give a crystalline product hydrochloride. to the aqueous phase of the filtrate, the suspension is basified with aqueous ammonia and the liberated base is extracted with benzene, dried over magnesium sulfate and evaporated under reduced pressure to give 7.5 g of crystalline base melting at 154-157 ^° C. The crude oil is obtained as an analytically pure base, melting at 158 DEG-160 DEG C. By neutralization with hydrogen chloride in an ethanol / ether mixture, the hydrochloride is obtained, which crystallizes from a mixture of ethanol and ether and melts in the pure state at 222 DEG-225 DEG.

Example 2

2- (benzylamino) benzo (c, d) indole (I, ^R1 = 11, n = 1, R ³ - phenyl)

A mixture of 8.5 g of naphthostyril in 150 ml of tetrahydrofuran, 26.7 g of benzylamine and 8.6 g of titanium tetrachloride in 30 ml of benzene is treated as before. 6.9 g of pure crystalline base melting at 179-181 ° C (ethanol) are obtained. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride, which crystallizes from said solvent mixture and melts in a pure state at 257-258 ° C.

Example 3

2- (2-Phenylethylamino) benz (c, d) indole (I,

Η R1 = n = 2; R ³ = phenyl)

As in the previous examples, 8.5 g of naphthostyril are reacted in 150 ml of tetrahydrofuran, 31 g of 2-phenylethylamine and 8.6 g of titanium tetrachloride in 30 ml of benzene. 11.0 g (80%) of an oily base are obtained, which yields crystalline hydrochloride melting at 256 DEG-260 DEG C. (ethanol).

Example 4

2- (2-Diethylamino) benzo (c, d) indole (I, R ^J = Η, n · 2, R ³ = diethylamino)

As in the previous examples, 8.45 g of naphthostyril in 150 ml of tetrahydrofuran, 31.5 g of 2-diethylaminoethylamine and 8.6 g of titanium tetrachloride in 30 ml of benzene are carried out. Yield: 11.0 g (83%) of crystalline base, mp 127 DEG -128 DEG C. (benzenetretrol ether). Neutralization of hydrogen chloride in ethanol and ether yielded dihydrochloride, which crystallized from a mixture of 95% ethanol and ether as a solvate with 2.5 H ₂ O, mp 237-240 ° C ⁿ

Example 5

2- (2 Morpholinoethylamino) benz (c, d) indole (I, R ¹ - Η, n - 2, R ³ - morpholino)

As in the previous cases, 8.45 g of naphthostyril in 150 ml of tetrahydrofuran, 35 g of N- (2-aminoethyl) morpholine and 8.6 g of titanium tetrachloride in 20 ml of benzene are carried out. 9.4 g (66%) of an oily base are obtained, which yields crystalline dihydrochloride, m.p. 292-294 ° C (aqueous ethanol).

2- (3-Morpholino-propylamino) benz (c, d) indole (I, R ¹ = Η, n = 3, R ³ morpholino)

As in the previous cases, 8.45 g of naphthostyril in 150 ml of tetrahydrofuran, 36 g of N- (3-aminopropyl) morpholine and 8.6 g of titanium tetrachloride in 20 ml of benzene are carried out. 8.7 g (58%) of crystalline base are obtained, m.p. 116 DEG-118 DEG C. (benzene-petroleum ether). This gives the dihydrochloride which crystallizes from 95% ethanol as the monohydrate, mp 280-292 ° C.

Example 7

2- (4-Methyl-1-piperazinyl) benz (c, d) indole (I, NR'R ² = 4-methylplperazino)

As in the previous cases, 8.45 g of naphthostyril are reacted in 150 ml of tetrahydrofuran, 25 g of 1-methylpiperazine and 8.6 g of titanium tetrachloride in 30 ml of benzene. 9.0 g (72%) of an oily base are obtained, which is converted to the dihydrochloride. This crystallizes from aqueous ethanol as a hemihydrate and melts in the pure state at 297-300 ° C.

Claims (1)

Cyclic amidines derived from benz (c, dindole or Formula I) CLAIMS in which either R ¹ is hydrogen and R ³ represents a radical (CH ₂₎ 'R ³ wherein n is 1-3 and R ³ is isopropyl, phenyl, diethylamino or 4-mtorfolinyl or in which the rest of the NR ¹ R-denotes 4-methyl-1-piperazinyl, and their hydrochlorides.