CS223538B1 - 4- (Aminoacylamidec) -e-hydrindacenes and their hydrochlorides - Google Patents

Abstract

The invention relates to the field of synthetic drugs. Its subject is 4-(ammoniacylamido)-s-hydrindacenes of the general formula I, <XK> Γ (T \ NHCO-X-R. in which X denotes -CH^-, -CH- or ch3 -CHgCHg- and R is a diethylamino, pyrrolidino, piperidino or morpholino residue, and their hydrochlorides. These substances can be prepared by heating the corresponding 4-(chloroacylamido)-s-hydrindacenes with excess amines R-H (R is the same as in formula I). The hydrochlorides of substances I are characterized by intensive local anesthetic, antiarrhythmic, partly also anticonvulsant and centrally depressant activity. They can be used for local anesthesia during surgical procedures, as drugs for heart rhythm disorders and finally as drugs for epilepsy

Description

The invention relates to the field of synthetic drugs. It is directed to 4- (ammoniacylamido) -s-hydrindacenes of general formula I, <XK>

Γ (T \

NHCO-X-R.

wherein X is -CH 2 -, -CH- or ch ₃

-CH 8 CH 8 - and R is a diethylamino, pyrrolidino, piperidino or morpholino residue, and their hydrochlorides. These may be prepared by heating the corresponding 4- (chloracylamido) -s-hydrindacenes with excess R-H amines (R is the same as in Formula I). The hydrochlorides of the compounds I are characterized by intensive locally anesthetic, antiarrhythmic, partly anticonvulsant and centrally depressant activity. They can be used for local anesthesia in surgical procedures, as medicines for heart rhythm disorders and finally for anti-epilepsy drugs.

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The invention relates to 4- (aminoacylamido) -s-hydrindacene of the general formula I,

NHCO-X-R (I) wherein X is -CHg-, -CH- or -CHgCHg and R is a residue

diethylamino, pyrrolidino, piperidino or morpholino, and their hydrochlorides.

The compounds of the invention of formula I and their hydrochlorides have pharmacodynamic activity which makes them useful as medicaments. The most typical activity of the compounds according to the invention is locally anesthetic activity for which they are useful for local anesthesia in surgical interventions. This activity is associated with a high degree of antiarrhythmic activity for which the compounds of the invention are useful in the treatment of cardiac rhythm disorders. From this viewpoint are important substances / according to the invention especially N- (s-hydrindacen-4-yl) -2-piperidinoacetaniidhydroehlorid (acute toxicity in mice, LD ^ ₀ «35 mg / kg iv), N- (s-hydrindacen- 4-yl) -2-diethylaminopropionamide hydrochloride (LD 50 q 30 mg / kg iv) and N- (s-hydrindacen-4-yl) -2-piperidinopropionamide hydrochloride (LD _{50 0} 35 mg / kg iv) The most typical of these are N- (s-hydrindacen-4-yl) -2-piperidinoacetamide hydrochloride, for which an average effective concentration of 0.01 to 0.05% was found in the first stage of testing, both in the infiltration anesthesia test (guinea pigs). ) as well as corneal anesthesia (rabbit eye).

In the second stage of testing, values of 0.1% were found for infil2

223,338, and 0.5% for corneal anesthesia. So it is

tesia) and at least twice as effective as procaine (corneal anesthesia). This substance was also evaluated for its antiarrhythmic effect by detecting the refractory phase of electrically irritated rabbit atria. Its effective concentration ED 50 is 5.3 x 10 6 M / ml. It is therefore practically as effective as quinidine (ED ^ g »

5.0 x 10 &lt; ⁸ &gt; M / ml).

Another compound of the invention, namely N- (s-hydrindacen-4-yl) -2-morpholinoacetamide hydrochloride (LD-g · 2.0 g / kg p.o ·), acts at oral doses of 100 to 300 mg / kg p.o. anticonvulsant in mice against pentetrazole. It can therefore be considered as a potential anti-epilepsy drug. Other substances according to the invention, namely N- (s-hydrindacen-4-yl) -2-diethylaminoacetamide hydrochloride (LD ^ g = 30 mg per kg iv), N- (s-hydrindacen-4-yl) -2-pyrrolidinopropionamide hydrochloride (hemihydrate) (LD 50 q 25 mg / kg iv) and N- (s-hydrindaeen-4-yl) -3-pyrrolidinopropionamide hydrochloride (LD 50 g and 35 mg / kg iv), at subcutaneous doses of 5-7 mg / kg slightly attenuates the motility of mice in a known environment; they therefore have the character of mild tranquilizer effects.

The compounds of the invention can be prepared from 4- (chloracylamido) s-hydrindacenes of formula IX, (II) wherein X is the same as in formula I, by heating with excess amines RH (R 6 as in formula I), i.e. diethylamine, pyrrolidine, piperidine or morpholine. In most cases, the reaction can be carried out in boiling benzene as the medium. V nekte-

excess amine and carry out the reaction at the boiling point of the amine. Finally, in the combination of X 1 -CH- and R = diethylamino CH _3, it is expedient to heat the reaction mixture in an autoclave to 140-150 ° C without the medium. Further details of the preparation of the compounds according to the invention are apparent from the examples.

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The starting materials of formula (II) are novel, the preparation of which is also described in the examples. They are obtained from the known 4-amino-s-hydrindacene (ZJejejlek, M. Bartosova and M.Protiva, Collect.Czech.Chem.Commun. 42, 1992, 1977) by reactions with chloroacetyl chloride, 2-chloropropionyl chloride (R.Leirau, Ber. Deut. Chem. Ges. 20, 1040, 1937; JPGreenstein, VEPrice and PMLeuthardt, J. Biol. Chem. 175, 953, 1948; Chem.

257, 1949) and 3-chloropropionyl chloride (R. Wolffenstein and J.Rolle, Ber.Deut.Chem.Ges. 41, 736, 1908) in boiling chloroform in the presence of potassium carbonate.

All of the compounds of formula I of the invention are crystalline compounds and their hydrochlorides, some of which are solvated with water, are also crystalline. The bases are water-insoluble, the hydrochlorides are more or less water-soluble and are therefore more suitable than the bases for pharmacological testing and for the preparation of dosage forms. All of the novel compounds described in the invention, i.e. the final compounds of formula I, their hydrochlorides and intermediates of formula II, were provided in terms of identity by assays and further by spectra, in particular by infrared and NMR spectra.

Example 1

N- (s-Hydrindacen-4-yl) -2-piperidinoacetamide. A mixture of 7.0 g of N- (s-hydrindacen-4-yl) chloroacetamide, 280 ml of benzene and 5.2 g of piperidine was refluxed for 8 h. After cooling, the precipitated piperidine hydrochloride (3.0 g) was removed by filtration, the filtrate was washed with water, dried over sodium sulfate and evaporated. 8.0 g (96%) of crude base melting at 89-92 ° C are obtained. The analytically pure material was obtained by crystallization from a mixture of benzene and hexane and melted at 119-120 ° C. Neutralization of the base dissolved in ether with ethanolic ethanolic HCl gives the hydrochloride which crystallizes from aqueous ethanol and melts at 253-254 ° C in pure form.

The starting material N- (s-hydrindacen-4-yl) chloroacetamide, which is new, is obtained as follows: To a solution of 21.6 g of 4-amino-hydrindacene (literature cited) in 100 ml of chloroform is added 20.7 g. of potassium carbonate and a stirred solution of 14.2 g of chloroacetyl chloride in 140 ml of chloroform are added dropwise over 50 min. The mixture was then refluxed for 90 min.

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After cooling, 180 ml of water are added and the product is extracted with chloroform. The extract was dried over sodium sulfate and evaporated. It is obtained

27.8 g (89%) of the crude product melting at 212-215 ° C. Crystallization from benzene gave a pure product with m.p. Mp 237-238 ° C. Example 2

N- (s-Hydrindacen-4-yl) -2-diethylaminoacetamide. Analogously to Example 1, 7.0 g of N- (s-hydrindacen-4-yl) chloroacetamide (see Example 1) is reacted with 7.5 g of diethylamine in 280 ml of boiling benzene. 6.0 g (75%) of crude base are obtained, which is initially oily but crystallizes soon. The pure base was obtained by crystallization from hexane and melted at 81-82 ° C. It gives the hydrochloride, which crystallizes from a mixture of ethanol and ether and melts in the pure state at 175-176 ° C,

Example 3

N- (s-Hydrindacen-4-yl) -2-pyrrolidinoacetamide. Analogously to Example 1, 8.0 g of N- (s-hydrindacen-4-yl) chloroacetamide (see Example 1) is reacted with 5.0 g of pyrrolidine in 280 ml of boiling benzene. 8.0 g (88%) of crude base melting at 138-141 ° C are obtained. The pure base was obtained by crystallization from a mixture of benzene and hexane and melted at 151-152 ° C. It gives the hydrochloride which crystallizes from a mixture of ethanol and ether and melts in a pure state at 254-255 ° C.

Example 4

N- (s-Hydrindacen-4-yl) -2-morpholinoacetamide. Similar to Example 1, a reaction of 7.0 g of N- (s-hydrindacen-4-yl) chloroacetamide (see Example 1) with 5.3 g. of morpholine in 280 ml of boiling benzene. 6.4 g (76%) of crude base are obtained, which after crystallization from a mixture of benzene and hexane melts at 148-149 ° C. This gives the hydrochloride which crystallizes from a mixture of aqueous ethanol and ether and melts in the pure state at 220-221 ° C.

Example 5

N- (s-Hydrindacen-4-yl) -3-diethylaminopropionamide · As in Example 1, 8.0 g of N- (s-hydrindacen-4-yl) -3-chloropropionamide is reacted with 7.3 g of diethylamine in 300 ml. of boiling benzene. 6.8 g (76%) of crude base are obtained, which crystallizes from a mixture of benzene and hexane and melts in the pure state at 153 to 154 C. It gives the hydrochloride which crystallizes as the monohydrate

223 538 5 from a mixture of aqueous ethanol and ether and melts at 182-183 ° C in pure form.

The starting N- (s-hydrindacen-4-yl) -3-chloropropionamide used is a novel substance and is obtained, for example, by the following procedure: Similarly as described in Example 1, 21.6 g of 4-amino-hydrindacene are reacted with 0 g of 3-chloropropionyl chloride (literature cited) and 20.7 g of potassium carbonate in 230 ml of chloroform. 32.1 g (97%) of crude product melting at 201-204 ° C are obtained. Crystallization from ethanol gave a pure material, melting at 211-212 ° C.

Example 6

N- (s-Hydrindacen-4-yl) -3-pyrrolidinopropionamide. Similar to Example 1, 8.0 g of K- (s-hydrindacen-4-yl) -3-chloropropionamide (see Example 5) was reacted with 4.7 g of pyrrolidine in 280 ml of boiling benzene. 8.2 g (91%) of crude base melting at 176-178 ° C are obtained. Crystallization from benzene / hexane gave pure base melting at 193-194 ° C. It gives the hydrochloride which crystallizes from a mixture of ethanol and ether and melts in the pure state at 242-243 ° C.

Example 7

N- (s-Hydrindacen-4-yl) -3-piperidinopropionamide. Analogously to Example 1, 8.0 g of N- (s-hydrindacen-4-yl) -3-chloropropionamide (see Example 5) is reacted with 5.6 g of piperidine in 300 ml of boiling benzene. 9.1 g (97%) of a crude base are obtained, which crystallizes from a mixture of benzene and hexane and melts in the pure state at 189-190 ° C. This gives the hydrochloride which crystallizes from a mixture of ethanol and ether and melts in pure state at 216-217 ° C. Example 8

N- (s-Hydrindacen-4-yl) -2-piperidinopropionamide. A mixture of 6.1 g of K- ( _s- hydrindacen-4-yl) -2-chloropropionamide and 15 ml of piperidine is refluxed for 5 h (bath temperature 130-150 ° C). Then it is poured into 150 ml of water, the precipitated product It is filtered, washed with water and dried in vacuo. 6.50 g (91%) of crude base melting at 122-124 ° C are obtained. Crystallization from ethanol gave a pure material, melting at 139-140 ° C. This gives the hydrochloride which crystallizes from a mixture of ethanol and ether and is pure at 219-220 ° C.

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The starting N- (s-hydrindacen-4-yl) -2-chloropropionamide used is a novel substance and is prepared, for example, by the following method. Similarly, as described in Example 1, 21.6 g of 4-amino-hydrindacene are reacted. (literature cited) with 19.0 g of 2-chloropropionyl chloride (literature cited) in 230 ml of chloroform in the presence of 20.7 g of potassium carbonate. 19.3 g (59%) of crude product melting at 208 DEG-210 DEG C. is obtained. The pure product was obtained by crystallization from dioxane, m.p. 218-219 ° C,

Example 9

N- (s-Hydrindacen-4-yl) -2-pyrrolidinopropionamide. Analogously to Example 8, 6.5 g of N-phenyldinden-4-yl) 2-chloropropionamide (see Example 8) are reacted with 15 ml of boiling pyrrolidine (bath 130-140 ° C) to give 6.70 g. (91%) of crude base melting at 156-158 ° C. Crystallization from ethanol gave pure product with m.p. Mp 171-172 ° C. It provides the hydrochloride which crystallizes from a mixture of aqueous ethanol and ether as the hemihydrate and melts in the pure state at 184-185 ° C.

Example 10

N- (s-Hydrindacen-4-yl) -2-morpholinopropionamide. Similar to Example 8, 5.9 g of N- (s-hydrindacen-4-yl) 2-chloropropionamide (see Example 8) and 15 ml of boiling morpholine (bath 140-150 ° C) were reacted. 5 g (92%) of crude base melting at 149-152 ° C. Crystallization from ethanol gave a pure material melting at 168-169 ° C. It yields the hydrochloride which crystallizes from a mixture of ethanol and ether and melts in the pure state at 228-229 ° C.

Example 11

N- (s-Hydrindacen-4-yl) -3-morpholinopropionamide. Similar to Example 8, 8.0 g of 1- (s-hydrindacen-4-yl) 3-chloropropionamide (see Example 5) is reacted with 25 ml of boiling morpholine. 8.2 g (87%) of crude base melting at 154-155 ° C are obtained. Crystallization from a mixture of benzene and hexane gives a pure melting point at 190-191 ° C. This gives the hydrochloride which crystallizes from aqueous ethanol and melts in the pure state at 219-220 ° C. Example 12

N- (s-Hydrindacen-4-yl) -2-diethylaminopropionamide. Mixture

6.5 g of N- (s-hydrindacen-4-yl) -2-chloropropionamide (see Example

223,538 γ

8) and 15 ml of diethylamine are heated in an autoclave at 140-150 ° C for 5 hours. A similar treatment as in Example 8 gave 6.2 g (88%) of the crude base melting at 70-73 ° C. Recrystallization from hexane gave the pure product m.p. 96 DEG-97 DEG C. It provides a hydrochloride which crystallizes from a mixture of ethanol and ether and melts at 229 DEG -230 DEG C. in pure state.

Claims (1)

4- (Amino-acylamido) -s-hydrindacenes of the general formula I, hmco-XK in which X represents -CHg-, -CH- or -CHgCHg- and R is a residue of ₃ diethylamino, pyrrolidino, piperidino or morpholino, and their hydrochlorides ·