DE2004818C3 - Basic substituted quinobenzazepines - Google Patents

Description

/ ■

K-N (III)

in which R ₁ and R _{2 have} the meaning given in claim 1, reacted by hydrogenating condensation or in a manner known per se 3 - oxo - 2,3,7,8 - tetrahydro -1 H - quino [1,8 - ab] [1] -benzazepine with amines of the general formula R ₂ -NH ₂ with elimination of water to form the imine of the general formula IV

NO,

(IV)

45

converts and reduces the imine or in a known manner 3 - oxo - 2,3,7,8 - tetrahydro-I H-quino [l, 8-ab] [l] benzazepine to the oxime of the formula V

55

NOH

6o

(V)

converts and the same to a compound of the general formula I (Rj = R ₂ = H) reduced or a 3-halo-2,3,7,8-tetrahydro-IH-quino [1.8- ab] [l ] benzazepine of the general formula VI

Shark

(D

in which R ₁ and R _{2 are} hydrogen atoms or straight-chain or branched alkyl radicals having 1 to 4 carbon atoms, where R ₁ and R _{2 can be} identical or different, and their salts.

2. A method for the preparation of compounds according to claim 1, characterized in that 3-oxo-2,3,7,8-tetrahydro-1 is used in a manner known per se H-quino [l, 8-ab] [l] benzazepine of the formula II

(VI)

with ammonia or a primary or secondary amine and optionally in reaction products in which R ₁ and / or R ₂ = hydrogen, the group —NR ₁ R ₂ subsequently within the scope of the _{meaning given for R 1} and R ₂ in claim 1 in alkylated in a manner known per se and the bases formed optionally converted into the salts with acids.

3. Drugs with effects on the central nervous system and effects in the peripheral vegetative Area containing one or more compounds according to claim 1.

The present invention relates to new, basic substituted 2,3,7,8-tetrahydro-l H-quino [l, 8-ab] [l] -benzazepines of the general formula I.

40

in which R ₁ and R ₂ denote hydrogen atoms or straight-chain or branched alkyl radicals having 1 to 4 carbon atoms, where R ₁ and R _{2 can be the} same or different, and their salts, processes for their preparation and pharmaceuticals.

Surprisingly, as has been found, these new compounds have valuable pharmacological properties Properties. They are intended to be used as medicinal products.

Of basic compounds of the main body 1 H-quino [l, 8-ab] [l] benzazepine are so far only ethereal 3 - (dialkylaminoalkoxy -) -1 - oxo - 7,8 - dihydro - 1 H - chino [1,8 - ab] [1! Benzazepine known (cf.monthsh. Chem. 93, 26-33 [1962]; US patent 30 52 678; British patent 9 12 289).

The 2,3,7,8-tetrahydro-1H-quino [l, 8-ab] [l] benzazepines according to the invention, which are basically substituted in the 3-position by NH ₂ , NH-alkyl or N (alkyl) _{2, are new} Fabrics.

They show a pronounced effect on the central nervous system. You have typical neuroleptics Properties; but also beneficial effects. Compared to Promazin lie at the same time thymoleptic effects. Besides that

possess the substances analgesic and antispasmodic Properties and not insignificant effects in the peripheral vegetative area. In Table 1 shows the 2 - methyl - 2 - diethylaminomethyl -1,2,6,7 - tetrahydroindoloPJaJ-a ^ benzoCOazepine hydrochloride known from DT-AS 11 53 376, thus a compound with a similar structure, in its thymoleptic and neuroleptic effects the new compounds according to the invention are shown in Table 1

formula 1
NR ₁ R, =

NHCH ₃
NH ₂

NHC ₂ H ₅
NHCH ₂ CH ₂ CH ₃

2-methyl-2-diethylaminomethyl-1,2,6,7-tetrahydroindolo [ 1,7a, 7-a, b] benzo [f] azepine hydrochloride

resembled. Applied in comparable doses, the known compound does not yet show the desired thymoleptic effect (expressed by the noradrenaline potentiation) and the neuroleptic effect (expressed by the hexobarbital potentiation), while the toxicity LD ₅₀ is similar to the toxicity values of the compounds according to the invention.

Toxicity LD ₅₀
(Mouse) Nor-adrenaline potentiation
Blood pressure
(Albino rat) % Hexobarbital
Certification
renewal
Cf. _ir U + 53 (Albino mouse) mg / kg i.v. mg / kg i.v. + 40 mg / kg se 25th 1.0 + 70 5 20th 0.5 - 32 20th 0.1 ± 0 7.5 15th - 35 47 <2.5 <50 none
effect

The compounds of the formula I are prepared by using a method known per se Way 3-oxo-2,3,7,8-tetrahydro-l H-quino [l, 8-ab] [l] -benzazepine of the formula II

(Π)

with an Ami η of the general formula III

Η — Ν

(ΠΙ)

(IV)

to the oxime of formula V

35

in which R ₁ and R _{2 have} the meaning given above, are reacted by hydrogenating condensation or, in a manner known per se, 3-oxo-2,3,7,8-tetrahydro-1H-quino [1,8-ab] [l ] benzazepine with amines of the general formula R ₂ —NH ₂ with elimination of water to form the imine of the general formula IV

NO,

implements and the 1min, z. B. by catalytic hydrogenation, reduced or in a manner known per se 3 - Oxo - 2,3,7,8 - tetrahydro -1 H - quino - [1,8 - ab] [I] -henzazerjine. z. B. by reaction with hydroxylamine,

NOH

(V)

implements and the same, e.g. B. by catalytic hydrogenation or by means of sodium amalgam, _{reduced to a compound of the general formula I (R 1} = R ₂ = H) or a 3-halogen - 2,3,7,8 - tetrahydro -1H - quino in a known manner [l, 8 - a, b] [l] benzazepine of the general formula VI
45

(Vl)

reacts with ammonia or a primary or secondary amine and optionally in reaction products in which R ₁ and / or R ₂ = hydrogen, the group —NR ₁ R ₂ subsequently within the scope of R ₁ and R ₂ , the meaning given above in per se alkylated in a known manner and the bases formed, if appropriate with acids, expediently with a non-toxic mineral acid or organic acid, converted into the salts.

The methods are preferably carried out in suitable solvents, e.g. B. in alcohols, if appropriate also performed under pressure.

The examples describe the novel compounds of the invention and preferred methods of using them Manufacturing.

example 1

3-Amino-2,3,7,8-tetrahydro-l H-quino [1,8-ab] [I] -

benzazepine

Oil of b.p. ooo = 128-132 ¹ C

20 g of 3-oxo-2,3,7,8-tetrahydro-1 H-quino [l, 8-ab] [l] benzazepine dissolved in 560ml of absolute alcohol. One adds a solution of ι ο 18.5 g of hydroxylamine hydrochloride in 66 ml of water and then 7.6 ml of pyridine are added. The reaction solution is refluxed for 6 hours. After cooling, it is poured into 2 liters of water, the Oxime crystallized out. It is sucked off, with water is washed and dried. The yield is 21 g.

The melting point of the oxime is 198 - 200 ° C.

The oxime is dissolved in 100 ml of dimethylformamide, treated with 900 mL of a solution saturated at 0 ⁰ C and ammonia methanol solution and in the presence of 40 g Raney nickel 4 Stundta at about 80 ° C and hydrogenated atm 96th

The catalyst is filtered off through a kieselguhr packing and the filtrate is concentrated in vacuo. It What remains is a dark-colored oil, from which 3-amino-2,3,7,8-tetrahydro-1 H-quino [l, 8-ab] [l] benzazepine is obtained in pure form.

The yield is 80%.

The hydrochloride is obtained from isopropanolic yo solution by addition of ethereal hydrochloric acid to slightly acid reaction.

After recrystallization from ethanol, the melting point of the hydrochloride is 202-20? ° C.

Example 2

2-methylamino-2,3,7,8-tetrahydro-l H-quino-

[1.8-ab] [l] benzazepine
Oil with a boiling point of 0.01 155-160 ° C

35

40

To prepare it, 150 g of 3-oxo-2,3,6,7-tetrahydro-1H-quino [l, 8-ab] [l] benzazepine are dissolved in 11% of anhydrous benzene; the solution is mixed with 10 g of anhydrous ammonium acetate and then heated on a water separator for about 7 hours while stirring and continuously introducing methylamine. The solvent is distilled off in vacuo, the condensation product remaining in oily form. It is taken up in 300 ml of methanol, 560 ml of a solution saturated at 0 ⁰ C with methylamine methanol solution and in the presence of 60 g Raney nickel in an autoclave at 80 ° C and hydrogenated atm 110th

. The catalyst is filtered off through a kieselguhr packing and the filtrate is completed in vacuo constricted. 149 g of a dark, viscous oil remain, from which by distillation in a fine vacuum 3 - methylamino - 2,3,7,8 - tetrahydro - 1 H-quino [l, 8-ab] [l] benzazepine is obtained. The yield is 86%.

The fumarate is made from isopropanolic solution by adding an iso-ft.s which is saturated with fumaric acid get propanol solution.

After recrystallization from dimethylformamide, the fumarate melts at 184-186 ° C.

Example 3

3-ethylamino-2,3,7,8-tetrahydro-l H-quino-

[1,8-ab] [i] benzazepine
oil, bp-O ₀ 140-144 ° C

It is manufactured according to the procedure in the example 2, starting from 25 g of 3 - oxo - 2,3,7,8 - tetrahydro- 1 H-quino [1,8-ab] [l] benzazepine and ethylamine. 22 g of 3-ethylamino-2,3,7,8-tetrahydro-1 are obtained H-quino [1,8-ab] benzazepine.

The hydrochloride is formed from isopropanolic solution by adding ethereal hydrochloric acid up to a weakly acidic reaction. It is recrystallized from acetone / ethanol; the hydrochloride melts at 167-168 ° C.

Example 4

3-propylamino-2,3,7,8-tetrahydro-l H-quino-

[1,8-ab] [1] benzazepine
Oil from _Bp . 00I 170-173 ^r O

It is prepared according to the method of Example 2, starting from 10 g of 3-oxo-2.3.7,8-tetrahydro-1 H-quino [l, 8-ab] [l] benzazepine and propylamine. 8 g of 3-propylamino-2,3,7,8-tetrahydro-1 are obtained H-quino [l, 8-ab] [l] benzazepine.

The compound provides a hydrochloride, which after recrystallization from isopropanol / ethano) at 174 - 175.5 C melts.

The compound is also obtained in the following way: 7.5 g of 3-bromo-2,3,7,8-tetrahydro-1 H-quino [1.8-ab] [l] benzazepine are dissolved in 450 ml of absolute toluene and mixed with 42 g of n-propylamine Heated under reflux for 10 hours. After the toluene has been distilled off in vacuo, the residue becomes treated with ether and 2N hydrochloric acid to remove neutral components. After separating the essential Phase is made alkaline and the deposited base is taken up again in ether. After drying and evaporation of the ether, the 3-propylamino-2,3,7,8-tetrahydro-1 remains H-quino [l, 8-ab] [l] beiuazepine in oily form. To form the hydrochloride the base is taken up in isopropanol and until a weakly acidic reaction with ethereal hydrochloric acid offset. After recrystallization from isopropanol, the melting point is 176-178 ° C.

Example 5

3 - sec-butylamino - 2,3,7,8 - tetrahydro -1 H - quino- [l, 8-ab] [l] benzazepine hydrochloride with a melting point of 180-181 ° C.

It is prepared according to the method according to Example 1, starting from 15 g of 3-oxo-2,3,7,8-tetrahydro - 1 H - quino [l, 8 - ab] [l] benzazepine, which with 25 g sec.Butylamine in the presence of 2 g anhydrous Sodium acetate reacted in benzene by heating to the boil for 9 hours on a water separator will. The solution is concentrated in vacuo and the oily residue in 800 ml of methanol with addition of 44 g of sec-butylamine and 2 g of anhydrous sodium acetate for 4.5 hours at 85 ° C and 95 atm Raney nickel hydrogenated.

The catalyst is filtered off through a kieselguhr packing and the filtrate is concentrated in vacuo. The The residue is taken up in benzene and the solution is extracted several times with dilute hydrochloric acid. the

combined acidic phases are made alkaline with sodium hydroxide solution and the deposited base is again dissolved in Ether added. The ethereal solution is dried over potassium carbonate and concentrated. the The oily residue is obtained directly from isopropanolic solution by adding ethereal hydrochloric acid crystalline hydrochloride of sec-butylamino-2,3,7,8-tetrahydro-1H -chino [l, 8 -ab] [l] benzazepine. After recrystallization from acetone / ether it shows one Melting point of 180-181 ° C.

Example 6

3-isopropylamino-2,3,7,8-tetrahydro-l H-quino-

[1,8-abj [1] benzazepine
oil from Kp.oo! 150-160 ⁰ C.

It is prepared according to the method of Example 5 by reacting 3-oxo-2,3,7,8-tetrahydro - 1 H - quino [l, 8 - ab] [l] benzazepine with isopropylamine.

Example 7

o-1 H-quino- [1,8-ab] [1] benzazepine hydrochloride vom
Melting point 203 ⁰ C

To prepare, 8 g of 3 - chloro - 2,3,7,8-tetrahydro - 1H - quino [l, 8 - ab] [l] benzazepine and 55 ml of dimethylamine are taken up in 1,400 ml of methanol and heated to 140 for 4 hours in an autoclave ⁰ C heated. The solvent is then evaporated off, the residue is dissolved in ether, extracted with 10% hydrochloric acid and the acidic phase is made alkaline with dilute sodium hydroxide solution. Here, the base separates out in an oily form, which is absorbed in ether. The ethereal solution is dried over potassium carbonate and then evaporated to dryness. The 3-dimethylamino-2,3,7,8-tetrahydro-1H-quino- [l, 8-ab] [is obtained from the residue from isopropanolic solution by adding ethereal hydrochloric acid. l] benzazepine isolated as crystalline hydrochloride, which melts ^{at 203 ° C. after recrystallization from ethanol.}

Claims (1)

Patent claims: 1. Basically substituted 2,3,7,8 - tetrahydrolH-quino [l, 8-ab] [l] benzazepines of the general formula I. (Π) with an amine of the general formula III