DE1795384B2 - lH-2,3-Benzoxazines, processes for their production and pharmaceuticals - Google Patents

Description

IO

in the R a hydrogen or a low molecular weight Alkyl group, R, a low molecular weight alkyl, the amino or isopropyljdenarainogruppe means.

Z 6-Chloro-4- (1-raetbyIbydrazino) -lH-23-benzoxazra.

3. o-ChloM-methylamino-1 H-2,3-benzoxazine.

4. 6-Chloro-4- (isopropylidene-hydrazino) -1 H-2,3-benzoxazine.

5. 6 - chloro - 4 - (2 - isopropylidene - I - methylhydruzino) -I H-2,3-benzoxazine.

6. A process for the preparation of the I H-2,3-benzoxazines according to claim I, characterized in that a 4-halogeno-l H-2,3-benzoxazine of the general formula II _{w is used in a manner known per se}

in which R is a hydrogen atom or a low molecular weight Alkyl group, R, a low molecular weight alkyl, the amino or isopropylidenaraino group means a process for their production as well as medicaments !, consisting of eowm such I H-2,3-Benzoxazine and usual HHFs and carriers.

The process for the preparation of these compounds consists in that in a manner known per se a 4-halogen-1 H-2,3-benzoxazine of the general formula II

halogen

Cl—

halogen

with at least an equimolar amount of a compound (II) 35 of the general formula III

with at least an equimolar amount of a compound of the general formula III

HN

40

HN

(III)

45

in which R has the above meaning and Y is a low molecular weight alkyl or amino group and, if desired, a compound obtained of the general formula IV

RN-NH ₂

Cl -

in which R has the above meaning and Y represents a low molecular weight alkyl or the amino group and, if desired, a compound of the general formula IV obtained

RN-NH ₂

(IV)

N
O

(IV)

55

in which R has the meaning given above, with converts an at least equimolar amount of acetone.

7. A pharmaceutical preparation consisting of a compound according to claim 1 and usual Auxiliaries and trays.

in which R has the meaning given above, with a converts at least an equimolar amount of acetone.

Although the reaction usually occurs between about equimolar amounts of the two reactants expires, the use of a more or less large excess of the compound is recommended of the general formula III. Depending on the nature of the starting materials, it can be advantageous to use them in a small amount of an organic solvent, e.g. B. a lower molecular alcohol, to solve. In this case the reaction temperature is at the reflux temperature of the reaction mixture, otherwise it is between 70 and 15 (FC.

I 795

IO

Time required to complete the 2UT implementation st generally between 0.5 and 6 hours. All products are usually made in good yields old.

If, if desired, the compounds with a 2-position unsubstituted hydrazine group in the heterocycle position are to be converted into the corresponding hydrazones by reaction with at least an equiraolar amount of acetone, this reaction takes place in an organic solvent, with the acetone also being included if necessary can serve as a solvent, the compounds according to the invention have interesting pharmacological properties and can be smoked in particular as tranquilizers but also as dativa, hypnotics and anti-inflammatory drugs.

For example, the 4-U-methyl-hydrazinolrchior-I HW-benzoxazine markedly reduces the spontaneous arousal in Krausen at a dose of 10 mg / kg (ip) . Furthermore, the effect of this compound on the secondary avoidance response is shown in rats at 15 mg kg for intraperitoneal administration and at 30 mg kg for oral administration; the inhibition of the primarily caused avoidance reflex occurs at 30 mg kg ii.pl and 60 mg / kg (oral).

The orifice-inhibiting effect of 4-methylftmino-D-chloro-1 H-2,3-benzoxazine was summed up in rats using V _{9 of} the LD ₅₀ (owl); it was 38.5% in the carraghenin-induced Udem test.

Comparative tests were carried out to test the pharmacological effect. As comparison substances in the tests to examine the tranquillisiereade and anti-anxiety efficacy on the one hand the recognized good remedy Meprobaraat (2 - methyl 2 - η - propyl -U- propanediol dicarbaroate) as well as four the claimed compounds, constitutionally very similar compounds according to FIG Belgian patent specification 695670 (see. Examples 2, 5, 9 and 10) are used. .

The secondary conditioned response of the test animals (mice and rats) according to the method of G. Maffii (J. Pharm. Pharmacol Vol . the suppression of which is caused by anti-anxiety and tranquillizing agents. _r "

The results of the comparative experiments summarized in the table below show the therapeutic results advantageous properties of the claimed compounds.

ifc

Η / number of animals which do not show any secondary retlex in the test according to M; iffn ^f i, per total number of treated animals

8/10

LD ,,, dose mg kg) img kg i.p i.p. mouse Ratle

Belgian
Patent specification
695 670

9/10 I Meprobamat

Cl

10/10 200

Number of animals that were tested according to Maffii *! show no secondary reflex, per total number of treated animals

60

5 10

500

Meprobamate

500

60

100

5.10

7/10

*) (I Phurm. Pharmacol. Vol. US 129 fl959] |.

1,796,384

continuation

links

NH-CH ₃

CH ₃ -N-CH ₃

NH-NH,

LD _5n

(mg kg)

ip.

mouse

400

1000

500

Img kgl

i.p

rat

60

100

Λπ / iihl of animals that are im Te "i to M" fm * l no secondary reflex / own, per total number of treated animals

30th

*) (J. Pharm. Pharmacol. Vol. U.S. 129 [I959] i

The compounds according to the invention can be used in various pharmaceutical preparations, e.g. B. in tablets or injection solutions. The dosage unit is for oral preparations at 10 to 100 mg, for intravenous or intramuscular at 10 to 40 mg.

example 1
δ-ChloM-methylamino-1 H-2,3-benzoxazine

3 g4,6-dichloro! H-2,3-benzoxazine were in one closed tube together with 25 g of monomethylamine heated to 120 C for 4 hours. That The mixture was cooled, taken up in diethyl ether and extracted with hydrochloric acid.

The ether layer was discarded and the aqueous phase was washed with 30% sodium hydroxide solution made basic and extracted with diethyl ether. The ether extracts were washed with water, dried over sodium sulfate and distilled in vacuo. The residue became from ethyl acetate crystallized, wobt! * 2.4 g of the desired compound. Fn. 147.5 to 149 ° C (yield 82%). were obtained.

Comparison"· links

NH-CH ₃

Belgian
Patent specification
695 670

CH ₃ -N-CH ₃

Belgian
Patent specification
695 670

(mg kg) img kg) May. rat 200 60 300 100 200 30th

Number of animals in the Te »i after ΜαΓίιι · | no secondary reflex / own, per weight

treated animals

5 10

I IO

8 IO

Belgian
Patent specification
695 670

Analysis: (for

Calculated ... C 55.00, H 4.58. N 14.24. Cl 18.03%: found .... C 55.29, H 4.70. N 13.62. Cl 17.84%.

Example 2 6-Chloro-4-dimethylamino-1 H-2,3-benzoxazine

I g 4.6-dichloro-l H-2,3-benzoxazine and 25 ml Dimcthylamin were heated in a sealed tube for 4 hours at 120 C ^J. The mixture was then cooled and transferred to a glass container: the tube was rinsed with water and diethyl ether.

Then it was extracted with hydrochloric acid: the organic phase was discarded, the aqueous layer was Made basic with 30% NaOH solution, then extracted several times with diethyl ether. the combined ether extracts were washed with water, dried over sodium sulfate and in vacuo distilled. The residue was made from diisopropyl ether crystallized, and 0.75 g of 6-chloro-4-dimethylamino-1 was obtained H-2,3-benzoxazine. M.p. 88 to 88.5 C (yield 72%).

Analysis for C ₁₀ H ₁₁ ClN ₂ O).

Calculated ... C 57.02, H 5.20, N 13.30. Cl 16.84%; found .... C 57.20, H 5.04, N 13.38, Cl 17.00%.

Example 3
6-chloro-4-hydrazino-1 H-2,3-bezoxazine

3.6 g of 4,6-dichloro-1 H-2,3-benzoxazine and 1.8 ml of anhydrous hydrazine were dissolved in 18 ml of absolute ethanol and refluxed for 30 minutes. The mixture was cooled and then distilled in vacuo. The residue was taken up in methylene chloride and the precipitated hydrazine hydrochloride was filtered off. The filtered solution was concentrated to dryness and the residue was crystallized from methanol. 2.10 g of 6-chloro-4-hydraztno-1 H-2,3-benzoxazine, melting point 148 to 4TC (yield 60%) were obtained.

Analysis: (for C ₈ H ₈ ClN ₃ O).

Calculated ... C 48.63, H 4.05, N 21.27. Cl 17.95%; found .... C 48.81, H 4.28, N 21.50. Cl 18.21%.

Example 4

6-chloro-4- (1-methylhydrazino) -1 H-2,3-benzoxazine

2.52 g of 4,6-dichloro-1 H-2,3-benzoxazine in 13 ml of absolute 1.73 g of methylhydrazine were added to ethanol. The mixture was taking for 30 minutes Boiled to reflux, cooled and distilled in vacuo. The residue was taken up in diethyl ether, and the insolubles were filtered off. The filtrate was evaporated to dryness and the residue was taken up in 10 ml of diisopropyl ether. To Cooling on ice for 72 hours was filtered. The so solid obtained was crystallized from ethyl acetate, yielding 2.0 g of the desired compound, m.p. 124 to 125 ° C (yield 65%).

Analysis: (for C ₉ H ₁₀ ClN ₃ O).

Calculated ... C 51.10, H 4.77, N 19.87. Cl 16.76%: found .... C 50.82, H 4.72, N 19.65. Cl 16.90%.

Example 5

ö-ChloM-Osopropyliden-hydrazino) -1 H-2,3-benzoxazine

0.15 g of 6-chloro-4-hydrazino-l H-2,3-benzoxazine were dissolved in 15 ml of anhydrous with gentle warming Dissolved acetone. Then the solution was left for 1 hour

stand for a long time, after which the solvent is added in vacuo

Room temperature was removed. The residue was taken up in hexane and left to stand for 2 days. After filtration, the solution was evaporated to dryness in vacuo, the residue was crystallized from the same solvent.

This gave 0.1 g of the desired compound, melting point 76 ° to 77 ° C. (yield 55%).

Analysis: (for C ₁₁ H ₁₂ ClNjO).

Calculated ... C 55.60, H 5.09, N 17.68, Cl 14.92%; found .... C 55.79, H 4.88, N 17.60, Cl 14.75%.

B e i s ρ i e 1 6

6-Ch't) r-4- (2-isopropylidene-1-methylhydrazino) -1 H-2.3-benzoxazine

0.5 g of 6-chloro-4- (l-methylhydrazino) -1 H-2,3-benzoxazine was dissolved in 25 ml of anhydrous acetone at room temperature. The solution was left to stand for 1 hour, then the solvent was removed in vacuo at room temperature. The residue was extracted several times with warm hexane (50 ml in total). The solid was discarded, the solution was evaporated to dryness in vacuo. When the residue was crystallized from diisopropyl ether, 0.25 g of the desired compound was obtained, melting point 105 to 106 ^° C. (yield 42%).

Analysis: (for C ₁₂ H ₁₄ ClN ₃ O).

Calculated ... C 57.25, H 5.61, N 16.70, Cl 14.09%: found .... C 57.22, H 5.59, N 16.50, Cl 13.85%.

409540/37

Claims (1)

I 795 Patent claims: I H-23 witnesses of the general form! I. R. (I) The present invention relates to I H-2J benzoxaanes the general form! J