DE1795384C3 - 1 H-2,3-Benzoxazines, processes for their production and pharmaceuticals - Google Patents

Description

Cl -

di)

35

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

HN

(ΠΙ)

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

RN-NH ₂

Cl—

Cl--

in which R is a hydrogen atom or a low molecular weight alkyl group, R _{1 is} a low molecular weight alkyl, the amino or isopropylidene amino group, a process for their preparation and pharmaceuticals consisting of such a 1 H-2,3-benzoxazine and customary auxiliaries 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-

/ V \
N

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

HN

(HI)

40

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)

50

CI--

(IV)

in which R has the abovementioned meaning, is reacted with an at least equimolar amount of acetone.

Although the reaction usually occurs between about equimolar amounts of the two reactants

in which R has the above meaning, expires with 6o, the use of one more is recommended

or less large excess of the compound of general formula III. Depending on the nature of the raw materials it can be advantageous to use this in a small amount of an organic solvent, z. 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 150 C.

converts an at least equimolar amount of acetone.

7. A pharmaceutical preparation consisting of a compound according to claim 1 and usual Auxiliary and carrier materials.

The time required for complete conversion is generally between 0.5 and 6 hours. All Products are usually obtained in good yields.

If, if desired, the compounds with a hydrazine group unsubstituted in the 2-position in 4-position of the heterocycle by reaction with at least an equimolar amount of acetone in the corresponding hydrazones are to be converted, this reaction takes place in an organic one Solvent, whereby the acetone itself can optionally also serve as a solvent.

The compounds according to the invention have interesting pharmacological properties and are especially used as tranquilizers but also as sedatives, hypnotics and anti-inflammatory drugs useful.

For example, 4- (1-methyl-hydra / .ino) -6-chloro-1 H-2,3-benzoxazine markedly reduced spontaneous arousal in mice 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 and at 30 mg / kg for oral administration; the inhibition of the primarily caused avoidance reflex occurs at 30 mg / kg ii.p! and 60 mg / kg (° ^ra1 )

The anti-inflammatory effect of 4-methylamino-6-chloro-1H-2,3-benzoxazine was determined in rats using Vs of the LD ₅₀ (oral); it was 38.5% in the edema induced by carraghenin.

Comparative tests were carried out to test the pharmacological effect. As reference substances in the tests to test for tranquillizing and anti-anxiety effects became on the one hand the recognized good remedy meprobamate (2 - methyl - 2 - η - propyl -1,3 - propanediol dicarbamate) and four of the claimed compounds constitutionally very similar compounds according to the Belgian patent specification 695 670 (cf.Examples 2, 5, 9 or 10) are used.

The secondary served as a criterion for the tranquilizing effectiveness of the compounds examined conditional reflex (secondary conditioned response) of the test animals (mice and rats) according to the Method by G. Maffii (J. Pharm. Pharmacol., Vol. 11 [1959], p. 129), the suppression of which by anti-anxiety and tranquillising agents.

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

links

CH

NH-N = C

CH ₃

CH ₁

LD ₅₁ , dose (mg kg) (mg Vy) i.p i.p. mouse Cold 500 15th

Number of animals in the

Test after

Maffii) show no secondary reflex,

per total number of

treated animals

CH ₁ -NN = C

CH ₃

500

300

30th

Number of animals in the

Test after

Maffii *) show no secondary reflex, per total number of

treated animals

15th

Belgian
Patent specification
695 670

Meprobamate

500

60

5 10

60

Meprobamate

500

100

5/10

7/10

♦ 1 (J. Pharm. Pharmacol. Vol. II, p. 129 [1959]).

links Cl \ Cl \ Cl Y NH-CH ₃ CH ₃ 1 / N -N-CH ₃ V I. A. [T / \ ι
^ O NH-NH ₂ I. fr IJo

₅₁₁

(measured kg)

i-P

mouse

400

1000

500

dose
(mg kg)

ip

Rough

60

100

30th

1,795,384 r continuation Comparative
connections r 6th You".".
I mg kg)
'P
rat number of
Animals that 'm
Test after
M jffii *)
no second
där condinglen
Reflex / own,
per (collectively
number of
treat
animals NH-CH ₃ Belgian
Patent specification
695 670 ]
UK,
(mg kg)
ip
mouse 60 10/10 Y N Belgian
Patent specification
695 670 200 CH ₁ -N -CH, 100 9/10 C.
V ' > O
'y 300 Belgian
Patent specification
695 670 30th 9/10
ί NHNH ₂ 200

A um hl of the animals in the Tesi to Mafrii »! not secondary Reflex / Eigen, pm Total number of animals treated

5.10

1 10

8/10

♦) (J.? Harm. Pharmacol. Vol. II, p. 129 [14 ']).

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

3 g4,6-dichloro-l H-2,3-benzoxazine were heated in a sealed tube together with 25 g of monomethylamine for 4 hours at 120 ⁰ C. 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 to give 2.4 g of the desired compound, melting point 147.5 to 149 ° C. (yield 82%).

Analysis: (for C ₉ H ₉ ClN ₂ O).

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%.

B e i s ρ i e 1 2

o-ChloM-dimethylamino-1 H-2,3-benzoxazine

1 g of 4,6-dichloro-l H-2,3-benzoxazine and 25 ml of dimethylamine were heated in a sealed tube for 4 hours at 120 ⁰ C. 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 and extracted several times with diethyl ether. The combined ether extracts were washed with water, dried over sodium sulfate and distilled in vacuo. The residue was crystallized from diisopropyl ether, and 0.75 g of 6-chloro-4-dimethylamino-1H-2,3-benzoxazine, melting point 88 to 88.5 ° C. (yield 72%) were obtained.

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
o-ChloM-hydrazino-1 H-2,3-benzoxazine

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-hydrazino-1 H-2,3-benzoxazine, melting point 148 ° to 149 ° C. (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) -lH-2,3-benzoxazine

2.52 g of 4,6-dichloro-1 H-2,3-benzoxazine in 13 ml of absolute ethanol were mixed with 1.73 g of methylhydrazine. The mixture was refluxed for 30 minutes, cooled and distilled in vacuo. The residue was taken up in diethyl ether. The insolubles were filtered off. The fillral was evaporated to dryness and the residue was taken up in 10 ml of diisopropyl ether. After _{cooling on ice for 2} hours, the mixture was filtered. The solid thus obtained was crystallized from ethyl acetate to give 2.0 g of the desired compound, mp. 124-125 ⁰ 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

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

0.15 g of 6-chloro-4-hydrazino-1 H-2,3-benzoxazine were dissolved in 15 ml of anhydrous acetone with gentle warming. Then the solution was left for 1 hour stand for a long time, after which the solvent was removed in vacuo at room temperature. The residue was taken up in hexane and left to stand for 2 days. After filtration, the solution was im 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 ClN ₃ O).

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

0.5 g of 6-chloro-4- (l-methylhydrazino) -l H-2,3-benzoxazine was dissolved in 25 ml of anhydrous acetone at room temperature. The solution was allowed 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%.

Claims (6)

Patent claims:
1. I H-2,3-benzoxarines of the general formula I The present invention relates to 1 H-2,3-benzoxazines of the general formula 1 (D in which R is a hydrogen atom or a low molecular weight alkyl group, R _{1 is} a low molecular weight alkyl, the amino or isopropylidene amino group. 2. 6-Chloro-4- (1-methylhydrazino) -1 H-2,3-benzoxazine. 3. 6-Chloro-4-methylamino-I H-2,3-benzoxazine. 4. 6-Chloro-4- (isopropylidene-hydrazino) -1 H-2,3-benzoxazine. 5. 6 - chloro - 4 - (2 - isopropylidene - 1 - methylhydrazinoj-1 H-2,3-benzoxazine. 6. Process for the preparation of the 1 H-2,3-Benzexazines according to claim I, characterized in that one in a known manner 4-halogen-1 H-2,3-benzoxazine of the general formula II halogen