Hydroxylamines with hypoglycemic activity

The invention relates to novel hydroxylamines, methods and intermediates for their preparation and to the use thereof.

Compounds of general formula I ##STR1## wherein

R¹ and R² represent a hydrogen atom, a straight-chain or branched alkyl with 1-4 C atoms or phenyl, or

R¹ +R² together represent an alkylidene group with 4-6 C atoms, and

R³ represents an o-, m-, or p-hydroxyaminophenyl group, have not been known so far.

Now it has been found that these compounds have valuable pharmacological properties, especially hypoglycemic activity, irrespective of the application route that can be an intravenous, subcutaneous or oral one. Hypoglycemic activity has been determined by standard tests on warm-blooded animals, e.g. mice. For example, see U.S. Pat. No. 5,286,744, issued Feb. 15, 1994, to Dumic et. al., the entire disclosure of which is hereby incorporated by reference.

According to the process of the present invention, compounds of the general formula I can be prepared in such a way that compounds of general formula II ##STR2## wherein

R¹ and R² have the above-given meaning and

R⁴ represents an o-, m- or p-nitrophenyl group,

are contacted with a reducing agent e.g. amalgams such as sodium amalgam, sulfide reducers such as H₂ S/NH₃ /EtOH or NaHS/CaCl₂, hydrazinc reducers such as N₂ H₄ ·H₂ O/Pd/C, zinc reducers such as Zn/CaCl₂ or Zn/NH₄ Cl, tin reducers such as SnCl₂ /^-- OH, organic reducers such as glucose or vitamin C, either electrochemically or by catalytic hydrogenation in the presence of palladium or platinum catalysts.

By catalytic hydrogenation the reduction is best performed in the presence of palladium catalysts such as Pd/BaSO₄ or Pd/C or platinum catalysts such as Pt/C in inert organic solvents of alcohol type such as methanol, ethanol or tert.-butanol, carboxylic acid esters such as ethyl acetate, under hydrogen pressure of 0-4 bar and at temperatures from -10° C. to +50 ° C.

Suitable starting materials of general formula II are compounds which are appropriately substituted in accordance with the definition of symbols R¹ and R² as given in general formula I and R⁴ as given in general formula II. They can be easily prepared by sulfonation of the corresponding dioxepinoazirines with o-, m- and p-nitro substituted benzenesulfochlorides (M. Dumic et al., WO 93 04067 of 04.03.1993).

With regard to what has been said above, the novel hydroxylamines of the general formula I represent effective hypoglycemic agents and by conventional processes of pharmaceutical technology they can be transformed into appropriate pharmaceutical formulations such as tablets, pills, powders, granules, solutions etc. with short-term or prolonged activity for the therapy of diabetes mellitus.

The present invention is illustrated, yet in no way limited, by the following examples.

EXAMPLE 1

General process for the preparation of novel hydroxylamines of the general formula I

The nitro derivative of the general formula II (0.50 g) is dissolved in an inert solvent and, after the addition of 5% Pd/C (0.05 g), it is hydrogenated for 60 minutes at the hydrogen pressure of 1 bar and at room temperature. The catalyst is filtered off by suction and the tiltrate is evaporated to dryness at reduced pressure. By recrystallization of the evaporation residue, a hydroxylamine of the general formula I is obtained.

EXAMPLE 2

In a manner analogous to the general process described in Example 1, from 0.50 g of derivative II (R¹ ═R² ═H, R⁴ ═NO₂ --C₆ H₄ --) by hydrogenation in 60 ml of ethyl acetate the compound I (R¹ ═R² ═H, R⁴ ═p--HONH--C₆ H₄ --) is obtained, m.p. 145°-147° C./ethyl acetate-petroleum ether.