Forms of organic salts of N,N'-diacetylcystine

Details Forms of organic salts of N,N'-diacetylcystine Forms of organic salts of N,N'-diacetylcystine

1997-12-18

2000-01-25

Krass, Frederick

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514562, 562557, C07C32359, A61K 31195, A61K 31225

Patent

active

060179597

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new hydrates of salts of N,N-diacetylcystine and to processes for the preparation thereof.


BACKGROUND OF THE INVENTION

N-acetyl-L-cysteine is a well-known compound which is used as a therapeutic agent against chronic obstructive pulmonary diseases and chronic bronchitis. Although the first patent was filed in 1964 (GB 954268), the mechanism of action of the compound has not been established. It is also known that the corresponding disulphide of N-acetyl-L-cysteine, i.e., N,N-diacetyl-L-cystine, L-DiNAC, acts as a potent immunostimulator (SE patent application No. 9002067-8), showing an activity comparable to contemporary immunostimulants such as sodium diethyl dithiocarbamate or 2,2'-dithiobisethanol.
It has recently been found that certain salts of DiNAC with organic bases exhibit a favourable combination of non-hygroscopicity and crystallinity which permits the isolation and formulation of these salts in solid form. They have the advantages of ease of crystallisation, non-hygroscopicity and chemical stability, as well as the immunomodulating activity of DiNAC, and are thus medically useful. These salts are described in WO 93/11104.
Salts composed of an organic base and N,N-diacetylcystine (DiNAC) are generally prepared by mixing DiNAC and the organic base, as defined above, each dissolved or dispersed in a solvent or solvent mixture. Solvents, such as water, alcohols, glycols, ketones, amides, sulphoxides or other polar solvents may be used; solvent mixtures may also be used. The salt either precipitates directly from the reaction mixture, or is obtained by the addition of a less polar solvent, by evaporation, or by lyophilisation. The reaction is performed at elevated temperature or room temperature, depending on the solubility in the medium. Alternatively, the salt can be prepared by oxidation of the appropriate N-acetyl cysteine salt in an aqueous or alcoholic solution, followed by precipitation as above. The oxidation may be effected either chemically, using, e.g., hydrogen peroxide or a halogen, or electrochemically.
The above methods provide the organic salts of DiNAC in anhydrous form.


DISCLOSURE OF THE INVENTION

We have now prepared novel hydrates of certain salts of N,N'-diacetylcystine. The invention, in one aspect, provides hydrated salts of N,N'-diacetylcystine, having the formula ##STR1## in which the N,N'-diacetylcystine is the D-, L-, or meso form, or any mixture thereof, N-benzyl-2-phenylethylamine, and dihydrate, respectively, provided that when, and only when, R.sup.+ is the protonated form of N-benzyl-2-phenylethylamine, x is 1.5.
The N,N'-diacetylcystine is preferably the L-form. The lysine is preferably L-lysine.
In another aspect, the invention provides a process for obtaining the hydrated salts. The process includes oxidising N-acetyl cysteine in the presence of lysine, ammonia or N-benzyl-2-phenylethylamine, or the protonated forms thereof, in an aqueous or alcoholic solution, preferably in the presence of a catalytic amount of an alkali metal hydroxide, and crystallising the hydrate using a solvent comprising an alcohol or a ketone, preferably ethanol or acetone.
When the hydrated salt is a dihydrate, or the sesquihydrate, the crystallisation is carried out using a solvent comprising an alcohol, preferably ethanol. When the hydrated salt is the lysinium monohydrate, the crystallisation is carried out using a solvent comprising an alcohol, preferably ethanol, and when the hydrated salt is the ammonium monohydrate, the crystallisation is carried out using a solvent comprising a ketone, preferably acetone.
When the hydrated salt is a dihydrate, or the sesquihydrate, the crystallisation is carried out using a solvent comprising an alcohol, preferably ethanol. When the hydrated salt is the lysinium monohydrate, the crystallisation is carried out using a solvent comprising an alcohol, preferably ethanol, and when the hydrated salt is the ammonium monohydrate, the crystallisation is carried out using a solvent comprising a ketone, preferably aceton

REFERENCES:
patent: 5385904 (1995-01-01), Andersson et al.

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