Cysteine derivatives of disulfide form

Details Cysteine derivatives of disulfide form Cysteine derivatives of disulfide form

1982-05-04

1985-05-14

Jiles, Henry R.

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

260455R, 562556, C07D21000, C07C153017, C07C14702, C07C10142

Patent

active

045171238

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to intra- or intermolecular disulfide compounds represented by the formula ##STR2## wherein R.sup.1 and R.sup.2 each is hydrogen, lower alkyl, aryl, aralkyl, lower alkanoyl or aroyl;


BACKGROUND OF THE TECHNICAL FIELD

Cysteine derivatives, represented by the formula [I] wherein R.sup.1 and R.sup.2 are hydrogen or acyl group, are known as useful agents for the treatment of liver damage, rheumatic diseases and cataracts (for example, Japanese Kokai Tokkyo Koho No. Sho 53-5112, 54-5916, 55-51020, 55-51021, 55-51054 and 55-92315 ).
But disulfide derivatives of the oxidized form of the compound, represented by the formula [I] wherein at least one of R.sup.1 and R.sup.2 is hydrogen, are not disclosed.


DETAILED DESCRIPTION OF THIS INVENTION

The compounds of this invention are novel compounds and we found that they show a suppresive effect toward liver damage and cataracts and have an antirheumatic effect.
The compounds of this invention are more stable than the known compounds mentioned above, so they have advantages for manufacturing and pharmaceutical preparation.
The compounds of this invention are synthesized by the following methods, exemplified by (a) and (b).
(a) The compounds of this invention are synthesized by oxidation (oxidizing agent is metal salts, oxygen, halogen, hydrogenperoxide, etc.) of the compounds represented by the formula [II], ##STR3## wherein R.sup.3 and R.sup.4 each is lower alkyl, aryl, aralkyl, loweralkanoyl or aroyl, but at least one of them is hydrogen.
(b) The compounds of this invention are synthesized by the reaction of the active derivative (for example, acid halide, mixed anhydride or active ester) of the compounds of the formula [III], -S-A-COOH, ##STR4## wherein R.sup.6 is hydrogen, lower alkyl, aryl, aralkyl, loweralkanoyl, aroyl or, ##STR5## from.
The compound of this invention, synthesized by the above methods, may be converted to the conventional salts such as sodium salt, potassium salt, magnesium salt, calcium salt, aluminium salt, ammonium salt, diethylamine salt, triethanolamine salt, etc. which are acceptable in drug.
The compounds of this invention include the stereoisomers because they have one or more asymmetric carbon atoms.
These stereoisomers are also within the scope of this invention.
Examples are shown below, although this invention is not limited to these Examples.
Best mode of making the invention


EXAMPLE 1

N,N'-Bis[2-methyl-2-(methylthio)propanoyl]-L-cystine
To a stirred solution of 3.1 g (13 mM) of L-cystine in 105 ml of 0.5 N sodium hydroxide, 4.0 g (26 mM) of 2-methyl-2-(methylthio)propanoyl chloride is added dropwise at 5.degree.-10.degree. C. After the addition the reaction mixture is stirred for 45 minutes at the same temperature and for additional 20 minutes at the room temperature. The reaction mixture is washed with ether, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried. Ehtyl acetate is distillated off and the residue is purified by silica gel column chromatography to give 5.1 g (83%) of the titled compound.
mp 128.degree.-129.degree. C. (ethyl acetate-n-hexane)
[.alpha]sub.D.sup.24 -157.9.degree. (c=0.9, methanol)
IR(nujol, cm.sup.-1) 3320, 1730, 1625, 1515 NMR (DMSO-d.sub.6, .delta.) 1.38(12H, s, (CH.sub.3).sub.2 C--), 2.00 (6H, s, CH.sub.3 S--), 3.13(4H, d, J=5.0 Hz, -CH.sub.2 S-), 4.27-4.67(2H, m, CHCOOH), 7.93(2H, d, J=8.0 Hz, --CONH--), 12.75(2H, s, COOH)
Elemental Analysis (C.sub.16 H.sub.28 N.sub.2 O.sub.6 S.sub.4) Calcd.: C, 40.65; H, 5.98; N, 5.93; Found: C, 40.88; H, 5.98; N, 5.69.


EXAMPLE 2

N,N'-[2,2'-Dithiobis(2-methylpropanoyl)]bis(S-methyl-L-cysteine) By substituting 5.0 g(37 mM) of S-methyl-L-cysteine and 2.9 g (19 mM) of 2,2'-dithiobis(2-methylpropanoyl)dichloride in the procedure of Example 1, 7.0 g (80%) of the titled compound is obtained.
mp 81.degree.-85.degree. C. (chloroform)
[.alpha]sub.D.sup.24 +4.3.degree. (c=1.0, methanol)
IR (nujol, cm.sup.-1)3310, 1725, 1610 NMR (DMSO-d.sub.6, .delta.) 1.43(12H, s

REFERENCES:
patent: 4241086 (1980-12-01), Iwao et al.
patent: 4255446 (1981-03-01), Iwao et al.
patent: 4305958 (1981-12-01), Fujita et al.
Santen, Chem. Abs., vol. 97, 6782f, p. 657.
Santen Chem. Abstracts, vol. 94, 36350u, p. 375 (1981).

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