Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1990-12-21
1992-11-24
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 24, C07H 19167
Patent
active
051663287
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
1. Technical Field
This invention relates to novel S-adenosylmethionine derivatives, which are high in fat-solubility and yet can, when used as medicament, readily release S-adenosylmethionine in the living body.
2. Background Art
S-adenosylmethionine (SAM) is known as a substance existing in the living body and also as a methyl donor in the metabolism of living organisms.
As pharmacological action of SAM, various actions such as prolongation of life of mouse under hypoxia, improvement of energy state of ischemic brain, improvement of cerebral energy metabolism and acidosis of the model with recirculated blood flow following ischemia, etc. have been heretofore found.
SAM is also known to show a variety of actions, i.e. inhibition of neuronal death following ischemia, improvement of cerebral glucose utility, inhibition of brain edema, improvement of EEG, improvement of evoked potential, ameliorative action on motor function, and therefore reported to be important as a cure for stroke. SAM, however, possesses water-soluble groups such as hydroxyl group, amino group, sulfonium group, carboxyl group, etc. in its molecule, therefore being poor in permeability through cell barrier and causing a problem in drug absorption when orally administered.
In order to render SAM orally applicable, the development of a SAM derivative, which 1) has a good permeability through cell barrier and 2) can release SAM promptly after permeation is desired.
As compounds satisfying requirement 1) above, (a) a compound obtainable by esterifying the carboxylic acid and the 2'- and 3'- hydroxyl groups while simultaneously acylating the amino group of SAM, (b) a compound obtainable by esterifying the 2'- and 3'- hydroxyl groups while simultaneously acylating the amino group of SAM, etc. have already been reported (Japanese Unexamined Patent Application Publication No. 57397/83 (TOKKAI-SHO 58-57397)). These derivatives, however, show poor susceptibility of hydrolysis in the living body as they contain amide bonds, and do not adequately fulfil requirement 2), i.e. prompt release of SAM after permeation through cell barrier. Accordingly, the development of a novel SAM derivative that can satisfy both requirements 1) and 2) above concurrently has been desired.
DISCLOSURE OF INVENTION
The object of this invention is to provide substances which are high in fat-solubility and are easy to permeate through cell barrier and yet can readily release SAM in the living body.
The present inventors have found that novel SAM derivatives represented by formula (I) below, i.e. acid-addition salts of compounds obtained by esterifying the hydroxyl groups only among the above-mentioned water-soluble groups of SAM, are high in fat-solubility, easily permeate through cell barrier and are capable of easily releasing SAM in the living body.
Accordingly, this invention provides novel SAM derivatives of the following formula (I) ##STR2## wherein R.sub.1 and R.sub.2 each represent straight or branched alkyl or alkenyl having 1-10 carbon atoms; m is 1-3; and A is an anion of inorganic or organic acids.
In the above-mentioned formula (I), examples of R.sub.1 and R.sub.2 include: for straight alkyl, methyl, ethyl, propyl, butyl and decyl; for branched alkyl, isopropyl and tert.butyl; and, for alkenyl, decenyl. Furthermore, m stands for 1-3 and A for an anion of inorganic or organic acids.
Examples of the derivatives of the above-mentioned formula to which to add an inorganic or organic acid include:
Compound A: 2',3'-O-dibutanoyl-S-adenosylmethionine methyl ester, and
Compound B: 2',3'-O-didecanoyl-S-adenosylmethionine methyl ester.
Examples of HA in the above-mentioned formula (I) include, for inorganic acid, hydrochloric, hydrobromic, sulfuric and phosphoric acids and, for organic acid, organic sulfonic acids such as methane-, ethane-, benzene- and p-toluenesulfonic acids and carboxylic acids such as citric, tartaric and succinic acids. Preferred examples are inorganic acids and organic sulfonic acids.
One of the most preferred examples of A.sup.- is
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Chemical Abstract; vol. 95; No. 3; Abstract No. 18222v; "S-adenosylmethionine excites rat cerebral cortical neurons"; p. 54; J. W. Phillis; Jul. 20, 1981.
Chemical Abstracts; vol. 108; No. 7; Abstract No. 49255z; p. 68; "S-adenosyl-L-methionine prevents ischemic neuronal death"; Y. Matsui et al., Feb. 15, 1988.
Endo Takeshi
Kurobe Hiroshi
Sugawara Tomokazu
Brown Johnnie R.
Crane L. E.
Fuji Kagaku Kogyo Kabushiki Kaisha
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