Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-01-17
2000-08-22
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435118, C12P 1716
Patent
active
061070645
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for producing a xanthine derivative having adenosine A.sub.1 receptor antagonizing activity, and exhibiting diuretic effect, renal-protecting effect, bronchodilatory effect, cerebral function improving effect, etc.
BACKGROUND ART
##STR3## (In the formulae, R.sup.A and R.sup.B are lower alkyl.)
A process for synthesizing a xanthine derivative (Compound A) is known in which uracil and a carboxylic acid or aldehyde are used as starting materials, as shown by the above formulae (Japanese Published Unexamined Patent Application No.173889/91). It is known that Compound A has activity of selectively antagonizing adenosine A.sub.1 receptor and shows diuretic effect, renal-protecting effect, bronchodilatory effect, etc. (Japanese Published Unexamined Patent Application No.173889/91), and cerebral function improving effect (Japanese Published Unexamined Patent Application No.270222/92).
It is also known that a xanthine derivative (Compound B) represented by the formula ##STR4## (wherein R.sup.C and R.sup.D are hydroxy-substituted or unsubstituted lower alkyl, and R.sup.E is substituted or unsubstituted tricycloalkyl of C.sub.7 -C.sub.12) shows anti-ulceractive effect and the like (Japanese Published Unexamined Patent Application No.58913/93), but no specific examples of the hydroxy-substituted compounds or no methods of producing such compounds are disclosed in the publication.
The present invention relates to a process for producing a xanthine derivative represented by formula (II), comprising converting a xanthine derivative represented by formula (I) {hereinafter, referred to as Compound (I) and this applies to the compounds of other formula numbers}: ##STR5## (wherein R.sup.1 and R.sup.2 independently represent hydrogen, or hydroxy-substituted, oxo-substituted, or unsubstituted lower alkyl) into a xanthine derivative represented by formula (II): ##STR6## (wherein R.sup.3 and R.sup.4 independently represent hydrogen, or hydroxy-substituted, oxo-substituted, or unsubstituted lower alkyl; R.sup.5 and R.sup.6 independently represent hydrogen, hydroxy, or oxo; with the proviso that R.sup.5 and R.sup.6 are both hydrogen, at least one of R.sup.3 and R.sup.4 is hydroxy-substituted or oxo-substituted lower alkyl; and X and Y both represent hydrogen or are combined with each other to form a single bond) in the presence of an enzyme source for catalyzing hydroxylation or carbonylation of Compound (I) into Compound (II), and collecting the produced Compound (II).
The present invention also provides a process for producing Compound (II), comprising converting a uracil derivative represented by formula (III): ##STR7## (wherein R.sup.1 and R.sup.2 have the same meanings as defined above) into a uracil derivative represented by formula (IV): ##STR8## (wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, X, and Y have the same meanings as defined above) in the presence of an enzyme source for catalyzing hydroxylation or carbonylation of Compound (III) into Compound (IV), and then closing a ring of Compound (IV) by dehydration.
The present invention further provides a xanthine derivative represented by formula (IIa): ##STR9## (wherein R.sup.3 and R.sup.4 have the same meanings as defined above), or a pharmaceutically acceptable salt thereof.
In the definitions of Compound (I), Compound (II), Compound (III), Compound (IV), and Compound (IIa), the lower alkyl means a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isoproyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
The enzyme source used in the present invention is not limited, and any enzymes, enzyme complexes, and substances containing them can be used as the enzyme source, so long as they have the activity of catalyzing a reaction for producing Compound (II) or Compound (IV) by regiospecific or stereospecific hydroxylation or carbonylation of Compound (I) or Compound (II).
Cytochrome P450 enzyme complexes, hydroxylase, etc. can be used as enzymes or enzyme comp
REFERENCES:
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patent: 3706801 (1972-12-01), Herr
patent: 5290782 (1994-03-01), Suzuki et al.
patent: 5338743 (1994-08-01), Shizokawa et al.
ATCC Catalogue of Fungi, 1991, p. 74.
Kieslich, K., Microbial Transformations of Non-Steroid Compounds, 1976, pp. 410-417.
Chemical Abstracts, vol. 118, No. 25, Jun. 21, 1993, Abstract No. 254632t.
Eguchi Tamotsu
Horiguchi Akira
Kusaka Hideaki
Mochida Kenichi
Nonaka Hiromi
Kyowa Hakko Kogyo Co. Ltd.
Marx Irene
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