Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Patent
1991-09-20
1993-06-29
Rizzo, Nicholas S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
544277, 5483265, 5483111, C07D47302, A61K 3152
Patent
active
052236196
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for the preparation of 9-substituted guanine derivatives of the general formula I ##STR1## in which R is C.sub.1 -C.sub.4 -alkyl optionally substituted with one or more hydroxy groups, or R is ##STR2## benzyl, ribosyl, 2'-deoxyribosyl or (CH.sub.2).sub.n -OR.sup.1 where n is 1 or 2, and R.sup.1 is CH.sub.2 CH.sub.2 OH or ##STR3## or salts thereof.
Compounds of this type are therapeutically active compounds having an antiviral activity or are intermediates for the preparation of compounds of interest in gene technology.
BACKGROUND ART
It is known (J. Org. Chem. 51 1277-1282 (1986)) that guanosine can be prepared from 4-carboxamide-5-amino-1-ribofuranosyl imidazole by a process in three steps which involves condensation with carbodiimide derivatives, cyclization with PdO present and treatment with NH.sub.4 OH. This process is not attractive because it requires use of the toxic compound phosgene to prepare the carbodiimide derivatives, and because the cyclization and the subsequent treatment with NH.sub.4 OH take a very long time.
It is also known that the compound of formula I in which R is H can be prepared by a process in which the compound of formula II ##STR4## is first methylated to form the corresponding thiometyl compound which is then cyclized in alkaline medium (A. Yamazaki, Nucl. Acids. Res., 3, 1976, 251-259). This process has the drawback that the toxic and evil swelling methylmercaptane is formed as a by-product, and besides the yield is poor. It is reported in the article that cyclization of the compound II using the heavy metal salt HgO is not possible.
DISCLOSURE OF THE INVENTION
However, surprisingly we have found that it is possible to carry out cyclization of N.sup.1 -substituted derivatives of compounds of formula II without methylating first and using a heavy metal salt in aqueous alkaline medium or using peroxy compounds.
The process according to the invention is characterised in that a 1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of the general formula III ##STR5## where R has the same meaning as in formula I is cyclized a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH.sup.- ions at a temperature from about 0.degree. C. to the reflux temperature, or temperature of about 0.degree.-30.degree. C. in the presence of tungstate ions as a catalyst. converted into a salt.
The starting compounds of formula III ##STR6## in which R is C.sub.1 -C.sub.4 -alkyl optionally substituted with one or more hydroxy groups, or R is ##STR7## benzyl, ribosyl, 2'-deoxyribosyl or (CH.sub.2).sub.n -OR.sup.1, where n is 1 or 2, and R.sup.1 is CH.sub.2 CH.sub.2 or ##STR8## or salts thereof are novel compounds, and the invention therefore further comprises these compounds as intermediates for the preparation of 9-substituted guanine derivatives of formula I.
The starting materials of formula III can be prepared by reaction of 1-substituted 5-amino-1H-imidazole-4-carboxamides of the formula IV ##STR9## in which R has the same meaning as in formula I and in which hydroxyl groups, if any, in R may be acylated, with acylisothiocyanate and subsequent hydrolysis to remove the N-acyl group and any other acyl groups.
The compounds of formula IV can be prepared by alkylation of the known compound 5-amino-1H-imidazole-4-carboxamide in a known manner.
BEST MODE FOR CARRYING OUT THE INVENTION
The process according to the invention in variant a) is preferably carried out using a copper salt as the heavy metal salt. Hereby a high yield is obtained with a cheap reagent.
Moreover, the process in variant a) is advantageously carried out in the way that the aqueous alkaline medium is provided with an alkali metal hydroxide, preferably sodium or potassium hydroxide.
The process according to the invention in variant b) is preferably carried out using hydrogen peroxide as the peroxy compound.
PREPARATION OF STARTING MATERIALS
Preparation o
REFERENCES:
patent: 4602089 (1986-07-01), Simm et al.
Houben-Weyl 5 lb, 1972, Dr. Otto Klein: "Olefine durch Dimerisierung bifunktioneller Verbindungen", pp. 418-420.
Nucleic Acids Research, vol. 3, No. 1, 1986, A. Yamazaki et al.: "Synthesis of guanosine and its derivatives from 5-amino-1-.beta.-D-ribofuranolsyl-4-imidazolecarboxamide. IV. A new route to guanosine via cyanamide derivative".
J. Chem. Soc. Perkin Trans. 1, 1987, C. B. Reese et al.: "The conversion of the 2',3'-O-isopropylidene derivative of 5-amino-1-.beta.-D-ribofuranosylmidazole-r-carboxamide (AICA RIBOSIDE) into 2',3'. -O-isopropylidene-isoquanosine", see pp. 1527-1531.
J. Org. Chem. vol. 51, 1986, Michael P. Groziak et al.: "A New and Efficient Synthesis of Guanosine".
Alhede Borge
Clausen Finn P.
Juhl-Christensen Jorgen
McCluskey Klaus K.
Preikschat Herbert
A/S Gea Farmaceutisk Fabrik
Rizzo Nicholas S.
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