Process for preparing xanthine derivatives, in particular 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

A process for preparing xanthine derivatives of formula I ##STR17## wherein R.sub.1 denotes hydrogen, C.sub.1 -C.sub.6 -alkyl or C.sub.3 -C.sub.6 -alkenyl;

• R.sub.2 denotes hydrogen, a C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.8 -alkenyl or C.sub.3 -C.sub.8 alkynyl group, or a C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.8 -alkenyl or C.sub.3 -C.sub.8 -alkynyl group, which may carry one of the following groups:
• --CH.sub.2 NR.sub.6 R.sub.7, OH (multiple substitution also possible), --OR.sub.8, --NR.sub.6 R.sub.7, --NHCOR.sub.8, --NHCONR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --S--R.sub.5, --NHCONH phenyl, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --SO.sub.2 --CH.sub.2 --CH.sub.2 --OH, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --CH.dbd.NOH, --COR.sub.9, --CH(OH)R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR18##
• 1. 3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted with methyl;
• R.sub.2 denotes phenyl-C.sub.1 -C.sub.6 -alkylene, phenyl-C.sub.2 -C.sub.6 -alkenylene or phenyl-C.sub.2 -C.sub.6 -alkynylene, the phenyl ring being optionally substituted either directly or via an alkylene group having 1 to 4 C atoms, by one or more of the following radicals:
• --C.sub.1 -C.sub.3 -alkyl, --CH.sub.2 NR.sub.6 R.sub.7, --NO.sub.2, --OH, --OR.sub.8, --CH.sub.2 --NH--SO.sub.2 --R.sub.8, --NHCONR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --CF.sub.3, cyclopropyl, --CH.sub.2 OH, --CH.sub.2 OR.sub.8, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --COR.sub.9, --CH(OH)R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR19##
• 1. 3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted by methyl;
• R.sub.2 denotes
• C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 alkylene,
• C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.6 -alkenylene,
• C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.6 -alkynylene,
• the cycloalkyl group being optionally substituted either directly or via an alkylene group having 1 to 4 C atoms, by --CN, --CH.sub.2 NR.sub.6 R.sub.7, .dbd.O, --OH, --OR.sub.8, --NR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --CH.sub.2 OH, --CH.sub.2 OR.sub.8, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --COR.sub.9, --CH(OH)R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR20##
• 1. 3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted by methyl;
• R.sub.2 denotes a group of the formula
• A-C.sub.1 l -C.sub.6 -alkylene,
• A-C.sub.2 -C.sub.6 -alkenylene,
• A-C.sub.2 -C.sub.6 -alkynylene,
• wherein A is a C-linked or N-linked 5-membered or 6-membered heterocyclic ring containing one nitrogen, oxygen or sulphur as the hetero atom, and which may be optionally mono- or poly-substituted by C.sub.1 -C.sub.4 -alkyl, halogen, --OR.sub.8, --NO.sub.2, --NH.sub.2, --CH.sub.2 NR.sub.6 R.sub.7, --OH, .dbd.O, --COOH, --SO.sub.3 H, --COR.sub.9, --SO.sub.2 --R.sub.8, or ##STR21## R.sub.3 denotes a C-linked saturated or unsaturated five, six or seven-membered heterocyclic ring containing one hetero atom selected from the group oxygen or sulphur, or
• R.sub.3 denotes a C.sub.4 to C.sub.8 cycloalkene, which may be substituted by C.sub.2 to C.sub.4 alkenyl, or
• R.sub.3 denotes a C.sub.4 to C.sub.8 -cycloalkanone, or a C.sub.4 to C.sub.8 -cycloalkanol, which may be substituted in the .alpha.-position by C.sub.2 to C.sub.6 -alkenyl, C.sub.2 to C.sub.6 -alkynyl, benzyl, CH.sub.2 OR.sub.4, CH.sub.2 COOH, or
• R.sub.3 denotes a C.sub.3 to C.sub.8 -cycloalkane which is optionally substituted by C.sub.1 to C.sub.6 -alkyl, .dbd.CH.sub.2, --OR.sub.4, --OR.sub.7, --(CH.sub.2).sub.I --COOH, --(CH.sub.2).sub.I --NR.sub.4 R.sub.4 (R.sub.4 same or different), --(CH.sub.2).sub.I --OR.sub.4, --(CH.sub.2).sub.I --OR.sub.7, wherein I denotes one of the numbers 0, 1, 2, 3 or 4, or a group .dbd.CA'H wherein A' denotes COOH, CH.dbd.CH--COOH, CH.sub.2 OR.sub.4 or CH.sub.2 OR.sub.7,
• or the C.sub.3 to C.sub.8 -cycloalkane is substituted by C.sub.1 to C.sub.6 alkyl, vinyl, allyl, phenyl, C.sub.1 -C.sub.4 -alkylphenyl, and carries as a second substituent a hydroxyl group in a geminal position to the first substituent;
• or
• R.sub.3 denotes a ketal of formula ##STR22## wherein Ra denotes C.sub.1 -C.sub.4 alkyl, and
• Rb denotes C.sub.1 -C.sub.4 alkyl, or
• Ra and Rb together form a C.sub.2 or C.sub.3 -alkylene bridge, which may be optionally mono- or di-substituted by C.sub.1 -C.sub.5 -alkyl;
• or
• R.sub.3 denotes a group of the formula ##STR23## or R.sub.3 denotes a group of the formula, ##STR24## or adamantane;
• or R.sub.3 denotes C.sub.3 -C.sub.7 -cycloalkyl, which is optionally substituted by .dbd.O, --OH, --OR.sub.8, or
• R.sub.3 denotes phenyl, which is optionally substituted by --OH, halogen, --OR.sub.8, C.sub.1 -C.sub.4 -alkyl, --NH.sub.2, --COOH, --SO.sub.3 H, --COOH, --OCH.sub.2 COOH, or
• R.sub.3 denotes a norbornane, norbornene, a C.sub.3 -C.sub.6 dicycloalkylmethyl or noradamantane group;
• or
• R.sub.3 denotes --CH.dbd.CH-phenyl, the phenyl ring being mono- or poly-substituted by methoxy, hydroxy or halogen;
• or
• R.sub.3 denotes a ›3.3.0!-bicyclooctan-;
• a ›3.3.0!-bicyclooctan-2-yl, or
• R.sub.3 denotes a C-linked piperidine or furan;
• R.sub.4 denotes hydrogen, methyl or benzyl, wherein the benzyl group may be substituted by 1 to 3 methoxy groups;
• CH.sub.3 --O--CH.sub.2 --, CH.sub.3 --S--CH.sub.2 --, ##STR25## or, --CH.sub.2 --CH.dbd.CH.sub.2 ;
• R.sub.5 denotes C.sub.1 -C.sub.4 -alkyl, which is optionally substituted by OH, NH.sub.2 or NR.sub.6 R.sub.7 ;
• R.sub.6 denotes hydrogen, a cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which may be optionally substituted by hydroxy, phenyl, amino or C.sub.1 to C.sub.8 -alkoxy;
• R.sub.7 denotes hydrogen, a cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which may be optionally substituted by hydroxy, phenyl, amino or C.sub.1 to C.sub.8 -alkoxy;
• or
• R.sub.6 and R.sub.7 together with the nitrogen atom form a saturated or unsaturated 5 or 6 ring, which may contain nitrogen, oxygen or sulphur as an additional hetero atom, wherein the heterocyclic ring may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, or may carry one of the following groups:
• --(CH.sub.2).sub.n --NH.sub.2, .dbd.O, --(CH.sub.2).sub.n NH--C.sub.1 -C.sub.4 -alkyl, --(CH.sub.2).sub.n --N(C.sub.1 -C.sub.8 -alkyl).sub.2, halogen, --OR.sub.8, --NO.sub.2, --NH.sub.2, --CH.sub.2 NR.sub.6 R.sub.7, --OH, --COOH, --SO.sub.3 H, --SO.sub.2 --R.sub.8,
• R.sub.8 denotes hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, benzyl or phenyl group, which is optionally substituted once or several times by OCH.sub.3 ;
• R.sub.9 denotes C.sub.1 -C.sub.4 -alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, phenyl, benzyl, C.sub.3 -C.sub.6 -cycloalkyl;
• R.sub.10 denotes --COOH, --CH.sub.2 OR.sub.8, hydrogen, C.sub.1 -C.sub.3 -alkyl, phenyl, --CH.sub.2 NR.sub.6 R.sub.7 ;
• R.sub.11 denotes hydrogen, phenyl, --CH.sub.3,
• characterised in that a uracil derivative of the formula A or B ##STR26## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the aforementioned meaning is dissolved in a suitable organic-aqueous solvent and cyclised in the presence of LiOH.

A process for preparing 1,3-dipropyl-8-(3-oxocyclopentyl) xanthine, characterised in that:

• (a) 2-carboxy-8,8-dimethyl-6,10-dioxaspiro›4,5!decane is reacted with 1,3-dipropyl-5,6-diaminouracil to produce an amide of formula VI:
• ##STR28## (b) the amide of formula VI is cyclised in a suitable solvent in the presence of LiOH/H.sub.2 O to produce a ketal of formula VII:
• ##STR29## and (c) the ketal of formula VII is contacted with acid to produce 1,3-dipropyl-8-(3-oxocyclopentyl) xanthine:
• ##STR30##