Sankyo Company, Limited

Misako Kimura

Masakatsu Kaneko

Yoshinobu Murofushi

Mitsuo Yamazaki

Yasuteru Iijima

Nobuyoshi Iwata

Fumio Nakagawa

New griseolic acid derivatives have various groups attached to the sugar part in place of the adenine group of griseolic acid itself. These groups are all purine derivatives or ring-opened purine analogs. The compounds are useful as inhibitors of phosphodiesterases.

Griseolic acid derivatives, their preparation and their use

A compound of the formula (I) is provided ##STR1## wherein A represents a group of the formula: ##STR2## R.sup.1 and R.sup.2 are independently hydrogen, halogen or a group of the formula --OR.sup.9 ; R.sup.9 is hydrogen, alkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl or a hydroxy-protecting group; R.sup.3 and R.sup.4 are independently carbamoyl or carboxy; R.sup.5 and R.sup.6 both represent hydrogen or together represent an extra carbon-carbon bond between the carbon atoms to which they are attached; and Z represents hydrogen or unsubstituted or substituted hydroxy; or a pharmaceutically acceptable salt or ester thereof. The compounds are useful as inhibitors of phosphodiesterases.

Griseolic acid compounds and their use as a phosphodiesterase inhibitor

A compound of the formula (I) is provided ##STR1## wherein A represents a group of the formula: ##STR2## R.sup.1 and R.sup.2 are independently hydrogen, halogen or a group of the formula --OR.sup.9 ; R.sup.3 and R.sup.4 are independently carbamoyl or carboxy; R.sup.5 and R.sup.a both represent hydrogen or together represent an extra carbon-carbon bond between the carbon atoms to which they are attached; and R.sup.9 is hydrogen, alkyl, alkysulfonyl, haloalkylsulfonyl, arylsulfonyl or a hydroxy-protecting group; or a pharmaceutically acceptable salt or ester thereof. The compounds are useful as inhibitors of phosphodiesterases.

Griseolic acid derivatives

A compound of the formula (I) is provided ##STR1## wherein A represents a group of the formula: ##STR2## R.sup.1 and R.sup.2 are independently hydrogen, halogen or a group of the formula --OR.sup.9 ; R.sup.9 is hydrogen, alkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl or a hydroxy-protecting group; R.sup.3 and R.sup.4 are independently carbamoyl or carboxy; R.sup.5 and R.sup.6 both represent hydrogen or together represent an extra carbon-carbon bond between the carbon atoms to which they are attached; and W represents an alkoxy or aralkoxy; or a pharmaceutically acceptable salt or ester thereof. The compounds are useful as inhibitors of phosphodiesterases.

Intermediates for griseolic acid derivatives

Griseolic acid and dihydrodesoxygriseolic acid derivatives having an alkyl or aralkyl group as a substituent on the amino group at the 6-position are prepared by reacting the unsubstituted compound with a compound R.sup.7 -X (where R.sup.7 is alkyl or aralkyl and X is halogen or sulfonyloxy). The group first substitutes and quaternizes the 1-nitrogen atom. The compound is then subjected to an appropriate combination of temperature and pH to cause ring cleavage, rearrangement and ring closure involving the 6-amino group and this quaternized 1-nitrogen to give a 6-alkylamino or 6-aralkylamino derivative.

Process for preparing griseolic acid derivatives

Griseolic acid derivatives of formula (I): ##STR1## wherein A represents: ##STR2## have enzyme-inhibitory activity, especially against cAMP PDE and cGMP PDE. When formulated as compositions with appropriate carriers or diluents, they may be used for the treatment of a variety of organic disorders and show toxicities less than griseolic acid itself.

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Tokyo, Japan

Misako Kimura