Ono Pharmaceutical Co., Ltd.

Katsuichi Shimoji

Masaki Hayashi

Yoshinobu Arai

Yoshitaka Konishi

Shuichi Ohuchida

Hirohisa Wakatsuka

Hiroyuki Ito

Masaaki Toda

Seiji Kori

Hajimu Miyake

Shinsuke Hashimoto

Sadahiko Iguchi

Hisashi Suga

Yoichi Iguchi

Yasuyuki Miyata

Yutaro Sasaki

Hayashi Masaki

This invention relates to glucopyranose compounds of formula (I) and (IA) ##STR1## and the non-toxic salts thereof wherein the substituents are as defined herein. Such materials possess enhancing activity of cellular immunity (e.g. mitogenic activity) to living tissue and therefore are useful as anti-tumor agents.

Glucopyranose derivatives

Prostaglandin I.sub.2 analogues of the formula: ##STR1## [wherein X represents trans-vinylene or an ethylene group unsubstituted or substituted by a bromine atom at the C-5 position, Y represents trans-vinylene or ethylene, R.sup.1 represents hydrogen or an alkyl group containing from 1 to 12 carbon atoms, R.sup.2 represents hydrogen or methyl or ethyl, R.sup.3 represents a single bond or an alkylene group containing from 1 to 4 carbon atoms, R.sup.4 represents hydrogen, an alkyl group containing from 1 to 8 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or a phenyl or phenoxy group unsubstituted or carrying at least one substituent selected from halogen atoms, the trifluoromethyl group and alkyl groups containing from 1 to 3 carbon atoms, and the wavy line  attached to the carbon atoms in positions 6, 11 and 15 depicted in the formula represents .alpha.- or .beta.-configuration or mixtures thereof] are new compounds possessing pharmacological properties typical of prostaglandins, for example PGI.sub.2, and are more stable than PGI.sub.2.

Prostaglandin 12 analogues and their pharmaceutical compositions

Prostaglandin analogues of the general formula: ##STR1## [wherein the ring A represents: ##STR2## the ring B represents: ##STR3## (wherein R.sup.6 represents hydrogen, methyl or ethyl, and r is zero, one or two), Y represents ethylene, cis- or trans-vinylene or ethynylene, Z represents a grouping of the formula: --(CH.sub.2).sub.m --, --(CH.sub.2).sub.3 --CHR.sup.7 --, --(CH.sub.2).sub.2 --CHR.sup.7 --CH.sub.2 --, --CH.sub.2 --CHR.sup.7 --(CH.sub.2).sub.2 --, --CHR.sup.7 --(CH.sub.2).sub.3 --, or trans--(CH.sub.2).sub.2 --CH.dbd.CH-- (wherein m is 3, 4 or 5, and R.sup.7 represents methyl or ethyl), R.sup.1 represents a grouping of the formula: --COOR.sup.8, ##STR4## or --CH.sub.2 OR.sup.11 (wherein R.sup.8 represents hydrogen, alkyl, aralkyl, cycloalkyl which is unsubstituted or substituted by at least one alkyl group, or R.sup.8 represents phenyl which is unsubstituted or substituted by halogen, trifluoromethyl, alkyl, alkoxy, alkylthio or phenyl, or represents naphthyl, 2,3- or 1,3-dihydroxypropyl, 2,3- or 1,3-bisalkanoyloxypropyl, a grouping of the formula: -D.sub.1 --COOR.sup.12, ##STR5## -D.sub.2 -R.sup.15 or -D.sub.3 -R.sup.16, wherein D.sub.1 represents alkylene, D.sub.2 represents alkylene, D.sub.3 represents a single bond or alkylene, R.sup.12, R.sup.13 and R.sup.14, each represent alkyl, R.sup.15 represents hydroxy, alkoxy or alkylthio and R.sup.16 represents a heterocyclic ring, or R.sup.8 represents a grouping of the formula: ##STR6## R.sup.9 and R.sup.10, each represent hydrogen, alkyl, alkylsulphonyl, alkanoyl or ##STR7## represents a heterocyclic ring, and R.sup.11 represents hydrogen or alkanoyl, R.sup.2 represents hydrogen, methyl or ethyl, R.sup.3 represents a single bond or alkylene, R.sup.4 represents hydrogen, alkyl, alkoxy, cycloalkyl or cycloalkyloxy unsubstituted or substituted by alkyl, or represents phenyl or phenoxy unsubstituted or substituted by halogen, trifluoromethyl or alkyl with the proviso that, when R.sup.3 represents a single bond, R.sup.4 does not represent alkoxy, cycloalkyloxy or phenoxy, R.sup.5 represents hydrogen, methyl or ethyl and with the proviso that, when one of the groups R.sup.5, R.sup.6 and R.sup.7 represents methyl or ethyl the other two groups are hydrogen atoms] and cyclodextrin clathrates, non-toxic salts and non-toxic acid addition salts thereof, possess selective strong stimulatory activity on uterine contraction in female mammals.

Prostacyclin analogues

Prostaglandin E.sub.1 analogues of the general formula: ##STR1## [wherein Y represents ethylene or trans-virylene, Z represents ethylene or trans-vinylene, R.sup.1 represents a hydrogen atom, an alkyl group containing 1 to 12 carbon atoms, an aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 6 carbon atoms, a phenyl group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group, alkyl group containing from 1 to 4 carbon atoms or phenyl group, a--C.sub.m H.sub.2m COOR.sup.5 group (wherein m represents an integer of from 1 to 12 and R.sup.5 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms ), a --C.sub.n H.sub.2n OR.sup.6 group (wherein R.sup.6 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n represents an integer of from 2 to 12), or a ##STR2## group (wherein R.sup.7 and R.sup.8 each represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), R.sup.2 represents a hydrogen atom or a methyl or ethyl group, R.sup.3 represents a single bond or an alkylene group containing from 1 to 4 carbon atoms, R.sup.4 represents a hydrogen atom, an alkyl group containing from 1 to 8 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or represents a phenyl or phenoxy group unsubstituted or substituted by at least one chlorine atom, trifuloromethyl group or alkyl group containing from 1 to 3 carbon atoms, and the wavy line attached to the C-11 and C-15 carbon atoms represents .alpha.- or .beta.-configuration or mixtures thereof] and cyclodextrin clathrates thereof, and, when R.sup.1 represents a hydrogen atom or a group C.sub.m H.sub.2m COOR.sup.5 in which R.sup.5 represents a hydrogen atom, non-toxic salts thereof and, when R.sup.1 represents a group ##STR3## non-toxic acid addition salts thereof, are new compounds and possess characteristic prostaglandin-like properties.

Prostaglandin analogues

Prostaglandin E.sub.1 analogues of the general formula: ##STR1## [wherein Y represents ethylene or trans-vinylene, Z represents ethylene or trans-vinylene, R.sup.1 represents a hydrogen atom, an alkyl group containing from 1 to 12 carbon atoms, an aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 6 carbon atoms, a phenyl group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group, alkyl group containing from 1 to 4 carbon atoms or phenyl group, a --C.sub.m H.sub.2m COOR.sup.5 group (wherein m represents an integer of from 1 to 12 and R.sup.5 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms), a --C.sub.n H.sub.2n OR.sup.6 group (wherein R.sup.6 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n represents an integer of from 2 to 12), or a ##STR2## group (wherein R.sup.7 and R.sup.8 each represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), R.sup.2 represents a hydrogen atom or a methyl or ethyl group, R.sup.3 represents a single bond or an alkylene group containing from 1 to 4 carbon atoms, R.sup.4 represents a hydrogen atom, an alkyl group containing from 1 to 8 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or represents a phenyl or phenoxy group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group or alkyl group containing from 1 to 3 carbon atoms, and the wavy line attached to the C-11 and C-15 carbon atoms represents .alpha.- or .beta.- configuration or mixtures thereof] and cyclodextrin clathrates thereof, and, when R.sup.1 represents a hydrogen atom or a group C.sub.m H.sub.2m COOR.sup.5 in which R.sup.5 represents a hydrogen atom, non-toxic salts thereof and, when R.sup.1 represents a group ##STR3## non-toxic acid addition salts thereof, are new compounds and possess characteristic prostaglandin-like properties.

Prostaglandin analogues of the general formula: ##STR1## [wherein Y represents ethylene or trans-vinylene, R.sup.1 represents a group --C.sub.m H.sub.2m COOR.sup.5, --C.sub.n H.sub.2n OR.sup.6 or ##STR2## (wherein R.sup.5 represents an alkyl group containing from 1 to 4 carbon atoms, R.sup.6 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, R.sup.7 and R.sup.8, which may be the same or different, each represents an alkyl group containing from 1 to 4 carbon atoms, m represents an integer of from 1 to 12 and n represents an integer of from 2 to 12), R.sup.2 represents a hydrogen atom or a methyl or ethyl group, R.sup.3 represents a single bond, or an alkylene group containing from 1 to 4 carbon atoms, R.sup.4 represents a hydrogen atom, an alkyl group containing from 1 to 8 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms in the ring, which may be unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or represents a phenyl or phenoxy group which may be unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group or alkyl group containing from 1 to 3 carbon atoms, the wavy line  attached to the carbon atoms in positions 11 and 15 represents .alpha.- or .beta.-configuration, or mixtures thereof, and the double bond between C.sub.5 -C.sub.6 is Z] and cyclodextrin clathrates thereof, and, when R.sup.1 represents a group ##STR3## in which n, R.sup.7 and R.sup.8 are as hereinbefore defined, non-toxic acid addition salts thereof, are new compounds and possess characteristic prostaglandin-like properties.

Prostaglandin I.sub.2 analogues

Prostaglandin I.sub.2 analogues of the formula: ##STR1## (wherein Y represents trans-vinylene or ethylene, R.sup.1 represents hydrogen or an alkyl group containing from 1 to 12 carbon atoms, R.sup.2 represents hydrogen, methyl or ethyl, R.sup.3 represents a single bond, or an alkylene group containing from 1 to 4 carbon atoms, R.sup.4, R.sup.5 and R.sup.6, which may be the same or different, each represent hydrogen or an alkyl group containing from 1 to 8 carbon atoms, n represents 3, 4, 5 or 6, the wavy line  attached to the carbon atoms in positions 11 and 15 depicted in the formula represents .alpha.- or .beta.-configuration or mixtures thereof, and the double bond between C.sub.6 -C.sub.6 is Z or E) are new compounds possessing pharmacological properties typical of prostaglandins, for example PGI.sub.2.

The present invention relates to compounds of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## B represents a single bond or a straight- or branched-chain alkylene group containing from 1 to 9 carbon atoms, W represents ethylene or trans-vinylene, X represents ethylene or cis-vinylene, Y represents ethylene or trans-vinylene, R represents a hydroxymethyl group or a grouping of the formula --COOR.sup.4, in which R.sup.4 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, R.sup.1 represents a hydrogen atom or a methyl or ethyl group, R.sup.2 represents a hydrogen atom or a methyl or ethyl group and R.sup.3 represents a hydrogen or chlorine atom or a hydroxy group and cyclodextrin clathrates of such alcohols, acids and esters and, when R.sup.4 in the formula --COOR.sup.4 represents a hydrogen atom, non-toxic salts thereof, and intermediates therefor. These compounds exhibit characteristic prostaglandin-like activity.

Growing community of inventors

Takatsuki, Japan

Katsuichi Shimoji