Ono Pharmaceutical Co., Ltd.

Hajimu Miyake

Masaki Hayashi

Seiji Kori

Tadao Okegawa

Kimiichiro Matsumoto

Takashi Yamato

Hisashi Suga

Katsuhiro Imaki

Takanori Okada

Yoshitaka Konishi

Hirohisa Wakatsuka

Katsuichi Shimoji

Takashi Muryobayashi

Sadahiko Iguchi

Hirofumi Endo

Akiyoshi Kawasaki

Yoichi Iguchi

Yasuyuki Miyata

The present invention relates to novel isomers of PGAs, PGDs, PGEs, PGFs, 6-keto-PGE.sub.1 s, 6-keto-PGF.sub.1 s, PGI.sub.2 s, 6,9.alpha.-nitrilo-PGI.sub.1 s and 6,9.alpha.-methano-PGI.sub.2 s, having a specific steric configuration, which are replaced by an alkyl (C.sub.1 to C.sub.8)-substituted cycloalkyl (C.sub.4 to C.sub.7) group in (1S,S) form, in (1S,R) form or in cis form at the 15-, 16- or 17-position of the PG skeleton, and, alkyl esters thereof, non-toxic salts thereof, non-toxic acid addition salts thereof and cyclodextrin clathrates thereof, possessing more potent PG-like pharmacological activity than other isomers.

Prostaglandin analogues, process for their preparation and

The present invention relates to novel isomers of PGAs, PGDs, PGEs, PGFs, 6-keto-PGE.sub.1 s, 6-keto-PGF.sub.1 s, PGI.sub.2 s, 6,9.alpha.-nitrilo-PGI.sub.1 s and 6,9.alpha.-methano-PGI.sub.2 s, having a specific steric configuration, which are replaced by an alkyl (C.sub.1 to C.sub.8)-substituted cycloalkyl (C.sub.4 to C.sub.7) group in 1S,S) form, in 1S,R) form or in cis form at the 15-, 16- or 17-position of the PG skeleton, and, alkyl esters thereof, non-toxic salts thereof, non-toxic acid addition salts thereof and cyclodextrin clathrates thereof, possessing more potent PG-like pharmacological activity than other isomers.

A novel 13-aza-14-oxo-TXA.sub.2 analogue of general formula: ##STR1## wherein symbol A represents --CH.sub.2 CH.sub.2 --(CH.sub.2).sub.m --, cis--CH.dbd.CH--(CH.sub.2).sub.m --, --CH.sub.2 O--(CH.sub.2).sub.m --, --S--(CH.sub.2).sub.m -- ##STR2## R.sup.2 represents a bond or a straight or branched alkylene or alkenylene group of from 1 to 10 carbon atom(s) unsubstituted or substituted;

13-aza-14-oxo-TXA.sub.2 analogues

Prostaglandin E.sub.1 analogues of general formula: ##STR1## [wherein R.sup.1 represents a bond or a straight- or branched-chain alkylene group containing from 1 to 5 carbon atom(s), and R.sup.2 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 8 carbon atom(s), a cycloalkyl group containing from 4 to 7 carbon atoms in the ring and unsubstituted or substituted by at least one stright- or branched-chain alkyl group containing from 1 to 8 carbon atom(s) or a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atoms, trifluoromethyl group or straight- or branched-chain alkyl group containing from 1 to 4 carbon atom(s), with the proviso that, when R.sup.1 represents a bond, R.sup.2 does not represent a phenoxy group,] possess inhibitory activity or gastric ulceration and cytoprotective activity.

Prostaglandin analogues

Prostaglandin analogues of the formula: ##STR1## (wherein R.sup.1 represents an alkyl group containing from 1 to 4 carbon atoms, R.sup.2 represents a single bond or an alkylene group containing from 1 to 5 carbon atoms, R.sup.3 represents a hydrogen atom, an alkyl or alkoxy group containing from 1 to 8 carbon atoms, a cycloalkyl or cycloalkyloxy group containing from 4 to 7 carbon atoms and being unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or alkyl group containing from 1 to 4 carbon atoms, R.sup.4 represents a hydrogen atom or a hydroxy-protecting group which may be removed under acidic conditions, X represents an ethylene group or a cis-vinylene group, the double bonds between the carbon atoms in positions 2 and 3 and between the carbon atoms in positions 13 and 14 are both in trans-configuration, and the wavy line attached to the carbon atom in position 15 represents .alpha.- or .beta.-configuration or a mixture thereof, provided that, when R.sup.2 represents a single bond, R.sup.3 does not represent an alkoxy group, a cycloalkoxy group or a phenoxy group) and cyclodextrin clathrates thereof are useful compounds: those in which R.sup.4 represents a hydrogen atom possess selective prostaglandin-like properties.

Trans-.DELTA..sup.2 -pge alkylsulphonyl amides

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 analogues of the formula: ##STR1## [wherein R.sup.1 represents hydrogen or alkyl of 1 to 12 carbon atoms, R.sup.2 represents a single bond or alkylene of from 1 to 5 carbon atoms, R.sup.3 represents hydrogen, alkyl or alkoxy of 1 to 8 carbon atoms, cycloalkyl or cycloalkyloxy of 4 to 7 carbon atoms unsubstituted or substituted by alkyl of 1 to 8 carbon atoms, or phenyl or phenoxy unsubstituted or substituted by halogen, trifluoromethyl or alkyl of 1 to 4 carbon atoms, one of R.sup.4 and R.sup.5 represents hydrogen and the other represents hydroxy or R.sup.4 and R.sup.5 together represent oxo, R.sup.6 represents hydrogen or a hydroxy-protecting group which may be removed under acidic conditions, the double bond between the carbon atoms in positions 13 and 14 is trans, the wavy line  attached to the carbon atom in position 15 represents .alpha.- or .beta.- configuration or a mixture thereof and, when one of R.sup.4 and R.sup.5 represents hydrogen and the other represents hydroxy, the configuration of the carbon atom in position 3 is R-- or S or a mixture thereof, provided that, when R.sup.2 represents a single bond, R.sup.3 does not represent alkoxy, cycloalkyloxy or phenoxy and when R.sup.6 represents a hydrogen atom, cyclodextrin clathrates thereof and, when R.sup.1 represents a hydrogen atom, non-toxic salts thereof, possess selective prostaglandin-like properties.

3-Hydroxy and 3-oxo-prostaglandin analogues

The present invention relates to 20-hydroxy prostaglandins of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## and X represents ethylene or cis-vinylene and Y represents trans-vinylene, or X and Y each represent ethylene, R represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, R.sup.1 , R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group, and n represents zero or an integer from 1 to 3 inclusive, and cyclodextrin clathrates of such acids and esters and, when R represents a hydrogen atom, the non-toxic salts thereof. These compounds exhibit characteristic prostaglandin activity.

20-Hydroxy-prostaglandins

Prostaglandins of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## X represents ethylene or cis-vinylene, Y represents ethylene or trans-vinylene, R 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 straight- or branched-chain alkyl group containing from 1 to 10 carbon atoms, R.sup.2 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, R.sup.3 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms, or a grouping of the formula: ##STR3## wherein R.sup.4 and R.sup.5 each represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl group containing from 1 to 3 carbon atoms, or R.sup.2 and R.sup.3 together represent an ethylene or trimethylene group and cyclodextrin clathrates of such acids and esters and, when R represents a hydrogen atom, non-toxic salts of such acids, are disclosed. These compounds exhibit characteristic prostaglandin activity, in particular, inhibitory activity on gastric secretion, luteolytic activity and so on.

Prostaglandin analogues of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## X represents ethylene or cis-vinylene, Y represents ethylene or trans-vinylene, R.sup.1 represents a straight- or branched-chain alkyl group containing from 4 to 10 carbon atoms, and R.sup.2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms and cyclodextrin clathrates of such acids and esters and, when R.sup.2 represents a hydrogen atom, non-toxic salts thereof, the bonds attaching the epidithio radical to the carbon atoms in the 9- and 11-positions in the grouping of formula VA being either botn in .alpha.-configuration or both in .beta.-configuration are disclosed. These compounds exhibit characteristic prostaglandin properties.

Dithio prostaglandin derivatives

The present invention relates to 17-oxo-17-phenyl-prostaglandins having the following structural formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## X represents ethylene or cis-vinylene, Y represents ethylene or trans-vinylene, R.sup.1 represents a hydrogen atom or a methyl or ethyl group, R.sup.2 and R.sup.3, which may be the same or different, each represent a hydrogen or halogen atom, a trifluoromethyl group or a straight- or branched-chain alkyl group containing from 1 to 3 carbon atoms, and R.sup.4 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms and cyclodextrin clathrates of such acids and esters, and when R.sup.4 represents a hydrogen atom, non-toxic salts thereof. These compounds exhibit characteristic prostaglandin activity, e.g., abortifacient activity, stimulation activity on uterine contraction, and so on.

17-Oxo-17-phenyl-prostaglandins

The present invention relates to compounds of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## B represents an oxygen or sulphur atom, R.sup.1 and R.sup.2, which may be the same or different, each represent a hydrogen or halogen atom, a trifluoromethyl group, or a straight- or branched-chain alkyl or alkoxy group containing from 1 to 4 carbon atoms, R represents a group of the formula --COOR.sup.3, in which R.sup.3 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, or a group of the formula --CH.sub.2 OR.sup.4, in which R.sup.4 represents a hydrogen atom or an alkylcarbonyl group containing from 2 to 5 carbon atoms and the double bonds depicted in positions C.sub.2 -C.sub.3, C.sub.5 -C.sub.6 and C.sub.13 -C.sub.14 are trans, cis and trans respectively, the cyclodextrin clathrates thereof and, when R.sup.3 in the group --COOR.sup.3 represents a hydrogen atom, non-toxic salts thereof. These compounds exhibit characteristics of prostaglandin-like activity.

16-Phenoxy and phenylthio prostaglandin derivatives

15-Cycloalkyl-prostaglandins of the formula:- ##STR1## wherein A represents a grouping of the formula:- ##STR2## X represents ethylene of cis-vinylene, Y represents ethylene or trans-vinylene, B represents ethylene or trans-vinylene, R represents hydrogen or alkyl of 1 through 4 carbon atoms, R.sup.1 represents cycloalkyl of 4 through 7 carbon atoms, and R.sup.2 represents hydrogen or alkyl of 1 through 12 carbon atoms, are new compounds possessing the useful pharmacological properties typical of prostaglandins; they are of especial interest in the inhibition of blood platelet aggregation.

15-Cycloalkyl-prostaglandins

A compound of the formula: ##STR1## wherein A represents a grouping of the formula: ##STR2## , R.sup.1 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, R.sup.2 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, X represents trans-vinylene or ethylene, and the wavy line indicates attachment of the hydroxy radical in .alpha.- or .beta.-configuration and cyclodextrin clathrates thereof and, when R.sup.2 represents a hydrogen atom, non-toxic salts thereof. These compounds exhibit characteristic prostaglandin activity.

16-METHYLENE-PROSTAGLANDIN COMPOUNDS

The present invention relates to 16-methylene prostaglandins. These compounds are useful as anti-ulcer agents, bronchodilators and so on.

Growing community of inventors

Takatsuki, Japan

Hajimu Miyake