Back to results
US 4,307,112 AGranted
9-Deoxy-9A-methylene isosteres of PGI.sub.2 and process for their preparation
AssigneeFarmitalia Carlo Erba S.p.A.
InventorsCarmelo Gandolfi, Carlo Passarotti, William Fava, Angelo Fumagalli, Franco Faustini, Roberto Ceserani
Life of this patent
Estimating the term…
Abstract
9-deoxy-9A-methylene-isosteres of PGI.sub.2, including processes for their preparation and pharmaceutical and veterinary compositions containing same, are disclosed. The compounds are useful as therapeutic agents, for example as anti-aggregating agents, disaggregating agents, and as vasodilators.
Claims21
Compounds having the following formula (I) ##STR64## wherein R is chosen from the group (a) a free carboxy group or an esterified carboxy group of formula --COOR.sub.9 wherein R.sub.9 is C.sub.1 -C.sub.12 alkyl or C.sub.2 -C.sub.12 alkenyl;
- (b) --C(OR').sub.3, where each R' group is independently C.sub.1 -C.sub.6 alkyl or phenyl;
- (c) --CH.sub.2 --R", where R" is hydroxy or C.sub.2 -C.sub.7 alkoxy;
- (d) ##STR65## where R.sub.a and R.sub.b are chosen independently from the group hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkanoyl and phenyl;
- (e) --C.tbd.N;
- (f) ##STR66## radical;
- (g) --CHO;
- (h) a ##STR67## radical where each X' is independently --O-- or --S-- and the R'.sub.a and R'.sub.b groups, whether the same or different, are C.sub.1 -C.sub.6 alkyl or together form a straight or branched C.sub.2 -C.sub.6 alkylene chain;
- D is chosen from the group;
- --CH.sub.2 --, >CH--OH, ##STR68## (cis), ##STR69## (trans), --C.tbd.C--, >C.dbd.O, --O--, --S--, and >N--R.sub.c, where R.sub.c may be hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.6 alkanoyl;
- one of R.sub.1 and R.sub.2 and, independently, one of R.sub.3 and R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, phenyl, phenyl-C.sub.1 -C.sub.6 alkyl, .alpha.-naphthyl-C.sub.1 -C.sub.6 alkyl, or .beta.-naphthyl-C.sub.1 -C.sub.6 alkyl and the other is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkoxy, phenyl-C.sub.1 -C.sub.6 alkoxy, .alpha.-naphthyl-C.sub.1 -C.sub.6 alkoxy, or .beta.-naphthyl-C.sub.1 -C.sub.6 alkoxy, or, R.sub.1 and R.sub.2 and, independently, R.sub.3 and R.sub.4 together form an oxo group;
- each R.sub.5 and R.sub.6, whether the same or different, may be hydrogen, C.sub.1 -C.sub.6 alkyl or halogen, or R.sub.5, R.sub.6 and the carbon atom to which they are bound from a >C.dbd.CH.sub.2 or ##STR70## radical;
- Y is --NH--CO-- or --NH--CH.sub.2 --;
- X is chosen from the group:
- --(CH.sub.2).sub.m.sbsp.3 -- in which m.sub.3 is zero or 1, ##STR71## --O--, --S-- and >N--R.sub.c with R.sub.c as defined above;
- m.sub.1, m.sub.2, n.sub.1 and n.sub.2, whether the same or different, may be zero or an integer between 1 and 12 such that each sum m.sub.1 +m.sub.2 and n.sub.1 +n.sub.2 is less than or equal to 15;
- p=q=1;
- R.sub.7 is chosen from the group:
- (a') hydrogen;
- (b') C.sub.1 -C.sub.4 alkyl;
- (c') a cycloaliphatic radical, either unsubstituted or substituted with one or more C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -alkoxy;
- (d') a phenyl, .alpha.-naphthyl or .beta.-naphthyl group, either unsubstituted or substituted with one or more of the following:
- halogen, halo-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, phenyl;
- (e') a five or six membered heteromonocyclic ring either containing an only one heteroatom chosen from oxygen, sulphur and nitrogen or containing one oxygen and one nitrogen atom or containing two nitrogen atoms, wherein the said five or six membered heteromonocyclic ring may be unsubstituted or substituted with one or more of the following:
- halogen, halo-C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, C.sub.1 -C.sub.6 alkyl;
- and the lactones derived from compounds with formula (I) wherein D is >CH--OH and R is --COOH and the pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) wherein R is --COOH .
22 more elements
Compounds having the following formula (I) ##STR72## wherein R is chosen from the group (a) a free carboxy group or an esterified carboxy group of formula --COOR.sub.9 wherein R.sub.9 is C.sub.1 -C.sub.12 alkyl or C.sub.2 -C.sub.12 alkenyl;
- (b) --C(OR').sub.3, where each R' group is independently C.sub.1 -C.sub.6 alkyl or phenyl;
- (c) --CH.sub.2 --R", where R" is hydroxy or C.sub.2 -C.sub.7 alkoxy;
- (d) ##STR73## where R.sub.a and R.sub.b are chosen independently from the group hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkanoyl and phenyl;
- (e) --C.tbd.N;
- (f) a ##STR74## radical;
- (g) --CHO;
- (h) a ##STR75## radical where each X' is independently --O-- or --S-- and the R'.sub.a and R'.sub.b groups, whether the same or different, are C.sub.1 -C.sub.6 alkyl or together form a straight or branched C.sub.2 -C.sub.6 alkylene chain;
- D is chosen from the group:
- --CH.sub.2 --, >CH--OH, ##STR76## (cis), ##STR77## (trans), --C.tbd.C--, >C.dbd.O, --O--, --S--, and >N--R.sub.c, where R.sub.c may be hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.6 alkanoyl;
- one of R.sub.1 and R.sub.2 and, independently, one of R.sub.3 and R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, phenyl, phenyl-C.sub.1 -C.sub.6 alkyl, .alpha.-naphthyl-C.sub.1 -C.sub.6 alkyl, or .beta.-naphthyl-C.sub.1 -C.sub.6 alkyl and the other is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkoxy, phenyl-C.sub.1 -C.sub.6 alkoxy, .alpha.-naphthyl-C.sub.1 -C.sub.6 alkoxy, or .beta.-naphthyl-C.sub.1 -C.sub.6 alkoxy, or, R.sub.1 and R.sub.2 and, independently, R.sub.3 and R.sub.4 together form an oxo group;
- each R.sub.5 and R.sub.6, whether the same or different, may be hydrogen, C.sub.1 -C.sub.6 alkyl or halogen, or R.sub.5, R.sub.6 and the carbon atom to which they are bound form a >C.dbd.CH.sub.2 or ##STR78## radical;
- Y is --NH--CO-- or --NH--CH.sub.2 ;
- X is chosen from the group:
- --(CH.sub.2).sub.m.spsb.3 -- in which m.sub.3 is zero or 1;
- ##STR79## --O--, --S-- and >N--R.sub.c with R.sub.c as defined above;
- m.sub.1, m.sub.2, n.sub.1 and n.sub.2, whether the same or different, may be zero or an integer between 1 and 12 such that each m.sub.1 +m.sub.2 and n.sub.1 +n.sub.2 is less than or equal to 15;
- p=q=1;
- R.sub.7 is chosen from the group:
- (a') hydrogen;
- (b') C.sub.1 -C.sub.4 -alkyl;
- (c') a cycloaliphatic radical, either unsubstituted or substituted with one or more C.sub.1 -C.sub.6 -alkyl or C.sub.1 -C.sub.6 -alkoxy;
- (d') a phenyl, .alpha.-naphthyl or .beta.-naphthyl group, either unsubstituted or substituted with one or more of the following:
- halogen, halo-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, phenyl;
- (e') a five or six membered heteromonocyclic ring chosen from the group consisting of tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl;
- and the lactones derived from compounds with formula (I) wherein D is >CH--OH and R is --COOH and the pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) wherein R is --COOH.
22 more elements
Compounds having the formula (I) reported in the previous claims wherein D, m.sub.1, m.sub.2, p, q, R.sub.1, R.sub.2, Y, R.sub.3, R.sub.4, R.sub.5, R.sub.6, X, n.sub.1 and n.sub.2 have the meanings reported in claim 31;
- R is a free or salified carboxy group;
- R.sub.7 is a straight or branched C.sub.1 -C.sub.4 alkyl, phenyl optionally substituted as described in claim 31, a C.sub.5 -C.sub.7 monocycloalkyl radical or a five or six membered heteromonocyclic ring as described in claim 2.
5t-11.alpha.,15S-dihydroxy-9a-deoxy-9a-methylene-13-a za-14-oxo-prostacycla-5-enoic acid and the pharmaceutically or veterinarily acceptable salts thereof and the methyl ester thereof.
5t-11.alpha.,15R-dihydroxy-9a-deoxy-9a-methylene-13- aza-14-oxo-prostacycla-5-enoic acid and the pharmaceutically or veterinarily acceptable salts thereof and the methyl ester thereof.
Dependencies are inferred from the claim text.