US 4,543,353 AGranted

Ester and amide derivatives of 13,14-didehydro prostaglandins

AssigneeFarmitalia Carlo Erba S.p.A.

InventorsFranco Faustini, Vittoria Villa, Carmelo Gandolfi, Enrico Di Salle

Life of this patent

Estimating the term…

Abstract

Esters of 13,14-didehydro prostaglandins have been prepared.

Claims7

Dependent claims

Optically active or racemic prostaglandin derivatives of Formula (I) ##STR20## wherein R is --O--(CH.sub.2).sub.n --Z, wherein n is an integer of 2 to 4 and Z is a group ##STR21## wherein each of R' and R" is C.sub.1 -C.sub.6 alkyl or R' and R", taken together with the nitrogen atom to which they are linked, form a ring chosen from imidazolidinyl, piperidino, piperazinyl and morpholino or Z is a group --OR"', wherein R"' is C.sub.1 -C.sub.6 alkyl;

the symbol represents a single bond, R.sub.1 is hydroxy, R.sub.2 is hydrogen and R.sub.3 is hydroxy, benzoyloxy or C.sub.2 -C.sub.6 alkanoyloxy, or R.sub.2 and R.sub.3, taken together, form an oxo group;
or the symbol represents a double bond, R.sub.1 is hydrogen and R.sub.2 and R.sub.3, taken together, form an oxo group, one of R.sub.4 and R.sub.5 is hydroxy and the other is hydrogen;
each of R.sub.6 and R.sub.7 is, independently, hydrogen, C.sub.1 -C.sub.4 alkyl or fluorine;
m is zero, 1 or 2;
R.sub.8 is cyclopentyl, cyclohexyl or cycloheptyl, and the pharmaceutically or veterinarily acceptable salts thereof.

2 more elements

A compound selected from the group consisting of:

5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-y noic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13- ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-pr ost-5en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl- prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en -13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5- en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohe xyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cycloh exyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost- 5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost -5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl ohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cy clohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyc lopentyl-prost-5en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)fluoro-18,19,20-trinor-17-cyc lopentyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-p rost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl- prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16 -cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor- 16-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en13ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-tr inor-17-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9.alpha., 11.alpha.,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13- ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-pr ost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl- prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en -13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-e n-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexy l-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cycloh exyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha., 15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha., 15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl ohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cy clohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl opentyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)fluoro-18,19,20-trinor-17-cyc lopentyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-p rost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl- prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16 -cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor- 16-cyclohexyl-prost-5en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-16methyl-18,19,20-trino r-17-cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-tr inor-17-cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-morpholino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-y noic acid 2-piperidino-ethyl ester;
5c-9.alpha., 11.alpha.,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-pr ost-5-en-3-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl -prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en -13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-e n-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohex yl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cycloh exyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost- 5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost -5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl ohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cy clohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl opentyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cy clopentyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-p rost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl- prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16 -cyclohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor- 16-cyclohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-tr inor-17-cyclohexyl-prost-5-en-13ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-piperidino-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-y noic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13- ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-pr ost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl- prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en -13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-e n-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5-c9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-19,20--dinor-18-cyclohe xyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cycloh exyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost- 5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost -5-en-13-ynoic acid 2-(N,N-dimethyl amino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl ohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cy clohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycl opentyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)fluoro-18,19,20-trinor-17-cyc lopentyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-p rost-5-en-13-ynoic acid 2(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl- prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16 -cyclohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor- 16-cyclohexyl-prost-5-en-13-ynoic acid acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-tr inor-17-cyclohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9.alpha.,11.alpha.,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trin or-17-cyclohexyl-prost-5-en-13-ynoic acid 2-(N,N-dimethylamino)-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoi c acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost- 5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-pros t-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13- ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13 -ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-p rost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl -prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en -13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-e n-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohex yl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycloh exyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopen tyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclop entyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost -5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-pros t-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyc lohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-c yclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-1 7-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
5c-9-oxo-11.alpha.,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor -17-cyclohexyl-prost-5-en-13-ynoic acid 2-ethoxy-ethyl ester;
and
5c-9-oxo-11.alpha.,15(R)-dihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-1 7-cyclohexyl-prost-5-en-13-ynoic acid
2-ethoxy-ethyl ester, and the pharmaceutically or veterinarily acceptable salts of the 2-(N,N-dimethylamino)-ethyl esters hereinbefore listed.

104 more elements

Dependencies are inferred from the claim text.

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