GB2120651A - 6,11-Epoxy prostaglandins and process for their preparation - Google Patents

6,11-Epoxy prostaglandins and process for their preparation Download PDF

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GB2120651A
GB2120651A GB08213217A GB8213217A GB2120651A GB 2120651 A GB2120651 A GB 2120651A GB 08213217 A GB08213217 A GB 08213217A GB 8213217 A GB8213217 A GB 8213217A GB 2120651 A GB2120651 A GB 2120651A
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alpha
oxide
prost
diol
6ssh
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Franco Faustini
Achille Panzeri
Vittoria Villa
Carmelo Gandolfi
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings

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Abstract

Optically active or racemic prostaglandins of formula <IMAGE> wherein one of U and U1 is H and the other -CH2-M-R where R is a) a free or esterified carboxylic group or a carboxylic amide or b) -CH2OH, -CHO, -COCH2OH, -C IDENTICAL N or <IMAGE> and M is either a bond or an alkylene, alkenylene, alkynylene or cyclopropylene group; R1/R2 is H/OH, OH/H, =O or =CH2; X is H or F; T is a group <IMAGE> wherein A is an alkylene, optionally substituted alkenylene or alkynylene group; R4/R5 is OH/H or various organic groups, H or various organic groups /OH or =O; k=0 or 1-5 and B is H, F or various organic groups; and the salts thereof, are useful as anti- aggregating/disaggregating agents, fertility control agents and hypotensive agents and may be used to treat bronchial asthma, to induce labour, to expel a dead foetus, and to prevent or treat ulcers.

Description

SPECIFICATION [3,2,1 ]Bicyclic prostaglandins and process for their preparation The present invention relates to new 2-oxa-[3,2,1 ]-bicyclic prostaglandins, to a method for their preparation and to pharmaceutical and veterinary compositions containing them. The compounds of the invention are optically active or racemic mixtures of optically active 2-oxa-[3,2,1]-bicyclic derivatives related to prostaglandins covered by the general formula (1)
wherein one of U and U1 is hydrogen and the other is the group -CH2-M-R wherein R is a member selected from the group consisting of: a) a free or esterified carboxy group or a carboxylic amide; b)-CH2OH,-CHO,-COCH2OH,-C#N and
M is a group chosen from: a')-(CH2)n-, wherein n is zero, 1, 2, 3, 4, 5 or 6; or b') -(CH2) -D-(CH2) -, wherein each of n, and n2, being the same or different, is zero, 1, 2, 3, or 4, but the sum of n, and n2 is not higher than 4; D is -CH=CH- (cis, trans or a mixture thereof), -C-C- or a cyclopropyl ring; one of R, and R2 is hydrogen and the other is hydroxy or R1 and R2, taken together, form an oxo group or, taken together with the carbon atom to which they are linked, form a methylene (CH2=) group; X is hydrogen or fluorine; T represents a
group wherein A is a member selected from the group consisting of a") (CH2)pCH2CH2, wherein p is zero or 1; b") trans
wherein Z is hydrogen, fluorine, chlorine or bromine and p is as defined above; and c")-(CH2)p-C#C-, wherein p is as defined above; one of R4 and R5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur, and the other is hydroxy ; or R4 and R5 taken together form an oxo group; k is zero or an integer up to 5; B is a member selected from the group consisting of: a"') hydrogen; fluorine or methyl; b"') phenyl; a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur;
wherein each of R6 and R7, which may be the same or different, is hydrogen, C1-C6 alkyl or fluorine; or R6 and R7, taken together with the carbon atom to which they are linked, form a
group or the radical
each of m, and m2, being the same or different, is zero or an integer of 1 to 6;E is a group chosen from: -0--S-and -(CH2)-, wherein m is zero or 1; and R8 is a member selected from the group consisting of: aV) hydrogen or C1-C4 alkyl; bV) a C3-C9 cycloaliphatic ring unsubstituted or substituted by one or more substituents chosen from C1-C6 alkyl and C1- C6 alkoxy; cIV) aryl unsubstituted or substituted by one or more substituents selected from halogen, halo-C 1-C6 alkyl, C1-C6 alkyl; and C1-C6 alkoxy; dIV) a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more substituents selected from halogen, halo-C 1-C6 alkyl and C1-C6 alkoxy; and the pharmaceutically and veterinarily acceptable salts thereof.
Besides the pharmaceutically or veterinarily acceptable salts of the compounds of formula (I), also the optical antipodes, i.e. the enantiomers, the racemic mixtures of the optical antipodes, the geometric isomers and the mixtures thereof and the mixtures of the diastereoisomers of the compounds of formula (I) are included in the scope of the present invention.
The alkyl, alkoxy, alkenyl and alkynyl groups may be branched or straight chain groups.
AC1-C6 alkyl group is, preferably, methyl, ethyl or propyl.
A C1-C6 alkoxy group is, preferably, methoxy, ethoxy or propoxy.
A C2-C6 alkenyl group is, preferably, vinyl.
A C2-C6 alkynyl group is, preferably, ethynyl.
An aryl group is, preferably, phenyi.
A halo-C1-C8 alkyl group is, for example, a C1-C6 alkyl group substituted by one or more halogen atoms, e.g. chlorine, fluorine or bromine, preferably, it is a trihalo-C1-C6 alkyl group, in particular, trifluoromethyl.
When R is an esterified carboxy group, the carboxylic acid group is, for example, esterified with aV) a phenol, which may be unsubstituted or substituted by one or more substituents chosen from C1- C6a alkoxy and carboxy-C1-C2-alkyl; or bV) a linear or branched aliphatic C1-C8 alcohol, which may be unsubstituted or substituted by one or more substituents chosen from C1-C6 alkoxy, di-(C1-C6)alkyl amino, piperidino, morpholino and 1 ',4'-piperazino, wherein the N'4 nitrogen atom is unsubstituted or substituted by a substituent chosen from C1-C4 alkyl, phenyl, piperidino or morpholino.
When R is a carboxylic amide, it is, for example, a group
wherein each of Ra and Rb represents, independently, aVI) hydroxy; bVI) C1-C6 alkyl unsubstituted or substituted by substituents chosen from di-(C1-C6)alkylamino group. piperidino, morpholino and 1',4'-piperazino, wherein the N'4 nitrogen atom is unsubstituted or substituted by C1-C4 alkyl, phenyl, morpholino and piperidino; cVI) C2-C6 alkanoyl; dVI) phenyl; eVI)-SO2NH2; mono-(C1-C6) alkyl- and di-(C1-C6) alkyl-sulphonamide; phenylsulphonamide or C1-C3 alkyl mono-substituted phenylsulphonamide.
When M is as defined above under b') and D is a cyclopropyl ring, the latter may be
or
preferably it is
When one of R4 and R5 is acryl, it is preferably phenyl.
When one of R4and R5 is a C3-C7 cycloaliphatic ring, it is preferably a C5-C7 cycloaliphatic ring, more preferably cyclopentyl and cyclohexyl.
When one of R4 and R5 is a saturated C3-C7 heteromonocyclic ring as defined above it is, for example, pyrane, thiopyrane, 1 ,4-dioxane, 1 4-oxathiane, 1 ,3-dioxane and 1 3-oxathiane.
When B is a C3C7 cycloaliphatic ring, it is preferably a C5-C7 cycloaliphatic ring, more preferably cyclopentyl and cyclohexyl.
When B is a saturated C3-C7 heteromonocyclic ring as defined above, it is, for example, pyrane, thiopyrane, 1,4-dioxane, 1,4-oxathiane, 1,3-dioxane and 1,3-oxathiane.
When R8 is a C3-C9 cycloaliphatic ring as defined above under bit), it is, preferably, a C5-C7 cycloaliphatic ring, more preferably cyclopentyl and cyclohexyl.
When R8 is an aryl ring as defined under c'V), it is, preferably phenyl.
When R8 is a saturated or unsaturated heteromonocyclic ring as defined above under d'V) it may be either a heteromonocyclic or heterobicyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen. Examples of preferred heterocyclic rings are: tetrahydrofuryl, hexahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) are e.g. those with pharmaceutically and veterinarily acceptable bases. Pharmaceutically and veterinarily acceptable bases are either inorganic bases such as, for example, alkali metal hydroxides and alkaline-earth metal hydroxides as well as aluminium and zinc hydroxides or organic bases e.g. organic amines such as, for example, methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, N-methyl-Nhexylamine, decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzylamine, dibenzylamine, a-phenyl-ethylamine"B-phenyl-ethylamine, ethylenediamine, diethylenetriamine, morpholine, piperidine, pyrrolidine, piperazine, as well as the alkyl derivatives of the latter four bases, mono-, di- and triethanolamine, ethyl-diethanolamine, N-methylethanolamine, 2-amino-1 -butanol, 2 amino-2-methyl- 1 -propanol, N-phenyl-ethanolamine, galactamine, N-methyl-glucamine, N-methylglucosamine, ephedrine, procaine, dehydroabietilamine, lysine, arginine and other a or p amino acids.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) and also those ones with pharmaceutically or veterinarily acceptable acids, i.e. with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids or with organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic and methanesulphonic, acids.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I), wherein R is an esterified carboxy group or a carboxylic amide containing a basic moiety are, for example, also those with pharmaceutically or veterinarily acceptable acids e.g.; those reported above.
Preferred salts of the invention are those of the compounds of formula (I), wherein R is --COOR,, wherein R, is a pharmaceutically or veterinarily acceptable cation deriving from one of the above mentioned bases.
Preferably R, in the compounds of this invention, is a free, salified or esterified group; in particular, when R is an esterified carboxy group, preferably, it is a group of formula --COOR,, wherein Rb is a C,--C, alkyl radical, in particular, methyl, propyl and heptyl; an alkoxy-alkyl radical, in particular, ethoxy-ethyl, methoxy-ethyl; a di-alkylamino-alkyl radical, in particular, dimethylamino-ethyl, diethylamino-ethyl, dimethylamino-propyl, diethylamino-propyl; or wherein Rb is a group chosen from
wherein c is zero or 1, 2 or 3. When in the compounds of the invention R is a group of formula COORb, wherein Rb includes a basic group, as defined above, this may be optionally salified with inorganic, preferably hydrochloric or sulphuric, acids or with organic, preferably maleic, fumaric or methanesulphonic, acids.
A preferred class of compounds of this invention are the compounds of formula (I), wherein one of U and U, is hydrogen and the other is the group -CH2-M-R wherein R is a free or esterified carboxy group and M is a (CH2) group, wherein n is 2, 3 or 4; one of R, and R2 is hydrogen and the other is hydroxy, or R, and R2, taken together, form an oxo group; X represents hydrogen or fluorine; T represents a
group, wherein A is a member selected from -CH2-CH2-, -CH=CZ- wherein Z is as defined above, -C=-C-; R4 and R5 are as defined above; k is zero or an integer up to 5; B is
wherein m1, m2, R6, R7, E and R8 are as defined above; and the pharmaceutically and veterinarily acceptable salts thereof.
In the general formula (I) and in all the formulae of this specification, the broken line (I II) indicates that a substituent bound to the 2-oxa-heptane ring is in the a-configuration, i.e. below the plane of the ring, and the substituent in the apex of the 2-oxa-[3,2,1 ]-bicyclic octane ring is syn in respect of the oxygen-ring atom. The heavy line () indicates that a substituent bound to the 2-oxa- heptane ring is in the p-configuration, i.e. above the plane ring and the substituent in the apex of the 2oxa-[3,2,1 ]-bicyclic octane ring is anti in respect of the oxygen-ring atom.The dotted line ( indicates S-configuration for the C-atom of the chain to which a substituent is bound; the wavy line attachment (#) indicates that a substituent does not possess a definite stereochemical identity, i.e. the substituted C-atom of a chain may be either in the S- or in the R-configuration.
In the formulae of this specification the atoms of the 2-oxa-bicyclo-[3,2,1 ]-octane ring may be related to the carbon and oxygen atoms of natural prostaglandins, i.e. PGF2a. The oxygen atom of the bicyclic ring may be considered as corresponding to the oxygen atom of the hydroxy group bound to the C"-carbon atom of PGF2tr and the C,-carbon atom of the bicyclic ring as equivalent to the C11- carbon atom of PGF2a.
Other correlations are the following: bicyclic ring numbering
Prostaglandin C-atoms numbering According to the above, when U is hydrogen and U1 is -CH2-M-R, the compounds of the invention are named 6ssH-6,11&alpha;-oxide-prostanoic acids; and the alkyl chain is in exo-configuration.
Alternatively, when U1 is hydrogen and U represents-CH2-M-R, the compounds of the invention are named 6&alpha;H-6,11&alpha;-oxide-prostanoic acids; and the alkyl chain is in endo-configuration.
When the reciprocal configuration of the two substituents is unknown, they are named 6(EH)6,1 1 a-oxide-prostanoic acids and the mixture of the two epimers is referred as 6(cr,P)H-6,1 1 a-oxideprostanoic acids.
The X substituent is named syn and the T substituent is named anti.
The 6PH-6,1 1 -oxide-prostanoic acid derivatives of this invention may be alternatively also named [2'-oxa-bicyclo-[3,2, 1 ]-8'-anti-alkyl-3 '-exo-yl]alkanoic acid and the 6aH-6,1 1 a-oxide- prostanoic acid derivative also named [2'-oxa-bicyclo-[3,2,1 ]-8'-anti-alkyl-3'-endo-ylialkanoic acid.
All the above notations refer to the natural compounds. The d,l- compounds are mixtures containing equimoiar amounts of nat- compounds, which possess the above reported absolute stereochemistry, and of ent- compounds, which are mirror-like images of the former. In the entcompounds the stereochemical configuration is the opposite of all the asymmetric centers with respect to the configuration of the natural compounds: the prefix "ent" means just this.
The prefixes nor, dinor, trinor, tetranor and so on are used in this specification to identify the compounds of formula (I), wherein one side chain is one, two, three, four and so on carbon atoms shorter than the analogous chain of natural prostaglandins. According to the above the model compounds 6aH-6,1 1 a-oxide-prostanoic acid and 6PH-6,1 1 a-oxide-prostanoic acid may, respectively, be represented by the following formulae (la) and (Ib):
Specific examples of preferred compounds of the invention are the following: 13t-6&alpha;H-6,1 1 a-oxide-9a,1 5S-diol-prost-1 3-enoic acid; 1 3t-6aH-6,1 1 &alpha;-oxide-9ss,1 5S-diol-prost-1 3-enoic acid; 1 3t-6aH-6,1 1 aoxide-9-oxo-1 5S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6aH-6,1 1&alpha;-oxide-9ss,1 5S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6aH-6,1 1 a-oxide-9-oxo-1 5S-ol-prost-1 3-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15S-ol-prost-13-enoic acid; 1 3t-6aH-6,1 1 1&alpha;-oxide-1 5-cyciohexyl-w-pentanor-9a,l 5S-diol-prost-1 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid;; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 1 3t-6aH-6,1 1 a-oxide-1 6R-fluoro-9&alpha;,1 5S-diol-prost-1 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 1 3t-6aH-6,1 1 a-oxide-1 2&alpha;-fluoro-9&alpha;,1 5S-diol-prost-1 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 1 3t-6aH-6,1 1&alpha;-oxide-1 4-fluoro-9a,1 5S-diol-prost-1 3-enoic acid; 1 3t-6aH-6,1 1&alpha;-oxide-1 7-phenyl-co-trinor-9a,1 5S-diol-prost-1 3-enoic acid; 1 3t-6aH-6, 11 a-oxide-1 7-cyclohexyl-w-trinor-9a, 1 5S-diol-prost-1 3-enoic acid; 13t-6&alpha;-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11 a-oxide-20-methyl-9a,1 5S-diol-prost-1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,1 1 a-oxide-20-methyl-1 6S-fluoro-9&alpha;,1 5S-diol-prost-1 3-ynoic acid; 6aH-6,1 1 a-oxide-20-methyl-1 6R-fluoro-9&alpha;,1 5S-diol-prost-1 3-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,1 1 a-oxide-9-oxo-1 5S-ol-prost-1 3-enoic acid; 6ssH-6,11 a-oxide-9a,1 5S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6ssH-6,1 1 a-oxide-9-oxo-1 5S-ol-prost-1 3-ynoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,1 1 a-oxide-i 6-phenoxy-o-tetranor-9-oxo- 1 5S-ol-prost-1 3-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-cyclohexyl-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 1 3t-6ssH-6,1 1 &alpha;-oxide-1 5-cyclohexyl-w-penta nor-9-oxo-l 5S-ol-prost-1 3-enoic acid; 6ssH-6, 11 a-oxide- 1 5-cyclohexyl-w-penta nor-9a, 1 5S-diol-prost- 1 3-ynoic acid; 6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid;; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; and 6ssH-6,1 1 &alpha;-oxide-20-methyl-1 6R-fluoro-9a,1 5S-diol-prost-1 3-ynoic acid, the 1 5-R epimers of the 6aH-6, 11 a-oxide and 6ssH,6, 11 a-oxide derivatives listed above; and the methyl esters, the ethoxyethyl esters, the morpholinoethyl esters, the piperidinoethyl esters and the pharmaceutically and veterinarily acceptable salts thereof.
The compounds of formula (I) can be prepared buy a process comprising: A) reducing an optically active compound, or a racemic mixture of compounds, of formula (1H,
wherein one of U' and U', is hydrogen and the other is
wherein M and R are as defined above and YO represents the anionic residue of an acid; one of R'2 and R', is hydrogen and the other is a protected hydroxy group; X is as defined above; T' represents a
group, wherein A, k and B are as defined above; one of R'4 and Rts is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur, and the other is hydroxy or a labile protecting group linked to the chain through an ethereal oxygen atom; or R'4 and R'5, taken together, form an oxo group, thus obtaining an optically active compound, or a racemic mixture of compounds, ol formula (III)
wherein one of U and U, is hydrogen and the other is -CH2-M-R wherein M and R are as defined above; and X, T', R', and R'2 are as defined above; and removing the hydroxy protecting group at the 9position and, removing, also, the hydroxy protecting group at the 1 5-position, if present, to obtain a compound of formula (i) wherein one of R, and R2 is hydrogen and the other is hydroxy, and U, U,, X and Tare as defined above; or B) oxidizing an optically active compound, or a racemic mixture of compounds, of formula (IV)
wherein one of R", and"2 is hydrogen and the other is hydroxy; T" represents a
group, wherein one of R"4 and R"5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur and the other is a labile protecting group linked to the chain through an ethereal oxygen atom or R"4 and R"5, taken together from an oxo group; and, X, A, B, k, U and U1 are as defined above, to obtain, after removal of the hydroxy protecting group at the 1 5position if present, an optically active compound, or a mixture of optically active compounds of formula (I), wherein R1 and R2, taken together form an oxo group and T, X, U and U, are as defined above and/or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, reacting a compound of formula (I), wherein R is a free carboxy group and the hydroxy groups are optionally protected as described above, with a base, followed, if required, by removal of the hydroxy protecting groups, to give a salt of a compound of formula (I) with a cation of a pharmaceutically or veterinarily acceptable base; and/or, if desired, esterifying a compound of formula (I) wherein R is a free carboxy group, and the hydroxy groups, if present, are optionally protected as described above, followed, if required, by removal of the hydroxy protecting groups, to give a compound of formula (I), wherein R is an esterified carboxy group; and/or, if desired, hydrolyzing a compound of formula (I), wherein R is an esterified carboxy group, and the hydroxy groups, if present, are optionally protected as described above, followed, if required, by removal of the hydroxy protecting groups, to give a compound of formula (I), wherein R is free carboxy group; and/or if desired, converting a compound of formula (I), wherein R, and R2, taken together form an oxo group, and the hydroxy group at the C,s-position, if present, is optionally protected as described above, into another compound of formula (I), wherein R and R2, taken together with the carbon atom to which they are linked form a methylene (CH2=) group, followed, if required, by removal of the hydroxy protecting group; and/or, if desired converting a compound of formula (I), wherein R is a free or esterified carboxy group and the hydroxy groups, if present are optionally protected as described above, into another compound of formula (I), wherein R is a carboxylic amide, followed, if required, by removal of the hydroxy protecting groups; and/or, if desired, separating a mixture of isomers into the single isomers.Protecting groups for the hydroxylic functions are ether or ester residues readily convertibie to hydroxyl groups under mild conditions, for instance acid hydrolysis. Examples of ether residues are acetal ethers, enol ethers and silyl ethers. The preferred groups are
wherein W is -0- or-CH2- and Alk is a lower alkyl group. An ester residue may derive both from carboxylic aliphatic and aromatic acids, preferably aromatic acid, e.g., benzoic acid.
When R', or R'2 is a protected hydroxy group, it is preferably protected in the form of an ester, and the acyl residue may be a generic R,,--CO group, where R is an alkyl, aralkyl, e.g. phenylalkyl, or cycloaliphatic or aromatic substituent, preferably R" is C1-C6 alkyl, in particular methyl.
The anionic residue of an acid ye is preferably selected from the group consisting of CNO, Brs, 10, R,--COOo, wherein R5 is an optionally halo-substituted CC,2 alkyl group, preferably C1-C6 alkyl or trifluoromethyl, and
wherein R10 is, e.g., hydrogen, C1-C6 alkyl, halogen, e.g., bromine, or trifluoromethyl.Preferably ye is Cle, Bre, CH 3C000, CF3COOe or
The reduction of the compound of formula (II) may be carried out by treatment with mixed hydrides such as alkali metal, e.g., sodium, potassium or lithium, borohydrides, with alkaline-earth metal, e.g., calcium or magnesium, borohydrides in an inert solvent, preferably a solvent miscible with water, such as tetrahydrofuran, dimethoxyethane or lower aliphatic alcohols, e.g. methanol or ethanol; or with tri(n-butyl)tin hydride in benzene or toluene, preferably benzene; or also by treatment with hydrazine hydrate in a lower aliphatic alcohol, e.g., methanol or ethanol as solvent, at temperatures varying from room temperature to the reflux temperature of the solvent used.
The removal of the known protecting groups bound to the ring or to the chain by an ethereal oxygen atom is, whenever required, performed under conditions of mild acid hydrolysis, for example with a mono- or polycarboxylic acid such as formic, acetic, oxalic, citric and tartaric acid, and in a solvent, which may be water, acetone, tetrahydrofuran, dimethoxyethane or a lower aliphatic alcohol, or with a sulphonic acid, e.g., p-toluenesulphonic acid in a solvent such as a lower aliphatic alcohol, dry methanol or dry ethanol, for example, or with a polystyrene-sulphonic resin. For example, 0.1 to 0.25 N poly-carboxylic acid (e.g., oxalic or citric acid) is used in the presence of a convenient low-boiling cosolvent which is miscible with water and which can be easily removed in vacuo at the end of the reaction.
Removal of protective acyl groups may be performed, e.g., by aqueous alcoholic saponification at room temperature or by gentle heating with a basic agent, as alkaline, e.g., sodium or potassium, bicarbonate or carbonate, or with LiOH. If desired the same removal may be carried out by trans esterification, e.g., working at room temperature with an excess of an anhydrous alcohol, in the presence of a catalytic amount of a base, e.g., potassium carbonate; as consequence all the previous existing esters are converted to esters of the alcohol used as solvent.
The oxidation of a compound of formula (IV) may be, e.g., carried out by the Moffat method, i.e.
DMSO-dicyclohexylcarbodiimide, (Am. Soc., 87, 5661, 1965), or Jones reagent, i.e. in acetone, N haloamides, e.g., N-CI- or N-Br-amides and thioethers, in the presence of a tert. amine, (G. I. Poos and all., Am. Soc. 75, 422, 1953), or Collins reagent, [Collins J. C., et all., Tetrah. Lett. 3363 (1968), Org.
Syn. 52, 5, (1972)] or its modifications.
The conversion of a compound of formula (I) into another compound of formula (I), e.g., salification, esterification, hydrolysis of the R moiety, conversion of an esterified or free R carboxy group into a carboxylic amide R group, may be carried out by well known methods.
For example, the conversion of a compound of formula (I) wherein R is an esterified carboxy group into a compound of formula (I) wherein R is a free carboxy group, if desired, may be carried out by the usual methods of saponification, e.g., by treatment with an alkali metal or alkaline-earth metal hydroxide in aqueous or alcoholic aqueous solution followed by acidification.
The conversion of a compound of formula (I) wherein R is a free or esterified carboxy group into a compound of formula (I) wherein R is -CH2-OH, if desired, may be carried out, e.g., by reducing the ester with LiAIH4 in diethyl ether or tetrahydrofuran at reflux temperature.
The conversion of a compound of formula (I), wherein R is a free carboxy group into another compound of formula (I) wherein R is a carboxylic amide, namely, e.g., a group
wherein Ra and Rb are as defined above, may be performed by treatment with an amine of formula NHRa Rb in the presence of a condensing agent, e.g., a carbodiimide such as dicyclohexylcarbodiimide.
Analogously the conversion of a compound of formula (I), wherein R is an esterified carboxy group into a compound of formula (I), wherein R is a carboxylic amide, namely, e.g., a group of formula
wherein Ra and Rb are as defined above, may be effected by treatment with an amine of formula NHRaRb in a suitable organic solvent at reflux temperature for 2-3 hours.
The conversion of a compound of formula (I) wherein R is a free carboxy group into a compound of formula (I) wherein R is the radicalCN or
may be carried out by converting the carboxy group into the corresponding halide, preferably chloride, e.g., by reaction with thionyl chloride or oxalyl chloride in dioxane or dichloroethane at reflux temperature, then reacting the halide, e.g., with ammonia, to give the amide, dehydrating the amide to nitrile, e.g., with p-toluenesulphonylchloride in pyridine at approximately 900C-i 000C, and finally reacting the nitrile with sodium azide and ammonium chloride in dimethylformamide at a temperature varying between the room temperature and 1 000C. But, preferably the hereabove reported conversion of the carboxy group into -CN or
is performed on the starting materials i.e., for example, and the compounds of formula (II), (IV) or (V).
The conversion of a compound of formula (I), wherein R1 and R2, taken together form an oxo group, into another compound of formula (I), wherein R1 and R2, taken with the carbon atom to which they are linked, form a methylene group, may be carried out by known methods, for example according to the method described by Johnson et all., J. Am. Chem. Soc., 95, 6462, (1973). Also the optional separation of the optically active compounds from a racemic mixture as well as the geometrical isomers from their mixtures may be effected by conventional methods.
For example, for practical reasons, it is more convenient to obtain compounds of formula (II), as a mixture of the two diastereoisomers, wherein U' is hydrogen in one diastereoisomer and U'1 is hydrogen in the other diastereoisomer, than to obtain the single diastereoisomers of the compounds of formula (II), therefore also the reduction products of formula (III) and, consequently, the products of formula (I) are obtained as a mixture of diastereoisomers.
These diastereoisomers may be separated by fractional crystallization, e.g., from diethyl ether, but more preferably by thin layer chromatography or by column chromatography or by high pressure chromatography.
The separation by thin layer preparative chromatography or by column chromatography is preferably carried out on a support of silica gel or magnesium silicate with methylene chloride, diethylether, isopropylether, ethylacetate, benzene, methyl acetate, cyclohexane or their mixtures as elution solvents.
The compounds of formula (II) may be prepared by treating a compound of formula (V)
wherein R'r, R'2, M, R, X and T' are as defined above, with a suitable source of Hg2+ ions, in a convenient solvent miscible with water, for example, a solvent chosen from tetrahydrofuran and lower alkyl alcohol, e.g. methanol and ethanol, at a temperature ranging from about OOC to about the boiling temperature of the reacting mixture; preferably, at room temperature.A suitable source of Hg2+ ions may be, for example, a bivalent salt of mercury having the general formula Hg y2, where Y is a radical capable of being converted into an anion yo as defined above, preferably Y is
The reaction time may range from about 5 minutes to about 2 or 3 days; but, if mercury trifluoroacetate is used, the reaction time may range from about 2 to about 8 hours and these conditions allow a selective reaction in respect to other unsaturated linkages, which may be present in the intermediate compound of formula (V).The ratio between a mercury salt, as defined above, and a compound of formula (V) depends on the specific mercury salt used; when mercury trifluoroacetate is used, the ratio between the mercury salt and a compound of formula (V) is preferably of about a 1.01 molar equivalent to about 1 molar equivalent.
The compounds of formula (V) may be obtained, starting from known A55-PGF" and PGFss compounds, according to Grieco P. A., et al., J. Med. Chem., 1 980, 23, 1072; and to Grieco P. A., et al., J. Med. Chem., 1981,24,839. The known A56-PGF,r and PGFss compounds may be prepared, e.g., as described by Corey E. J. et al., Ann. of New York Acad. of Sciences, 1971, 24, 180, by Fried J. et al., J.
Med. Chem., 1973,16,429, Bundy G. L., et al., Amer. Chem. Soc., i972,94,2i24,byGandolfi et al., II Farmaco Ed. Sc., 1972, 27, 1125, in the U.S. Pat. No. 3,935,254, Derwent Farmdoc 20717 X, in the German Offenlegungsschrift No. 26 11 788 (Derwent Farmdoc 61615X), in the German Offenlegungsschrift No. 26 10 503 (Derwent Farmdoc 59715X), in the German Offenlegungsschrift No. 26 27 422 (Derwent Farmdoc 85028X), in the U.S. Pat. No. 3,706,789, in the U.S. Pat. No.
3,728,382, in the U.S. Pat. No. 3,903,131, in the U.S. Pat. No. 3,962,293, in the U.S. Pat. No.
3,969,380, in the U.S. Pat No. 3,890,372, in the U.S. Pat. No. 3,636,120, in the U.S. Pat. No.
3,883,513, in the U.S. Pat. No. 3,932,389, in the U.S. Pat. No. 3,932,479, and in the British Pat. No.
1,483,880.
The compounds of the invention, i.e., 6H-6,i 1 a-oxide prostanoic acids, may be considered as isomers of known compounds, namely the 6H-6,9a-oxide prostanoic acids, described for example, in Derwent 1 2220B/07-Abstract of DE 2,808,006; Derwent 42605B/23-Abstract GB 2,009,148; Derwent 2643 5B/1 4--Abstract of EP1 ,270; U.S. Patents 4,123,441 and 4,206,127.
In fact from the chemical point of view the compounds of formula (I) are 2-oxa bicycio[3,2,1]octane derivatives, where an oxide tetrahydropyrane ring is formed between the C11- and the C6-carbon atoms of the prostaglandin framework while the said known 6H-6,9a-oxide prostanoic acids are 2-oxa-bicyclo[3.3.0]octane derivatives, where an oxide tetrahydrofurane ring is formed between the C9- and C6-carbon atoms of the same prostaglandin framework.Both the above mentioned 6H-6,9a-oxide prostanoic acid derivatives, and the 6H-6,1 1 a-oxide prostanoic acid derivatives of the invention are structurally related to PAL2, which has also been designated as prostacyclin, prostaglandin 12, PGX and epoprostenol. PIG 12, which is synthetized by the blood vessel wall, is the most active endogenous inhibitor of platelet aggregation known as well as to be a powerful vasodilator. PGl2 appears to have a wide range of pharmacological properties, which for instance make it useful, e.g. in the form of sodium salt and in solution at alkaline pH where it is chemically stable, for administration by infusion route in the renal dialysis, cardiopulmonary by-pass and charcoal hemoperfusion.
PGl2 was also beneficially evaluated, among others, in pulmonary hypertension, cancer, e.g., as antimetastatic agent, angina, obstructive lung disease, bronchial asthma, artherioscierosis obliterans and thrombotic thrombocytopenic purpura. The major disadvantage of PGI2 is its very short half-life, which is of only 3 minutes at 370C. This very short half-life of PGl2 at physiological pH is sometimes an unsurmountable drawback, which also precludes the diffusion of the use of PAL2.
As the known isomeric 6H-6,9a-oxide prostanoic acids, also named PGI1 analogs, the new 6H 6,1 ia-oxide prostanoic acid derivatives object of the invention are stable compounds which may be used instead of PGl2 in many therapeutical applications.
The compounds of the invention have pharmacological actions similar to those of the natural prostacyclin and prostaglandins and so they may be used both in human and veterinary medicine in the same therapeutical indications of prostacyclin and prostaglandins.
For instance, the compounds of the invention are active as anti-aggregating agents as is shown, e.g., by the fact that they were found to strongly inhibit the platelet aggregation induced by ADP in human platelet rich plasma. In view of their platelet antiaggregant activity, the compounds of the invention are particularly useful in mammals for inhibiting platelet aggregation, for preventing and inhibiting thrombus formation, for decreasing the adhesiveness of the platelets and, owing to their disaggregant activity, for dissolving recently formed clots. The anti-aggregant/disaggregant activity is also associated, with a relaxation of the coronary arteries.Owing to these activities the compounds are useful e.g., in treatment and prevention of thrombosis and myocardial infarct, in treatment of atherosclerosis, and, in general, in all syndromes ethiologically based on or associated with lipid inbalance or hyperlipidemia, as well as in treatment of geriatric patients for presentation of cerebral ischemic episodes, and in long-term treatment after myocardial infarct.
When the compounds of the invention are given as anti-aggregating or disaggregating agents, the routes of administration are the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary from 0.005 to 10 mg/kg/day. The exact dose will depend on the condition of the patient, his weight, his age and the route of administration.
The compounds of the invention also show a considerable bronchodilatory activity and so they are useful, for example, for treatment of obstructive pulmonary diseases such as, e.g., bronchial asthma.
For treatment of the obstructive pulmonary disorders, for example bronchial asthma, the compounds of the invention can be given by different routes: orally, in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups: by inhalation, as aerosols or solutions for the nebulizer: by insufflation, in powdered form.
Doses of the order of 0.01 1 mg/kg can be given from 1 to 4 times a day, with the exact dose depending on the age, weight, and condition of the patient and on the route of administration. For use as antiasthmatics, the compounds of the invention can be combined with other antiasthmatic agents, such as sympathicomimetic drugs like isoproteronol, ephedrine, xanthine derivatives, such as theophylline and aminophylline, or corticosteroids. In addition, the compounds covered by the invention exhibit uterus contracting activity as is shown, e.g., by the fact that they were found to be active in the in vitro test on uterus of estrogenized rat and in the in vivo test on the intrauterine pressure of the ovariectomized rabbit.Owing to this uterus contracting activity the compounds may be used, e.g. in place of oxytocin, to induce labor or expel a dead fetus, both in human and veterinary obstetrics. For this application, the compounds are given intravenously at a dose of approximately 0.01 g/kg/minute until the end of labor, or by mouth. At the same dosage, the compounds of the invention dilate the uterine cervix, facilitating therapeutic abortion and, in that situation are given preferably in the form of vaginal tablets or suppositories.
The compounds covered by this invention are also luteolytic and so are useful in fertility control, with the advantage that they stimulate the smooth muscles much less and so are free of the side effects of natural prostaglandins like vomiting and diarrhea.
Dosages similar to those used for the uterus contracting application are also useful for the luteolytic application. The compounds of the invention are also active on the gastrointestinai tract as cytoprotective, antiulcerogenic and antisecretory agents as is shown, e.g., by the fact that they were found to be active in curing lesions induced by non steroid anti-inflammatory drugs, in preventing ulcers induced by the method of Togagi-Okabe [(Japan J. Pharmac. vol. 18, 9 (1968)], and in inhibiting gastric secretion according to the method of Shay et al. [Gastroenter. vol. 26, 906 (1954)]. Owing to this activity the compounds of the invention may be used, for example, to reduce and control excessive gastric secretion in mammals. In this way they minimize or eliminate the formation of gastrointestinal ulcers and accelerate the cure of any ulcers already present in the gastrointestinal tract. They are administered in this case by intravenous infusion or by intravenous, subcutaneous or intramuscular injection; doses for intravenous infusion range from 0.1 Fug to 500 Itg/kilo/minute. The total daily dose for both injection and infusion is on the order of 0.1-20 mk/kg depending on the age, weight and condition of the patient or animal and on the administration method.
Furthermore the compounds object of the invention exhibit hypotensive activity in mammals as is shown, e.g., by the fact that they were found active in the limb perfusion test where perfusion was made through the left femoral artery of the rat with a constant perfusion pressure. The compounds of the invention also show vasodilatory activity. The dosages and methods of administration of the compounds, when used as hypotensive and vasodilatory agents, are about the same as those used for the anti-aggregating application.
Examples of particuiarly useful compounds in particular as far as the antiaggregating application is concerned, are the compounds: 13t-6aH-6,11 a-oxide-9-oxo-1 15S-ol-prost- 3-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 1 3t-6aH-6,1 6&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; and 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; The toxicity of the compounds of the invention, e.g., those hereabove mentioned, is quite negligible, so that they can be safely used in therapy.
As previously stated, the compounds of the invention can be given, either to humans or animals, in a variety of dosage forms, e.g., orally in the form of tablets, capsules or liquids; rectally, in the form of suppositories; parenterally, subcutaneously or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosois or solutions for nebuüzers: in the form of sterile implants for prolonged action; or intravaginally in the form, e.g., of bougies.
The invention includes pharmaceutical and veterinary compositions containing a compound of the invention and a pharmaceutically or veterinarily acceptable carrier and/or diluents. The carrier or diluent and the form of the compositions can be any conventionally used.
For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred.
For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or nonaqueous media may be used; for tissue implants, a sterile tablet or silicone rubber capsule containing or impregnated with the compound is used.
Conventional carriers or diluents are, for example, water, gelatine, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, steric acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils.
For administration by nebulizer, a suspension or a solution of the compound of the invention, preferably in the form of a salt, such as the sodium salt in water, can be used. Alternatively, the pharmaceutical preparation can be in the form of a suspension or of a solution of the compound of the invention in one of the usual liquefied propellants, such as dichloro-difluoromethane or dichlorotetrafluoroethane, administered from a pressurized container such as an aerosol bomb. When the compound is not soluble in the propellant it may be necessary to add a cosolvent, such as ethanol, dipropylene glycol and/or a surfactant to the pharmaceutical formulation.
The invention is illustrated but not limited by the following examples, wherein the abbreviations THP, DIOX, DMSO, THF, DMF, Et20, EtOH, DM tB silyl ether refer to tetrahydropyranyl, dioxanyl, dimethylsulphoxide, tetrahydrofuran, dimethylformamide, diethyl ether, ethanol and dimethyl tert. butyl silyl ether, respectively.
Example 1 A solution of 1.22 g of the methyl ester of 5-cis-i 3-trans-9a,i 1 &alpha;,15S-triol-prosta-5,13-dienoic acid-9-acetate in 15 ml of THF is added to 1.92 g of mercuric trifluoro-acetate in 15 ml of THF. The mixture is warmed to 300C and stirred for 3 hours, then 0.170 g of sodium borohydride are added portionwise with stirring and external cooling. After 30 minutes of stirring the mixture is decanted from the precipitate, which is washed with THF; 10 ml of water are added and the solution is concentrated under reduced pressure and the aqueous residue extracted with ethyl acetate.The combined organic extracts, after washing with water until neutral, afford upon removal of the solvent 1.18 g of crude 13t 6EH-6,1 1 a-oxide-9a,1 5S-diol-prost-1 3-enoic acid methyl ester, 9-acetate. The crude product is adsorbed on silica gel and eluted with gradient starting from ethyl acetate: hexane=l :1 and at the end with ethylacetate to give 0.55 g of pure 1 3t-6aH-6,i 1 cg-oxide-9cz, 1 5S-diol-prost- 1 3-enoic acid methyl ester, 9-acetate [ce]D=+2,3; [a]365=+ 14,6 (c=1 EtOH) and 0.30 g of pure 1 3t-6pH-6,1 1 a- oxide-9a,1 5S-diol-prost-1 3-enoic acid methyl ester, 9-acetate [a]=+3,i c=1 EtOH).
N.M.R. (CDCl3) S 5.45 (m 2H C13,14vinyl), 5.18 (m 1 H C9), 3.6, 4.2 (m 3H C6 " 15), 3.6 (s 3H COOCH3), 2.08, (s 3H CH3COO).
Example 2 Following the procedure of example 1, starting from the appropriate 9-acyloxy derivatives the following 6,1 oxide analogues methyl esters, 9-acetate are obtained: 1 3t-6aH-6,1 1 a-oxide-9/3,1 5S-diol-prost-l 3-enoic acid; 6aH-6, 11 a-oxide-9a,1 5S-diol-prostanoic acid; 6aH-6,1 1 cr-oxide-9/3,1 5S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid;; 13t-6aH-6,11 ia-oxide-i 5-cyclohexyl-w-pentanor-9a,1 5S-diol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6aH-6,1 a-oxide- 5-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-1 3-ynoic acid; 6aH-6,1 ia-oxide-i 5-cyclohexyl-w-pentanor-9,i 5S-diol-prost-1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid;; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,1 ia-oxide-i 7-cyclohexyl-w-trinor-9a,1 5S-diol-prost-i 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid 6aH-6,11 a-oxide-20-methyl-9a,1 5S-diol-prost-1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6, 11 a-oxide-20-ethyl- 1 6S-fluoro-9a, 1 5R-diol-prost- 1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trino-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trino-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; ; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6H-6,1 1&alpha;-oxide-1m 6-fluoro-l 6-methyl-9a, 1 SS-diol-prost-l 3-ynoic acid; and the above listed compounds as 15-epimers.
Example 3 According to the method described in example 1 and starting from the appropriate 9-acyloxy derivatives the following 6,11-oxide bicyclic prostan-derivatives as amides, N-methylamides, N,N'dimethylamides, N-ethylamides, N,N'-diethylamides, methanesulphonamides and ptoluenesulphonamides, 9-acetate are obtained:: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH;-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid;; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid;; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha; ;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; and the above listed compounds as 15-epimers.
Example 4 To a stirred solution of 0.350g of 13t-6#H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester, 9-acetate in 10 ml of dry methyl alcohol 0.03 g of potassium carbonate are added. The mixture is stirred for 2 hours at room temperature then the potassium carbonate is filtered off and the solvent is removed in vacuo. The residue is dissolved in ethylacetate, washed with saturated sodium chloride solution and water and stirred in dry sodium sulphate. The salt is filtered and, after removing of the solvent, the residue is chromatographed on silica gel using ethylacetate:cyclohexane=7:3 as eluent.
The eluate yields 0.220 g of pure 13t-6#H-6,11 &alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester [&alpha;]D=+5.7; [a]365=+24.9; (c=1 EtOH).
N.M.R. (CDCl3) X 5.56 (dd 1 H C,4), 5.42 (dd 1 H C13),4.59 (m 1 H C9),4.15 (bd 1 H C11), 4.05 (q 1 H C15), 3.98 (m 1 H C6), 3.67 (s 3H COOCH3).
The pure product is adsorbed on silica gel and eluted with gradient starting from ethylacetate:hexane=1 :1 and at the end with ethylacetate to give pure 13t-6&alpha;H-6,11 a-oxide-9a,i 5S- diol-prost-13-enoic acid methyl ester and 13t-6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester.
Following the same procedure the following 6,11-oxides as methyl esters are obtained: 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic-acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoci acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6aH-6,11 ia-oxide-i 6-phenoxy-w-tetranor-9i 55-diol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid;; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic-acid;; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic; acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,1 1 cE-oxide-20-ethyl-16S-fluoro-9cz,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6pH-6,11 a-oxide-l 6-phenoxy-w-tetranor-9P, 1 SS-diol-prost-l 3-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cycloehxyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha; ;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; and the above listed compounds as 15 epimers.
Example 5 A solution of 0.470 g of 6&alpha;H-6,11 &alpha;-oxide-9&alpha;-15S-diol-prost-13-ynoic acid methyl ester, 9acetate in 10 ml of methanol is treated with 10 ml of 1N lithium hydroxide solution and stirred at room temperature for 6 hours. The solvent is removed and the aqueous layer is extracted with ethylacetate; the organic phase is discharged and the aqueous layer is acidified to pH 6.2 with aqueous saturated solution of sodium monophosphate and extracted with ethyl acetate. The solvent is distilled under vacuum and 0.380 g of 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid are obtained [&alpha;]D+6.2; [a]365+37; (C=1 EtOH).According to the procedure hereabove described the following 6,11 oxide free acids are obtained: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic-acid; 13t-6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 1 3t-6aH-6, 11 a-oxide-i 5-cyclohexyl--pentanor-9a, 1 55-diol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid;; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid;; 6&alpha;H-6,11&alpha;-oxide-20-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid;; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6}5H-6,11 a-oxide-16S,R-fluoro-9cg,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6pH-6,1 ia-oxide-i 7-cyclohexyl-co-trinor-9a,1 55-diol-prost-i3-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid;; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 1 3t-6aH-6,1 1&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-1 3-enoic acid;; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,1 1 a-oxide-20-methyl-1 6S-fluoro-9a,1 5S-diol-prost-i 3-ynoic acid; 6aH-6,11 a-oxide-20-methyl- 6R-fluoro-9a,1 5S-diol-prost-i 3-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid;; 6ssH-6,11 a-oxide-20-methyl- 1 6S4luoro-9a, 1 55-diol-prost-1 3-ynoic acid; and 6ssH-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid, and the above listed compounds as 15-epimers.
Example 6 1 3t-6aH-6,1 1 &alpha;-oxide-9&alpha;,1 1 5S-diol-prost-i 3-enoic acid methyl ester, 9-acetate (0.55 9) is dissolved in 20 ml of dry benzene and (0.12 g) of 2,3-dihydropyran and 2.5 mg of p-toluene-sulphonic acid are added. The mixture is kept at room temperature for 3 hours, then washed with 3% solution of sodium bicarbonate and water until neutral. After removal of the solvent in vacuo, the residue is chromatographed on silica gel and eluted with cyclohexane:ethylacetate:pyridine=80:20:0.1 to give 0.62 g of 1 3t-6aH-6,i 1 &alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester, 9-acetate 15-THP ether.
Example 7 To a solution of 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-16S-fluoro-prost-13-enoic acid methyl ester, 9-acetate (0.43 g) in 10 ml of methylene chloride 0.4 ml of triethylamine are added and cooling with water bath 0.23 g of dimethyl tert-butyl chlorosilane and 2 mg of dimethylaminopyridine are added.
The mixture is stirred for 30 minutes and diluted with 20 ml of hexane, the salts are removed by filtration and the organic phase is washed with water and evaporated to dryness: 0.60 g of crude product are obtained. The crude product is chromatographed on silica gel and eluted with hexane:ethylacetate=50:50 to give 0.52 g of pure 1 3t-6aH-6,1 1 &alpha;-oxide-9&alpha;,15S-diol-16S-fluoro- prost-13-enoic acid methyl ester, 9-acetate 1 5-dimethyl-ter-butyl silyl ether.
Example 8 To a solution of 0.50 g of 13t-6&alpha;H-6,1 1 1&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester, g-acetate-15-THP-ether in 10 ml of dry methyl alcohol 0.03 g of potassium carbonate are added.
The mixture is stirred for 2 hours at room temperature then the insoluble salt is removed by filtration and the solvent is removed in vacuum.
The residue is dissolved in ethyl acetate washed with saturated sodium chloride solution and water and dried on sodium sulphate.
The salt is filtered and after the solvent is distilled under vacuum the residue gives 0.42 g of 13t 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid methyl ester, 15-THP-ether.
Example 9 Into a stirred solution of 0.79 g of 6aH-6,1 1 a-oxide-9a,l SS-diol-prost-l 3-ynoic acid methyl ester,9-acetate-15-ter-butyl-dimethyl-silyl ether in 15 ml of methanol 10 ml of 1 N lithium hydroxide solution are dropped and the mixture is stirred at room temperature for 6 hours. The solvent is removed and the aqueous phase is extracted with ethylacetate. The organic layer is discharged and the aqueous phase is acidified to pH 6.2 with aqueous saturated solution of sodium mono-phosphate and extracted with ethylacetate. The solvent is distilled under vacuum and 0.68 g of 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol- prost-13-ynoic acid, 1 5-ter-butyl-dimethyl-silyl ether are obtained.
Example 10 With external cooling bath, a solution of 0.80 g of 1 3t-6aH-6,1 1 ci-oxide-ga,l SS-diol-prost-l 3- enoic acid 15-THP-ether in 20 ml of acetone is cooled to -300C. Then a solution of 2.1 ml of Jones reagent [Bowden et al. J. Chem. Soc. 39 (1946)] is dropped slowly into the mixture.
The reaction mixture is stirred at -300C for 30 minutes at which time the reaction is quenched by addition of 0.5 ml of isopropanol.
After stirring for additional 1 5 minutes the resulting mixture is left to raise room temperature.
75 ml of benzene are added to the solution and the benzenic phase is washed until neutral with saturated (NH4)2SO4 solution.
The combined aqueous fractions are extracted with benzene and the organic phases are collected, dried on sodium sulphate evaporated to dryness affording 0.78 g of 13t-6&alpha;H-6,11 1 a-oxide- 9-oxo-15S-hydroxy-prost-13-enoic acid, 15-THP ether.
Example 11 A solution of 0.70 g of 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid, 15-ter-butyl dimethyl silyl ether in 6 ml of dry benzene and 2 ml of DMSO is treated with 0.41 g of N,N'dicyclohexylcarbodiimide and 0.7 ml of pyridine and 0.3 ml of trifluoroacetic acid.
The reaction mixture is stirred 1 hour at room temperature, then is filtered and washed with benzene. Then the organic phase is washed with water and dried on sodium sulphate.
The solvent is distilled in vacuum at low temperature and the residue gives 0.65 g of 6&alpha;H-6,11 a oxide-9-oxo- 1 55-hydroxy-prost- 1 3-ynoic acid, 1 5-ter-butyl-dimethyl-silyl ether.
Example 12 According to the procedures reported in examples 10 and lithe following 6,11 a-oxide-9-oxo derivatives as free acids, methyl esters, amides, N-methyl-amides, N,N'-dimethylamides, Nethylamides, N,N'-diethylamides, methanesulphonamides and p-toluenesulphonamides are obtained both as 15-THP ethers and as 1 5-tert-butyl-dimethyl-silyl ethers.
13t-6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6aH-6,11 a-oxide-i 6-phenoxy-a,-tetranor-9-oxo- 1 55-ol-prost- 1 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;;-oxide-16S,R-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6aH-6,11 ia-oxide-i 7-phenyl-w-trinor-9-oxo-1 5S-ol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic-acid; 13t-6&alpha;;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6aH-6,11 a-oxide-20-methyl-9-oxo- 1 SS-ol-prost-l 3-ynoic acid; 6aH-6,i 1 a-oxide-20-ethyl-9-oxo-1 5S-ol-prost-1 3-ynoic acid; 6aH-6, 11 a-oxide-20-ethyl- 1 6S-fluoro-9-oxo- 1 5R-ol-prost- 1 3-ynoic acid;; 6aH-6, 11 a-oxide-20-ethyl- 1 6R4l uoro-9-oxo- 1 55-ol-prost- 1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9-oxo-15S-ol-prost-13ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15Sol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha; ;-oxide-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-prost-13-enoic acid; 1 3t-6H-6,1 ia-oxide-i 7-phenyl-co-trinor-9-oxo-1 5S-ol-prost-1 3-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic-acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6pH-6,11 ia-oxide-i 6-fluoro-i 7-phenyl-w-trinor-9-oxo-1 5S-ol-prost-1 3-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-of-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-15S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid;; 6pH-6,i 1 a-oxide-20-ethyl-1 6R4luoro-9-oxo-1 5S-ol-prost-i 3-ynoic acid; 6ssH-6,11 ia-oxide-i 64luoro-1 6-methyl-9-oxo-1 5S-ol-prost-i 3-ynoic acid; and the above listed compounds as 15-epimers.
Example 13 A solution of 0.2 g of 1 3t-6aH-6,1 1 &alpha;-oxide-9-oxo-15S-hydroxy-prost-13-enoic acid-i 5-THP- ether in 7 ml of acetone is heated at 400C for 12 hours in the presence of 5 ml of 0.2 N aqueous oxalic acid.
The acetone is evaporated in vacuum and the resulting mixture is extracted with ethyl ether and washed until with aqueous saturated (NH4)2SO4. Organic phase is dried on sodium sulphate and evaporated to dryness.
The residue is chromatographed on acid washed silica gel using ethylacetate:cyclohexane=20:80 as eluent, 0.1 g of pure 13t-6&alpha;H-6,11 a-oxide-9-oxo-i 55-hydroxy- prost-i 3-enoic acid are obtained [&alpha;]D+42.0; [cg]365+191.7; (c=1 EtOH).
N.M.R. (CDCl3) a 5.48 (m 2H C1314 vinyl), 3.68 (m H C6), 4.03 (m H C15), 4.51 (bs H C11),0.90 (t 3H CH3).
Example 14 All the 6,1 i-oxide-9-oxo-1 5-THP ethers obtained according to the procedure described in example 10 and reported in examples 10 and 12 are converted in the same way as reported in example 13 in the following herebelow listed corresponding cyclic prostaglandins as free acids, methyl esters, N-methylamides, N,N'-dimethylamides, N-ethylamides, N,N'-diethylamides, methanesulphonamides, p-toluenesulphonamides and amides:: 13t-6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6aH-6,11 ia-oxide-i 5-cyclohexyl-w-pentanor-9-oxo-i 55-ol-prost-i 3-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-entanor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;;-oxide-16S,R-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6aH-6,11 ia-oxide-i 7-phenyl-co-trinor-9-oxo-1 5S-ol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6aH-6, ii a-oxide-20-ethyl- 1 6R-fluoro-9-oxo- 1 55-ol-prost- 1 3-ynoic acid;; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11 a-oxide-9-oxo-i 55-ol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-16R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'tetrahydrofuryl)-#-trino-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11 cg-oxide-20-methyl-9-oxo- 5S-ol-prost-i 3-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9-oxo-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-20-ethyl-16R-fluoro-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11 ia-oxide-i 6-fluoro-i 6-methyl-9-oxo-1 5S-ol-prost-i 3-ynoic acid; and the above listed compounds as 1 5-epimers.
Example 15 A solution of 0.4 g of 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-hydroxy-prost-13-ynoic acid;-15-DMtB silyl ether in 12 ml of THF is treated with 0.5 g of tetrabutylammonium fluoride. The resulting mixture is stirred for 12 hours at room temperature and concentrated to small volume to give a residue which is purified on acid washed silica gel using ethylacetate:cyclohexane=20:80 as eluent to afford 0.2 g of pure 6aH-6,11 &alpha;-oxide-9-oxo-15S-hydroxy-prost-13-ynoic acid.
Example 16 All the 6,11-oxide-9-oxo-15-DMtB silyl ethers obtained according to the procedure described in example ii and reported in example ii and in example 12 are converted in the same way as reported in example 15 in the following herebelow listed corresponding cyclic prostaglandins as free acids, methyl esters, N-methylamides, N,N'-dimethylamides, N-ethylamides, N,N'-diethylamides, methanesulphonamides, p-toluenesulphonamides and amides:: 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha; ;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-(2'tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid;; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;
;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trnor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; and the above listed compounds as 15-epimers.
Example 17 A solution of 0.175 g of methylphenyl-N-methylsulfoximine (Johnson et all. J. Am. Chem. Soc.
1973, 95, 6462) in 3 ml of THF is cooled to 0 C and 1 ml of 1 N methylmagnesium chloride (in THF) is dropped in.
After fifteen minutes at 0 C the sulfoximine anion solution is cooled to 780 and added dropwise into a solution of 1 3t-6aH-6,i 1 &alpha;-oxide-9-oxo-1 5S-hydroxy-16-fluoro-16-methyl-prost-13- enoic acid methyl ester-15-dimethyl-tertbutyl-silyl ether (0.32 g) in THF (5 ml), and the yellow solution is stirred at -780C for 3 hours.
The solution is quenched with 20 ml of saturated solution of ammonium chloride and 20 g of ice and then extracted with ethyl ether, washed with water and evaporated. The residue is dissolved in 5 ml of THF, 0.7 ml of water and 0.7 ml of acetic acid then 1 g of aluminium amalgam is added and the mixture is stirred at room temperature for 1 hour. The solution is decanted and washed with sodium phosphate, ammonium sulphate solution and the solvent is removed in vacuum.
The crude residue is purified on silica gel using hexane, ethyl acetate 80:20 and pure 0.120 g, 1 3t-6aH-6,i 1 a-oxide-9-deoxy-9-methylene-i 5S-hydroxy-i 64luoro-i 6-methyl-prost-i 3-enoic acid methyl ester-15-DMtB silyl ether are obtained.
Following the same procedure the following 6,11 a-oxide-9-deoxy-Y-methylene derivatives as free acids, methyl esters, N-methylamides, N,N'-dimethylamides, N-ethylamides, N,N'-diethylamides, methanesulphonamides, amides and p-toluenesulphonamides as 15-DMtB silyl ethers are obtained: 13t-6&alpha;-6,11 cz-oxide-9-deoxy-9-methylene- 15S-ol-prost- 3-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-entanor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid;; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-deoxy-9-methylene-15S-ol-prost-13-ynoi acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-dexoy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6aH-6,11 -oxide-17-(2'-tetrahydrofuryl)- -trinor-9-deoxy-9-methylene-15S-ol-prost-13enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid;; 6aH-6, 11 a-oxide-i 7-(2 'Aetrahydrnfuryl)-wtrinor-9-deoxy-9-methylene- 1 55-ol-prost- 1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9-deoxy-9-methylene-15S-ol-pro st-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-16-fluoro-16-methyl-prost-13-ynoic acid; 13t-6pH-6,11 a-oxide-9-deoxy-9-methylene- 15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prostanoic acid;; 6ssH-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6pH-6,11 a-oxide-i 5-cyclohexyl-w-pentanor-9-deoxy-9-methylene- 1 55-ol-prost- 1 3-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-16S,R-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-fluoro-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-20-ethyl-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6aH-6,11 ia-oxide-i 6R-fluoro-9-deoxy-9-methylene-1 5S-ol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6aH-6,i 1 a-oxide-20-methyl-i 65-fluoro-9-deoxy-9-methylene-i 5S-ol-prost-1 3-ynoic acid;; 6aH-6,1 1 a-oxide-20-methyl-i 6R-fluoro-9-deoxy-9-methylene-i 5S-ol-prost-i 3-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11 a-oxide- GS-fluoro-9-deoxy-9-methylene-l SS-ol-prost-l 3-enoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-16S-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; and 6ssH-6,11&alpha;-oxide-20-methyl-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; and the above listed compounds as 15-epimers.
Example 18 A solution of 0.120 g of 13t-6&alpha;H-6,11 &alpha;-oxide-9-deoxy-9-methylene-15S-hydroxy-16-fluoro- 16-methyl-prost-13-enoic acid methyl ester-15-DMtB silyl ether in 10 ml of THF is treated with 0.3 g of tetrabutylammonium fluoride. The reaction mixture is stirred for 10 hours at room temperature and concentrated to small volume. The oily crude residue is purified on acid washed silica gel using ethylacetate:hexane=25:75 as eluent to afford 0.065 g of pure 1 3t-6aH-6,i 1 a-oxide-9-deoxy-9 methylene-l SS-hydroxy-l 6-fluoro-l 6-methyl-prost-l 3-enoic acid methyl ester.
Following the same procedure the herebelow listed products as free acids, methyl esters, amides and N-methylamides, N,N'-dimethylamides, N-ethylamides, N,N'-diethylamides, methanesulphonamides and p-toluenesulphonamides are obtained: 13t-6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-hydroxy-16-fluoro-16-methyl-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-dexoy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9-deoxy-9-methylene-15S-of-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-entanor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6aH-6,11 &alpha;-oxide-12 2a-fluoro-9-deoxy-9-methylene-l SS-ol-prost-l 3-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-14-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 1 3t-6aH-6, 11 c-oxide- 6-fluoro- 1 7-phenyl-w-trinor-9-deoxy-9-methylene- 15S-ol-prost- 13enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid;; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;-H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6aH-6,1 1 a-oxide-20-methyl-9-deoxy-9-methylene-i 5S-ol-prost-i 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-16-fluoro-16-methyl-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-16S,R-fluoro-9-deoxy-9-methylene-16R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9-deoxy-9-methylene-16S-ol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13- enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-20-ethyl-16S-fluoro-9-deoxy-9-methylene-15R-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9-dexoy-9-methylene-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9-deoxy-9-methylene-15S-ol-prost-13-ynoic acid, and the above listed compounds as 1 5-epimers.
Example 19 CuCI (0.017 g) was added to a solution of 1.373 g of dicyclohexylcarbodiimide (DCC) in 0.661 g of 2-ethoxyethanol cooled at OOC. The mixture is stirred for 1 hour at OOC, then it is allowed to rise to room temperature and kept at this temperature for 24 hours. The mixture is diluted with hexane (5 ml), filtered on silica gel and washed with hexane.
The solvent is removed to obtain 1.00 g of pure dicyclohexyl-2-ethoxy-ethylisourea that is dissolved in 10 ml of dry THF and added to a solution of 1 g of 13t-6&alpha;H-6,11 a-oxide-9a,i 5S-diol-20- methyl-prost-13-enoic acid in 10 ml of dry THF. The mixture is warmed to 600C for 6 hours, the solvent is removed under vacuum and the crude product is purified on silica gel using ethylacetate hexane=50:50 as eluent Pure 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-20-methyl-prost-13-enoic acid 2- ethoxy-ethyl ester (0.890 g) is collected, [sg]D=+4-2; (c=1 EtOH).
Example 20 According to the procedure described in example 19 the following bicyclic prostaglandin derivatives as 2-ethoxyethyl esters are obtained: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-#-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-dil-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;15S-diolprost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;5S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha; ;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6pH-6,11 ia-oxide-i 5-cyclohexyl-w-pentanor-9a,i 55-diol-prost-i 3-enoic acid; 13t-6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trior-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trior-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11 a-oxide- 7-cyclohexyl-w-trinor-9a, 1 SS-diol-prost-l 3-ynoic acid;; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-16S-fluoro-9&alpha;;,15S-diol-prost-13-ynoic acid; and 6ssH-6,11 a-oxide-20-methyl-16R-fiuoro-9a,15S-diol-prost-13-ynoic acid, and the above listed compounds as 15-epimers.
Example 21 In a modified procedure of the example 19 reacting in the same conditions the isourea derivatives obtained in the usual way from DCC and N-hydroxyethylmorpholine or N-hydroxyethylpiperidine, with bicyclic 6,11 a-oxide-prostene-derivatives the following 2-piperidino-ethyl esters and 2-morpholinoethyl esters are obtained:: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-20-methyl-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid;; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6aH-6,1 1 ia-oxide-i 5-cyclohexyl-w-pentanor-9a,i 5S-diol-prost-i 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; ; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6aH-6,11 ia-oxide-i 7-cyclohexyl-w-trinor-9a,i 55-diol-prost-i 3-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 1 3t-6aH-6,1 ia-oxide-i 6-fluoro-1 7-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6aH-6,11 1&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,1 5S-diol-prost-i 3-enoic acid;; 6aH-6, 11 cr-oxide-l 7-phenyl-w-trinor-9a, 1 SS-diol-prost-l 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,i 1 &alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6aH-6, ii a-oxide-20-ethyl- 16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;;-oxide-16-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6,11 a-oxide-20-methyl-16S-fluoro-9cg,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11 ct-oxide-20-methyl-16S-fluoro-9a,15S-diol-prost-13-ynoic acid; and 6ssH-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; and the above listed compounds as 1 5-epimers.
Example 22 A solution of 13-trans-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15R-diol-16S-fluoro-prost-13-enoic acid (0.26 g) in 5 ml of ethyl ether is treated with 1.5 ml of 0.5 M ether solution of diazomethane at room temperature.
The solution is evaporated to dryness and 0.26 g of pure 13-trans-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15R- diol-16S-fluoro-prost-13-enoic acid methyl ester is obtained, [&alpha;]D=+7.2;(c=1 CHCl3).
Example 23 A solution of 6(&alpha;,ssH)-6,11&alpha;-oxide-9&alpha;,15R-diol-16S-16-fluoro-16-methyl-prost-13-ynoic acid methyl ester (0.45 g) in 10 ml of dry methyl alcohol is cooled with cooling bath at-10 C and dry NH3 is bubbled into this solution until saturation.
The reaction vessel is closed and the mixture is maintained at room temperature for about 24 hours; then the NH3 is stripped with N2 and the solvent is removed under vacuum.
The crude residue is purified with preparative chromatographic technique on silica gel using hexane, ethylacetate 1:1 as eluent: 0.36 g of pure 6(&alpha;,ssH)-6,11&alpha;-oxide-9&alpha;,15R-diol-16S-16-fluoro- 1 6-methyl-prost-i 3-ynoic acid amide, [&alpha;]D=+12; (c=l EtOH).
Starting from the 6(&alpha;,ssH)-6,11&alpha;,-oxide-9&alpha;,15S-diol-16S-16-fluoro-16-methyl-prost-13-ynoic acid methyl ester the corresponding amide is obtained [&alpha;]D+18.2; (c=1 EtOH). Following the same procedure the amides of the following acids are obtained:: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid;; 6aH-6,11 a-oxide-i 7-cyclohexyl--trinor-9a, 1 55-diol-prost- 1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acic; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6aH-6, ii a-oxide-20-ethyl- 1 6S-fluoro-9a,1 5R-diol-prost- 1 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;;-oxide-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 13t-6AH-6,11 a-oxide-i 6-phenoxy-w-tetranor-9a,1 5S-diol-prost-i 3-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S,R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;;,15S-diol-post-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-fluoro-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha; ;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16S-fluoro-9&alpha;,15R-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-ethyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16-fluoro-16-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;;,15S-diol-prost-13-ynoic acid; 6aH-6,1 1 a-oxide-20-methyl-1 6S-fluoro-9a,i 5S-diol-prost-i 3-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-16r-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11 a-oxide-20-methyl-i 6S-fluoro-9a, 1 5S-diol-prost-i 3-ynoic acid; and 6ssH-6,11 a-oxide-20-methyl- 16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid, and the above listed compounds as 15-epimers.
Example 24 13t-6&alpha;H-6,11 &alpha;-oxide-9-oxo-15S-hydroxy-prost-13-enoic acid (0.5 g) is dissolved in the stoichiometric amount of 0.1 N sodium hydroxide and the solution is lyophilized to obtain 0.53 g of white powdered crystals of 13t-6aH-6,11 &alpha;-oxide-9-oxo-15S-hydroxy-prost-13-enoic acid sodium salt.
Formulation Example 1 Pharmaceutical composition is manufactured by dissolving 20 mg of 13t-6&alpha;H-6,11 a-oxide-9oxo-15S-hydroxy-prost-13-enoic acid sodium salt in ethanol (10 ml); the solution is added with stirring to mannitol (10 g), then dried at 400C for 90 minutes. The powdered product is sieved through a 30mesh sieve and is used to fill capsules of gelatine containing from 20 to 100 g of the sodium salt of 13t-6&alpha;H-6,11&alpha;-oxide-9-oxo-15(S)-hydroxy-prost-13-enoic acid Formulation Example 2 13t-6&alpha;H-6,11 1&alpha;-oxide-9-oxo-15S-hydroxy-porst-13-enoic acid (100 mg) is dissolved in ethanol (110 ml) and the solution is added to an aqueous solution (100 ml) of sodium carbonate (500 mg).
Isotonic saline solution is added to give final volume of 500 ml.
The solution is then sterilized and 3 ml ampoules are filled with 1 ml portions to give 0.2 mg of 13t-6&alpha;H-6,11 &alpha;-oxide-9-oxo-15S-hydroxy-prost-13-enoic acid (in the form of its sodium salt) per ampouie.
The contents of an ampoule in a suitable volume of sterile water or physiological saline give a solution ready for administration or infusion.

Claims (10)

Claims
1. Optically active or racemic prostaglandins of formula (I)
wherein one of U and U, is hydrogen and the other is the group -CH 2-M-R wherein R is a member selected from the group consisting of: a) a free or esterified carboxy group or a carboxylic amide; b)-CH2OH,-CHO,-COCH2OH-C#N and
M is a group chosen from: a')-(CH2)n-, wherein n is zero, 1,2,3,4,5 or 6; or b') -(CH2) -D-(CH2) -, wherein each of n1 and n2, being the same or different, is zero, 1,2, 3, or 4, but the sum of n1 and n2 is not higher than 4;Dis-CH=CH-(cis, trans or a mixture thereof), -C#C-or a cyclopropyl ring; one of R, and R2 is hydrogen and the other is hydroxy or R1 and R2, taken together, form an oxo group or, taken together with the carbon atom to which they are linked, form a methylene (CH2=) group; X is hydrogen or fluorine; T represents a
group wherein A is a member selected from the group consisting of: a")-(CH2)p-CH2-CH2-, wherein p is zero or 1; b") trans
wherein Z is hydrogen, fluorine, chlorine or bromine and p is as defined above; and c"),-(CH2)p-C#C wherein p is as defined above; one of R4 and R5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C5 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur, and the other is hydroxy; or R4 and R5 taken together form an oxo group; k is zero or an integer up to 5; B is a member selected from the group consisting of: a"') hydrogen; fluorine or methyl; b"') phenyl; a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur;
wherein each of R6 and R7, which may be the same or different, is hydrogen, C1-C6 alkyl or fluorine; or R6 and R7, taken together with the carbon atom to which they are linked, form a
group or the radical
each of m1 and m2, being the same or different, is zero or an integer of 1 to 6;E is a group chosen from: -O-, -S- and -(CH2)m-, wherein m is zero or 1; and R8 is a member selected from the group consisting of : aIV) hydrogen or C1-C4 alkyl; bIV) a C3-C9 cycloaliphatic ring unsubstituted or substituted by one or more substituents chosen from C1-C6 alkyl and C1- C6 alkoxy; cIV) aryl unsubstituted or substituted by one or more substituents selected from halogen, halo-C1-C6 alkyl, C1-C6 alkyl; and C1-C6 alkoxy; dIV) a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more substituents selected from halogen, halo-C1-C6 alkyl and C1-C6 alkoxy; and the pharmaceutically and veterinarily acceptable salts thereof.
2. A compound having formula (I), according to claim 1, wherein one of U and U, is hydrogen and the other is the group -CH2-M-R, wherein R is a free or esterified carboxy group and M is a -(CH2)n-group, wherein n is 2, 3 or 4; one of R1 and R2 is hydrogen and the other is hydroxy, or R1 and R2, taken together, form an oxo group; X represents hydrogen or fluorine; T represents a
group, wherein A is a member selected from -CH2-CH2-, -CH2=CZ- wherein Z is as defined in claim 1, -C#C-; R4 and R5 are as defined in claim 1;k is zero or an integer up to 5; B is
wherein m1, m2, Re, R7, E and R8 are as defined in claim 1; and the pharmaceutically and veterinarily acceptable salts thereof.
3. A compound selected from the group consisting of: 13t-6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6&alpha;H-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid; 13t-6&alpha;;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-14-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6&alpha;H-6,11&alpha;-oxide-17-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha;H-6,11&alpha;-oxide-20-methyl-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6&alpha; ;H-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9ss,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prostanoic acid; 6ssH-6,11&alpha;-oxide-9-oxo-15S-ol-prost-13-ynoic acid;; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9ss15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-16-phenoxy-#-tetranor-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9ss,15S-diol-prost-13-ynoic acid;; 6ssH-6,11&alpha;-oxide-15-cyclohexyl-#-pentanor-9-oxo-15S-ol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-12&alpha;-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9-oxo-15S-ol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-14-fluoro-9&alpha;;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-phenyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-17-cyclohexyl-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 13t-6ssH-6,11&alpha;-oxide-(2'-tetrahydrofuryl)-#-trinor-9&alpha;,15S-diol-prost-13-enoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-butyl-9&alpha;,15S-diol-prost-13-ynoic acid; 6ssH-6,11&alpha;-oxide-20-methyl-16S-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid; and 6ssH-6,11&alpha;-oxide-20-methyl-16R-fluoro-9&alpha;,15S-diol-prost-13-ynoic acid;, the 15-R epimers of the 6&alpha;H-6,11&alpha;-oxide and 6ssH,6,11&alpha;-oxide derivatives listed above; and the methyl esters, the ethoxyethyl esters, the morpholinoethyl esters, the piperidinoethyl esters and the pharmaceutically and veterinarily acceptable salts thereof.
4. Process for the preparation of a compound of formula (I) according to claim 1, said process comprising: A) reducing an optically active compound, or a racemic mixture of compounds, of formula (II)
wherein one of U' and U', is hydrogen and the other is
wherein M and R are as defined in claim 1 and yo represents the anionic residue of an acid; one of R'2 and R' is hydrogen and the other is a protected hydroxy group; X is as defined in claim 1; T' represents a
group, wherein A, k and B are as defined in claim 1; one of R'4 and R'5 is hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur, and the other is hydroxy or a labile protecting group linked to the chain through an ethereal oxygen atom; or R'4 and R'5, taken together, form an oxo group, thus obtaining an optically active compound, or a racemic mixture of compounds, of formula (III)
wherein one of U and U, is hydrogen and the other is -CH2-M-R wherein M and Rare as defined in claim 1; wherein Xis as defined in claim 1 and T', R'" and R'2 are as defined above; and removing the hydroxy protecting group at the 9-position and, removing, also, the hydroxy protecting group at the 1 5-position, if present, to obtain a compound of formula (I) wherein one of R, and R2 is hydrogen and the other is hydroxy, and U, U1, X and Tare as defined in claim 1; or B) oxidizing an optically active compound, or a racemic mixture of compounds, of formula (IV)
wherein one of R", and R", is hydrogen and the other is hydroxy; T" represents a
group, wherein one of R"4 and R"5 is hydrogen, C1-C6 alkyl, 02-C6 alkyl, C2-C6 alkynyl, aryl, a C3-C7 cycloaliphatic ring or a saturated C3-C7 heteromonocyclic ring containing one or more heteroatoms chosen from oxygen and sulphur and the other is a labile protecting group linked to the chain through an ethereal oxygen atom or R"4 and R"5,taken together from an oxo group; and, X, A, B, k, U and U, are as defined in claim 1, to obtain, after removal of the hydroxy protecting group at the 15position if present, an optically active compound, or a mixture of optically active compounds of formula (I), wherein R1 and R2, taken together form an oxo group and T, X, U and U, are as defined in claim 1 and/or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, reacting a compound of formula (I), wherein R is a free carboxy group and the hydroxy groups are optionally protected as described above, with a base, followed, if required, by removal of the hydroxy protecting groups, to give a salt of a compound of formula (I) with a cation of a pharmaceutically or veterinarily acceptable base; and/or, if desired, esterifying a compound of formula (I) wherein R is a free carboxy group, and the hydroxy groups, if present, are optionally protected as described above, followed, if required, by removal of the hydroxy protecting groups, to give a compound of formula (I), wherein R is an esterified carboxy group; and/or, if desired, hydrolyzing a compound of formula (I), wherein R is an esterified carboxy group, and the hydroxy groups, if present, are optionally protected as described above, followed, if required, by removal of the hydroxy protecting groups, to give a compound of formula (I), wherein R is free carboxy group; and/or if desired, converting a compound of formula (I), wherein R, and R2, taken together form an oxo group, and the hydroxy group at the Ct5-position, if present, is optionally protected as described above, into another compound of formula (I), wherein R1 and R2, taken together with the carbon atom to which they are linked form a methylene (CH2=) group, followed, if required, by removal of the hydroxy protecting group; and/or, if desired converting a compound of formula (I), wherein R is a free or esterified carboxy group and the hydroxy groups if present, are optionally protected as described above, into another compound of formula (I), wherein R is a carboxylic amide, followed, if required, by removal of the hydroxy protecting groups; and/or, if desired, separating a mixture of isomers into the single isomers.
5. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) or a pharmaceutically acceptable salt thereof.
6. A compound, or a salt thereof according to claim 1 or a pharmaceutical composition according to claim 5 for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.
7. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 5 for use in administration to human patients or animals as anti-aggregating/disaggregating agents, to treat bronchial asthma, to induce labor, to expel a dead fetus, as fertility controi agents, to prevent the formation of gastrointestinal ulcers or to treat ulcers already present and as hypotensive agents.
8. A compound according to claim 1 specifically identified herein which is other than those identified in claim 3.
9. A process according to claim 4 substantially as hereinbefore described with reference to any one of Examples 1 to 24.
10. A composition according to claim 5 substantially as hereinbefore described with reference to Formulation Example 1 or 2.
GB08213217A 1982-05-07 1982-05-07 6,11-epoxy prostaglandins and process for their preparation Expired GB2120651B (en)

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