GB2129427A - 15-Cycloaliphatic derivatives of 13,14-didehydrocarboprostacyclins and process for their preparation - Google Patents

15-Cycloaliphatic derivatives of 13,14-didehydrocarboprostacyclins and process for their preparation Download PDF

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GB2129427A
GB2129427A GB08326187A GB8326187A GB2129427A GB 2129427 A GB2129427 A GB 2129427A GB 08326187 A GB08326187 A GB 08326187A GB 8326187 A GB8326187 A GB 8326187A GB 2129427 A GB2129427 A GB 2129427A
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Prior art keywords
deoxy
pentanor
methylene
prostacycl
dihydroxy
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GB2129427B (en
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Nicola Mongelli
Carmelo Gandolfi
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5435—Cycloaliphatic phosphonium compounds

Abstract

Compounds of the formula (I> <IMAGE> wherein R is hydrogen or a C1-C6 alkyl group optionally substituted by a group <IMAGE> wherein each of R3 and R4 is, independently, hydrogen or C1-C6 alkyl, or R3 and R4, taken together with the nitrogen atom to which they are linked, form a pentatomic or hexatomic heteromonocyclic ring optionally containing a further heteroatom chosen from O and S; n is zero or an integer of 1 to 5; one of R1 and R2 is hydrogen or C1-C6 alkyl and the other is hydroxy; and B represents: a) a C4-C7 monocycloaliphatic group either unsubstituted or substituted by one or more substituents chosen from C1- C6 alkyl, C2-C6 alkenyl and C1-C6 alkylidene; b) norbornyl; or c) adamantyl, and the pharmaceutically or veterinarily acceptable salts thereof, are useful as blood platelet anti-aggregating and dis-aggregating agents.

Description

SPECIFICATION 1 5-Cycloaliphatic derivatives of 13,1 4-didehydro-carboprostacyclins and process for their preparation The present invention relates to new 1 5-cycloaliphatic derivatives of 13,1 4-didehydro- carboprostacyclins, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.
Prostacyclins are a well known class of compounds having the basic structure of orostacvclin, or PGl2
Literature referring to prostacyclin includes, for example; Nature, 263, 663, (1976); J. Am. Chem.
Soc. 99,4182 (1977); Prostaglandins 12, 915 (1976); and J. Am. Chem. Soc. 99, 2006 (1977).
Carboprostacyclins are a well known class of compounds too, having a basic structure which differs from the structure of prostacyclin in that the 6,9-epoxy group of PGl2 is replaced by a 6,9methylene group. Thus, the most representative compound of this class is just carboprostacyclin, or carbo-PGl2
Literature relating to carboprostacyclin and derivatives thereof includes, for example, UK patent 2012265B, UK patent 2014143B, UK patent 2019847B, UK patent 2017699B, UK patent 2013661 B and European patent 11591.
In the hereabove cited UK patents 2012265B, 2014143B and 2019847B no description is given of carboprostacyclins carrying a cycloaliphatic group on the bottom chain, or chain, of the carbo PGl2 structure, i.e. on the chain linked to the 12-position.
UK patent 201 7699B describes carboprostacyclin compounds having a cycloalkyl group on said chain, including some wherein the cycloalkyl group is bonded to the 1 5-position of the carbo-PGI2 structure: however only compounds having a single bond or a trans double bond, between the 13- and the 14-position, but not a triple bond, are described therein. UK patent 201 3661 B describes carboprostacyclin derivatives having a cycloaliphatic group on the chain and a triple bond on the 13,14-position but the possibility that the o-cycloaliphatic group is bonded to the 1 5-position of the carbo-PGI2 structure is not therein contemplated for cycloaliphatic groups with more than three carbon atoms.
European patent 11591 describes carboprostacyclin compounds whose general formula involves the presence of a cycloalkyl group at the 1 5 position of the co-c ha in and of a triple bond at the 13,14position: no specific mention is however made in said European patent 11 591 either of compounds having a cycloalkyl group anywhere on the co-chain or of compounds having a triple bond at the 13 1 4-position. The present invention provides just carboprostacyclin compounds characterized by having a cycloaliphatic substituent on the 1 5-position of the chain and, at the same time, an acetylenic bond, i.e. a triple bond, at the 13,14-position of the carbo-PGI2 structure.More precisely the invention provides optically active or racemic 15-cycloaliphatic derivatives of 13,1 4-didehydro carboprostacyclins of the following general formula (I)
wherein R is hydrogen or a C1-C6 alkyl group optionally substituted by a group
wherein each of R3 and R4 is, independently, hydrogen or C1-C6 alkyl, or R3 and R4, taken together with the nitrogen atom to which they are linked, form a pentatomic or hexatomic heteromonocyclic ring optionally containing a further heteroatom chosen from 0 and S; n is zero or an integer of 1 to 5; one of R, and R2 is hydrogen or C1-C6 alkyl and the other is hydroxy: and B represents: a) a C4-C7 monocycloaliphatic group either unsubstituted or substituted by one or more substituents chosen from C1-C6 alkyl, C2-C6 alkenyl and C1-C6 alkylidene; b) norbornyl; or c) adamantyl, and the pharmaceutically or veterinarily acceptable salts of the compounds of formula (I).
The invention also includes the pharmaceutical and veterinary compositions containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof. All the possible isomers of formula (I), both stereoisomers, e.g. cis (or Z) and trans (or E) isomers, and optical isomers, i.e. enantiomers, and diastereoisomers, and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I) are included in the scope of the invention. In this application, a dashed line ("') refers to a ring substituent in the a-configurntion, that is, below the plane of the ring, to a bicyclo octane substituent in the endo configuration, and to a side chain substituent in the a-configuration.A wedge line ( < ), on the other hand, refers to a ring substituent in the p-configuration, that is above the plane of the ring, to a bicyclo octane substituent in the exo-configuration, and to a side chain substituent in the p-configuration.
Furthermore, the absolute "R" or "S" configurations of the chiral centers are assigned according to the sequence-rule procedure of JUPAC for the Nomenclature of Organic Chemistry (J.O.C. 35. 9 2849,1970).
Where unspecified "R,S" mixtures are intended.
In the compounds of this invention, there are 2 possible geometric isomers arising from the configuration of the double bond exocyclic to the bicyclo octane ring depending on whether the chain linked to this double bond (chain ce) is on the same side as or the opposite side from the chain (chain ) linked to the 12-position on the bicyclo octane ring: in the first case, the exocyclic double bond is defined as Z, i.e. cis; in the second, it is E, i.e. trans. The symbol ~ in formula (I) means that both geometric isomers are covered by this invention, both separately and in mixtures.
Furthermore each Z or E or Z,E compound may be a racemate (+) or an optically active compound, i.e. a (+) or (-) enantiomer.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) include both the salts of the compounds of formula (I) wherein R is hydrogen with a pharmaceutically or veterinarily acceptable inorganic or organic base, and the salts of the compounds of formula (I) wherein R is an alkyl group substituted by a
group with a pharmaceutically or veterinarily acceptable inorganic acid. Acceptable inorganic bases may be, for example, the hydroxides of alkali, e.g. sodium or potassium, or alkaline earth, e.g. calcium or magnesium, metals, zinc and aluminium.Acceptable organic bases may be, for example, amines like methylamine, diethylamine, trimethylamine, ethylamine, dibutyiamine, triisopropylamine, Nmethylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, P-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar aliphatic aromatic and heterocyclic amines like piperidine, morphoiine, pyrrolidine, piperazine, as well as substituted derivatives like 1methylpiperidine, 4-ethylmorpholine, 1 -isopropylpyrrolidine, 2-methylpyrrolidine, 1 ,4dimethylpiperazine, 2-methylpiperidine, hydrophilic derivatives like mono-, di- and triethanolamine, 2 amino-2-butanol, 2-amino-1 -butanol, 2-amino-2-ethyl- 1 3-propanediol, 2-amino-2-methyl- 1 - propanol, tris-(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, ephedrine, procain, and a and P amino acids like lysine and arginine. Pharmaceutically or veterinarily acceptable inorganic acids include, for example, hydrochloric, hydrobromic, nitric, sulfuric; while organic acids include, for example, citric, fumaric, tartaric, malic, maleic, methanesulfonic and ethanesulfonic.
The alkyl, alkenyl and alkylidene groups may be branched or straight chain groups.
A C1-C6 alkyl group is, preferably, a C1-C4 alkyl group, in particular methyl, ethyl or tert-butyl.
A C2-C6 alkenyl group is, preferably, a C2-C4 alkenyl group, in particular vinyl or allyl.
A C1-CG alkylidene group is, preferably, a C1-C4 alkylidene group, in particular methylene (i.e.
=CH2) or isopropylidene (i.e.
A group
wherein R3 and R4 are, independently, hydrogen or C1-Ca alkyl is, preferably, amino, methylamino, dimethylamino or diethylamino.
A group
wherein R3 and R4 taken together with the nitrogen atom to which they are linked form a heteromonocyclic ring as defined above, is, preferably, a hexatomic or pentatomic heteromonocyclic ring optionally containing oxygen or sulphur, preferably oxygen, as additional heteroatom.
Examples of hexatomic rings are piperidino, morpholino and thiomorpholino; an example of pentatomic ring is pyrrolidino.
Preferred rings are the hexatomic rings, in particular piperidino and morpholino.
When in the above formula (I) R is an unsubstituted C1-C6 alkyl group it is, preferably, methyl or ethyl, most preferably methyl.
When R is a C1-C6 alkyl group substituted by
it is, preferably a C1-C3 alkyl group, in particular ethyl, substituted by a group
5 10 15 20 25 30 35 which is preferably chosen from amino, methylamino, dimethylamino, diethylamino, piperidino, morpholino or thiomorpholino.
Preferred R groups are hydrogen, methyl, p-diethylaminoethyl, p-piperidinoethyl and - morpholinoethyl.
When B is a C4-C7 monocycloaliphatic group it may be either a saturated or unsaturated monocycloaliphatic group optionally substituted as reported above.
Examples of saturated monocycloaliphatic groups are cycloalkyl groups like cyclobutyl, cyclopentyl and cyclohexyl; examples of unsaturated cycloaliphatic groups are cycloalkenyl groups like cyclohexenyl and cyclopentenyl.
When B is norbornyl it is, preferably, 7-norbornyl.
Preferably B is a C4-C7 monocycloalkyl group and, more preferably, a cyclopentyl or cyclohexyl group, either unsubstituted or substituted by a substituent chosen from C1-C4 alkyl, in particular methyl, ethyl or tert. butyl; C2-C4 alkenyl, in particular vinyl or ailyl; and C1-C4 alkylidene, in particular methylene or isopropylidene.
Most preferred group B is cyclopentyl either unsubstituted or substituted as reported hereabove.
Preferably one of R1 and R2 is hydrogen and the other is hydroxy.
Preferably n is 3 or 4.
Preferred salts are the salts of the compounds of formula (I) wherein R is hydrogen with a pharmaceutically or veterinarily acceptable base, e.g. one of the bases listed above.
A preferred class of compounds under this invention is represented by the compounds of formula (I) wherein R is hydrogen, C1-C6 alkyl, ss-piperidino-C1-C3 alkyl or ss-morpholino-C1-C3 alkyl; n is 3 or 4; one of R1 and R2 is hydrogen and the other is hydroxy; and B is cyclopentyl or cyclohexyl, either unsubstituted or substituted by a substituent chosen from C1-C4 alkyl, C2-C4 alkenyl and C1-C4 alkylidene, and the pharmaceutically or veterinarily acceptable salts thereof.
In the above preferred class of compounds with formula (I) B is, most preferably, cyclopentyl either unsubstituted or substituted as therein reported.
When in the above preferred class of compounds of the invention R is C1-C6 alkyl, this is, preferably, methyl or ethyl; when R is -piperidino-C1-C3 alkyl, it is, preferably, i3-piperidinoethyl; when R is ss-morpholino-C1-C3 alkyl, it is, preferably, ss-morpholinoethyl.
When B is cyclopentyl or cyclohexyl substituted by C1-C4 alkyl, the alkyl is, preferably, methyl or ethyl; when B is cyclopentyl or cyclohexyl substituted by C2-C4 alkenyl, the alkenyl is, preferably, vinyl; when B is cyclopentyl or cyclohexyl substituted by C1-C4 alkylidene, the alkylidene is, preferably, isopropylidene.
The nomenclature used to identify the specific compounds falling within the invention is the same illustrated in the above mentioned patent 2013661 B.
According to such a nomenclature, relating to the prostacyclanoic acid structure, the compounds of the invention are referred to as 9a-deoxy-9a-methyiene-prostacycl-5-en-l 3-ynoic acid derivatives with the addition that the prefix "5Z" or "5E" or 5(Z,E) is used to identify the configuration of the double bond exocyclic to the bicyclooctane system.
When unspecified a racemic compound is intended.
As an example of this nomenclature, the compound of formula (I) wherein R is hydrogen, n is 3, R, is hydroxy, R2 is hydrogen, B is cyclohexyl and the configuration of the exocyclic double bond carrying the a-chain is "E" is named; 5E-11 cE,15S-dihydroxy-9a-deoxy-9a-methylene-ss-pentanor-15-cycloheXyl-prostacycl-5-en-13- ynoic acid.
Specific examples of preferred compounds under this invention are the following compounds, both in the form of racemates and in the form of (+) enantiomers: 5E- 11 ,15S-dihydroxy-9a-deoxy-9a-methylene-c()-pentanor- 15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha; ;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyciohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid;; SZ-1 1 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 S-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene] cyclopentyl]prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy 9a methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid; 5(Z,E)- 11 &alpha;,15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5- [(3'-ethyl)-cycl opentyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5 (Z,E)- 11 &alpha;, 15S-di hydroxy-9 a-deoxy-9 a-methyle ne-w-pe ntanor- 1 5-cycl ohexyl-p rostacycl-5-en- 13-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; and the pharmaceutically or veterinarily acceptable salts thereof and the C1-C6 alkyl-esters, ss- piperidinoethylesters and p-morpholinoethyl-esters thereof.
Among the specific preferred compounds indicated above, the (+) enantiometer are particularly preferred.
The compounds of the invention are prepared by a process comprising reacting a compound of formule (H)
wherein B is as defined above, R5 is hydrogen or a hydroxy protecting group, one of R', and R'2 is hydrogen or C1-C6 alkyl and the other is a group XR5 wherein R5 is as here-above defined, and Y is -C--C- or -CH=CZ- wherein Z is chlorine, bromine or iodine, with a Wittig reagent of formula (@@)
wherein n and R are as defined above and R6 is an aryl or alkyl group, and removing the protecting groups possibly present, and, if desired, esterifying an obtained compound of formula (I) wherein R is hydrogen to give a compound of formula (I) wherein R is C1-C6 alkyl optionally substituted as reported above, or saponifying an obtained compound of formula (I) wherein R is C1-C6 alkyl optionally substituted as reported above to give a compound of formula (I) wherein R is hydrogen, or a salt thereof, and/or, if desired, salifying a compound of formula (I) or obtaining a free compound from a salt, and/or, if desired separating a mixture of isomers of formula (I) into the single isomers. When in the compound of formula (@@) Y is-CH=CZ-, the halogen Z is, preferably, bromine.
When in the compound of formula (@@) R5 is a hydroxy protecting group it is, for example, an ether or ester residue which may be readily split under mild conditions, for instance by acid hydrolysis.
Preferred groups include silyl ether residues: for instance trialkylsilyl like trimethyl, dimethyl-tert-butyl, dimethyl-isopropyl, or dimethylethylsilyl; and also acetal and enol ether residues; for instance, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, oxathianyl or groups such as
where Alk is C1-C6 alkyl.
When in the compound of formula (III) R6 is aryl it is preferably, phenyl; when R6 is C1-C6 alkyl ethyl is preferred. The reaction between a compound of formula (Il) and a compound of formula (III) is preferably carried out in the presence of a solvent and, preferably, using an excess of the Wittig reagent of formula (III), e.g. from about 1.5 to about 5 moles of Witting reagent per 1 mole of the compound of formula (II). The solvent may be any solvent which, can in general, be used for Wittig reactions.
Preferably it is an inert organic solvent chosen from ethers, both linear and cyclic, e.g. diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; aliphatic or aromatic hydrocarbons, e.g. n-hexane, nheptane, benzene, toluene or xylene; dialkylsulphoxides, e.g. dimethylsulphoxide; aliphatic acid dialkylamides, e.g. dimethylformamide or dimethylacetamide, halogenated hydrocarbons, e.g.
dichloromethane or chloroform; and phosphoric acid triamides, hexamethylphosphoramide for example. Dimethylsulphoxide is a particularly preferred solvent. The reaction temperature may range from about -1 00 C to the reflux temperature of the solvent used although room temperature is particularly preferred. The reaction is normally carried out in the presence of a base which may be, for example, potassium tert. butoxide or sodium hydride and, preferably, operating under nitrogen atmosphere.
Preferably a compound of formula (II) is used wherein Y is --CH=CZ-- wherein Z is as defined above, preferably bromine or iodine, in particular bromine, as, in this instance, both the triple bond formation and the alkylation with the Wittig reagent take place at the same time in an only one step. In this case it is preferred to use not less than about two moles of compound (Ill) per mole of compound (II). A greater excess of the Wittig reagent, up to 5 moles per mole of compound (II), may be, however, employed and in this way the reaction times can be considerably reduced. The time required by the reaction may vary, depending upon the used reaction conditions, within the range from 0.5 to 24 hours.The removal of the hydroxy protecting groups possibly present in the product of the Wittig reaction may be carried out following known conventional procedures. For example ether residue protecting groups may be removed by mild acid hydrolysis, for instance with mono- or poly-carboxylic acids, such as, e.g., acetic, formic, citric, oxalic, or tartaric, in a solvent such as, e.g., water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol, or with a sulfonic acid such as, e.g., p-toluenesulfonic, in a low molecular weight alcohol such as, e.g., anhydrous ethanol or methanol, or with a polystyrene-sulfonic resin. For example, a 0.1--0.2 5N polycarboxylic acid (like oxalic or citric) is used with a suitable low-boiling solvent miscible with water and readily removable under vacuum at the end of the reaction.Silyl ether residues may be selectively removed in the presence of other protecting groups with F- ions in solvents such as, e.g., tetrahydrofuran and dimethylformamide.
Ester protecting groups may be removed by following typical saponification procedures.
The optional esterification of a compound of formula (I) wherein R is hydrogen to give a compound of formula (I) wherein R is C1-C6 alkyl optionally substituted by
wherein R3and R4 are as defined above, may be carried out following the usual and known esterification procedures of the organic chemistry.
Thus, for example, to obtain a compound wherein R1 is unsubstituted C15 alkyl the esterification may be carried out using the appropriate diazoalkane in an inert organic solvent, e.g.
diethylether, ethylacetate, methylene chloride, acetone or their mixtures at temperatures from about -1 00C to about 200 C, preferably at about 0 C; or using the appropriate alkylhalide, for example in acetone or N,N-dimethylformamide in the presence of a base which may be, for instance, sodium or potassium carbonate or bicarbonate.To obtain a compound wherein R is C1-C6 alkyl substituted by a group
wherein R3 and R4 are as defined above, the esterification may be carried out reacting the free acid with the appropriate alcohol (i.e. aminoalcohol) in the presence of dicyclohexylcarbodiimide, or with the condensation product between the alcohol and dicyclohexylcarbodiimide, in an inert organic solvent such as, e.g., tetrahydrofuran, chloroform, methylene chloride, preferably in the presence of a base, e.g.
sodium bicarbonate or pyridine.
Also the optional saponification of a compound of formula (III) wherein R is C1-C6 alkyl optionally substituted as reported above may be carried out by conventional procedures, for example by reaction with an aqueous solution of an alkali metal, e.g. sodium or potassium, hydroxide or carbonate in the presence of a water miscible solvent, e.g. dioxane, tetrahydrofuran, methanol or ethanol, preferably at room temperature. The saponification product may be recovered as a salt, e.g.
alkali metal salt, or, previous possible acidification, as a free acid.
The optional salification of a compound of formula (I) and the optional preparation of a free compound from its salt as well as the optional separation of a mixture of isomers into the single isomers may be carried out by usual methods known per se. In particular, for example, single isomers may be obtained from their mixture by means of, e.g., fractional crystallization from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid at low, medium or high pressure. For column and thin layer chromatography, for instance, silica gel or magnesium silicate may be used as support with a solvent such as, e.g., cyclohexane, n-hexane, benzene, methylene chloride, diethyl ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.
Thus, for example, the above illustrated reaction between a compound (II) and a compound (III) gives a mixture of geometric isomers in that the new exocyclic double bond formed in the reaction may be Z or E: if desired, the individual geometric isomers may be separated by one of the above reported techniques.
The compounds of formula (II) may be prepared by following known procedures, for example those described for preparing the analogous compounds in the above mentioned UK patent 201 2265B, UK patent 2017699B, UK patent 2013661 B, and European patent 11591.
In particular, for example, a compound of formula (II) may be obtained by the following steps: 1) reaction of a compound of formula (IV)
wherein Rs is as defined above and G is a protected carbonyl group, with a Wittig reagent of formula (V)
or with a modified Wittig reagent of formula (Va)
wherein B and R6 are as defined above and M is a cation, to obtain a compound of formula (VI)
wherein G, Rs and B are as defined above; 2) halogenation of an obtained compound of formula (Vl) to give a compound of formula (all)
wherein G, Rsf Z and B are as defined above;; 3) reduction or nucleophilic addition on the free oxo group of the compound (VII) followed by separation of the obtained mixture of the Sand R alcohols and optional protection of the newly formed hydroxy group, to give a compound of formula (VIII)
wherein G, R5, Z, B, R'1 and R'2 are as defined above; 4) optional dehydrohalogenation of a compound of formula (VIII) to obtain a compound of formula (VIIIa)
wherein G, R5, B, R'1 and R'2 are as defined above; and 5) removal of the carbonyl protecting group and G and optional removal of the hydroxy protecting groups possibly present either in a compound of formula (VIII) or in a compound of formula (VIlla).
In the compound of formula (IV) the protected carbonyl group G is a carbonyl group preferably protected as acetal orthioacetal, for example a dimethoxyacetal, a diethoxyacetal, a dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as ketal or thioketal, for example an ethylendioxyketal a propylendithioketal a propylendioxyketal an ethylenedithioketal preferably an ethylenedioxyketal.
In a compound of formula (V) R6 is, preferably, a phenyl group.
In a compound of formula (Va) R6 is, preferably, a methyl group and the cation M is, preferably, an alkali metal cation, sodium or potassium in particular.
The reaction between a compound of formula (IV) and a compound of formula (V) or (Va) may be carried out using, approximately, the same reaction conditions reported above for the reaction between a compound of formula (II) and a compound of formula (ill).
The halogenation of a compound of formula (VI) to give a compound of formula (VII) may be carried out following known standard procedures, for example by treatment with pyridinium bromide perbromide.
The reduction of the free oxo group in the compound of formula (VII), leading to a mixture of secondary S and R alcohols, may be performed by conventional method, e.g. by treatment with a mixed hydride such as, for instance, NaBH4 or LiAIH4, preferably NaBH4, using the usual reaction conditions reported in the organic chemistry for this kind of reduction. The nucleophilic addition on the free oxo group of the compound of formula (VII), leading to a mixture of tertiary Sand R alcohols, may be carried out in a conventional way too, for example by reaction with a Grignard reagent of formula RxMgZ wherein Rx is C1-C5 alkyl and Z is a halogen atom as defined above, according to standard reaction conditions.
The separation of the obtained mixture of either secondary or tertiary S and R alcohols may be carried out by the already indicated fractional crystallization or chromatography techniques.
The optional protection of the newly formed hydroxy group may be carried out by any known conventional etherification or esterification procedure.
The optional dehydrohalogenation of a compound of formula (VIII) to give a compound of formula (Vllla) may be performed by treatment with an appropriate base according to conventional procedures too, and standard procedures may be followed also for removing the carbonyl protecting group, and, if desired, the hydroxy protecting groups, in a compound of formula (VIII) or (Vllla).
In particular, mild acid hydrolysis as reported above is preferred to remove acetal or thoacetal carbonyl protecting groups.
The compounds of formula (Ill) and (IV) arc- known compounds and may be prepared by known methods e.g. those described in UK patent 2013661 B.
The compounds of formula (V) and (Va) may be prepared by the same prqcedure used to obtain a compound of formula (III), e.g. that described in UK patent 2013661 B for the preparation of analogous compounds.
in particular, for example, a compound of formula (V) may be prepared reacting a compound of formula (IX)
wherein B is as defined above and Hal is a halogen atom, with an excess amount of a compound of formula (R6)3P wherein R6 is as defined above, triphenylphosphine for instance, in an organic solvent such as, e.g., benzene, acetonitrile or diethylether, and then treating the product phosphonium salt with an equivalent amount of an inorganic base, e.g. NaOH or KOH.
Analogously, a compound of formula (Va) may be prepared from a compound of formula (X)
wherein R6 and.B are as defined above, with a suitable base carrying the M+ cation, which base may be, for instance, an alkalimetal hydride such as, e.g., sodium or potassium hydride, an alkali metal alkoxide such as, e.g. sodium or potassium tert. butoxide, an alkali metal salt of a carboxyamide such as, e.g., N sodioacetamide and N-sodiosuccinimide.
The compounds of formula (IX) and (X) are in turn prepared using standard methods, for example those described by Corey et al. in J. Amer. Chem. Soc., 90, 3247 (1968) and 88, 5654 (1966).
The compounds of formula (I) exhibit substantially the same pharmacological activities known for carboprostacyclins and illustrated, for instance, in the previously mentioned UK patents 2012265B, 2014143B,2019847B,2017699B,2013661 B and European patent 11591.
In particular, the compounds of formula (I) show high platelet antiaggregating and disaggregating activity in that they strongly inhibit, prevent and reverse the blood platelet aggregation.
The following table reports, for example, the data concerning the platelet antiaggregating activity obtained for the compound of the invention (+)5E-1 1 err,1 5S-dihydroxy-9a-deoxy-9a-methylene pentanor-l 5-cyclopentylprostacycl-5-en-l 3-ynoic acid in comparison with the data obtained for the compound (+)5E,13E-11ce,15S. dihydroxy-9a-deoxy-9a-methyíene-prostacycl-5,13-dienoic acid, i.e.
( +)SE-carboprostacyclin.
Table
Compounds IC1 ng/ml (+)5E-carboprostacycíin 30 (+) SE- 11 a, 1 SS-dihydroxy-9a-deoxy-9a- methylene-co-pentanor-1 15-cyclopentyl prostacycl-5-en-1 3-ynoic acid 2.7 The IC100 reported values, represent the dose of compound which has been found to produce the 100% inhibition of the platelet aggregation induced in vitro by 0.4 yg/ml ADP in guinea pig platelet rich plasma.Precisely the data reported in the above table were obtained by the following technique: blood was drawn from the abdominal aorta of male albino guinea pigs fasted for 16 hours and of average weight 450 g, after light ether anaesthesia, using as anticoagulant a 3.8% solution of sodium citrate in distilled water (1 part sodium citrate solution and 9 parts blood).
The platelet rich plasma (PRP) of each single animal was collected by centrifugation of the blood at 1000 rpm for 8 minutes; after checking spontaneous aggregation, the PRP found suitable were combined in a single pool and the platelet count made. If necessary, the number of platelets was corrected with autologous platelet poor plasma (PPP), to obtain a PRP pool containing 750,000 platelets/mm3.
Platelet aggregation was investigated with an Elvi Mod. 840 aggregometer connected to a 2channel Servogor 2S type RE 573 recorder. The reagents were placed in the aggregometer in the following order: 0.4 ml PRP, 0.08 ml physiological saline and 0.01 ml of solution of the test compound or solvent. After incubating at 370C for 5 minutes, the aggregating agent (ADP 0.4 yg/ml) was added.
The aggregation tracing was monitored for 10 minutes after addition of the aggregating agent (PRP agitation speed: 800 rpm). All the dilutions of the test compound were tested on the sane pool of PRP collected from 5-6 guinea pigs. The data reported in the above table clearly show that the antiaggregating activity of the compound of the invention is much greater than that of the reference compound.
The high platelet anti-aggregating and disaggregating activity exhibited by the compounds of formula (I) indicates their use to inhibit platelet aggregation, to decrease adhesions, to prevent clot formation, and to dissolve recently-formed clots. The platelet anti-aggregating activity is also associated with a relaxation of the coronary arteries. Thus the compounds of formula (I) can be useful, e.g., in preventing and treating myocardial infarctions, and, in general, in treating and preventing thromboses, in treating conditions like atherosclerosis, arteriosclerosis, and, more generally, hyperlipidemia.
The compounds of the invention also exhibit a certain vasodilatory, i.e. hypotensive, effect and so they may be useful for treating the syndromes caused by arterial hypertension.
While the compounds of formula (I) have particular utility as selective anti-aggregating and/or disaggregating agents and, in addition, as vasodilating, i.e. hypotensive, agents, they may also be used for treating obstructive pulmonary diseases such as, e.g., bronchial asthma, or to take advantage of their anti-ulcerogenic and antisecretory activities, as is shown, e.g. by the fact that they have been found to be active in the bronchodilation test on the awake or anaesthetized guinea-pig [Prostaglandins and Medicine vol. 2, 459-466 (1979)], in preventing ethanol-induced, stress-induced or ASA-induced gastric ulcers and indomethacin-induced intestinal ulcers [Gastroenterology 77, 761-767 (1979), and Prostaglandins and Medicine vol. 5, 131-139 (1980)], and in inhibiting gastric secretion according to the method of Shay et al. [Gastroenterology 26, 906 (1954)].
When the compounds of the invention are given as anti-aggregating or disaggregating agents, the routes of administration can be the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary, for adult humans, 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 dosages and methods of administration of the compounds, when used as hypotensive and vasodilatory agents, are about the same as those used for the antiaggregating application.
For the 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 0.01-4 mg/kg can be given from 1 to 4 times a day to adult humans 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 isoproterenol, ephedrine, xanthine derivatives, such as theophylline and aminophylline, or corticosteroids.
For the anti-ulcerogenic and anti-secretory applications the compound of the invention can be administered, for example, by intravenous infusion or by intravenous, subcutaneous or intramuscular injection; doses for intravenous infusion range from 0.1 g to 500 yg/kilo/minute. The total daily dose for both injection and infusion is about 0.1-20 mg/kg depending on the age, weight and condition of the patient and on the administration method. Also rectal administration and oral administration are useful for these kinds of applications.
The toxicity of the compounds of the invention, e.g. the specific one 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 aerosols or solutions for nebulizers; in the form of sterile implants for prolonged action; or intravaginally in the form, e.g., of bougies.
As already said, the invention includes pharmaceutical and veterinary compositions containing a compound of the invention and a pharmaceutically or veterinarily acceptable carrier and/or diluent. The carrier or diluent and the form of the compositions can be any conventionaily 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, stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils.
For administration by suppositories suitable carriers may be, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
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 surfactant, to the pharmaceutical formulation.
The abbreviationsTHF, DMSO and DMF used in the examples stand, respectively, for tetrahydrofuran, dimethylsulphoxide and dimethylformamide.
The following examples illustrate but do not limit in any way the invention.
Example 1 To a solution of dimethoxymethylphosphonate (62 g) in tetrahydrofuran (500 ml) cooled to -700C, BuLi (0.8 moles) in n-hexane (460 ml) was added and then a 0.25 M solution of methoxycarbonylcyclohexane (35.5 g) in THF (150 ml) was added too. The reaction mixture was cooled and kept at -700C for 1 hour, then stirred at room temperature for 3 hours.
The solution was cooled at10 C and then treated with a solution of acetic acid (50 ml) in THF (50 ml), filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride, the organic phase was washed, dried and distilled in vacuo.
After distillation dimethyl-(2-cyclohexyl-2-oxo-ethyl)-phosphonate was recovered (36.5 g; b.p.
0.8 mmHg: 132-1340C).
In similar way starting from the appropriate cycloaliphatic carboxylic acid methyl esters, the following compounds were obtained: dimethyl-(2-cyclobutyl-2-oxo-ethyl)-phosphonate; dimethyl-(2-cyclopentyl-2-oxo-ethyl)-phosphonate; dimethyl-[2-(3'-methyl-cyclopentyl)-2-oxo-ethyl]-phosphonate; dimethyl-[2-(3'-ethyl-cyclopentyl)-2-oxo-ethyl]-phosphonate; di methyl-[2-(3'-isopropylidene-cyclopentyl)-2-oXo-ethyl]-phosphonate; dimethyl-[2-(4'-methyl-cyclohexyl)-2-oxo-ethyl]-phosphonate; dimethyl-[2-(4'-tert. butyl-cyclohexyl)-2-oxo-ethyl]-phosphonate; dimethyl-[2-(4'-vinyl-cyclohexyl)-2-oxo-ethyl]-phosphonate; and dimethyl-[2-(4'-isopropylidene-cyclohexyl)-2-oxo-ethyl]-phosphonate.
Example 2 To a stirred suspension of triphenylmethylphosphonium iodide (11 8.3 g) and potassium tert.
butoxide (68 g) in dry toluene (350 ml) 4-ethylcyclohexanecarboxylic acid phenoxy ester (78.9 g) was added maintaining the temperature at about 400 C. Then the mixture was refluxed for 5 hours, cooled at room temperature and treated under vigorous stirring with water (120 ml). The organic phase was washed with water then treated with acetic acid (80 ml) and with a solution of potassium iodide (80 g) in water (70 ml).
Under vigorous sitrring n-hexane (70 ml) was added and the precipitate was filtered obtaining trimethyl-2-oxo-2-(4'-ethylcyclohexyl)-ethylphosphonium iodide (108 g).
To a solution of this compound in water (130 ml) few drops of phenolphthalein were added and the mixture was treated under vigorous stirring with methylene chloride (130 ml) and with 1 N NaOH until weakly basic pH. The methylene chloride was separated, washed with water, dried and evaporated to dryness. The residue was taken up with diethyl ether and n-hexane (10:90) and the precipitate was filtered to give 4-ethylcyclohexylcarbonylmethylidentriphenylphosphorane.
In similar way the cyclopentylcarbonylmethylidentriphenylphosphorane was prepared.
Example 3 A solution of 3-oxo-3,3-ethylendioxy-6-exo-formyl-7-endo-hydroxy-7-(2'-tetrahydropyranyloxy)- bicyclo[3.3.0]octane (6 g) in benzene (20 ml) was added to a stirred suspension of the sodium salt of dimethyl-(2-cyclohexyl-2-oxo-ethyl)-phosphonate in benzene which sodium salt was previously prepared by adding a solution of the phosphonate (6.08 g) in benzene (10 ml) to a suspension of 80% NaH (0.78 g) in benzene (100 ml).
The coupling of aldehyde to the phosphonate was completed in 1 5 minutes; then the reaction mixture was washed with water, dried and evaporated to dryness.
The residue was purified by column chromatography affording 6 g of 3-oxo-3,3-ethylendioxy-6exo-( 1 '-trans-3'-oxo-3'-cyclohexyl-prop- 1 -enyl)-7-endo-hydroxy-7-(2'-tetrahydropyranyloxy)- bicyclo[3.3.0]octane.
Example 4 To a solution of 3,3-ethylendioxy-3-oxo-6-exo-formyl-7-endo-hydroxy-7-(2'- tetrahydropyranyloxy)-bicyclo[3.3.0]octane (3 g) in benzene (30 ml) 1.01 molar equivalents of 4ethylcyclohexylcarbonylmethylidenetriphenylphosphorane ylide were added. After 2 hours the mixture was absorbed on silica gel column and eluted with n-hexane-ethylacetate affording 3-oxo-6-exo-[1 '- trans-3 '-oxo-3 '-(4'-ethylcyclohexyl)-prop- 1 -enyl]-7-endo-hydroxy-7-(2'-tetra hydropyranyloxy)- bicyclo[3.3.0]octane (2.86 g).
Example 5 Using in the procedure of the Example 4 3,3-ethylendioxy-3-oxo-6-exo-formyi-7-endo-hydroxy- 7-acetate-bicyclo[3.3.0.]octane and the cyclopentylcarbonylmethylidentriphenylphosphorane the 3oxo-6-exo-( 1 '-trans-3'-oxo-3'-cyclopentylprop- 1 -enyl)-7-endo-hydroxy-7-acetate- bicyclo[3.3.0]octane was obtained.
Example 6 Using in the procedure of the Example 3 the appropriate phosphonates prepared using the procedure of the Example 1 the following compounds were obtained: 3-oxo-3,3-ethylendioxy-6-exo-(1'-trans-3'-oxo-3'-cyclobutyl-prop-1-enyl)-7-endo-hydroxy-7 (2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3 ,3-ethylend ioxy-6-exo-( 1 '-tra ns-3'-oxo-3 '-cyclopentyl-prop- 1 -enyl)-7-endo-hydroxy-7 (2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-3'-oxo-3'-[(3"-methyl)-cyclopentyl]-prop- 1 -enyl 1-7 endo-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane;; 3-oxo-3 ,3-ethylendi oxy-6-exo-[ 1 -tra ns-3'-oxo-3'-[(3"-ethylcyclopentyl]-propyl- 1 -enyl J-7-endo- hydroxy-7-(2'-tetrahydropyra nyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-{1'-trans-3'-oxo-3'-[(3"-isopropylidene)-cyclopentyl]-prop-1-enyl]7-endo-hydroxy-7-(2'-tetrahydropyanyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethyl endioxy-6-exo-1 1 '-tra ns-3'-oxo-3' -[ (48-mëthyl)-cyciohexyl] prop- 1 -enyl 1-7- endo-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane;; 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-3'-oxo-3'-[(4"-tert. butyl)-cyclohexyl]prop- 1 -enyl 1-7- endo-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-3'-oxo-3'-[(4"-vinyl)-cyclohexyl]prop-1 -enyl|-7-endo- hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-{1'-trans-3'-oxo-3'-[(4"-isopropylidene)-cyclohexyl]prop-1-enyl]7-endo-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane.
Example 7 A solution of 3-oxo-3,3-ethylendioxy-6-exo-{1'-trans-3'-cyclohexyl-prop-1'-enyl)-7-hydroxy-7- (2-tetrahydropyranyloxy)-bicyclo[3.3.0]octane (4 g) in pyridine (40 ml) was treated under stirring with pyridinehydrotribromide (4.8 g) for 2 hours. The mixture was diluted with aqueous 30% NaH2PO4 solution (250 ml) and exhaustively extracted with ethylacetate.
The collected organic phases were washed with water, dried and evaporated to dryness. After SiO2 column chromatography (n-hexane-ethylacetate 70:30) 2.5 g of 3-oxo-3,3-ethylendioxy-6-exo (1 '-tra ns-2'-bromo-3 '-oxo-3 '-cyclohexyl-prop- 1 '-enyl)-7-hydroxy-7-(2"-tetrahydropyranyloxy)- bicyclo[3.3.0]octane were obtained.
Using analogous procedure the following compounds were obtained: 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-2'-bromo-3'-oxo-3'-cyclopentyl-prop- 1 '-enyl)-7- hydroxy-7-(2"-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo- 1 '-trans-2'-bromo-3'-oxo-3'-[ (3"-methyl)-cyclopentyl]prop-1 'enyl]-7-hydroxy-7-(2"-tetrahydropyranyloxy-bicyclo[3.3.0]octane; 3-oxo-3,3-ethyle ndioxy-6-exo-l 1 '-trans-2'-bromo-3'-oxo-3'-[(3"-ethyl-cyclopentyl]-prop- 1'enyl )-7-hydroxy-7-(2"-tetra hydropyra nyloxy)-bicyclo[3.3 .O]octane; 3-oxo-3,3-ethylendioxy-6-exo-(1'-trans-2'-bromo-3'-oxo-3'-[(3"-isopropylidene)cyclopentyl]prop-1'-enyl]-7-hydroxy-7-(2"-tetrahydropranyloxy)-bicyclo[3.3.0]octane;; 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-2'-bromo-3'-oxo-3'-[(4"-methyl)-cyclohexyl]prop-1 1'- enyl]-7-hydroxy-7-(2"-tetrahydropyanyloxy)-bicyclo[3.3.0]octane; 3-oxo-3 ,3-ethylendioxy-6-exo-l 1 '-tra ns-2'-bromo-3'-oxo3'-[(4"-tert. butyl)-cycloh exyliprop- 1'- enyl]-7-hydroxy-7-(2"-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-[1'-trans-2'-bromo-3'-oxo-3'-[(4"-ethyl)-cyclohexyl]prop-1'enyl]-7-hydroxy-7-(2"-tetrahydropyranyloxy)-bicyclo[3.3.0]octane; 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-2'-bromo-3'-oxo-3'-cyclopentyl-prop- 1 '-enyl)-7hydroxy-7-acetate-bicyclo[3.3.0]octane and the 7-acetate derivatives of the other hereabove mentioned compounds.
Example 8 A solution of 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-3'-oxo-3'-[(48-vinyl)-cyclohexyl]-prop-1'- enyl]-7-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane (4 g) in pyridine (40 ml) was treated with 2.2 molar equivalents of pyridinehydrotribromide for 2 hours. The reaction mixture was diluted with an aqueous 30% NaH2PO4 solution, extracted with ethyl acetate, washed with water until neutral and dried. The solvent was evaporated in vacuo and the residue was dissolved in acetone and treated for 12 hours at room temperature with an excess of sodium iodide (10 g).The red solution was treated with 1 N aqueous sodium thiosulphate till decolourization diluted with water, extracted with ethyl acetate and after usual work-up and SiO2 gel chromatography 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans2'-bromo-3'-oxo-3'-[(4"-vinyl)-cyclohexyl]-prop-1'-enyl]-7-hydroxy-7-(2'-tetrahydropyanyloxy)bicyclo[3.3.0]octane (1.82 g) was obtained.
In similar way the compound 3-oxo-3,3-ethylendioxy-6-exo-( 1 '-trans-2'-bromo-3'-oxo-3'-[(4"isopropylidene)-cyclohexyl]-prop-1'-enyl]-7-hydroxy-7-(2'-tetrahydropyranyloxy)-bicyclo[3.3.0]octane was obtained.
Example 9 To a stirred solution of NaBH4 (0.75 mg) in MeOH (30 ml) cooled at -1 00C a solution of 3-oxo3,3-ethylendioxy-6-exo-( 1 '-trans-2'-bromo-3'-oxo-3'-cyclohexyl-prop- 1 '-enyl)-.7-hydroxy-7-(2' tetrahydropyranyloxy)-bicyclo[3.3.O]octane (2.5 g) in MeOH (15 ml) was added. After 1 hour the reaction mixture was diluted with 30% aqueous NaH2PO4 (200 ml) and extracted with ethylacetate.
The organic phase was collected, dried and, after evaporation in vacuo of the solvent, the residue was taken up with acetone (20 ml). After addition of aqueous 1 N oxalic acid solution (20 ml) the mixture was heated at 400C for 15 hours. Then the acetone was removed in vacuo, the aqueous emulsion was extracted with ethylacetate. The organic extracts were collected, washed with water, dried over MgSO4 and the solvent was evaporated.
The residue was chromatographed on silica gel with ethylacetate:n-hexane 80:20, affording in the order 3-oxo-6-exo-( 1 '-trans-2'-bromo-3' R-hydroxy-3'-cyclohexyl-prop- 1 '-enyl)-7-endo-hydroxybicyclo[3.3.0]octane (0.48 g) and 3-oxo-6-exo-(1'-trans-2'-bromo-3'S-hydroxy-3'-cyclohexyl-prop-1'- enyl)-7-endo-hydroxy-bicyclo[3.3,0]octan (0.88 g).
Example 10 Using in the procedure of the Example 9 the a-brnmo-a,'3-unsaturnted ketones obtained in the Examples 7 and 8 the following bromo-allylic alcohols were obtained: 3-oxo-6-exo-( 1 '-tra ns-2 '-bromo-3' S-hydroxy-3'-cyclopentyl-prop- 1 '-enyl)-7-endo-hydroxy- bicyclo[3.3.0]octane; 3-oxo-6-exo-[ 1 '-trans-2'-bromo-3'S-hydroxy-3'-[(3"-methyl)-cyclopentyl]-prop- 1 '-enyl 1-7- endo-hydroxy-bicyclo[3.3.0]octane; 3oxo-6-exo-[ 1 '-trans-2'-bromo-3' S-hydroxy-3'-[(3"-ethyl)-cyclopentyl]-prop- 1 '-enyl 1-7-endo hydroxy-bicyclo[3.3.0]octane; ; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(3"-isopropylidene)-cyclopentyl]-prop-1'-enyl 7-endo-hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-( 1 '-trans-2'-bromo-3'S-hydroxy-3'-cyclobutyl-prop-1 '-enyl)-7-endo-hydroxy- bicyclo[3.3.0]octane; 3-oxo-6-exo-[ 1 '-trans-2'-bromo-3'-S-hydroxy-3'-[(4"-methyl)-cycloheXyl]-prop- 1 '-enyl t-7- endo-hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(4"-ethyl)-cyclohexyl]-prop-1'-enyl]-7-endo hydroxy-bicyclo[3.3.O]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(4"-t-butyl)-cyclohexyl]-prop-1'-enyl]-7-endohydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1 '-tra ns-2'-bromo-3' S-hyd roxy-3'-[(4"-vinyl )-cyclohexyl]-prop- 1 '-enyl t-7-endo- hydroxy-bicyclo[3.3.0]octane;; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(4"-isopropylidene)-cyclohexyl]-prop-1'-enyl7-endo-hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-( 1 '-trans-2'-bromo-3' S-hydroxy-3'-cyclopentyl-prop- 1 '-enyl)-7-endo-hydroxy-7acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1 '-tra ns-2'-bromo-3 ' S-hydroxy-3'-[(3"-methyl)-cycl openyl]-prop- 1 '-enyl }-7- endo-hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1 '-tra ns-2'-bromo-3' S-hyd roxy-3'-[(3"-ethyl)-cyclopentyl]-prop- 1 '-enyl @-7-endo- hydroxy-7 -a cetate-bicyclo [3.3.0]octane; 3-oxo-6-exo-[1 '-tra ns-2'-bromo-3' S-hydroxy-3'-[(3"-isopropyl idene)-cyclopentyl]-prop- 1 '-enyl @- 7 endo hydroxy 7-acotate bicyclo[3.3.0]octane;; 3-oxo-6-exo-( 1 '-tra ns-2'-bromo-3' S-hydroxy-3 '-cyclobutyl-prop- 1 '-enyl)-7-endo-hydroxy-7acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo- 1 '-tra ns-2'-bromo-3 ' S-hyd roxy-3'-[(4"-methyl)-cyclohexyl]-prop- 1 '-enyl 1-7-endo- hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-{ 1 '-tra ns-2'-bromo-3 ' S-hyd roxy-3'-[(4"-ethyl)-cyclohexyl]-prop- 1 '-enyl }-7-endo- hydroxy-7-acetate-bicyclo[3.3 .O]octane; 3-oxo-6-exo-{ 1 '-trans-2'-bromo-3'S-hydroxy-3'-[(4"-t-butyl)-cyclohexyl]-prop-1 '-enyli-7-endo- hydroxy-7-acetate-bicyclo[3.3 .0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(4"-vinyl)-cyclohexyl]-prop-1'-enyl]-7-endohydroxy-7-acetate-bicyclo[3.3.0]octane;; 3-oxo-6-exo-[1'-trans-2'-bromo-3'S-hydroxy-3'-[(4"-isopropylidene)-cyclohexyl]-prop-1'-entyl]7-endo-hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-(1'-trans-2'-bromo-3'R-hydroxy-3'-cyclopentyl-prop-1'-enyl)-7-endo-hydroxybicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(3"-methyl)-cyclopentyl]-prop-1'-enyl]-7endo-hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-{ 1 '-tra ns-2'-bromo-3' R-hyd roxy-3'-[(3"-ethyl)-cyclopentyl]-prop- 1 '-enyl -7-endo- hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(3"-isopropylidene)-cyclopentyl]-prop-1'-enyl]7-endo-hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-(1'-trans-2'-bromo-3'R-hydroxy-3'-cyclobutylprop-1'-enyl)-7-endo-hydroxy bicyclo[3.3.0]octane;; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-methyl)-cyclohexyl]-prop-1'-enyl]-7endo-hydroxy-bicyclo[3.3.0joctane; 3-oxo-6-exo-[ 1 '-tra ns-2'-bromo-3' R-hyd roxy-3'-[(4"-ethyl)-cyclohexyl]-prop- 1 '-enyl -7-endo- hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[ 1 '-trans-2'-bromo-3' R-hyd roxy-3'-[(4"-t-butyl-cyclohexyl]-prop- 1 '-enyl )-7-endo- hydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[ 1 '-tra ns-2'-bromo-3 ' R-hydroxy-3'-[(4"-vinyl)-cyclohexyl]-prop- 1 '-enyl}-7-endohydroxy-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-isopropylidene)-cyclohexyl]-prop-1'-enyl] 7-endo-hydroxy-bicyclo[3.3.0]octane;; 3-oxo-6-exo-( 1 '-trans-2'-bromo-3' R-hyd roxy-3'-cyclopentylprop- 1 '-enyl)-7-endo-hydroxy-7 acetate-bicyclo[3.3.O]octane; 3-oxo-6-exo-[1 '-trans-2'-bromo-3' R-hyd roxy3'-[(3N-methyl )-cyclopentyl]-prop- 1 '-enyl )-7- endo-hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-{ 1 '-trans-2'-bromo-3' R-hyd roxy-3 '-[(3"-ethyl)-cyclopentyl]-prop- 1 '-enyl 1-7-endo- hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-(1 '-tra ns-2'-bromo-3' R-hyd roxy-3'-[(3"-isopropyl idene)-cyclopentyl]-prop- 1'-enyl]- 7-endo-hydroxy-7-acetate-bicyclo[3.3.0]octane;; 3-oxo-6-exo-( 1 '-trans-2'-bromo-3' R-hydroxy-3'-cyclobutyl-prop- 1 '-enyl)-7-endo-hydroxy-7acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-methyl)-cyclohexyl]-prop-1'-enyl]-7-endo hydroxy-7-acetate-bicyclo[3.3.0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-ethyl)-cyclohexyl]-prop-1'-enyl]-7-endo hydroxy-7-acetate-bicyclo[3.3,0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-t-butyl)-cyclohexyl]prop-1'-enyl]-7-endo hydroxy-7-acetate-bicyclo [3.3 .O]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-vinyl)-cyclohexyl]-prop-1'-enyl]-7-endo hydroxy-7-acetate-bicyclo[3.3.0]octane;; 3-oxo-6-exo-[1'-trans-2'-bromo-3'R-hydroxy-3'-[(4"-isopropylidene)-cyclohexyl]-prop-1'-enyl] 7-endo-hydroxy-7-acetate-bicyclo[3.3.0]octane.
Example 11 Under nitrogen atmosphere 4-carboxy-butyl-triphenylphosphonium bromide (6.5 g) was added to a mixture of potassium tert. butoxide (3.2 g) and DMSO (32 ml); then this mixture was treated with a solution of 3-oxo-6-exo-( 1 '-trans-2'-bromo-3'-cyclohexyl-3' S-hydroxy-prop-1 '-enyl)-7-hydroxy bicyclo[3.3.0]octane (0.88 g) in DMSO (3 ml).
After 3 hours the reaction mixture was diluted with water, acidified with 2NH2SO4 and extracted with diethyl ether.
The ethereal phase was extracted with 1 NNaOH aqueous solution; the aqueous alkaline extracts were collected; acidified to pH 5 and extracted with n-pentane-diethyl ether (20:80). The final organic extracts were collected, washed with water, dried and evaporated to dryness.
The residue was chromatographed on silica gel [eluent: diethyl ether (100 ml) acetic acid (0.4 ml)] so obtaining in the order 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13ynoic acid (0.12 g), NMR (CDCl3) # p.p.m.: 5.27 (1H, t) H5 ; 4.17 (1H, d) H15; 4.00 (1H, m) H11; and 5E-1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-cyclohexyl-prostacycl-5-en- 13ynoic acid (0.18 g), NMR (CDCl3) p.p.m.: 5.26 (1 H, t) H5; 4.17 (1 H, d) H15; 4.01 (1 (1H, m) H11.
By proceeding analogously the following compounds were obtained: 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid; SE-1 1 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 S-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) S p.p.m.: 0.98 (3H, d); 3.99 (1H, m); 4.19 (1H, broad d); 5.25 ( 1 H, m); S E-1 1 a,1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-ynoic acid, NMR (CDCl3) a p.p.m.: 0.91 (3H, d); 1.31 (2H, m); 3.95 (1 H, m); 4.21 (1 H, broad d); 5.27 (1H, m); 5E-1 1 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-tert. butyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 1.70 (6H,s); 4.01 (1H,m); 4.22 (1H, broad d); 5.27 (1 H, m); 5Z- 11 a, 1 5S-di hyd roxy-9 a-deoxy-9a-methylene-#-pentanor- 1 5-cyclobutyl-prostacycl-5-en- 13ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)cyclohexyl]prostacycI-5-en-1 3-ynoic acid, NMR (CDCI,) 6 p.p.m.: 0.98 (3H, d); 3.99 (1H, m); 4.19 (1H, broad d); 5.26 (1 H, m); 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 0.91 (3H,d); 1.31 (2H, m); 3.95 (1H, m); 4.21 (1 H, broad d); 5.28 (1 H, m); 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)- cyclohexyl]prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 1.70 (6H, s); 4.01 (1H, m); 2.22 (1H, broad d); 5.28 (1 H, m); 5(Z,E)- 1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-1 5-cyclobutyl-prostacycl-5-en1 3-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)- 1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5 [(4'-vinyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid; ; 5-(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid; and 5(Z,E)- 11 a, 1 5S-di hyd roxy-9 a-deoxy-9 a-methyle ne-cl)-pentanor- 1 5-cyclohexyl-prostacycl-5-en- 1 3-ynoic acid.
Example 12 Under nitrogen atmosphere 4-carboxy-butyl-triphenyl-phosphonium bromide (6.5 g) was added to a mixture of potassium tert. butoxide (3.2 g) and DMSO (32 ml); then this mixture was treated with a solution of 3-oxo-6-exo-( 1 '-trans-2'-bromo-3'-cyclopentyl-3'S-hydroxy-prop-1 '-enyl)-7-hydroxybicyclo[3.3.0]octane (0.84 g) in DMSO (3 ml).
After 3 hours the reaction mixture was diluted with water, acidified with 2N H2SO4 and extracted with diethyl ether.
The ethereal phase was extracted with 1 N NaOH aqueous solution; the aqueous alkaline extracts were collected; acidified to pH 5 and extracted with n-pentane: diethyl ether (20:80). The final organic extracts were collected, washed with water, dried and evaporated to dryness.
The residue containing 5(Z,E,)-11&alpha;15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15- cyclopentyl-prostacycl-5-en-1 3-ynoic acid was chromatographed on silica gel [eluant: diethyl ether (100 ml) acetic acid (0.4 ml)] so obtaining in the order 5Z-1 1a,1 SS-dihydroxy-9a-deoxy-9a methylene-co-pentanor-1 5-cyclopentyl-prostacycl-5-en-l 3-ynoic acid (0.10 g), NMR (CDCl3) S p.p.m.: 3.93 (1 H, broad m); 4.22 (1 H, broad d); 4.55 (3H, broad m); 5.24 (1 H, m); and 5E-11 a,1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-1 5-cyclopentyl-prostacycl-5-en1 3-ynoic acid (0.17 g), NMR (CDCl3) # p.p.m.: 3.93 ( 1 H, broad m); 4.22 ( 1 H, broad d); 4.55 (3H, broad m); 5.22 (1 H, m).
By analogous procedure the following compounds were obtained: 5(Z,E)-11 &alpha;, 1 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-1 5-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)- 11 &alpha;, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(3'-ethyl)-cyclopentyl] prostacycl-5-en-1 3-ynoic acid; S(Z,E)- 11 a,1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-1 5-[(3'-tert. butyl)-cyclopentyl] prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid, NMR (CDCl3) S p.p.m.: 0.93 (3H, d); 3.97 ( 1 H, m); 4.20 ( 1 H, broad d); 5.24 ( 1 H, m); 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) S p.p.m.: 0.93 (3H, d); 1.33 (2H, m); 3.94 (1H, m); 4.17 (1H, broad d); 5.25 (1H, m); 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 1.70 (6H, s); 4.03 (1H, m); 4.22 (1H, broad d); 5.27 (1 H, m); SZ-1 1 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-1 5-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid, NMR (CDCl3) # p.p.m.: 0.97 (3H, d); 3.97 ( 1 H, m); 4.20 ( 1 H, broad d); 5.25 (1 H, m); 5Z-1 1 a, 1 5 S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-[(3'-ethyl)-cyclopentyl] prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 0.93 (3H, d); 1.33 (2H, m); 3.94 (1H, m); 4.17 (1 H, broad d); 5.26 (1 H, m); SZ-1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-[(3'-tert. butyl)-cyclopentyl] prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-1 3-ynoic acid, NMR (CDCl3) # p.p.m.: 1.70 (6H, s); 4.03 (1 H, m); 4.22 ( 1 H, broad d); 5.28 ( 1 H, m).
Example 13 Under nitrogen atmosphere 4-carboxy-butyl-triphenyl-phosphonium bromide (6.5 g) was added to a mixture of potassium tert. butoxide (3.2 g) and DMSO (32 ml); then this mixture was treated with a solution of (+)3-oxo-6-exo-(1'-tras-2'-bromo-3'-cyclopentyl-3'S-hydroxy-prop-1'-enyl)-7-hydroxy bicyclo[3.3.0]octane (0.84 g) in DMSO (3 ml).
After 3 hours the reaction mixture was diluted with water, acidified with 2N H2SO4 and extracted with diethyl ether.
The ethereal phase was extracted with 1 N NaOH aqueous solution; the aqueous alkaline extracts were collected; acidified to pH 5 and extracted with n-pentane: diethyl ether (20:80). The final organic extracts were collec' - d, washed with water, dried and evaporated to dryness.
The residue co taining (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15- cyclopentyl-prostacycl-5-en-l 3-ynoic acid was chromatographed on silica gel [eluant: diethyl ether (100 ml) acetic acid (0.4 ml)] so obtaining in the order (+)5Z-11 a,15S-dihydroxy-9a-deoxy-9a- methylene-o-pentanor-1 5-cyclopentyl-prostacycl-5-en-l 3-ynoic acid (0.11 g), NMR (CDCl3) # p.p.m.: 3.93 (1H, broad m); 4.22 (1H, broad d); 4.55 (3H, broad m); 5.23 (1H, m); and (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid (0.17 g), NMR (CDCl3) a p.p.m.: 3.93 (1 H, broad m); 4.22 (1 H, broad d); 4.55 (3H, broad m); 5.22 (1H, m).
By analogous procedure the following compounds were obtained: (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-1 3-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)- cyclopentyl]prostacycl-5-en-13-ynoic acid; (+)5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) a p.p.m.: 0.97 (3H, d); 3.97 (1H, m); 4.20 (1H, broad d); 5.24(1 H, m); (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid, NMR (CDCl3) # p.p.m.: 0.93 (3H, d); 1.33 (2H, m); 3.94 (1H, m); 4.17 (1 H, broad d); 5.25 (1 H, m); (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl]prostacycl-5-en-13-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid, NMR (CDC13) S p.p.m.: 1.70 (6H, s); 4.03 (1H, m); 4.22 (1H, broad d): 5.27 (1H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 0.97 (3H, d); 3.97 (1 H, m); 4.20 (1 H, broad d); 5.25 (1 H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid, NMR (CDCI3) S p.p.m.: 0.93 (3H, d); 1.33 (2H, m); 3.94 (1H, m); 4.17 (1 H, broad d); 5.26 (1 H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. buty)-cyclopentyl]prostacycl-5-en-13-ynoic acid; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; (+)5Z-11 ay,15S-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(3'-isopropylidene) cyclopentyl]-prostacycl-5-en-l 3-ynoic acid, NMR (CDCl3) S p.p.m.: 1.70 (6H, s); 4.03 (1 H, m); 4.22 (1 H, broad d); 5.28 (1 H, m).
(+)5Z-11 ,15S-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-15-cycloheXyl-prostacycl-5-en- 13-ynoic acid (0.12 g) NMR (CDCl3) # p.p.m.; 5.27 (1 H, t) H5; 4.17 (1 H, d) H15; 4.00 (1H, m) H1; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en13-ynoic acid (0.18 g), NMR (CDCI,)G p.p.m.: 5.26 (1H, t) H,; 4.17 (1H, d) H,,; 4.01 (1 H, m) H11; (+)5E-11 cE,15S-dihydroxy-9a-deoxy-9a-methylene-U-pentanor-15-cyclobutyl-prostacycl-5-en- 13-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)- cyclohexyl]prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 0.98 (3H, d); 3.99 (1 H, m); 4.19 (1 H, broad d); 5.25 (1 H, m); (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid, NMR (CDCl3) # p.p.m.: 0.91 (3H, d); 1.31 (2H, m); 3.95 (1 H, m); 4.21 (1 H, broad d); 5.27 (1 H, m); (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl] prostacycl-5-en-1 3-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohesyl] prostacycl-5-en-1 3-ynoic acid; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prosta cycl-5-e n-l 3-ynoic acid, NMR (CDCl3) a p.p.m.: 1.70 (6H, s); 4.01(1 H, m); 4.22 (1 H, broad d); 5.27 (1 H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en- 1 3-ynoic acid; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]prostacycl-5-en-l 3-ynoic acid, NMR (CDCI,) 6 p.p.m.: 0.98 (3H, d); 3.99 (1H, m); 4.19 (1H. broad d); 5.26 ( 1 H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid, NMR (CDCl3) b p.p.m.: 0.91 (3H, d); 1.31 (2H, m); 3.95 (1 H, m); 4.21 (1 H, broad d); 5.28 (1 H, m); (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-1 3-ynoic acid; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; (+) SZ-1 1 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-isopropylidene)- cyclohexyl-prostacycl-5-en-1 3-ynoic acid, NMR (CDC13) â p.p.m.: 1.70 (6H, s); 4.01(1 H, m); 4.22 (1 H, broad d); 5.28 (1 H, m); (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5- en-1 3-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; (+)5(Z,E)-11 a, 1 5s-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl) cyclohexyl]-prostacycl-5-en-1 3-ynoic acid;; (+) S(Z,E)- 11 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-vinyl)-cyclohexyl]prostacycl-5-en-1 3-ynoic acid; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-1 3-ynoic acid; and (+)5(Z,E)-11&alpha;, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-cyclohexyl-prostacycl-5en-1 3-ynoic acid.
Example 14 Dry potassium carbonate (0.26 g) was added to a solution of 5E-1 1 a,1 5S-dihydroxy-9a-deoxy- 9a-methylene-co-pentanor-1 5-[(4'-vinyl-cyclohexyl]-prostacycl-5-en-1 3-ynoic acid (0.5 g) and methyliodide (0.18 ml) in dry DMF (3.2 ml).
The mixture was stirred at room temperature for 4 hours.
The inorganic material was filtered, and the organic solution was diluted with water (20 ml) and exhaustively extracted with diethyl ether. The ethereal extracts were collected, washed with water and evaporated affording the 5E- 11 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-vinyl)- cyclohexyl]-prostacycl-5-en-1 3-ynoic acid methyl ester.
In analogous fashion the following methyl esters were obtained: SE-1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-cyclohexyl-prostacycl-5-en- 1 3-ynoic acid methyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; 5E-1 1 a,1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-1 5-[(4'-tert. butyl)-cyclohexyi]- prostacycl-5-en-1 3-ynoic acid methyl ester; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-1 3-ynoic acid methyl ester; SE-1 1 a,1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-1 5-cyclobutyl-prostacycl-5-en- 13ynoic acid methyl ester; SZ-1 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-cyclohexyl-prostacycl-5-en-l 3- ynoic acid methyl ester; SZ-1 1 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-methyl)-cyclohexyl]prostacycl-5-en-1 3-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid methyl ester; 5Z-1 1 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prosta cycl-5-en-l 3-ynoic acid methyl ester; 5Z-11 ,15S-dihydroxy-9a-deoxy-9a-methylene--pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid methyl ester;; 5(Z,E)- 11 a, 1 ,15S-di hyd roxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-m ethyl)-cycl ohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5(Z,E)- 11 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)cyclohexyl]-prostacycl-5-en- 13-ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5(Z,E)-11 cE,15S-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-1 5-[(4'-isopropylidene) cyclohexyl]-prostacycl-5-en-l 3-ynoic acid methyl ester; and 5(Z,E)- 11 a, 1 5 S-di hyd roxy-9 adeoxy-9a-methylene-co-pentanor-1 S-cyclobutyl-prostacycl-5-en- 13-ynoic acid methyl ester.
Example 15 Dry potassium carbonate (0.26 g) was added to a solution of 5E-11 a,1 SS-dihydroxy-9a-deoxy- 9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en-13-ynoic acid (0.48 g) and methyliodide (0.52 ml) in dry DMF (3.2 ml).
The mixture was stirred at room temperature for 4 hours.
The organic material was filtered, and the organic solution was diluted with water (20 ml) and exhaustively extracted with diethyl ether. The ethereal extracts were collected, washed with water and evaporated affording the 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid methyl ester (0.41 g) NMR (CDCl3) # p.p.m.: 3.55 (2H, broad m); 3.65 (3H, s); 3.93 (1 H, broad m); 4.22 (1 H, broad d); 5.22 (1 H, m).
By analogous procedure the following methyl esters were obtained: 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5 E- 1 a, 1 S-di hyd roxy-9 a-deoxy-g a-methyl e ne-w-pentanor- 1 5-[(3'-ethyl)-cycl ope ntyl]- prostacycl-5-en-13-ynoi acid methyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl]prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prosta cycl-5-en-l 3-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prpstacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl]prostacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)- cyclopentyl]-prostadycl-5-en-l 3-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-S-en-1 3-ynoic acid methyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; ; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl] prostacycl-5-en-1 3-ynoic acid methyl ester; S(Z,E)- 11 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor- 1 S-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; and 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester.
Example 16 Dry potassium carbonate (0.26 g) was added to a solution of (+) 5E-11&alpha;, 15S-dihydroxy-9a- deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en-13-ynoic acid (0.48 g) and methylidodide (0.52 ml) in dry DMF (3.2 ml.) The mixture was stirred at room temperature for 4 hours.
The organic material was filtered, and the organic solution was diluted with water (20 ml) and exhaustively extracted with diethyl ether. The ethereal extracts were collected, washed with water and evaporated affording the (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15- cyclopentyl-prostacycl-5-en-13-ynoic acid methyl ester (0.41 g) NMR (CDCl3) # p.p.m.: 3.55 (2H, broad m); 3.65 (3H, s); 3.93 (1 H, broad m); 4.22 (1 H, broad d); 5.22 (1 H, m).
By analogous procedure the following methyl esters were obtained: (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)-cyclopentyl]prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl e (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- 13-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl e (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)- prostacycl-5-en-13-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl - cyclopentyl]- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5- en-13-ynoiac acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-tert. butyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5- 13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid methyl ester; (+)5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacyl-5-en- 13-ynoic acid methyl ester; (+)5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclophexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid methyl ester; (+)5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en- 13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5- en-1 3-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclophexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclophexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ter.t butyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclophexyl]- prostacycl-5-en-13-ynoic acid methyl ester; (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en- 13-ynoic acid methyl ester; and (+)5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5- en-13-ynoic acid methyl ester.
Example 17 A solution of 5E-11 a,1 SS-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-1 5-cyclohexyl- prostacycl-5-en-13-ynoic acid (0.2 g) in THF (3 ml) was treated with 0.25 g of O-ss(piperidinoethyl)- dicyclohexyl-iso-urea for 15 hours at reflux temperature. The solvent was evaporated in the vacuo and the residue was partitioned between diethyl ether and 5% aqueous NaHCO3.
The organic phase was separated, washed with water dried and evaporated to dryness.
Chromatographic purification of SiO2 gel [eluent: CHCI3 (90); MeOH (10); NH4OH (0.1)] afforded 5E 11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13-ynoic acid-p-piperidino ethyl ester; By analogous procedure the following compounds were obtained:: 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid -p-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)- cyclohexyl]-prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid-p-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prsotacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5 E-11 cr,15S-di hyd roxy-9a-deoxy-9a-methylene-co-pentanor- 15-cyclopentyl-prostacycl-5-en- 13-ynoic acid-ss-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-S-en-1 3-ynoic acid-ss-piperidino ethyl ester; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid-p-piperidino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid-p-piperidino ethyl ester; 5Z-11 cE,15S-dihydroxy-9a-deoxy-9a-methylene-co-pentanor-15-cycloheXyi-prostacycl-5-en-13- ynoic acid-13-piperidino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5Z-11&alpha; ;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid--piperidino ethyl ester; 5Z-11 cE,15S-dihydroxy-9a-deoxy-9a-methylene-el)-pentanor-15-[(4'-tert. butyl)-cyciohexyl]- prostacycl-5-en-1 3-ynoic acid-ss-piperidino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid-ss 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid-ss-piperidino ethyl ester; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino e 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino e 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino e 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino e 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prstacycl-5-en-13-ynoic acid-ss-piperidino ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino ehtyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid-ss-piperidino ehtyl ester; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prstacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid-ss-piperidino ethyl ester; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid-p-piperidino ethyl ester, and the (+) enantiomers of all the hereabove listed compounds.
Example 18 Using in the procedure of the Example 17 O-ss(morpholino-ethyl)-dicyclohexyl-iso-urea, 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid-ss-morpholino-ethyl ester was obtained.
In analogous fashion the following compounds were prepared: 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostqacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid-ss-morpholino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid-ss-morpholino ethyl ester; 5Z- 11 a, 1 5 S-di hyd roxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-[(4'-methyl)-cycl o hexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl] prostacycl-5-en-1 3-ynoic acid-ss-morpholino ethyl ester;; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 1 3-ynoic acid-ss-morpholino ethyl ester; 5Z- 11 a, 1 55-di hydroxy-9 a-deoxy-9 a-methyle ne-#-pentanor- 1 5-[(3'-methyl)-cycl opentyl]prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester;; SZ- 11 a, 1 55-di hydroxy-9a-deoxy-9a-methylene-co-pentanor- 15-[(3'-ethyl )-cyclopentyl]prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5Z- 1 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 15-[(3'-isopropyl idene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid-p-morpholino ethyl ester; 5Z-11 ,15S-dihydroxy-9a-deoxy-9a-methylene-es-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid-ss-morpholino ethyl ester; 5(Z,E)- 11 &alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-cyclohexyl-prostacycl-5-en- 13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)- 11 &alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor- 1 5-[(4'-ethyl )-cyclohexyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl] prostacyci-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)- 11 &alpha; 15S-di hyd roxy-9a-deoxy-9 a-methylene-co-pentanor-1 5-[(4'-vinyl)-cycl ohexyl] prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en- 3-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid-p-morpholino ethyl ester; 5(Z,E)-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en- 13-ynoic acid-ss-morpholino ethyl ester, and the (+) enantiomers of all the hereabove listed compounds.
Example 19 Using in the procedure of the Examples 11 and 13 3-carboxy-propyl-triphenylphosonium bromide,5-ca rboxy-n-pentyl-triphenylphosphoni u m bromide and 6-ca rboxy-n-hexyltriphenylphosphonium bromide, instead of 4-carboxy-butyl-triphenylphosphonium bromide, the following compounds were, respectively, obtained:: 5E, 11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-1 3-ynoic acid; 5 11 ,15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-&commat;-pentanor- 1 5-cyclohexyl prostacycl-5-en- 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-cyclohexylprostacycl-5-en-13-ynoic acid; and 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-1 3-ynoic acid.
By analogous procedure, using the above indicated phosphonium bromides and the appropriate bicyclo[3.3.0]octane derivatives the following compounds were prepared too: 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-tert. butyl) cyclohexyl]-prostacycl-l 5-en-13-ynoic acid; 5 E- 11 a, 1 55-di hydroxy-9a-deoxy-9 a-methylene-2-nor-co-pentanor- 5-[(4'-vi nyl)-cycl ohexylj- prostacycl-5-en-1 3-ynoic acid;; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E- 11 ,15S-di hyd roxy-9a-deoxy-9a-methylene-2-nor--pentanor- 15-cyclopentyl-prostacyci-5- en-i 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-S-en-i 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5E-11(L, 1 SS-dihydroxy-Sa-deoxy-9a-methylene-2-nor S-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid;; 5E- 11 a, 1 55-di hydroxy-9a-dexoy-9a-methylene-2-nor-#-pentanor-1 5-cyclobutyl-prostacycl-5- en-1 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-methyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid.
5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-ethyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-tert. butyl) cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-vinyl) cyciohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclopentyl- prostacycl-5-en- 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'-ethyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclobutyl- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(4'-methyl)- cyclohexyl]-prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(4'-ethyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(4'-tert. butyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(4'-vinyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; SE-i 1 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-co-pentanor- 15-[(4'isopropylidene)-cyclohexyl]-prostacycl-5-en-13-ynoic acid;; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(3'-ethyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(3'- isopropylidene)-cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5E-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclobutyl- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-tert. butyl) cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en- 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(4'-ixopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid;; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclopentyl-prostacycl-5- en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-(s-pentanor-15-cyclobutyi-prostacycl-5- en-i 3-ynoic acid; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-methyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-ethyl)- cyclohexyl]-prostacycl-S-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-tert. butyl) cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-vinyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prosta cycl-5-e n-l 3-ynoic acid;; 5Z-11 a, 1 55-di hyd roxy-9a-deoxy-9a-methyle ne-2a-homo-co-pentanor- 1 5-cyclopentyl prostacycl-S-en-i 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'-ethyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-[(3'isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclobutyl- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-[(4'-methyl)- cyclohexyl]-prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-[(4'-ethyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid.
5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-[(4'-tert. butyl)- cyclohexyl]-prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-[(4'-vinyl)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-dihomo-#-pentanor-15-[(4'- isopropylidene)-cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5Z-11 a, 1 55-di hyd roxy-9 a-deoxy-9a-methylene-2a,2b-dihomo-co-pentanor- 1 5-cyclopentyl prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(3'-methyl)- cyclopentyl]-prostacycl-5-en-13-ynoic acid;; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-[(3'-ethyl)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a, 2b-nor-#-pentanor-15-[(3'- isopropylidene)-cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclobutyl- prostacycl-5-en-13-ynoic acid, and the (+) enantiomers of all the hereabove listed compounds.
Example 20 Using the esterification procedures described in the Examples 14, 1 5, 1 6, 1 7 and 18 the methyl esters, p-piperidino ethyl ester and p-morphoíino ethyl esters of the compounds obtained in the Example 19 were prepared, in particular: SE-il a, 1 55-di hyd roxy-9 a-deoxy-9a-methyle ne-2-nor-co-pentanor-1 S-cyclohexyl-prostacycl-5en-13-ynoic acid methyl ester; 5Z-11&alpha;, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-13-ynoic acid methyl ester; 5E-11 a, 1 SS-dihydroxy-9a-deoxy-9a-methylene-2a-homo-co-pentanor-1 5-cyclohexylprostacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-1 3-ynoic acid methyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-1 3-ynoic acid p-piperidino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-1 3-ynoic acid ss-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acud ss-piperidino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid p-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-1 3-ynoic acid p-piperidino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid p-piperidino ethyl ester; SE- 11 a, 1 5S-dihydroxy-9a-deoxy-9a-methylene-2-nor-cs-pentanor-1 5-cyclohexyl-prostacycl-5- en-1 3-ynoic acid p-morpholino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclohexyl-prostacycl-5- en-I 3-ynoic acid ss-morpholino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid /3-morpholino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclohexyl- prostacycl5-en-l 3-ynoic acid ss-morpholino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid p-morpholino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclohexyl- prostacycl-5-en-13-ynoic acid-ss-morpholino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclopentyl-prostacycl-5- en-l 3-ynoic acid methyl ester; 5Z-11 ,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-cl)-pentanor-15-cyclopentyl-prostacycl-5- en- 1 3-ynoic acid methyl ester; 5E-11&alpha;15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid methyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-S-en-1 3-ynoic acid methyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid methyl ester; 5Z-11 ,15S-dihyd roxy-9 a-deoxy-9a-methyle ne-2a,2b-di homo-co-pentanor- 1 5-cyclopentylprostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclopentyl-prostacycl-5- en-1 3-ynoic acid /3-piperidino ethyl ester; 5Z- 11 &alpha; 15S-di hyd roxy-9a-deoxy-9a-methyle ne-2-nor-o-pe ntanor-l 5-cyclopentyl-prostacycl-5- en-1 3-ynoic acid ss-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid p-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid ,B-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid ss-piperidino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-1 3-ynoic acid ss-piperidino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclopentyl-prostacycl-5- en-i 3-ynoic acid p-morpholino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-#-pentanor-15-cyclopentyl-prostacycl-5- en-i 3-ynoic acid ss-morpholino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid p-morpholino ethyl ester; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid /3-morpholino ethyl ester; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-2a,2b-dihomo-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid ss-morpholino ethyl ester; 5Z- 11 &alpha; 15S-di hydroxy-9a-deoxy-9a-methylene-2 a,2b-dihomo-w-pentanor-l 5-cyclopentyl- prostacycl-5-en-13-ynoic acid ss-morpholino ethyl ester, and the (+) enantiomers of all the hereabove listed compounds.
Example 21 Using in the procedure of the Example 11 the bicyclo[3.3.0]octane-3'R-hydroxy derivatives obtained in the Examples 9 and 10, the 15R-hydroxy epimers of all the compounds obtained in the Examples 11 to 20 were prepared, in particular: 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid; 5Z-11 ,15R-di hyd roxy-9a-deoxy-9a-methyiene--pentanor- 1 5-[(4'-methyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl] prostacycl-5-en-1 3-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5Z-11 ,15 R-di hydroxy-9 a-deoxy-9 a-methylene--pentanor- 15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5Z-11 ,15R-dihydroxy-9a-deoxy-9a-methylene-c.)-pentanor- 1 5-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-postacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutayl-prostacycl-5-en-13- ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en 13-ynoic acid; 5(Z,E)- ii &alpha; 15R-di hyd roxy-9a-deoxy-9a-methylene-co-pentanor- 1 5-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-tert. butyl)-cyclohexyl]prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopenyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclobutyl-prostacycl-5-en- 13-ynoic acid, and the (+) enantiomers of the hereabove listed compounds.
Example 22 Using the esterification procedure described in the Example 1 4 the methyl esters of the compounds obtained in the Example 21 were prepared, in particular: 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11 ,15R-dihydroxy-9a-deoxy-9a-methyiene-cs-pentanor-15-[(4'-tert. butyl)-cyclohexyl] prostacycl-S-en-13-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-vinyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-l 3-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deox-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en-13- ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en-13- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-ethyl)-cyclopentyl]- prostacycl-S-en-1 3-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-(3'-tert. butyl)-cyclopentyl]prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-vinyl)-cyclopenyl]- prostacycl-5-en-13-ynoic acid methyl ester; 5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene) cyclopentyl]-prostacycl-5-en-1 3-ynoic acid methyl ester; 5E-11 ,15R-dihydroxy-9a-deOxy-9a-methylene-s-pentanor-15-cyclobutyl-prostacycl-5-en-13- ynoic acid methyl ester, and the (+) enantiomers of the above listed compounds.
Example 23 A solution of (+)5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl- prostacycl-5-en-1 3-ynoic acid (0.60 g) in 5 ml of ethanol was treated with a stoichiometric amount of 01 N NaOH aqueous solution. The alcohol was removed in vacuo and the aqueous solution was lyophiliaed to give 0.62 g of dry (+)5E-5E-11&alpha; 15R-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15- cyclopentyl-prostacycl-5-en-13-ynoic acid sodium salt.
Example 24 A solution of (+)5 E-1 1 &alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid (500 ,ug) in ethanol (6 ml) was sterilized by passage through a bacteriaretaining filter. Portions of 0.1 ml were placed into 1 ml ampoules which were then sealed.
The content of an ampoule was diluted with 1 ml of tris-HCI buffer solution having pH 8.6 to give a solution ready for administration by injection.

Claims (22)

Claims
1. An optically active or racemic compound of the following formula (I)
wherein 5 R is hydrogen or a C1-C6 alkyl group optionally substituted by a group 5
wherein each of R3 and R4 is, independently, hydrogen or C1-C6 alkyl, or R3 and R4, taken together with the nitrogen atom to which they are linked, form a pentatomic or hexatomic heteromonocyclic ring optionally containing a further heteroatom chosen from 0 and S; n is zero or an integer of 1 to 5; one of R1 and R2 is hydrogen or C1-C6 alkyl and the other is hydroxy; and B represents: a) a C4-C7 monocycloaliphatic group either unsubstituted or substituted by one or more substituents chosen from C1-- C6 alkyl, C2-C6 alkenyl and C1-C6 alkylidene; b) norbornyl; or c) adamantyl, and the pharmaceutically or vertinarily acceptable salts thereof.
- An optically active orracemic compound having the formula (I) reported above in claim 1 wherein: R is hydrogen, C1-C6 alkyl, ss-piperidino-C1-C3 alkyl or -morpholino-C1-C3 alkyl; n is 3 or 4; one of R1 and R2 is hydrogen and the other is hydroxy; and B is cyclopentyl or cyclohexyl, either unsubstituted or substituted by a substituent chosen from C1-C4 alkyl, C2-C4 alkenyl and C1-C4 alkylidene, and the pharmaceutically or veterinarily acceptable salts thereof.
3. An optically active or racemic compound according to claim 2 wherein B is cyclopentyl unsubstituted or substituted as described in claim 2.
4. A compound, either racemate or (+) enantiomer, chosen from the group consisting of: 5 E-1 1 &alpha; 15S-di hyd roxy-9a-deoxy-9 a-methylene-co-pentanor-1 5-[(3'-methyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-entyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-methyl)-cyclohexl]- prostacycl-S-en-1 3-ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-entyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en-13-ynoic acid; and the pharmaceutically or veterinarily acceptable salts thereof and the C1-C6 alkyl-esters, ,3- piperidinoethyl and p-morpholinoethyl esters thereof.
5. A compound, either racemate or (+) enantiomer, chosen from the group consisting of: 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-mentyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-entyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en-13- yonic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-mentyl)-cyclohexyl]- prostacycl-5-en-13-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-entyl)-cyclohexyl]- prostacycl-S-enl 3-ynoic acid; 5Z-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en- 13-ynoic acid; and the pharmaceutically or veterinarily acceptable salts thereof and the C1-C6 alkyl-esters, p- piperidinoethyl and ,B-morpholinoethyl esters thereof.
6. A compound, either racemate or (+) enantiomer, chosen from the group consisting of: 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl-prostacycl-5-en- 13-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-mentyl)-cyclopentyl]- prostacycl-S-en-1 3-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-entyl)-cyclopentyl]- prostacycl-5-en-13-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(3'-isopropylidene)- cyclopentyl]-prostacycl-5-en-l 3-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclohexyl-prostacycl-5-en- 13-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-mentyl)-cyclohexyl]- prostacycl-5-en-1 3-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-ethyl)-cyclohexyl]- prostacycl-S-en-1 3-ynoic acid; 5(Z,E)-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-[(4'-isopropylidene)- cyclohexyl]-prostacycl-5-en- 13-ynoic acid; and the pharmaceutically or veterinarily acceptable salts thereof and the C1-C6 alkyl-esters. ss- piperidinoethyl-esters and p-morpholinoethyl-esters thereof.
7. The compound 5E-11&alpha; 15S-dihydroxy-9a-deoxy-9a-methylene-#-pentanor-15-cyclopentyl- prostacycl-5-en-13-ynoic acid, either racemate or (+) enantiomer, and the pharmaceutically or veterinarily acceptable salts thereof.
8. A C1-C6 alkyl ester of the compound of claim 7.
9. A C1-C6 alkyl ester according to claim 8 wherein the ester if the methyl ester.
10. The p-piperidino-ethyl ester of the compound of claim 7.
11. The ,B-morpholino-ethyl ester of the compound of claim 7.
12. A process for the preparation of a compound having the formula (I) reported above in claim 1, the said process comprising reacting a compound of formula (@)
wherein B is as defined in claim 1, R5 is hydrogen or a hydroxy protecting group, one of R'1 and R'2 is hydrogen or C1-C6 alkyl and the other is a group KR5 wherein R5 is as hereabove defined, and Y is -C-C- or-CH=CZ- wherein Z is chlorine, bromine or iodine, with a Wittig reagent of formula (@)
wherein n and R are as defined in claim 1, and R6 is an aryl or alkyl group, and removing the protecting groups possibly present, and, if desired, esterifying an obtained compound of formula (I) wherein R is hydrogen to give a compound of formula (I) wherein R is C1-C6 alkyl optionally substituted as indicated in claim 1, or saponifying an obtained compound of formula (I) wherein R is C1-C6 alkyl optlonally substituted as indicated in claim 1, to give a compound of formula (1) wherein R is hydrogen, or a salt thereof, and/or, if desired, sallfying a compound of formula (I) or obtaining a free compound from a salt, and/or, if desired separating a mixture of isomers of formula (I) into the single isomers.
13. A pharmaceutical or veterinary composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as claimed in claim 1.
14. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, hereinbefore specified other than a compound of formula (I) or salt or ester thereof claimed in any one of claims 4 to ii.
15. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, for use as a blood platelet anti-aggregating or disaggregating agent.
16. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, for use as a vasodilating agent.
17. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, for use in treating obstructive pulmonary diseases.
18. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, for use as an anti-ulcerogenic or antisecretory agent.
19. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 11 to 13, 19 or 21.
20. A process for the esterification of a compound of formula (I) as defined in claim 1 in which R is hydrogen, said process being substantially as hereinbefore described in any one of Examples 14 to 18,20or22.
21. A process for the preparation of a pharmaceutically or veterinarily acceptable salt of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in Example 23.
22. A pharmaceutical composition substantially as hereinbefore described in Example 24.
GB08326187A 1982-10-01 1983-09-30 15-cycloaliphatic derivatives of 13,14-didehydrocarboprostacyclins and process for their preparation Expired GB2129427B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601244A1 (en) * 1986-07-08 1988-01-15 Kotobuki Seiyaku Co Ltd CARBACYCLINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURE, AND THERAPEUTIC AGENTS CONTAINING THESE COMPOUNDS.
EP0369563A1 (en) * 1988-11-17 1990-05-23 Schering Aktiengesellschaft Process for the preparation of carbacyclin derivatives by stereoselective introduction of the 5,6 double bond
US5117037A (en) * 1989-12-05 1992-05-26 Sagami Chemical Research Center Toa Eiyo Ltd. Cis-bicyclo[4,3.0]non-2-end derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2017699A (en) * 1978-03-31 1979-10-10 Ono Pharmaceutical Co 6,9-methano-pgi2 analogues
EP0011591A1 (en) * 1978-10-19 1980-05-28 Schering Aktiengesellschaft Prostane derivatives, their production and pharmaceutical compositions containing them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2017699A (en) * 1978-03-31 1979-10-10 Ono Pharmaceutical Co 6,9-methano-pgi2 analogues
EP0011591A1 (en) * 1978-10-19 1980-05-28 Schering Aktiengesellschaft Prostane derivatives, their production and pharmaceutical compositions containing them

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601244A1 (en) * 1986-07-08 1988-01-15 Kotobuki Seiyaku Co Ltd CARBACYCLINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURE, AND THERAPEUTIC AGENTS CONTAINING THESE COMPOUNDS.
EP0369563A1 (en) * 1988-11-17 1990-05-23 Schering Aktiengesellschaft Process for the preparation of carbacyclin derivatives by stereoselective introduction of the 5,6 double bond
DE3839155A1 (en) * 1988-11-17 1990-05-23 Schering Ag PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES BY STEREOSELECTIVE INTRODUCTION OF 5,6-DUAL BINDING
WO1990005720A1 (en) * 1988-11-17 1990-05-31 Schering Aktiengesellschaft Berlin Und Bergkamen Process for producing carbacyclin derivatives by stereoselective introduction of the 5.6 double bond
AU648498B2 (en) * 1988-11-17 1994-04-28 Schering Aktiengesellschaft Berlin Und Bergkamen Process for producing carbacyclin derivatives by stereoselective introduction of the 5.6 double bond
US5117037A (en) * 1989-12-05 1992-05-26 Sagami Chemical Research Center Toa Eiyo Ltd. Cis-bicyclo[4,3.0]non-2-end derivatives

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